SUBJECT PHARMACOLOGY 1 TOPIC General Principles of Pharmacology

IG NUMBER IG-PHA-325LC WEEK NO 1

TERM PRELIM SESSION 2 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of The lesson is intended to introduce the general principles of pharmacology,
Session enumerate end define the branches of pharmacology and review the different
pharmacokinetic principles.

Objectives 1. Define pharmacology.

2. Identify the principles governing pharmacology.
3. Review the students of the different pharmacokinetic principles.
4. Enumerate the different transport processes.

Materials 1. Basic and Clinical Pharmacology by Katzung, latest edition

2. Comprehensive Pharmacy Review latest edition
3. Applied Biopharmaceutics and Pharmacokinetics, latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.

Lesson General Principles of Pharmacology

Outline
What is Pharmacology?

• Pharmacology can be defined as the study of substances that interact with living
systems through chemical processes by binding to regulatory molecules and
activating or inhibiting normal body processes.

What is Pharmacodynamics?

• Pharmacodynamics is the study of the action of drugs on the living organism.

• It is a branch of pharmacology that focuses on the study of the biochemical and
physiologic effects of drugs and the mechanisms by which they produce such
effects.

What is Pharmacokinetics?

• Pharmacokinetics refers to the disposition of drugs in the body.

• It refers to the movement of drugs within the biological systems, as affected by
uptake, distribution, elimination and biotransformation.

Define Drug.

• Drug is any substance, other than food, that is used in the prevention, diagnosis,
alleviation, treatment, or cure of disease.

What are the classifications of drug according to use?

A. Classification according to use

1. Functional modifiers
Alter or modulate normal functions
Analgesic =sensation of pain
Anti-hypertensive drug = lowers Blood pressure
 2. Replenishes
Supplement or replace normal or endogenous substance

Insulin- IDDM or Type I DM

IV fluids and salts- dehydration, electrolyte imbalance
Hormone- Hormone replacement therapy

3. Diagnostic agents
BaSO4 – for roentgenographic examination

4. Chemotherapeutic agent
• Selective toxicity

Antineoplastic drugs/anticancer drugs

REVIEW OF PHARMACOKINETIC PRINCIPLES

What is the fate of the drug in vivo?

A. LADME

What happens during liberation?

What is the objective of this process?
What are the dosage forms that undergo liberation process?

1. LIBERATION- release of the active ingredient (drug) from its dosage form

A. Disintegration- a state in which any residue of the tablet, except fragments of

insoluble coating, remaining on the screen of the test apparatus in the soft mass
have no palpably firm core.

B. Dissolution- a process by which a chemical or drug becomes dissolved in a

solvent.

Objective: produce an aqueous form of the drug which is important prior to

absorption.
Exceptions: oral solutions
Elixirs

How is drug absorbed?

What are the factors that limit drug absorption?
How do those factors affect drug absorption?
At what organs do absorption mostly takes place?
What are the transport mechanisms involved in absorbing drugs?
Do all drugs undergo absorption?
Differentiate Active with Passive transport.

2. ABSORPTION - RATE and EXTENT of DRUG

- entry into the systemic circulation

FACTORS AFFECTING ABSORPTION:

1. Dose size administered - dose = drug absorption

2. Degree of perfusion of the absorbing environment
blood supply = greater extent/ faster absorption
 3. Areas of the absorbing surface
4. pH of the absorbing environment
eg. Weak acid better absorbed in the stomach
5. Gastric emptying rate – time it takes for the stomach to empty its contents
6. Dosage form
7. Drug solubility- for a drug to be absorbed, its solubility must correspond to the
characteristics of the absorption site.
8. First-pass effect- some drugs are partially metabolized in the liver or portal vein
before passing into circulatory system.
9. Enterohepatic recycling- some drugs travel intact through the biliary tract after
initial absorption and are then reabsorbed into bloodstream through the intestine

TRANSPORT MECHANISMS
- means of movement of drug molecule across cell membrane

EXAMPLES OF TRANSPORT MECHANISMS

1. PASSIVE DIFFUSION/ PASSIVE TRANSPORT

- higher concentration to lower concentration
- movement of small lipophilic molecule along a conc. Gradient
- non energy requiring
a. only nonionized molecules can pass through cell membranes
b. weakly acidic drugs can only be absorbed through the stomach which is acidic.
c. Weakly alkaline drugs can be absorbed through the intestine, which is alkaline.

2. CARRIER MEDIATED DIFFUSION

- FACILITATED TRANSPORT
FACILITATED DIFFUSION
- a passive process requiring no cellular energy
- drug moves along a concentration gradient
- saturable and structurally selective
DRUG + CARRIER SUBSTANCE ( PROTEIN OR ENZYME )

3. CONVECTIVE TRANSPORT
- small drug molecules simply move along with fluid through the pores in cell walls
- MEDIATED through “water-filled pores/channels/aquaporins”

Eg. Grains of sand flowing down a drain along with running water

4. PINOCYTOSIS
- cell drinking
- ATP requiring transport
- Transport of large hydrophilic molecules

5. ACTIVE TRANSPORT
- from lower concentration to higher concentration
- “pushing a rock uphill”
- requires cellular energy

What are the different factors affecting the rate and extent of drug distribution?
Differentiate bound from unbound/free drug?
When is drug on its active form?

3. DISTRIBUTION
• Site of administration to the site of action (tissues or organs)
• The extent to which the drug passes into different tissues and fluid compartments
 in the body.

FACTORS AFFECTING THE RATE AND EXTENT OF DRUG DISTRIBUTION

1. BLOOD FLOW – regional blood flow

- Tissues with decrease regional blood flow (bones, adipose tissues, middle
ear)

2. PROTEIN BINDING CAPACITY

DRUG + PROTEIN (ALBUMIN) = DRUG ALBUMIN COMLEX

(pharmacologically inactive)

FREE DRUG – drug that is unbound to plasma proteins

- only the “unbound” or free drug is available to distribute out of
blood vessels and act on the body cells to elicit the desired effect

3. BBB and PLACENTAL BARRIER

- Allows only nonionized, unbound drug to enter brain.

What are the two phases of biotransformation?

What is a prodrug?
Explain the First-pass effect.
What is the principal organ involved in biotransformation?
What is the objective of this process?
What is bioavailability?
How does biotransformation affect the bioavailability of the drug?

4. METABOLISM/BIOTRANSFORMATION
• The chemical process by which the body converts an agent from its original form
to a more water-soluble form that can be excreted.
objective:
convert drug to forms which are less toxic, less active or inactive,
easily excreted
exception:
PRODRUG – inactive molecule converted to an active molecule

Eg. Enalapril (ACE inhibitor) – enalaprilat

LIVER- most important site of drug metabolism, but it may also occur in renal
tissue, lungs, plasma or intestinal mucosa.

FIRST PASS EFFECT (FPE)

- metabolism occuring before reaching systemic circulation
-  bioavailability

BIOAVAILABILITY – fraction of drug that reaches the systemic circulation

DESCRIPTION OF BIOTRANSFORMATION PROCESS

1. A drug is usually converted by enzymes from its active form to an inert
metabolite.
2. Other drugs are biotransformed to both active and inert metabolites
3. Some drugs are metabolized from an inactive form to a more active metabolite

What is the difference between elimination and excretion?

What is the primary organ in drug excretion?
What are the different routes of excretion?
 Differentiate elimination from excretion.

4. EXCRETION – removal of intact drug.

Elimination- refers to the irreversible removal of drug from the body by all routes
of elimination.

ROUTES TO EXCRETE DRUGS

1. KIDNEY – most important/ primary organ in drug excretion for polar drugs.
a. Glomerular Filtration – a passive process by which small molecules and
drugs are filtered.
b. Tubular reabsorption – a passive process that follows Fick’s Law of
diffusion.
c. Active tubular secretion - a carrier-mediated active transport system that
requires energy.
2. SKIN- sweat
3. SALIVA
4. LUNGS – anesthetic
5. BILE – an active process that needs high drug concentrations for it to be
saturated.
- eg. Cefamandole, diazepam, digoxin, spironolactone, chloramphenicol
6. FECES- if the drug is given parenterally, an then observed in the feces, one can
assess that some of the drug was excreted in the bile.
- if given orally, some of the fecal drug excreted could represent
unabsorbed drug.

FACTORS AFFECTING/INFLUENCING DRUG EFFECTS

1. WEIGHT –  adipose tissue > toxic effects

2. AGE
Infants – underdeveloped liver enzyme system =  toxic effect

Chloramphenicol – gray baby syndrome

Geriatric patients – deteriorating body functions

3. Gender-for IM injection
Male>Female in terms of vascular muscles
- Effects faster in male than female
4. PATHOLOGICAL FACTORS
- liver disease =  biotransformation of drugs =  toxic effects

5. GENETIC FACTORS
- ASIANS are fast acetylators
Acetylation (metabolizing INH) =  antitubercular effects

Assessment A short examination regarding the topic discussed will be given the next meeting.
SUBJECT PHARMACOLOGY 1 TOPIC Pharmacodynamics/Kinetics
IG NUMBER IG-PHA-325LC WEEK NO 2
TERM PRELIM SESSION 3 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of The lesson is intended to discuss the different pharmacodynamic principles, and to
Session familiarize the students with the different drug-receptor theories.

Objectives 1. To define pharmacodynamics.

2. To discuss the different target and non-target proteins
3. To define receptors and enumerate the different drug-receptor theories
4. To discuss the relationship between drug concentration and effect

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review , Latest edition
3. Applied Biopharmaceutics and Pharmacokinetics , Latest edition
Pharmacodynamic Principles
Lesson
Outline
What is Pharmacodynamics?

Pharmacodynamics
- A branch of pharmacology that focuses on the study of the biochemical and
physiological effects of drugs and the mechanisms by which they produce such
effects.

Mechanisms of Drug Action

A. Cell Surface Receptors
1. Receptors can be proteins, glycoproteins, or nucleic acids. Receptors can be
located at the cell surface, within the cytoplasm, or inside the nucleus.
2. The binding of drugs to receptors is highly specific and can involve a variety of
interactions, including hydrophobic interactions and van der waals forces with
ionic, hydrogen and covalent bonds. The type of interaction and the binding
affinity can influence the duration and reversibility of the drug action.
3. The interaction and the binding affinity are related to the chemical structureof
both the drug and ligand. Chemical modification of the structure of the drug
molecule can change the pharmacological and pharmacokinetic properties of the
drug.
4. Through structure-activity relationship studies, a synthetic drug analogue can be
developed to achieve a high selectivity of drug action- a desirable ratio of
therapeutic to toxic effect with a better-tolerated side-effect profile.
B. Signal Transduction by cell-surface receptors
1. Cell-surface receptors are composed of extracellular domains that bind the
ligands.
2. The ligand binding serves as triggering signal that can be propagated in the
target cell through intracellular regulatory molecules, known as second
messengers or effectors.
3. Ligand-binding of receptors often leads to interaction of the receptors with the
cytoplasmic effectors, which in turn become activated.
C. Signaling mediated by intracellular receptors
- Thyroid hormone, steroid hormones, vitamin D and the retinoids act through
binding cytoplasmic receptors, which translocate into the nucleus.
D. Target cell desensitization and hypersensitization
1. Cells have the ability to respond to endogenous regulatory molecules or
exogenously added drugs over a wide range of cencentrations.
 2. Cell regulation can occur at different levels along signal transduction pathway.
3. Down-regulation and desensitization
a. Down-regulation of receptors is caused by continuous prolonged exposure
of receptors to drugs that disrupt the homeostatic equilibrium and result in
altered levels of the receptors. This disruption involves endocytosis of
ligand-bound receptors, resulting in sequestration of receptors from the cell
surface and possibly accelerated degradation of the receptors, or
inactivation of the receptors.
b. Desensitization is the result of down-regulation. The target cells become
desensitized, and the effect of subsequent exposure to the same
concentration of the drug is reduced.
c. Hyperreactivity or supersensitivity to receptor agonist is expected when
target cells are subject to long-term exposure to receptor antagonists
followed by abrupt cessation of drug administration. This can involve
receptor up-regulation through synthesis of new receptors.

SITES OF DRUG ACTION

Target protein- biologic site of action of drugs

1. Structural protein
Microtubule- important site of action
Drugs that inhibit microtubule synthesis/ spindle protein

A. Griseofulvin
B. Vinca alkaloids
C. Colchicine

2. Regulatory proteins

A. Channels/transport
Volgate-gated Na channel
Volgate-gated Ca channel

e.g. drugs act on:

Na channel- Local anesthetic

Ca++ channel – Ca++ channel blockers

B. Carrier molecules
Na+-K+ ATPase pump- Digitalis glycosides

C. Enzymes
Xanthine oxidase - allopurinol
Cyclooxygenase - NSAID’s
ACE - ACE inhibitors
MAO - MAOI
Phenelzine
Isocarbozacid
Trancylpromine
Acetylcholinesterase- Tensilon

Assignment Read Receptor-Occupancy Theory

SUBJECT PHARMACOLOGY 1 TOPIC RECEPTORS
IG NUMBER IG-PHA-325LC WEEK NO 2
TERM PRELIM SESSION 4 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the different drug effects in the body. The lesson
Session covers concepts of agonism, antagonism and allosteric modulation.

Objectives 1. To define receptors

2. To identify the different classifications of receptors
3. To discuss the realtionship between drug concentration and effect

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review , Latest edition
3. Applied Biopharmaceutics and Pharmacokinetics , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.

Lesson Define Receptors

Outline Differentiate Receptor from a ligand.
What are the different types of receptors?
What are the characteristics of drug receptors?

Receptors

-Functional macromoleular components of cells with specific stereochemical

configuration and in which a ligand interacts

Ligand- any chemical that has ability to bind to a receptor

Type of Receptors

A. Type I receptor - ionotropic receptor

- Controls movement of ions

- Found in cell membranes
- Stimulated in milliseconds

GABA receptors control Cl- ions

Benzodiazepines
Barbiturates

B. Type II receptors - G-protein linked receptor

Activate G-protein generation of second messengers

- location: cell membrane

- onset: in seconds

C. Type III receptors/tyrosine kinase-linked receptors

Tyrosine kinase- enzyme involved in the phosphorylation of

other enzymes
glucokinase
 Glucose glucose-6-phosphate

- location: nucleus
- onset: hours

e.g. Receptor for Insulin – utilization of glucose

D. Type IV receptor/gene transcription-linked receptors

Central dogma -replication (DNA copied into complimentary DNA)

-transcription (DNA template is copied to RNA)
-translation (RNA synthesize protein)

-location: nucleus
-onset: hours

Characteristic of drug receptors

1. Affinity
• Ability to bind to receptor or target protein
• w/ or w/o effect

2. Intrinsic/biological property
• Ability to generate a series of biochemical effect leading to an effect.

What is Receptor Occupancy Theory?

What are the different assumptions proposed by this theory?
What is the importance of Quantal dose relationship?
Differentiate Graded dose from log dose-response curve.
What is the significance of the values obtained in log dose-response curve?
Differentiate efficacy from potency.
If a drug is said to be potent, will it be effective?

RELATIONSHIP BETWEEN DRUG CONCENTRATION AND EFFECT

A. Occupancy Theory
- States that the occupancy of the drug molecule at one receptor site does not
change the affinity of other drug molecules to complex at other binding sites. As
drug molecules occupy more receptors, a greater pharmacologic response is
obtained until a maximum response is reached.
- The following assumptions were made in this concept:
- The drug molecule combines with the receptor molecule as a bimolecular
association and the resulting drug-receptor complex dissociates as a
unimolecular entity.
- The binding of drug with the receptor is fully reversible.
- A single type of binding site with one site per molecule is assumed.
B. Dose Response Relationship
- Generally, the higher the dose, the higher the concentration at its site of
action and the greater the effect of the drug, up to a maximum effect.
- Higher drug concentrations/doses will not produce an effect greater than the
maximum effect.
C. Quantal Dose Relationship
- It describes the relationship between the number of patients inhibiting a
defined response produced by a specified dose of the drug.
- It follows a bell-shaped distribution.
D. Graded dose- Response Curve
 - It describes the relationship between the magnitude of the effect of a drug in
an individual and the doses of the drug.
- Generally, as the dose of the drug increases, the effect produce will reach a
maximum level.
- It allows comparison for drug efficacies and potencies.
- Efficacy of a drug is measured by its maximum effect.
- Potency of a drug is a relative measure that compares the different doses
of different drugs needed to produce the same effect.
E. Log dose-Response Curve
- It describes the relationship between the drug effect and the log of the dose.
- It facilitates comparison of potency and efficacy among different drugs with
the same mechanism of action.
- The efficacy of a drug is determined by the height of its log dose-
response curve; the higher the curve, the greater the log dose-
response curve and efficacy.
- Determining their ED50 can compare the potency of two drugs. The
smaller the ED50, the greater the potency.
- A competitive antagonist shifts the log dose-response curve to the
right, and the shift is parallel. A greater concentration of the agonist is
required to produce the same response than when the competitive
antagonist is absent.
- A noncompetitive antagonist binds to the same receptor or binds to
another site that prevents the agonist from producing a response. The
shift of the log dose-response curve is to the right and nonparallel,
resulting in lower log dose-response curve.

FOUR VARIABLES:
1. maximal efficavy
2. slope
3. potency
4. ceiling dose

MAXIMAL EFFICACY / RESPONSE (E)

-maximal effect that can be produced by a drug when the dose response
curve reaches it plateau

SLOPE
- reflects the ability of the drug to produce an effect. The STEEPER the slope, the
more readily the drug will bind with receptors.

POTENCY
- describes the relationship between the dose of the drug and the intensity of its
effect.

10 mg morphine = 1 mg hydromorphine

 equally effective hence a mg hydromorphone is more potent than morphine

D. CEILING DOSE (Ceiling effect)

Assessment A short examination next meeting.

SUBJECT PHARMACOLOGY 1 TOPIC AGONISM, ANTAGONISM,
ALLOSTERIC MODULATION
IG NUMBER IG-PHA-325LC WEEK NO 3
TERM PRELIM SESSION 5 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the different drug effects in the body. The lesson
Session covers concepts of agonism, antagonism and allosteric modulation.

Objectives 1. To identify the different classifications of drug according to thir interaction with
receptors
2. To classify drugs according their interaction with physiologic enzymes
3. To classify drugs according to their interaction with nucleic acids

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3. Applied Biopharmaceutics and Pharmacokinetics, Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.

Lesson Concepts of Agonism, Antagonism, and Allosteric modulation

Outline
What is an agonist?
What are the subclassifications of agonism?
Differentiate partial from full agonism.
What is an antagonist?
What are the different types of antagonism?
What is the difference of chemical antagonism with the other three types?
Give examples of each type of antagonism.

I. Classification of drugs according to receptor interaction

1. AGONIST
• Able to bind
• With intrinsic activity
a. Full agonist
- Full response
- Stimulate all different variant of receptors even the new
receptors
b. Partial agonist
- Less than the expected response
2. ANTAGONIST
• With affinity but no intrinsic activity
• It prevents the binding if agonist

2.1 PHARMACOLOGIC ANTAGONIST

- utilizes the same receptor
- produce an effect opposite of agonist by binding to the same
receptor
a. COMPETITIVE ANTAGONISM
- compete for the same receptor
b. NON-COMPETITIVE ANTAGONISM
- interacts with the nonligand binding site of the receptor, such
that normal binding of the endogenous ligand to the receptor is
irreversibly inhibited.
 2.2 PHYSIOLOGIC ANTAGONIST
- occurs when the drugs act independently at different receptor
sites, often yielding opposing actions.
e.g. HISTAMINE + EPINEPHRINE
(anaphylactic reaction)

2.3 CHEMICAL ANTAGONIST

- no receptor is involved
- occurs when two drugs bind with each other to form an
inactive compound.

Protamine SO4 + Heparin SO4 → forms a complex devoid of action

Action →neutralization
Chelating agents
Deferoxamine – Iron (Fe)

2.4 PARTIAL ANTAGONIST

- inhibits the endogenous ligand from binding the receptor but
possess some intrinsic activity.

How do enzymes affect the action of a drug?

What are the actions of a drug towards the enzymes?
What does allosteric binding mean?
Define enzyme induction.
Define enzyme inhibition.

II. Classification of drugs according to their interaction with enzymes

1. Activation, or increased enzyme activity, can result from induction of enzyme.
a. Allosteric binding. It triggers a conformational change in the enzyme system
and alters its affinity for substrate binding.
b. Coenzymes. Optimizes enzyme activity. Activates enzymes by complexation
and stereochemical interaction.
2. Inhibition, or decreased enzyme activity, can result from drugs that interact with
apoenzyme, coenzyme, or even the whole enzyme complex. The drug might
modify or destroy the apoenzyme’s protein conformation, react with coenzyme,
or bind with the enzyme complex.
a. Reversible inhibition results from noncovalent interaction between the
enzyme and the drug. The drug is free to associate or dissociate from the
enzyme, and equilibrium exists between the bound and free drug.
b. Irreversible inhibition results from a stable, covalent interaction between
the enzyme and the drug. The drug cannot freely dissociate from the
enzyme once it is bound to it.
c. Competitive inhibition occurs when there is mutually exclusive binding of
the substrate and the inhibitor. Increasing the concentration of the
substrate reverses the inhibition.
d. Noncompetitive inhibition occurs when a drug binds to an allosteric site on
the enzyme. Induces a conformational change in the enzyme that inhibits
enzyme action, even if a substrate is bound to an enzyme. Increasing
substrate concentration cannot overcome this type of inhibition.

What are the effects of analogues in the original RNA/DNA template?

How does alteration in the template appears to be an appreciable effect of a drug?
To what medical conditions are these drugs called for?
Give examples of drugs that alter nucleotide function.

III. Classification of drugs according to its interaction with DNA/RNA Function

 1. Inhibition of Nucleotide biosynthesis occurs when folate, purine, and pyrimidine
antimetabolites interfere with the biosynthesis of purine and pyrimidine building
blocks.
a. Folic acid analogues inhibit purine and thymidylate synthesis by inhibiting
dihydrofolate reductase.
b. Purine analogues act as antagonists in the synthesis of purine bases. These
analogues do not act as active inhibitors until they are converted to their
respective nucleotides.
c. Pyrimidine analogues inhibit the synthesis of thymidylic acid by inhibiting
thymidine synthetase. As with purine analogues, they must be first
converted to their respective nucleotide before they could exert their effect.

2. Inhibition of DNA or RNA biosynthesis occurs when drugs interfere with nucleic
acid synthesis. They are used primarily as antineoplastics in cancer
chemotherapy.
a. Drugs that interfere with DNA replication and function include intercalating
agents, alkylating agents, and antimetabolites.
b. Drugs that can damage and destroy DNA include compounds that can
produce free radicals and compounds that can inhibit topoisomerases.
c. Drugs that can interfere with microtubule assembly in the metaphase of cell
mitosis.

Define synergism.
What is the mathematical representation of an additive effect? Of synergistic effect?
Of Potentiating effect?
Give examples of drugs that exhibit additive effect.
Give examples of a synergism.
Give examples of potentiation.

DRUG EFFECT
The degree or extent of pharmacologic response or drug effect resulting from
drug action is determined in part by

1. availability of receptor sites

– few receptors occupied → less response
2. location and function of the receptors with which the drug interacts
3. whether the drug affects the target tissues or organs directly or indirectly
4. the concentration of the drug at the receptor site
-  concentration =  effects

ENHANCEMENT OF DRUG EFFECTS

A. ADDITION
- A drug effect that is equal in the magnitude to the sum of the individual
effects of two drugs.
- Two different drugs with the same effect are given together.
- 1+1=2
B. SYNERGISM
- The effect of two drugs is greater in magnitude than the sum of the individual
effects of the two drugs.
- Two drugs with same effect are given together.
- 1+1=3
C. POTENTIATION
- Occurs when one drug, lacking an effect of its own, increases the effect of
another drug that is active.
- 1+0=2
Assessment A short examination regarding the topic discussed will be given next meeting.
SUBJECT PHARMACOLOGY 1 TOPIC DRUG DEVELOPMENT
IG NUMBER IG-PHA-325LC WEEK NO 3
TERM PRELIM SESSION 6 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the different pharmacotherapeutic principles. This
Session topic includes subtopics about drug development and clinical trials

Objectives 1. To discuss drug development and clinical trials

2. To identify the factors that affect clinical responses

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3. Applied Biopharmaceutics and Pharmacokinetics, Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.
Lesson
Outline Pharmacotherapeutic Principles

DRUG DEVELOPMENT AND CLINICAL TRIALS

Define active pharmaceutical ingredient.

Define excipients.
What are the stages of drug development?
What are the different factors that affect clinical response?
What is tolerance?

A. Active Pharmaceutical Ingredient

1. A drug substance is the component that produces pharmacological activity.
2. It may be produced by chemical synthesis, recovery from a natural product,
enzymatic reaction, recombinant DNA technology, fermentation, or a
combination of these processes.
B. Drug Product
1. It is the finished dosage form that contains the active pharmaceutical ingredient,
with other excipients or inert substances.
C. Drug products containing new chemical entities. The following steps should be
done sequentially:
1. Preclinical stage
a. Animal pharmacology and toxology data are obtained to determine the
safety and efficacy of the drug.
b. No attempt is made to develop a final formulation during the preclinical
stage.
c. Nonclinical studies are nonhuman studies that may continue at any stage of
research to obtain additional information concerning the pharmacology and
toxicology of the drug.
2. Phase I
a. Clinical testing takes place after IND application is submitted.
b. Healthy volunteers are used in phase I clinical studies to determine drug
tolerance and toxicity.
c. Toxicologic studies including acute, chronic, subchronic, mutagenicity, and
other toxicologic studies in various animal species are planned during this
phase.
3. Phase II
a. A limited number of patients with the disease condition for which the drug
was developed are treated under close supervision.
b. Dose response studies and pharmacokinetics are performed to determine the
 optimum dosage regimen for treating the disease. Safety is measured by
attempting to determine the therapeutic index.
c. A final drug formulation is developed.
d. Chronic toxicity are started in two species, which will normally last more than
2 years’ duration.
4. Phase III
a. Large-scale, multicenter clinical studies are performed with the final dosage
form developed in phase II. These studies are done to determine the safety
and efficacy of the drug product in a large patient population with the
disease or condition to which the product is developed.
b. Adverse effects are monitored.
5. Submission for New Drug Application.
6. Phase IV
a. Manufacturing scale-up activities occur. Scale-up is the increase in the batch
size.
b. The drug formulation may be modified slightly as a result of data obtained
during manufacturing scale-up and validation process.
7. Phase V
a. Additional clinical studies may be performed in special populations such as
the elderly, pediatric, renal-impaired patients, and others to obtain
information on the efficacy of the drug in these subjects.

FACTORS AFFECTING CLINICAL RESPONSE

1. Diseases and disorders
a. GI system abnormalities
b. Renal impairment from disease or aging
- reduces drug clearance for drugs primarily dependent on the kidney for
elimination.
c. Hepatic dysfunction
- Exerts a complex influence on drug pharmacokinetics.
- Two process may be altered, blood flow rate in delivering drug to the liver
and the capacity of enzymes to metabolize the drug
d. Thyroid gland abnormalities
- Hypothyroidism, which slows drug metabolism
- Hyperthyroidism, which speeds up drug metabolism
e. Circulatory system abnormalities
- Atherosclerosis
- Peripheral vascular diseases secondary to diabetes
- Shock
2. Physiologic factors
a. Extremes of age
- results in reduction in renal and hepatic clearances.
b. Genetic variation
- variation in acetylation rates
c. Circadian variations
d. Tolerance- reduced response to a drug, often due to prior exposure to that
drug
e. Muscle mass and level of body fat
3. Drug Interactions
4. Drug-food interactions.
a. Some drugs bind with food and impair vitamin and mineral absorption.
b. Food alters bioavailability of drugs absorbed in the GI Tract.

Assessment A short quiz regarding the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC AUTACOID PHARMACOLOGY
IG NUMBER IG-PHA-325LC WEEK NO 4
TERM PRELIM SESSION 7 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss Histamine pharmacology, its structure-activity
Session relationship, the mechanisms of its pharmacologic and physiologic actions, its
different physiologic effects and therapeutic uses, and the adverse effects associated
to it.

Objective 1. To discuss the chemical structure of histamine

2. To enumerate the physiologic role of histamine
3. To discuss the synthesis, storage and release of histamine
4. To enumerate the different histamine agonist
5. To discuss the different therapeutic uses of histamine

Materials 1.Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3.Applied Biopharmaceutics and Pharmacokinetics, Latest edition
4.Stedman’s Concise Medical Dictionary 2nd ed.

Lesson
Outline Histamine Pharmacology

What is the amino acid precursor of Histamine?

What are the physiologic and pharmacologic effects of histamine?
What is the co-factor required in the formation of histamine?
How is histamine synthesized in the body?
What are the two physiologic processes that would lead to histamine release?

Histamine and Antihistamines

A. Histamine. Histamine is a small molecule produced by decarboxylation of the

amino acid histidine;
• it is catalyzed by the enzyme L-histidine decarboxylase in a reaction that
requires pyridoxal phosphate.

1. Synthesis
a. Histamine is found in many tissues, including the brain; it is stored and found
in the highest amounts in mast cells and basophils. Mast cells, which are
especially abundant in the respiratory tract, skin (especially hands and feet),
gastrointestinal tract, and blood vessels, store histamine in a granule bound
in a complex with heparin, adenosine triphosphate (ATP), and an acidic
protein.
b. Release of histamine can occur by two processes:
(1) Energy- and Ca2+-dependent degranulation reaction. Immunoglobulin E
(IgE) fixation to mast cells (sensitization) and subsequent exposure to a
specific antigen induce the release of histamine from mast cells;
complement activation (Immunoglobulin G- or immunoglobulin M-
mediated) may also induce degranulation.
(2) Energy- and Ca2+ - independent release (displacement). Drugs such as
morphine, tubocurarine, guanethidine, and amine antibiotics induce
displacement. In addition, mast cell damage, which is caused by noxious
agents such as venom or by mechanical trauma, can release histamine.
 2. Mechanism of action

a. Histamine (H1) – receptors

(1) H1-receptors are found in the brain, heart, bronchi, gastrointestinal tract,
and vascular smooth muscles.
(2) H1-receptors are membrane-bound and coupled to G-proteins, and their
activation causes an increase in phospholipase C activity, leading to
increases in diacylglycerol and intracellular Ca2+.
(3) Activation of H1-receptors in the brain increases wakefulness.
(4) Activation of H1-receptors in vessels causes vasodilation and an increase
in permeability.
(5)Activation of H1-receptors typically stimulates nonvascular smooth muscle.
b. Histamine (H2)receptors
(1) H2-receptors are membrane-bound; they are found in the brain, heart,
vasculature, and parietal cells.
(2) The response of H2-receptors is coupled to cyclic AMP (cAMP).
(3) Activation of H2-receptors on nerve cells causes a decrease in histamine
release; the activation of H3-receptors on the vagal nerve may cause
decreased acetylcholine (ACh) release.

B. Histamine agonists

1. Prototypes. These agents include histamine, betazole (histalog), and impromidine.

a. Betazole has approximately tenfold greater activity at H2-receptors than at H1-
receptors.
b. Impromidine is an investigational agent; its ratio of H 2:H1 activity is about
10,000.
c. R-alpha methylhistamine is an H3-specific agonist.
2. Uses. The uses of histamine agonists are primarily diagnostic.
a. These agents are used in allergy testing to assess histamine sensitivity,
b. and in the test of gastric secretory function (they have been largely
supplanted for this use by pentagastrin (Ppeptavlon), a synthetic peptide
analog of gastrin with fewer adverse effects.)
3. Adverse effects. The adverse effects of these agents can be quite severe; they
include flushing, a burning sensation, hypotension, tachycardia, and
bronchoconstriction.

Assignment
Read Histamine antagonists.
SUBJECT PHARMACOLOGY 1 TOPIC HISTAMINE ANTAGONISTS
IG NUMBER IG-PHA-325LC WEEK NO 4
TERM PRELIM SESSION 8 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss Histamine pharmacology, its structure-activity
Session relationship, the mechanisms of its pharmacologic and physiologic actions, its
different physiologic effects and therapeutic uses, and the adverse effects associated
to it.

Objectives 1. To discuss the different histamine antagonists

2. To discuss the mechanisms of action of histamine anatgonists
3. To enumerate the therapeutic indications of histamine antagonists
4. To identify the different adverse effects associated with the use of histamine
antagonists

Materials 1.Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3.Applied Biopharmaceutics and Pharmacokinetics, Latest edition
4.Stedman’s Concise Medical Dictionary 2nd ed.

Lesson Histamine Antagonists

Outline
What are the chemical classifications of 1st generation H1 receptor antagonists?
Differentiate the effects of 1 st generation from 2nd generation H1 receptor
antagonists.
What are the adverse effects of H1-receptor antagonists?
What are the physiologic effects of H2 receptor antagonists?
At what organ/system does H2 receptor predominates?
What drugs inhibit histamine release?
What is the chemical name of histamine?
What type of antagonism does H1 receptor antagonists exhibit?

I. Histamine (H1)-receptor antagonists.

H1-receptor antagonists are competitive inhibitors at the H1-receptor.

A. Classification
a. First-generation agents
(1) Alkylamines
(a) Alkylamines include chlorpheniramine and brompheniramine.
(b) These agents produce slight sedation.
(c) Alkylamines are the antihistamines used most frequently in the United
States.
(2) Ethanolamines
(a) Ethanolamines include diphenhydramine, doxylamine, and clemastine
(Tavist); dimenhydrinate is an equimolar combination of
diphenhydramine and 8-chlorotheophylline.
(b) Ethanolamines produce marked sedation; doxylamine is marketed
only as a sleeping aid.
(c) Ethanolamines also act as antiemetics.
(3) Ethylenediamines
 (a) Ethylenediamines include pyrilamine, antazoline, and tripelennamine.
(b) Ethylenediamines produce moderate sedation and can cause
gastrointestinal upset.
(4) Piperazines
(a) Piperazines include meclizine and cyclizine.
(b) Piperazines produce marked adverse gastrointestinal effects and
moderate sedation.
(c) These agents are antiemetic.
(5) Phenothiazines
(a) Phenothiazines include promethazine and cyproheptadine.
(b) Phenothazines produce marked sedation.
(c) These agents have antiemetic activity.
(d) Phenothiazines are also weak alpha-adrenoceptor antagonists
(6) Methylpiperidines
(a) Methylpiperidines include cyproheptadine (periactin).
(b) Methylpiperidines have antihistamine, anticholinergic, and
antiserotonin activities.
b. Second-generation (nonsedating agents)
(1) Piperidines
(a) Terfenadine (Seldane)
a.1 Terfenadine is metabolized to the active metabolite
fexofenadine by a specific cytochrome P-450. This enzyme is inhibited
by certaim antibiotics (erythromycin) and antifungal agents
(ketoconazole).
a.2 The parent drug can interfere with cardiac potassium channels,
producing ventricular tachycardia; this can occur with large doses of
terfenadine or if other drugs block the P-450.
(b) Fexofenadine (Allegra). has been approved as a safer antihistamine of
this class.
(c) Astemizole (Hismanal). There are some reports of ventricular
tachycardia associated with astemizole; the mechanism of action is
likely the same as with terfenadine.
(d) Loratadine (Claritin). Poor CNS penetration.
(2) Alkylamines: acravistine (Semprex-D). Acravistine is not associated with
cardiac effects.
(3) Cetirizine (Zyrtec)
i. Cetirizine is not associated with cardiac abnormalities.
ii. Cetirizine has poor penetration into the CNS.
iii. Cetirizine is less sedating; it is ineffective for motion sickness or
antiemesis.

B. Pharmacologic properties of H1 Receptor Antagonists

(1) Histamine (H1)-receptor antagonists are well absorbed after oral
administration. The effects of these agents are usually seen in 30 minutes (with
maximal effects at 1-2 hours); the duration of action is 3-6 hours for first-
generation compounds and 3-24 hours for second-generation compounds.
(2) H1-receptor antagonists are lipid-soluble; most first-generation agents cross
the blood-brain barrier, a property reduced with second-generation agents.
(3) H1-receptor antagonists are metabolized in the liver; many induce microsomal
enzymes and alter their own metabolism and that of other drugs.

C. Pharmacologic actions of H1 Receptor Antagonists

(1)Many H1-receptor antagonists, especially the ethanolamine, phenothiazones,

and ethylenediamines, have muscarinic-cholinergic antagonist activity.
(2) Most of these agents are effective local anesthetics, probably due to a
blockade of sodium channels in the excitable tissues. Dimenhydrinate and
 promethazine are potent local anesthetics.
(3) H1-receptor antagonists relax histamine-induced contraction of bronchial
smooth muscle and have some use in allergic bronchospasm.
(4)These agents block the vasodilator action of histamine.
(5) H1-receptor antagonists inhibit histamine-induced increases in capillary
permeability.
(6)These agents block mucus secretion and sensory nerve stimulation.
(7) H1-receptor antagonists frequently cause CNS depression (marked by
sedation, decreased alertness, and decreased appetite). In children and some
adults, these agents stimulate the CNS.

D. Therapeutic uses of H1 Receptor Antagonist

1. Treatment of allergic rhinitis and conjunctivitis. These agents are also used to
treat the common cold based on their anticholinergic properties, but they are only
marginally effective for this use. Diphenhydramine also has an antitussive effect not
mediated by H1-receptor antagonism.
2. Treatment of urticaria and atopic dermatitis, including hives
3. Sedatives. Several (doxylamine, diphenhydramine) are marketed as over-the-
counter (OTC) sleep aids.
a. Prevention of motion sickness
b. Appetite suppressants.

E. Adverse effects (significantly reduced with second-generation agents)

1. H1-receptor antagonists produce sedation (synergistic with alcohol and other
depressants) dizziness, and loss of appetite.
2. These agents can cause gastrointestinal upset, nausea, and constipation or
diarrhea.
3. H1-receptor antagonists produce anticholinergic effects (dry mouth, blurred
vision, and urine retention).

II. Histamine (H2)-receptor antagonists

1. Histamine (H2)-receptor antagonists include cimetidine (Tagamet), ranitidine
(Zantac), famotidine (Pepcid AC), and nizatidine (Axid).
2. These agents are competitive antagonists at the H2-receptor, which
predominates, in the gastric parietal cell.
3. H2-receptor antagonists are used in the treatment of gastrointestinal disorders,
including heartburn and acid-induced indigestion.
4. These agents promote the healing of gastric and duodenal ulcers and are used
to treat hypersecretory states such as Zollinger-Ellison syndrome.

III. Inhibitors of histamine release:cromolyn (Intal), nedocromil sodium (Tilade)

a. These are poorly absorbed salts; they must be administered by inhalation.
b. They inhibit the release of histamine and other autacoids from the mast cell.
c. Each is used prophylactically in the treatment of asthma.
d. These agents produce adverse effects that are usually confined to the site of
application; these effects include sore throat and dry mouth.
e. Nedocromil sodium appears to be more effective in reducing bronchospasm
caused by exercise or cold air.

Assessment A chapter examination regarding histamine pharmacology will be given next meeting
SUBJECT PHARMACOLOGY 1 TOPIC SEROTONIN
AGONISTS/ANTAGONISTS
IG NUMBER IG-PHA-325LC WEEK NO 5
TERM PRELIM SESSION 9 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This topic is intended to discuss Serotonin pharmacology which includes subtopics
Session regarding the synthesis, storage and release of serotonin, the physiologic effects and
pharmacologic uses, the different serotonin agonists and antagonists and the adverse
effects associated with the uuse of the agents.

Objectives 1. To discuss the biosynthesis and distribution of serotonin agonists

2. To discuss the mechanism of action of serotonin physiologically
3. To discuss the effects of derotonin at different serotonin receptor subytpes
4. To discuss the different serotonin agonists
5. To discuss the therapeutic indications of serotonin agonists
6. To enumerate the different adverse effects associated with the use of serotonin
agonists
7. To enumerate the different serotonin antagonists
8. To discuss the mechanisms of action of serotonin antagonists
9. To discuss the classifications of serotonin antagonists according to their effects at
different receptor subtypes
10. To discuss the pharmacologic uses of serotonin antagonists
11. To dicuss the adverse effects associated with the use of serotonin antagonists

Materials 1.Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition

Lesson Serotonin Pharmacology

Outline
What is the chemical name of Serotonin?
What is the amino acid precursor of serotonin?
What cells produce the most number of serotonin?
What are the physiologic effects of serotonin?
What are the two processes involved in the synthesis of serotonin in the body?
What are the different types of Serotonin receptors?

I. Serotonin (5-hydroxytryptamine, 5HT)

A. Biosynthesis and distribution

1. Serotonin is synthesized from the amino acid L-tryptophan by hydroxylation and

decarboxylation.
2. Approximately 90% of serotonin is found in the enterochromaffin cells of the
gastrointestinal tract. Much of the remaining 10% is found in the platelets; small
amounts are found in other tissues, including the brain. Platelets acquire serotonin
from the circulation during passage through the intestine by a specific and highly
active uptake mechanism.
3. Serotonin is stored in granules as a complex with adenosine triphosphate (ATP).
4. The major breakdown product of serotonin is 5-hydroxyindoleacetic acid (5-HIAA).
B. Mechanism of action. Serotonin acts on several classes of 5HT-receptors, which are
located on cell membranes of many tissues:

1. 5HT1 (subtypes 5HT1A through 5HT1B) receptors are coupled to an inhibition in

cAMP; stimulation contracts arterial smooth muscle, especially in carotid and cranial
circulation. At presynaptic sites, neuronal serotonin release is inhibited.
2. 5HT2 (subtypes 5HT2A through 5HT2c). 5HT2 receptors are coupled to an increase
in phospholipase C activity; stimulation causes contraction of vascular and intestinal
smooth muscle and increases microcirculation and vascular permeability. Stimulation
of this receptor on platelet membranes causes platelet aggregation; in the CNS, this
receptor mediates hallucinogenic effects.
3. 5HT3. 5HT3 receptors are coupled to a Na+-K+ ion channel. Stimulation of this
receptor in the area postrema causes nausea and vomiting; stimulation on peripheral
sensory neurons causes pain.
4. 5HT4. 5HT4 receptors increase cAMP; in the gastrointestinal tract, these receptors
mediate an increase in secretion and peristalsis.
5. 5HT5, 5HT6, and 5HT7. These receptors have been cloned and appear to be
coupled to various second-messengers, but their function is unclear.

II. Serotonin agonists

1. Buspirone (Buspar)
a. Buspirone is a relatively specific 5HT1a-receptor agonist.
b. Buspirone is useful for the management of anxiety disorders.
2. Sumatriptan (Imitrex)
a. Sumatriptan is a 5HT1D-receptor agonist.
b. Sumatriptan promotes the contraction of vessels in carotid circulation, with
minimal effects on other organs. This reduces the rebound vasodilation
associated with migraine headaches.
c. Sumatriptan is used for the treatment of acute migraine.
3. Trazodone (Desyrel)
a. The parent drug is metabolized to m-chlorophenylpiperazine, an activator of
5HT1B and 5HT2 receptors.
b. Trazodone is used to treat depression.
4. Cisapride (Propulsid)
a. Cisapride is a specific 5HT4 agonist that increases gastrointestinal motility,
probably due to increased acetylcholine release by neurons in the myenteric
plexus.
b. Cisapride speeds gastric emptying and increases lower esophageal pressure.
c. Cisapride is used to treat nocturnal heartburn due to reflux, constipation, and
anorexia nervosa.

Serotonin antagonists

Give examples of serotonin antagonists.

What is the mechanism of action of serotonin antagonists?
What are the different receptor subtypes?
What are the adverse effects of serotonin antagonists?
What are the indications of serotonin antagonists?
Give other serotonergic agents.

1. Cycloheptadine (Periactin)
a. Cyproheptadine is a potent H1-receptor antagonist of the phenothiazine class;
it blocks both 5HT1- and 5HT2-receptors.
b. Cyproheptadine is used most frequently to limit diarrhea and intestinal spasms
produced by serotonin-secreting carcinoid tumors and postgastrectomy
dumping syndrome.
 c. Cyproheptadine produces sedation and anticholinergic actions.
2. Ondansetron (Periactin)
a. Ondansetron is a 5HT3-receptor antagonist.
b. Ondansetron is highly effective in treating the nausea and vomiting associated
with chemotheraphy and radiation theraphy.
c. Administered intravenously or orally.
3. Granisetron (Kytril)
a. Similar in action and use to ondansetron.
b. Blocks 5HT3 receptors.
c. May be administered intravenously or orally.
4. Ketanserin (Sufrexal)
a. Ketanserin is a specific 5HT2-receptor antagonist; it also antagonizes alpha-
adrenergic, H1-, and dopamine receptors.
b. Ketanserin is an investigational drug that has been found to lower blood
pressure in experimentally induced hypertension.
5. Clozapine (Clozaril)
a. Clozapine is a specific 5HT2A- and 5HT2C – receptor antagonist.
b. Clozapine is an antipsychotic with reduced extrapyramidal effects.
6. Risperidone (Risperdal)
a. Risperidone is an antagonist at 5HT2A-, 5HT2C-, and dopamine (D2)-receptors.
b. Risperidone is an atypical antischizophrenic agent with reduced extrapyramidal
activity.

IV. Other serotonergic agents

1. Fluoxetine (Prozac). The actions of fluoxetine as an antidepressant are presumed
to be due to decreased serotonin uptake into neurons.
2. Dexfenfluramine (Redux)
a. Dexfenfluramine reduces serotonin reuptake into nerve terminals.
b. Dexfenfluramine is approved for the treatment of obesity.
c. Dexfenfluramine causes rare but serious adverse effects on the cardiovascular
system, including pulmonary hypertension.
SUBJECT PHARMACOLOGY 1 TOPIC EICOSANOIDS
IG NUMBER IG-PHA-325LC WEEK NO 5
TERM PRELIM SESSION 10 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This topic is intended to discuss the pharmacologic properties of eicosanoids. The
Session effects of eicosanoids in the body, its medical properties as well as the toxicity
associated with the use of eicosanoids would be also discussed.

Objectives 1. To give an overview about eicosanoids

2. To discuss how eicosanoids are synthesized in the body
3. To discuss the physiologic role of eicosanoids
4. To discuss the therapeutic uses of eicosanoids
5. To discuss how drugs inhibit eicosanoid synthesis

Materials 1. Basic and Clinical Pharmacology Latest edition

2. Comprehensive Pharmacy Review Latest edition.
3. Pharmacotherapy: A Pathophysiologic Approach 4th ed.

Lesson Eicosanoids
Outline
What is the fatty acid precursor of eicosanoids?
What are the physiologic effects of eicosanoids?
How does eicosanoids contribute to inflammation?
What are the therapeutic uses of eicosanoids?
What is the difference between thromboxanes and prostaglandins?
What pathway leads to the formation of prostaglandins?
What pathway leads to the formation of leukotrienes?

A. Overview
1. Eicosanoids are a large group of autacoids with potent effects on virtually
every tissue in the body; these agents are derived from metabolism of 20-
carbon, unsaturated fatty acids (eicosanoic acids).
2. The eicosanoids include the prostaglandins, thromboxanes, leukotrienes,
hydroperoxyeicosatetraenoic acids (HPETEs), and hydroeicosatertraenoic acids
(HETEs).

B. Biosynthesis
1. Arachidonic acid, the most common precursor of the eicosanoids, is formed by
two pathways:
a. Phospholipase A2- mediated production from membrane phospholipids;
this pathway is inhibited by glucocorticoids.
b. Phopholipase C in concert with diglyceride lipase can also produce free
arachidonate.
2. Eicosanoids are synthesized by two pathways:
a. The prostaglandin H synthase (COX, cyclooxygenase) pathway produces
thromboxane, the primary prostaglandins (prostaglandin E, or PGE; the
prostaglandin F, or PGF; and prostaglandin D, or PGD), and
prostaglandin (PGI2).
(1) There are two forms of COX: Type 1 is located in endothelial
cells, kidney, gastrointestinal tract, and many other locations; type 2
is found in great abundance in connective tissues.
 (2) The type 1 enzyme is expressed at fairly constant levels and
may provide protective action on gastric mucosa and in the kidney.
(3) The type 2 enzyme is highly inducible by numerous factors
associated with inflammation. Current theories suggest that the type
2 isoforms is predominantly associated with eicosanoids production
in inflammation.
b. The lipoxygenase pathway produces the HPETEs, HETEs, and the
leukotrienes.
(1) 5-Lipoxygenase produces 5_HPETEs, which are subsequently
converted to 5_HETEs and then to leukotienes.
(2) 12-Lipoxygenase produces 12-HPTES, which are converted to 12-
HETEs).
c. Additional metabolites of the HPETEs, hepoxillinsm and lipoxins, have
been identified, but their biological roles in unclear.
3. The eicosanoids all have short plasma half-lives (typically 0.5-5 minutes).
Most catabolism occurs in the lung.
a. Prostaglandins are metabolized by prostaglandin 15-OH dehydrogenase
(PDGH) to 15-keto metabolites, which are excreted in the urine.
b. Thromboxane A2 (TXA2) is rapidly hydrated to the less active TXB2.
c. PGI2 is hydrolyzed to 6-keto-PGF.
4. Various eicosanoids are synthesized throughout the body; synthesis can be
very tissue-specific:
a. PGI2 is synthesized in endothelial and vascular smooth musclecells.
b. Thromboxane syntghesis occurs primarily in platelets.
c. HPETEs, HETEs, and the leukotrienes are synthesized predominantly in
mast cells, white blood cells, airway epithelium, and platelets.

C. Actions. There is no universal mediator of eicosanoids action. A separate cell

surface receptor appears to mediate the activities of each class metabolite. Virtually
of all the known second-messenger systems have been implicated in the action of the
eicosanoids, including stimulation or inhibition of cAMP and cGMP and alteration in
Ca2+ flux.
1. Vascular smooth muscle
a. PGE2 and PGI2 are potent vasodilators in most vascular beds. PGE2 also
antagonizes the effects of vasoconstrictor substances such as
norephinephrine.
b. PGF causes arteriolar vasodilation and constriction of superficial veins.
c. Thromboxane is a potent vasoconstrictor.
2. Inflammation
a. PGE2 and PGI2 cause an increase in blood flow, and promote but do not
cause, edema. PGE also potentiates the effect of other inflammatory
agents such as bradykinin.
b. HETEs and leukotrienes cause chemotaxis of neutrophils and eosinophils.
3. Bronchial smooth muscle
a. PGFs cause smooth muscle contraction.
b. PGEs cause smooth muscle dilation.
c. Leukotienes and thromboxane are potent bronchoconstrictors, and are
most likely candidates for mediating allergic bronchospasms. The
leukotrienes LTC4 and LTD4 are the components of slow reacting
sunstance of anaphylaxis (SRS-A).
4. Uterine smooth muscle. PGE2 and PGF2 cause contaction of uterine smooth
muscle in pregnant women. The nonpregnant uterus has a more variable
response to prostaglandins; PGF2 causes contraction, and PGE2 causes
relaxation.
5. Gastrointestinal tract
a. PGE2 and PGF2 increase the rate of longitudinal contraction in the gut
and decrease transit time.
 b. The leukotrienes are potent stimulators of gastrointestinal smooth
muscle. PGE2 and PGI2 inhibit acid and pepsinogen secretion in the
stomach. In addition, prostaglandins increase mucus, water, and
electrolyte secretion in the stomach and the intestine.
6. Blood
a. TXA2 is a potent inducer of plateley aggregation.
b. PGI2 and PGE2 inhibit platelet aggregation.
c. PGEs induce erythropoiesis by stimulating the renal release of
erythropoietin.
d. 5-HPETE stimulates release of histamine; PGI2 and PGD inhibits
histamine release.

D. Therapeutic uses
1. Induction of labor at term. Induction of labor is produced by infusion of PGF2
(carboprost tromethamine) (Hemabate) or PGE2 (dinoprostone) (Prostin E).
2. Therapeutic abortion. Infusion of carboprost tromethamine or administration of
vaginal suppositories containing dinoprostone is effective in inducing abortion in the
second trimester. Currently, these prostaglandins are combined with mifepristone
(RU486) to induce first-trimester abortion.
3. Maintenance of ductus arteriosus. This action is produced by PGE1 (prostin VR)
infusion; PGE1 will maintain patency of the ductus arteriosus, which may be desitable
before syrgery.
4. Treatment of peptic ulcer. Misoprostol (cytotec), a methylated derivative of PGE1,
is approved for use in patients taking high doses of nonsteroidal anti-inflammatory
drugs (NSAIDs) to reduce gastric ulceration.

E. Adverse effects. Adverse effects of eicosanoids include local pain and irritation,
bronchospasm, and gastrointestinal disturbances, including nausea, vomiting,
cramping, and diarrhea.

F. Pharmacological inhibition of eicosanoids synthesis

1. Phospholipase A2-mediated release of eicosanoic precursors, such as arachidonic
acid, is inhibited by glucocorticoids (glucocorticoids induce the synthesis of a protein
called lipocortin, which may mediate this inhibition).
2. Aspirin and most NSAIDs inhibit synthesis of prostaglandin G (PGG) and
prostaglandin H (PGH) by their action on the cyclooxygenase pathways. Aspirin can
increase the synthesis of eicosanoids through the lipoxygenase pathway, perhaps by
increasing substrate concentration.
3. Eicosatetraenoic acid is an arachidonic acid analog that inhibits both
cyclooxygenase and lipoxygenase activity.
4. Imidazole derivatives such as dazoxiben appear to inhibit thromboxane synthase
preferentially.

Kinins
- One of a number of widely differing substances having pronounced and dramatic
physiological effects; some of the substances under this group are plant growth
regulators; others are polypeptides, formed in the blood by proteolysis secondary to
some pathologic process, that stimulate visceral smooth muscle but relax vascular
smooth muscle, thus, producing vasodilatation.

How does the body synthesize kinins?

What are the physiologic effects of kinins?
What are the pharmacologic uses of kinins?
What is the role of kinins in inflammation?

A. Biosynthesis
1. Kinins are found in the circulation and tissues as larger molecular weight
 precursors, kininogens. Specific serine proteases called kallikreins convert
kininogens to the active kinins. Hagenman factor, trypsin, and kinins activate
Kallikreins.
2. The major kinins are a group of related peptides with potent actions as
vasodilators.
a. Bradykinin. Bradykinin has the following amino acid sequence:
ArgPro-Pro-Gly-Phe-Ser-Pro-Phe-Arg.
b. Lysyl-bradykinin (kallidin) has additional lysine residue on the N-
terminus of the bradykinin.
c. The des-Arg (removal of the C-terminal argiine) metabolites of both
bradykinin and kallidin are biologically active.
B. Actions
1. The effects of kinins are mediated by specific bradykinin receptors (B1 and
B2- receptors).
2. Kinins produce vasodilation by relaxation of precapillary arteriolar smooth
muscle (10 times more potent than histamine), as well as vasoconstriction of
capacitance vessels; these combined effects cause a rapid but transient fall in
bloof pressure.
3. Kinins stimulate gastrointestinal smooth muscle.
4. These agents increase renal blood flow and enhance chloride transport.
5. Kinins may play a role in the inflammatory process.
6. Kinins activate peripheral nerve endings that sense pain.

C. Therapeutic uses
1. Aprotinin (Trasylol) inhibits kallikreins and, thus, the formation of kinins; it
also inhibits other proteases, including plasmin.
2. Aprotinin is approved for use during cardiac bypass surgery based on its
anticoagulation properties that reduce the amount of blood needed for
transfusion during extracorporeal procedures.
3. Agents that alter kinin release are under investigation for the treatment of
inflammation.

Assignment Prepare for the midterm exam

SUBJECT PHARMACOLOGY 1 TOPIC ANS-1
IG NUMBER IG-PHA-325LC WEEK NO 7
TERM MIDTERM SESSION 11 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to dicuss the Nervous system and its divisions.
Session

Objectives 1. To discuss the different divisions of Nervous System

2. To identify what comprises the autonomic nervous system
3. To enumerate the neurotransmitters associated with autonomic nervous system
4. To enumerate the effects of autonomic nervous system in different organ systems
5. To discuss the synthesis and release of the autonomic nervous system
neurotransmitters

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition

Lesson NERVOUS SYSTEM

Outline
What are the different divisions of Nervous System?
What comprises the autonomic nervous system?
What is the origin of the parasympathetic nervous system?
What is the origin of the sympathetic nervous system?
What is the neurotransmitter of the parasympathetic nervous system?
How is the neurotransmitter synthesized and stored by the body?
What is the neurotransmitter of the sympathetic nervous system?
How is the neurotransmitter of synthesized and stored by the body?
What is the amino acid precursor of Norpepinephrine?
What endocrine organ synthesizes dopamine and epinephrine?
What enzyme catalyzes the formation of acetylcholine?
What enzyme catalyzes the conversion of Norepinephrine to epinephrine?

I. DIVISIONS
a. CENTRAL NERVOUS SYSTEM (CNS)
a.1 brain
a.2 spinal cord
b. PERIPHERAL NERVOUS SYSTEM (PNS)
Collection of nerves and ganglia scattered throughout the brain
Consists of 12 pairs of cranial nerves, 31 pairs of spinal nerves and
their branches to the entire body.
Transmits information to and from the CNS

a. somatic nervous system

b. autonomic nervous system

Autonomic Nervous System

• also called visceral or involuntary nervous system
innervates cardiac muscles, smooth muscles and glands

A. Divisions of ANS

1. Sympathetic nervous system

• the thoraco-lumbar outflow (nerves exit from the thoracic and lumbar segments
of the spinal cord)
 • activates those organs necessary during stressful situations such as exercise,
anxiety and fear
• for “fight-flight responses like increased heart rate and sweating

2. Parasympathetic nervous system

• the cranio-sacral outflow(nerves exit from the cervical and sacral segments of the
spinal cord)
• dominant in relaxed or non-stressful situations for repose and repair (rest and
digest) response like moving the bowel and emptying the bladder

NEUROTRANSMITTERS
1 Acetylcholine- neurotransmitter released by pre-ganglionic neurons in both the
sympathetic and the parasympathetic divisions
• RELEASED by the POST-GANGLIONIC NEURONS in the
PARASYMPATHETIC DIVISION

Cholinergic nerve fibers- fibers that release Ach

Cholinomimetic or PARASYMPATHOMIMETIC- agents that act like Ach
ACETYLCHOLINESTERASE (cholinesterse)- responsible for the inactivation of Ach

2. NOREPINEPHRINE- is the neurotransmitter released by most postganglionic neuron

in the sympathetic divison
Adrenergic nerve fibers- fibers that release NE
ADRENERGIC OR SYMPATHOMIMETIC- agents that act like NE
MAO AND COMT- enzymes that inactivate NE/Epi
**MAO (Monoamine oxidase inhibitor)
**COMT (Catechol-O-methyl transferase)

Synthesis of Acetylcholine (ACh)

Choline acetyltransferase (ChAT)

Acetyl-CoA + Choline Acetylcholine

Synthesis of NE
Tyrosine
Tyrosine hydroxylase

Dopa
Dopa decarboxylase

Dopamine
Dopamine b-hydroxylase

Norepinephrine

Assessment A short examination about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC ANS-1
IG NUMBER IG-PHA-325LC WEEK NO 7
TERM MIDTERM SESSION 12 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is inetended to dicuss the Functions of Autonomic Nervous System and its
Session effect in different organs.

Objectives 1. To discuss the effects of ANS in different organs

2. To discuss the two subdivisions of ANS
3. To discuss the physiologic effects of the two subdivisions of ANS

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition.

Lesson Functions of Autonomic Nervous System

Outline
What are the different effects of Autonomic Nervous System to different organs?
What are the subtypes of adrenergic receptors?
Where are the adrenergic receptors located?
What are the subtypes of cholinergic receptors?
Where are the cholinergic receptors located?

Organ Sympathetic response Parasympathetic response

Myocardium Increase rate Decrease rate
Bronchioles Dilate Constrict
Iris Dilate Constrict
Salivary Glands Decrease Increase
Stomach Decrease Increase
Urinary bladder Relaxation Contraction
Liver Glycogenolysis NONE
Blood vessel(viscera) Constrict NONE
Blood vessel(skeletal) Dilate NONE

Autonomic pathway

Pregangionic nerve fiber- terminates and synapses in an autonomic ganglion

Postganglionic nerve fiber- originates in a ganglion and terminates in smooth cardiac
muscle or a gland.

THUS, A NERVE IMPULSE ORIGINATING IN THE CNS FIRST SYNAPSES AT THE END
OF A PREGANGLIONIC FIBER IN A GANGLION, AND THEN SYNAPSES AT A POST
GANGLIONIC FIBER IN A MUSCLE FIBER OR GLAND.

Adrenergic nerve fibers- fibers that release NE

ADRENERGIC OR SYMPATHOMIMETIC- agents that act like NE

MAO AND COMT- enzymes that inactivate NE/Epi
**MAO (Monoamine oxidase inhibitor)
**COMT (Catechol-O-methyl transferase)
 RECEPTORS of the AUTONOMIC NERVOUS SYTEM

ADRENERGIC RECEPTORS
Subtypes of adrenergic receptors
1. Alpha receptor
Location
1.1 alpha 1 smooth muscle tissue of peripheral vessels,
trigone and sphincter of the bladder, male
sex organ, and other tissues
1.2 alpha 2 located in pre-synaptic neurons

2. Beta receptor
2.1 Beta 1 
2.2 Beta 2 bronchial smooth muscle

CHOLINERGIC RECEPTORS
Subtypes
1. Muscarinic receptor Located only in postganglionic effector cells
2. Nicotinic receptor NMJ, ganglia of both ANS divisions
Assessment
A short examination about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC PARASYMPATHETIC DRUGS
IG NUMBER IG-PHA-325LC WEEK NO 8
TERM MIDTERM SESSION 13 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the effects of the Paraympathetic Nervous System
Session in the body, and the different agents that mimic the effects of the Parasympathetic
Nervous System.
Objectives
1. To discuss the receptors of the Parasympathetic nervous system
2. To enumerate the effects of parasympathomimetic agents in the receptors
located at different organs
3. To discuss the mechanisms of action of different cholinergic agonists
4. To classify the cholinergic agonists according to their chemical structure and
duration of actions

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3. Stedman’s Concise Medical Dictionary, Latest edition

Lesson PARASYMPATHETIC NERVOUS SYSTEM

Outline
What is the neurotransmitter of the Parasympathetic Nervous system?
What are the types of cholinergic receptors?
What are the physiologic effects of Cholinomimetic drugs?
How does cholinesterase inhibitors work?
Differentiate the mechanisms of action of indirect and direct-acting cholinomimetics.
Give examples of direct-acting cholinomimetics.
Give examples of indirect-acting chilino

Cholinergic – responding to acetylcholine, refers to receptor sites stimulated by

acetylcholine as well as neurons that releasing acetylcholine.

Cholinergic receptor – receptor sites on effectors that respond to acetylcholine

1. Nicotinic receptors – cholinergic receptors that also respond to stimulation by
nicotine
2. Muscarinic receptors

CHOLINERGIC AGONIST
PARASYMPATHOMIMETIC

1. Direct acting cholinomimetics

- may be produced by replacing the acetyl group of acetlcholine.
- A carbamoyl group substituting the methyl group of the beta-carbon.
- Substitutions provide resistance to acetylcholinesterases and thus, have
longer duration of action.
• Acetylcholine → used in the diagnosis of endothelial dysfunction
- the natural endogenous mediator and most potent cholinergic agonist.
- An ester of acetic acid and choline, a quaternary amino alcohol
- Unstable and is quickly hydrolyzed both in vivo and in vitro.
- Short acting and not satisfactory as a therapeutic agent.

Betanechol → urinary retention

 → stimulate peristaltic movement
Metacholine- stable cholinergic agonist
Carbachol
Pilocarpine → tx of glaucoma
Nicotine → smoking deterrent
2. Indirect acting cholinomimetics – inhibits enzyme Acetylcholinesterase
• Reversible- Carbamates: Physostigmine and Neostigmine
• Irreversible- Organophosphates: Isofluorophate and echothiophate

B. Short-acting cholinomimetic

*Edrophonium (Tensilon) → diagnosis of Myasthenia gravis

C. Intermediate acting cholinomimetic

*Physostigmine → tx of myasthenia gravis

*Neostigmine
*Pyridostigmine
*Ambenomium
*Demecarium

C. Long acting cholinomimetic Organophosphates

• Echothiophate
• Isofluorophate
• Malathion
• Parathion

Action of Organophosphate cholinesterase inhibitors

Reversible in the first 24-48 hours
Irreversible due to ageing of Phosphate(PO4) bond beyond 24-48 hours

Pharmacology
1. Cholinergic responses are mediated by both muscarinic and nicotinic receptors.
2. Cholinergic agonists act by mimicking the activity of endogenous acetylcholine at
muscarinic and nicotinic receptor sites.
a. Direct acting agonists interact directly with nicotinic and muscarinic
receptors.
b. Indirect acting agonists inhibit or block the activity of cholinesterase
enzymes, which metabolize endogenous acetylcholine to inactive
metabolites.

Cholinoceptor-Mediated Responses to Cholinergic agonists

Organ Response

Heart
AV Node Decreased conduction velocity(negative dromotropy)
Atria,ventricles Decreased contraction force(negative inotropy)
SA node Decreased contraction rate(negative chronotropy)
Eye
Sphicter muscle Contraction, miosis
Ciliary muscle Contraction, accommodates near vision
Lung
Bronchial
 Treatment of Organophosphate poisoning

1. Regenerator compounds
Used early in the course of poisoning
Facilitate removal of binding of Organophosphate to ACHE
Oxime derivatives (pralidoxime)

2. Physiologic antidote
Atropine –long term administration of acetylcholine is needed
Remove the enzyme to which organoP04 is bound

Assignment Tabulate the physiologic effects of the parasympathomimetic agents.

Assessment A short examination about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC Parasympatholytic agents
IG NUMBER IG-PHA-325LC WEEK NO 8
TERM MIDTERM SESSION 14 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the pharmacology of the agents that reverse the
Session effect of parasympathetic nervous system.

Objectives 1. To enumerate the different parasympatholytic agents

2. To enumerate the effects of parasympatholytic agents
3. To discuss the mechanisms of action of parasympatholytics
4. To enumerate the adverse effects associated with the use of parasympatholytics

1. Basic and Clinical Pharmcology Latest edition

Materials 2. Comprehensive Pharmacy Review Latest edition

PARASYMPATHOLYTIC DRUGS
Lesson
Outline What is the mechanism of action of parasympatholytics?
What is the prototype of anti-cholinergic drugs?
What are the effects of parasympatholytics?
What are the components of Twilight sleep?
Give examples of ganglionic blockers.

Parasympatholytics/Anti-cholinergic
1. Antimuscarinic
2. Antinicotinic

Anti-muscarinic
Atropine- Prototype drug

Effects

Eyes mydriasis (pupillodilation)

Cyclopegia (paralysis of ciliary muscle)

Bronchi bronchodilation
GIT Relaxation of intestinal walls and closure of sphincters
(constipation)
GUT Relaxation of bladder walls and closure of sphincters
(urinary retention)
Exocrine Absence of sweat (anhidrosis)
body temperature (hyperthermia)

Salivary, bronchial, instestinal glandular secretion

secretion

Heart tachycardia,

Atropine
A tertiary amine
CNS effects seizures, psychosis, anxiety, restlessness
Effects according to target organ/tissue

1. CNS 1. Scopolamine- anti-motion sickness

component of an obstetric anesthetic called “twilight
sleep”
Twilight sleep ( Morphine + scopolamine) -
sedation and Relaxation, dreamless sleep, anterograde
amnesia
2. Biperiden
3. Benztropine
4. Trihexyphenidyl

2. Eyes (pupils) 1. Atropine used as mydriatics

2. Homatropine relieves spasms of ciliary
3. Tropicamide muscles due to cyclopegic
4. cyclopentolate effect

3. Heart Atropine Used for symptoms of

bradycardia
Alternative drug for PEA
(pulseless electrical activity)

Electrochemical dissociation
with observable electrical activity but
w/o cardiac contraction

4. Bronchi Ipratropium Bronchodilators for COPD

Oxytropium
Tiotropium

5. GIT Pirenzepine/Telenzepine Adjunct in peptic ulcer

disease
Prophantheline used in hypermotility
disorders
Dicyclomine
Glycopyrrolate

6. GUT Dicyclomine Used in urinary incontinence

Glycopyrrolate

Anti-nicotinic

• according to the nicotinic receptors they inhibit

1. ganglionic blockers inhibit NN
2. neuromuscularblockers inhibit NM

Ganglionic blockers
Block both nicotinic receptors in sympathetic and parasympathetic ganglia
Non selective response
1. Hexamethonium
2. Mecamylamine
3. Trimethaphan
 Effects
Pupils Para (miosis) mydriasis
Heart Para (bradycardia) tachycardia
GIT Para (diarrhea) constipation
GUT Para (urination) Urinary retention
Blood vessels S (vasoconstriction) vasodilation(hypotension)
Sweat glands S( sweating) absence of sweating

Trimethaphan- alternative drug for hypertensive crisis.

Assignment Tabulate the effects of parasympatholytic drugs in the body

Assessment A short examination about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC Sympathomimetic Drugs.
IG NUMBER IG-PHA-325LC WEEK NO 9
TERM MIDTERM SESSION 15 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This topic is intended to dicuss the pharmacology of Sympathomimetic Drugs.
Session
1. To discuss the physiologic effects of the Sympathetic Nervous System
Objectives 2. To discuss the therapeutic indications of adrenergic agonists
3. To discuss the mechanisms of action of sympathomimetics
4. To classify the sympathomimetic drugs according to their mechanisms of action
5. To enumerate the adverse effects associated with the use of sympathomimetics

1. Basic and Clinical Pharmacology Latest edition

2. Comprehensive Pharmacy Review Latest edition

Materials SYMPATHETIC NERVOUS SYSTEM

What are the effects of adrenergic agonist?

Lesson What is the neurotransmitter involved in sympathetic nervous system?
Outline Give examples of adrenergic agonists.
Give the therapeutic indications of adrenergic agonists.

I. Adrenergic agonist – a drug that stimulates the adrenergic receptors of the

sympathetic nervous system, either directly (by reacting with receptor sites) or
indirectly (by increasing norepinephrine levels)

Sympathomimetics – drugs that mimic the effects of Sympathetic Nervous System

A. Chemistry

1. direct acting sympathomimetic- acts directly on alpha/beta receptors, producing

effects similar to those that occur following stimulation of parasympathetic nerves
or release of the hormone NE from the adrenal medulla
a. Cathecolamines are biosynthesized from tyrosine, an amino acid.
b. The ethylamine chain common to these agonists is essential to their activity.
c. N-substituents alter drug activity. Small substituents produce alpha-receptor
activity; larger substituents produce beta-receptor.
d. Removal of the para(4) hydroxyl group leaves only alpha-receptor activity.
e. The meta(3) hydroxyl group is essential for direct alpha and beta-activity.
f. Cathecolamines are inactivated by methylation of the meta hydroxyl group
(catalyzed by Catechol O-methyl transferase, COMT) and by oxidative
deamination (catalyzed by monoamine oxidase,MAO).

Phenylephrine- nasal decongestant

Isoproterenol- used in asthma
Norepinephrine – Tx of shock
Epinephrine- used in anaphylactic shock/asthma

2. INDIRECT ACTING AGONISTS- chemically related to the cathecolamines, but they

do not interact directly with adrenergic receptors. These mostly synthetic
compounds induce their pharmacological effects by enhancing the release of
endogenous neurotransmitters. Physiologically, therefore, they have effects similar
 to the cathecolamine neurotransmitters, hence their nickname sympathomimetic
amines.
a. Indirect-acting sympathomimetic amines may have one, two, or no hydroxyl
groups. The fewer the hydroxyl groups, the higher the lipophilicity, and the
greater the absorption and duration of activity after oral administration. Faster
and greater absorption also implies less intestinal destruction of the drug.
b. Alkyl substitution at the alpha-carbon retard destruction of the phenol and phenyl
compounds and increases lipophilic character, contributing to prolonged activity.
c. N-substitution with bulky groups increases direct beta-receptor activity, as with
the direct-acting agents.

B. Pharmacology
1. Adrenergic peripheral responses are mediated both alpha and beta-
adrenoceptors.
A. Alpha Receptors:

a. Postjuctional alpha1-adrenergic receptors. They are found in the radial smooth

muscle of the iris; in the arteries, arterioles, and veins; in the pilomotor smooth
muscle of the hair follicles; in the heart; and in sphincters of the gastrointestinal
tract.
b. Drugs that are alpha2-selective agonists cause excitatory responses such as
vasoconstriction and smooth muscle contraction.
c. Prejunctional alpha2-adrenergic receptors mediate the inhibition of adrenergic
neurotransmitter release.
d. Drugs that are alpha2-selective agonists also inhibit lipolysis in fat cells and
promote platelet aggregation.

B. Beta Receptors:

a. Postjunctional Beta1-adrenergic receptors. They are found mainly in the

myocardium, where their stimulation increases the force and rate of myocardial
contraction.
b. Postjunctional Beta2-adrenergic receptors. They are found in bronchiolar and
vascular smooth muscle, where their stimulation causes smooth-muscle
dilatation or relaxation.
c. Postjunctional Beta3-adrenergic receptors. It is expressed in fat cells, and their
stimulation causes lipolysis. A number of beta3-agonists are under development
as potential anti-obesity agents.

2. Direct-acting adrenergic agonists produce their effects primarily by direct

stimulation of adrenergic stimulation. They may be receptor-selective, as with
drugs listed above, or they may be non-selective.
3. Indirect-acting adrenergic agonists work through other primary mechanisms,
which ultimately lead to receptor effects. Tyramine acts by releasing
norepinephrine from storage sites in adrenergic neurons, while cocaine blocks
the reuptake of norepinephrine, thereby increasing the duration and activity of
transmitter at the synapse.
C. Therapeutic Indications
1. Epinephrine, an alpha and beta agonist, is indicated to treat bronchospasm and
hypersensitivity reactions and is the agent of choice for anaphylactic reactions. It
is also used to prolong the activity of local anesthetic solutions and to restore
cardiac activity in cardiac arrest. It is also used topically in the treatment of
glaucoma, presumably decresaing intraocular pressure by enhancing outflow of
aqueous humor and through vasoconstriction-induced decrease in production of
aqueous humor. Local application of epinephrine is used to arrest blood flow in
epistaxis and gingival surgery.
2. Phenylephrine, an alpha1 selective agonist, is used to provide pressor activity in
 hypotensive emergencies, to prolong the activity of local anesthetic solutions, and
to receive paroxysmal atrial tachycardia.
3. Phenylephrine or phenylpropanolamine is systematically given for nasal
congestion.
4. Oxymetazoline and xylometazoline, also alpah-1 agonist, are locally applied to
relieve nasal congestion.
5. Clonide and related alpha2-selective agonists, are used as hypertensives based on
their inhibition of central sympathetic outflow. Apraclonidine is used topically to
decrease intraocular pressure during surgery.
6. Isoproterenol, a beta-adrenergic agonist, is used as a bronchodilator and as a
cardiac stimulant in shock and cardiac arrest.
7. Dobutamine, a relatively beta1-selective agonist, is used to improve myocardial
function in congestive heart failure in emergency situtations.
8. Terbutaline and other beta2-selective agonists are used as systemic or local
bronchodilators in the treatment of bronchospastic conditions such as asthma.
9. The beta2-selective agonist, ritodrine is used to relax uterine smooth muscle in
the treatment of premature labor.
D. Adverse Effects
1. Cardiac dysrhythmias
2. Cerebral hemmorhage
3. Pulmonary hypertension and edema
4. Anxiety
5. Headache
6. Rebound nasal congestion

Assignment Tabulate the effects of adrenergic agonists in the body.

Assessment A short examination about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC ADRENERGIC ANTAGONISTS
IG NUMBER IG-PHA-325LC WEEK NO 9
TERM MIDTERM SESSION 16 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the pharmacology of the different adrenergic
Session antagonists.

Objectives 1. To discuss the subclassifications of adrenergic antagonists

2. To enumerate the therapeutic uses of adrenergic antagonists
3. To enumerate the different adverse effects associated with the use of adrenergic
antagonists

Materials 1. Basic and Clinical Pharmacology , Latest edition

2. Comprehensive Pharmacy Review , Latest edition

Lesson ADRENERGIC ANTAGONISTS

Outline What are the classifications of adenergic antagonists according to receptor subtype
interaction?
Differentiate the effects of catecholamines on alpha and beta-receptors.
What are the subclassifications of alpha-receptor antagonists?
What are the subclassifications of beta-receptor antagonists according to their
receptor selectivity?
What are the therapeutic indications of adrenergic antagonists?
Enumerate the different adverse effects associated with the use of adrenergic
antagonists.

A. ALPHA ADRENERGIC ANTAGONISTS have varied structures and have little

resemblane to the adrenergic agonists. Antagonists include ergot
alkaloids(ergotamine), dibenzamines(phenoxybenzamine), benzolines(tolazoline)
and the quinazolines(prazosin).

B. BETA ADRENERGIC ANTAGONISTS are structurally similar to beta-agonists. The

catechol ring can be replaced by a variety of other ring systems without a loss of
antagonistic activity. The lemth of the side chain is important, and the side chain
hydroxyl group as well as the propyl or other bulky substitutions on the chain
nitrogen are essential for interaction with beta-receptors.

Sympatholytic or adrenergic blocking agents – a drug that lyses or blocks the effects
of the sympathetic nervous system

1. alpha adrenergic blocking agents

A. non-selective alpha blocking agents
a. reversible-phentolamine (used in hypertension)
b. irrevesible-phenoxybenzamine (used in pheochromocytoma-
tumor in the adrenal medulla)
B. selective alpha1 adrenergic blocking agents
• used in hypertension (anti-hypetensive agent)
• used in benign prostatic hyperplasia

suffix
-zosin postsynaptic alpha-receptor blockers
terazosin, prazosin
2. beta-blockers
NON-SELECTIVE- Propranolol (prototype agent)
A. CARDIOSelective (B1 blocker)
Bisoprolol
Esmolol
Atenolol
Acebutolol
Metoprolol
B. with ISA (Intrinsic sympathomimetic activity)
Pindolol
Acebutolol
Labetalol
C. WITH MSA (MEMBRANE SATBILIZING ACTIVITY)
Should not be given as ophthalmic drops
Pindolol
Acebultol
Labetalol
Propranolol
Metoprolol
3. Mixed alpha-beta blocking effect
Carvedilol
Labetalol

C. Therapeutic Indications
1. Alpha-1 antagonists may be selective or nonselective. Phenoxybenzamine is
an irreversible antagonist because it forms covalent bonds with alpha-
receptors.
2. Phenoxybenzamine and phentolamine are used to relieve vasospasm in
Raynaud’s syndrome and for acute hypertensive emergencies resulting from
pheochromocytoma or from intake of MAO inhibitors or sympathomimetics.
3. Tolazoline, a similar agent, is used to treat neonatal pulmonary
hypertension.
4. Labetalol, an agent that possess both selective alpha-1 blocking activity and
nonselective beta-blocking activity, is used in the treatment of
hypertension.
5. Propranolol, a nonselective beta-antagonist, is used for prophylaxis of
angina pectoris, supraventricular and ventricular dysrhythmias and migraine
headache. It is also used as an anti-hypertensive, a negative inotropic
agent in hypertrophic obstructive cardiomyopathy, and a negative
chronotropic agent in anxiety and hyperthyroidism.
6. Beta-1 selective antagonists are used in the treatment of
hypertension,tachyarrhythmias and angina.
a. Metoprolol
b. Betaxolol
c. Atenolol
d. Acebutolol
7. Both beta-1 selective (betaxolol) and nonselective (timolol) blockers
decrease ciliary body production of aqueous humor and may be used in the
topical treatment of glaucoma.
D. Adverse Effects
1. Prazosin can cause sudden syncope with the first dose, orthostatic
hypotension, dizziness, headache, drowsiness, palpitations, fluid retention
and priapism.
2. Phenoxybenzamine can cause orthostatic hypotension, tachycardia,
inhibition of ejaculation, misosis and nasal congestion.
3. Propranolol can cause bradycardia and congestive heart failure, increased
airway resistance, hypertriglyceridemia, blood dyscrasias, psoriais,
 depression, hallucinations, and transient hearing loss. Withdrawal from this
drug should be tapered since sudden withdrawal is cardiotoxic.
4. Metoprolol has adverse effects similar to those of propranolol, except that it
is less likely to increase airway resistance.

Assignment Tabulate the effects of adrenergic antagonists and their therapeutic indications.

Assessment A short examination about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC skeletal muscle relaxants
IG NUMBER IG-PHA-325LC WEEK NO 10
TERM MIDTERM SESSION 17 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of The students are introduced to the pharmacology of skeletal muscle relaxants
Session

Objectives 1. To discuss Skeletal muscle relaxants,

2. To elaborate the mechanisms of action of these agents
3. To discuss the adverse effects associated with these agents.

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3. Stedman’s Concise Medical Dictionary, Latest edition

Lesson SKELETAL MUSCLE RELAXANTS

Outline • Drugs that affect skeletal muscle function fall into two major therapeutic groups:
b. Those used during surgical procedures and ICU to promote skeletal muscle
paralysis (neuromuscular blocking agents)
c. Those used to reduce spasticity in a variety of neurologic conditions
(spasmolytics)

I. NEUROMUSCULAR BLOCKING AGENTS

• Agents that are used to reduce spasticity in a variety of neurologic conditions.
• These agents interfere with transmission at the neuromuscular end-plate and are
not central nervous system acting drugs.
HISTORY
• 16th century- European explorers found that the natives of the Amazon basin of
South America were using an arrow poison that produced death by skeletal
muscle paralysis.
• Curare- South American Arrow Poison
- d-tubocurarine- the active principle that provide an enormous influence on
the practice of anesthesia and surgery and have been very useful in defining
normal neuromuscular physiologic mechanisms.
Normal Neuromuscular Function
• Arrival of impulse at the motor nerve terminal ->influx of calcium->release of
acetylcholine>diffusion of acetylcholine across the synaptic cleft>acetylcholine-
nicotinic receptor interaction at the motor end plate>opening of the sodium
channels>depolarization
• To additional types of acetylcholine receptors are associated with neuromuscular
apparatus:
a. The receptor found at the presynaptic motor axon terminal that mobilizes
additional neurotransmitter for subsequent release by mobilizing more
acetylcholine vesicles at the motor plate end.
b. The receptor found at the perijunctional cells and not normally involved in
transmission but under some conditions, these receptors proliferate
sufficiently to affect neuromuscular transmission.
• Blockade of end-plate function is accomplished by two mechanisms:
a. Pharmacologic blockade of the physiologic agonist acetylcholine. This group is
the non-depolarizing group. The prototype is tubocurarine.
b. An excess of depolarizing agonist can produce Block of transmission. The
prototype of the depoklarizing group is succinylcholine.
A. CHEMISTRY
1. Neuromuscular blocking agents can be competitive or depolarizing. They act by
blocking the effects of acetylcholine at nerve-muscle junction of skeletal muscles.
2. The competitive nondepolarizing agents include the naturally occurring alkaloids of
curare, which are bulky and rigid molecules, as well as several synthetic
analogues.
3. The non-competitive depolarizing agents include succinylcholine and gallamine.
4. All of the neuromuscular blocking drugs are highly polar and inactive ahen
administered orally. They are always given intravenously.
5. Isoquinoline nondepolarizing drugs include tubocurarine, atracurium, doxacurium
and mivacurium.
6. Steroid derivatives of the nondepolarizing subgroup are pancuronium, vecuronium,
pipecuronium and rocuronium.

A. Pharmacology
1. The competitive nondepolarizing agents compete with acetylcholine for nicotinic
receptors at the neuromuscular junction. The agents decrease the end plate
potential so that the depolarization threshold is not reached. Competitive
nondepolarizing agents produce a surmountable blockade of neuromuscular
transmission in that adminstration of cholinesterase inhibitors or prejunctional
release of a large quantity of acetylcholine can relieve the blockade. In small
clinical doses and at low frequencies of stimulation, nondepolarizing muscle
relaxants act predominantly at the nicotinic receptor sites to compete with
acetylcholine. In larger doses, these drugs also enter the pore of an ion channel
to cause blockade. Nondepolarizing relaxants may also block prejunctional sodium
channel but not calcium channels. These agents produce a surmountable
blockade.
a. The surmountable block is a consequence of the postsynaptic blockade
produced by these agents as a result of tetanic stimulation, by releasing a
large quantity of acetylcholine, followed by a transient posttetanic
breakthrough or relief of the block.
b. The prinicipal active alkaloid in curare is tubocurarine. A closely related
trimethylate derivative is metocurine. Their most important structural feature
is the presence of tertiary-quaternary amine in which the distance between
the two cations is rigidly fixed at about 14 angstrom, twice the length of the
crirical receptor-binding moiety of acetylcholine.
c. A number of potent analogues have been developed. These include the
structurally similar isoquinolines atracurium, doxacurium, and mivacurium, as
well as the steroid derivative pancuronium, vecuroniumand pipecuronium.
d. The route of elimination is strongly correlated with its duration.
e. All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-hydroxy
or 3,17-dihydroxy products, mainly in the liver.
f. The 3-hydroxy metabolite may cause prolonged paralysis because it is more
slowly cleared than the parent compound.
g. The intemediate-duration muscle relaxants include vecuronium and
rocuronium and are more dependent on biliary excretion or hepatic
metabolism for their elimination. They are more commonly used than the
long-acting ones.
h. Vecuronium has a steroid nucleus like that of pancuronium differing only in
one nitrogen that is tertiary rather than quaternary.
i. Rocuronium has a pharmacokinetic profile similar to vecuronium.
j. Rapacuronium is the newest neuromuscular blocker and has the most rapid
onset. It is the preferred agent for rapid-sequence induction of anesthesia
and endotracheal intubation.
k. Atracurium is an isoquinoline derivative with many same characteristics as
vecuronium. The main product of metabolism is laudanosine and a related
quaternary acid, neither possess neuromuscular blocking properties.
 l. Cisatracurium, one of the stereoisomers of atracurium but is less dependent
on hepatic inactivation, forms less laudanosine, and releases less histamine
from tissue stores.
m. Mivacurium and rapacuronium belong to the short-duration muscle relaxants.
n. The duration of action of mivacurium is prolonged among patients with
impaired renal function.
2. The noncompetitive depolarizing agents desensitize the nicotinic receptors at the
neuromuscular junction. These agents react with nicotinic receptors, decreasing
receptor sensitivity in a manner similar to that of excess released acetylcholine.
They depolarize the excitable membrane for a prolonged period; the membrane
then becomes unresponsive.
a. Noncompetitive agents are slender alipathic molecules.
b. Succinylcholine has a short duration(5-10 minutes) of action compared with
the other neuromuscular blocking agents. This results from its simple ester
functional group, which is rapidly hydrolyzed by plasma and liver
pseudocholinesterases. Its action may be prolonged, however, in patients
with an abnormal genetic variant of pseudocholinesterase, which has only
20% of the activity of the normal pseudocholinesterase.
- Phase I block(depolarizing). Succinylcholine reacts with the nicotinic
receptor to open the channel and cause depolarization at the motor end
plate , and this would spread and depolarize adjacent membranes causing
generalized disorganized contraction of muscle motor units. Succinylcholine
is not metabolized at the synapse resulting to suatined depolarization of
membranes making them unresponsive to additional impulses.
Furthermore, because excitation-concentration coupling requires end plate
repolarization and repetitive firing to maintain muscle tension, a flaccid
paralysis results. Phase I block is augmented, not reversed by
cholinesterase inhibitors.
- Phase II block(desensitizing)- the continued exposure to succinylcholine
results in the decrease of of initial end plate depolarization and the
mambrane becomes repolarized. Despite this repolarization, the membraine
is not easily depolarized because it is desensitized. During the latter part of
phase 2, the characteristics of the blockade are nearly identical to those of
a nondepolarizing block and are reversed by acetylcholinesterase inhibitors.
c. The initial metabolite of succinylcholine, succinylmonocholine is a weaker
neuromuscular blocker, which is further metabolized to succinic acid and
choline.
d. Neuromuscular blockade by both succinylcholine and mivacurium is prolonged
among patients with an abnormal variant of plasma cholinesterase of genetic
origin.
e. Dibucaine number- a test for the ability to metabolize succinylcholine. Under
normal conditions, dibucaine inhibits the normal enzyme about 80% and
abnormal enzyme only 20%.

B.Therapeutic Indications. Neuromuscular blocking agents, which cause only

skeletal muscle paralysis, are used to:
1. Promote skeletal muscle relaxation and facilitate endotracheal intubation, as an
adjunct to surgical anesthesia
2. Limit trauma associated with skeletal muscle contraction during
electroconvulsive shock therapy
3. Relax the skeletal muscles and facilitate bone placement and manipulations
during orthopedic procedures.
4. Neuromuscular blockers are ofeten desirable to control ventilation to provide
adequate volumes and expansion of lungs. These agents eliminate chest wall
resistance and ineffective spontaneous ventilation.
5. Neuromuscular blockers are sometimes used to attenuate or eliminate the
peripheral manifestations of convulsions from such causes as epilepsy or local
 anesthetic toxicity. These agents only eliminate the muscular manifestations of
seizures, since they do not cross the blood-brain barrier.
C. Adverse Effects
1. Competitive nondepolarizing agents can cause respiratory paralysis, histamine
release, bronchospasm and hypotension, tachycardia and hypertension
(pancuronium).
2. Noncompetitive depolarizing agents can cause respiratory paralysis, muscle
fasciculations with apin, extraocular muscle contraction with increased
intraocular pressure, and increased intragastric pressure. In addition,
succinylcholine may cause muscarinic responses such as bradycardia,
increased glandular secretions, and cardiac arrest. In combination with the
anesthetic halothane, succinylcholine may cause malignat hyperthermia in
gentically predisposed individuals.
D. Reversal of Nondepolarizing Blockade
• The cholinesterase inhibitors effectivey antagonize the neuromuscular blockade
caused by nondepolarizing drugs.
• Neostigmine and pyridostigmine reverses the block by increasing the availability
of acetylcholine at the muscle end plate, mainly by inhibition of
acetylcholinesterase. To a lesser extent, these agents also increase the release
of transmitter from the motor nerve terminal.
• Edrophonium antagonizes the blockade purely by inhibiting acetylcholinesterase
and is less efective than neostigmine.
• Neostigmine also decreases the activity of plasma cholinesterase. Because
mivacurium is metabolized by plasma cholinesterase, the interaction between
these two drugs is unpredictable. On one hand, the neuromuscular blockade is
antagonized because of increased acetylcholine at the synapse. On the other
hand, mivacurium concentration may be higher because of decreased plasma
cholinesterase. The former effect usually dominates clinically.
E. Significant Drug Interactions
1. With Anesthetics. Inhaled anesthetics augment the neuromuscular blockade
from nondepolarizing muscle relaxants in dose-dependent fashion.
a. Isoflurane, sevoflurane, desflurane and enflurane(in decreasing order)
augment more than halothane, which in turn augments more than nitrous
oxide-barbiturate-benzodiazepine-opioid anesthesia.
b. The most important factors involved in the interaction are the following:
- depression at the sites proximal to the neuromuscular junction
- increased muscle blood flow allowing a larger fraction of the injected
muscle relaxant to reach the neuromuscular junction(Isoflurane)
- decreased sensitivity of the postjunctional membrane to depolarization.
2. With Antibiotics. Enhancement of neuromuscular blockade, especially with
aminoglycosides. It was shown that antibiotics depress the evoked release of
acetylcholine similar to that caused by magnesium. The mechanism of this
prejunctional effect appears to be blockade of the P-type calcium channels.
The same antibiotics also have postjunctional activity.
3. With local anesthetics and antiarrhythmics.
- in large doses- local anesthetics block transmission
- in smaller doses- enhance neuromuscular block
- in low doses- depress posttetanic potentiation
- in higher doses- block acetylcholine-induced muscle contraction
- similar effects are demonstrated with antiarrhythmics
4. Other Neuromuscular blockers
- depolarizing muscle relaxants are antagonized by nondepolarizing
blockers.
- To prevent fasciculations associated with succinylcholine administration, a
small, nonparalyzing dose of a nondepolarizer is often given before
succinylcholine.
II. SPASMOLYTICS
• Spasticity is characterized by an increase in tonic stretch reflexes and flexor
muscle spasms together with muscle weakness.
• It is often associated with cerebral palsy, multiple sclerosis, and stroke.
• The mechanisms underlying clinical spasticity appear to involve not the stretch
reflex arc itself but of higher centers (upper motor neuron), with lesions on the
descending pathways that results in hyperexcitability of alpha motorneurons in
the cord.
A. DIAZEPAM
• Acts on the GABAa synapses, but its site of action in reducing spasticity is at least
partly in the spinal cord, because it is effective in patients with cord transection.
• Initial dose is 4 mg/d and gradually increased to a maximum of 60 mg/d.
B. BACLOFEN
• P-chlorophenyl-GABA was designed to be an orally active GABA-mimetic agent.
• An active spasmolytic and acts as a GABA agonist at GABAb receptors.
• Acts through hyperpolarization, by increasing potassium conductance that serves
as a presynaptic inhibitory function by reducing calcium influx, thereby reducing
the release of excitatory transmitters in both the brain and spinal cord.
• It also reduces pain among patients with spasticity by inhibiting the release of
substance P in the spinal cord.
• It is as effective as diazepam in reducing spasticity and acauses much less
sedation. In addition, it does not reduce general muscle strength as dantrolene.
• It is rapidly and completely absorbed after oral administration.
• Toxicity of this drug includes drowsiness. Increased seizure activity has been
reported in epileptic patients.
• Withdrawal of baclofen must be done slowly.
• It was also found to be effective in preventing migraine attacks to some patients.
C. TIZANIDINE
• Possess alpha2-agonist effects, but it reduces spasticity in doses that cause less
hypotension than clonidine.
• Reinforces both presynaptic and postsynaptic inhibition in the cord.
• Inhibits nociceptive transmission in the spinal dorsal horn.
• Adverse effects include drowsiness, hypotension, dry mouth and asthenia.
D. OTHER DRUGS
• Gabapentin-spasmolytic to patients with multiple sclerosis.
• Progabide- GABAA and GABAB agonistand has active metabolites, including GABA
itself.
• Glycine- inhibitory amino acid neurotransmitter; active when given orally and
readily passes BBB.
• Idrocilamide-newer agent
• Riluzole- a newer agent in the treatment of amyotrophic lateral sclerosis; inhibits
glutamatergic transmission in the CNS.
E. DANTROLENE
• A hydantoin derivative
• Reduces skeletal muscle strength by interfering with excitation-contraction
coupling in the muscle fiber.
• Acts by interfering the release of activator calcium via the sarcoplasmic reticulum
calcium channel by binding to the same receptor utilized by ryanodine.
• Used in the treatment of malignant hyperthermia, a rare disorder triggered by a
variety of stimuli, including general anesthesia and neuromuscular blocking drugs.
A trigger event results in sudden and prolonged release of calcium, resulting in
the accumulation of laction acid, and increased body temperature.
F. BOTULINUM TOXIN
• Used in cerebral palsy

DRUGS USED FOR ACUTE LOCAL SPASM

• Cyclobenzaprine-prototype
 - Structurally related to TCA and has some properties in common with them.
- Ineffective in muscle spasm due to spinal cord injury or cerebral palsy
- Have strong muscarinic actions, produce marked sedation and causes transient
visual hallucinations and confusion in some.
• Carisoprodol, Chlorphenesin, Chlorzoxazone, Metaxalone, Methocarbamol and
Orphenadrine
Assessment Short quiz about the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC LOCAL ANESTHETICS AND
general anesthetics
IG NUMBER IG-PHA-325LC WEEK NO 10
TERM MIDTERM SESSION 18 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of The students are introduced to the pharmacology of Local and General anesthetics
Session

Objectives 1. To discuss Local and General anesthetics

2. To elaborate the mechanisms of action of these agents
3. To discuss the adverse effects associated with these agents.

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Comprehensive Pharmacy Review, Latest edition
3. Stedman’s Concise Medical Dictionary, Latest edition

Lesson
Outline GENERAL AND LOCAL ANESTHETICS

General anesthetics
• Induce combined state of analgesia, amnesia, loss of consciousness, inhibition of
sensory and autonomic reflexes, and skeletal muscle relaxation.
• The first scientific demonstration of drug-induced anesthesia during surgery was
in 1846, when William Morton used diethyl ether.
• James Simpson-discovered chloroform in Scotland
• 1790’s- Sir Humphry Davy discovered nitrous oxide
• 1930’s- Intravenous thiopental was introduced
• 1940’s- curare was used in anesthesia to achieve skeletal muscle relaxation
• 1956- the first modern halogenated hydrocarbon, halothane was introduced.

Characteristics
➢ Induce anesthesia rapidly and smoothly
➢ Permit rapid recovery of the patient once administration of the agent ceases

A. Chemistry

1. Volatile or inhalational anesthetics

a. Inorganic agents- Nitrous oxide
b. Non-flammable halogenated hydrocarbons- halothane
c. Ethers- Methoxyflurane, isoflurane, desflurane, sevoflurane)

2. Non-volatile or intravenous anesthetics- administered IV or occasionally IM

a. water soluble and short acting agents include the utrashort acting barbituraters
(thiopental, methohexital, thiamylal), cyclohexylamines (ketamine),
benzodiazepines (diazepam, midazolam), butyrophenones (droperidol) and
opioid analgesics (morphine, fentanyl)
b. The imidazole, etomidate, is prepared as an aqueous propylene glycol solution,
which is compatible with many preanesthetics
c. The dialkylphenol, PROPOFOL is administered as an emulsion, which should not
be mixed with other therapeutic agents before administration.

STAGES OF ANESTHESIA
• Guedel’s signs- a traditional description of the signs and stages of anesthesia
 derives mainly from observation of the effects of diethyl ether, which has a slow
onset of central action owing to its high solubility in blood.
I. STAGE OF ANALGESIA: Analgesia without amnesia. In the later part of stage 1,
both analgesia and amnesia ensue.
II. STAGE OF EXCITEMENT: Delirious and excited but definitely amnesic. Irregular
respiration both in volume and rate, and retching and vomiting can occur.
III. STAGE OF SURGICAL ANESTHESIA: This stage begins with recurrence of
regular respiration and extends to complete cessation of spontaneous respiration.
Four planes of stage III have been described in terms of changes in ocular
movements, eye reflexes, and pupil size, which under specified conditions may
represent signs of increasing depth of anesthesia.
IV. STAGE OF MEDULLARY DEPRESSION: When spontaneous respiration ceases,
stage IV is present. The stage of anesthesia includes severe depression of the
vasomotor center in the medulla as well as the respiratory center. Without full
circulatory and respiratory support, death rapidly ensues.
• Atropine is used to decrease secretions, also dilates pupils.
• Tubocurarine and Succinylcholine are administered to affect muscle tone.
• Opioid analgesics exert depressant effects on respiration.
• The most reliable indications that stage III has been achieved are the loss of
eyelash reflexand establishment of a respiratory pattern that is regular in rate and
depth.

INHALED ANESTHETICS
• Depth of anesthesia is determined by the concentrations of anesthetics in the
central nervous system.
• The concentration of an individual gas in a mixture of gases is proportionate to its
partial pressure or tension.
• BLOOD:GAS PARTITION COEFFICIENT- a useful index of solubility and defines
the relative affinity of an anesthetic for the blood compared to air.
• Desflurane, nitrous oxide, sevoflurane- are not very soluble in blood; have low
blood:gas partition coefficients.
• Methoxyflurane- very soluble in blood.
• Inverse relationship exists between blood solubility of an anesthetic and the rate
of rise in arterial blood. The higher the blood:gas partition coefficient, the slower
the induction of anesthesia.
• AN increase in the inspired anesthetic concentration will increase the rate of
induction of anesthesia by increasing the rate of transfer into the blood.
• Enflurane, isoflurane, and halothane- have relatively slow onset of anesthetic
effect.
• AN increase in pulmonary ventilation is accompanied by only a slight increase in
arterial tension of an anesthetic with low blood solubility or low coefficient but
can significantly increase tension of agents with moderate or high blood solubility.
• Depression of respiration by other pharmacologic agents, including opioid
analgesics, may slow the onset of anesthesia of some inhaled anesthetics if
ventilation is not controlled.
• AN increase in pulmonary blood flow slows the rate of rise in arterial tension,
particularly for those anesthetics with moderate to high solubility. A decrease in
pulmonary blood flow has an opposite effect and increases the rate of rise of
arterial tension of inhaled anesthetics.
• Highly perfused tissues exert greatest influence on arterio-venous concentration
gradient.
• The time to recover from inhalation anesthetics depends on the rate of
elimination of anesthetics from the brain after the inspired concentration of
anesthetic has been decreased.
• Inhaled anesthetics that are relatively insoluble in blood and brain are eliminated
at faster rates than more soluble anesthetics.
• The “washout” of nitrous oxide, desflurane, and sevoflurane occurs at a rapid
 rate, which leads to rapid recovery from anesthetic effects.
• Halothane is approximately twice as soluble in brain tissue and five times more
soluble in blood tha nitrous oxide. Its elimination therfore takes place more
slowly, and recovery from halothane anesthesia is less rapid.
• Clearance of inhaled anesthetics by the lungs into the expired air is the major
route of their elimination from the body
• In terms of the extent of metabolism of inhaled anesthetics the rank order is:
methoxyflurane>halothane>enflurane>sevoflurane>isoflurane>desflurane>nitro
us oxide

B. Pharmacology
1. General anesthetics depress the CNS, producing a reversible loss of consciousness
and loss of all forms of sensation
2. Inhalational anesthetics are absorbed and are primarily excreted through the
lungs. Frequently these drugs are supplemented with analgesics, a skeletal muscle
relaxant, and an antimuscarinic agent

Analgesics permit a reduction in the required concentration of inhalational

anesthetics

Skeletal muscle relaxants cause adequate muscle relaxation during surgery

Anti-muscarinic agents decrease bronchial secretions

3. Non-volatile anesthetics are usually administered IV (thiobarbiturates,
benzodiazepines)

C. Therapeutic indications
1. Inhalational anesthetics are indicated to provide general surgical anesthesia
2. Non volatile anesthetics- indicated to induce drowsiness and provide
relaxation
3. Use of some previously popular volatile anesthetics has been discontinued
because of serious toxicity (chloroform) or because of the flammable and
explosive properties of the compounds (cyclopropane, diethylether)

D. Adverse effects
Depress respiration, circulation, and the CNS
They can decrease hepatic and kidney function (methoxyflurane)
Cause cardiac dysrrhytmia as a result of increased myocardial sensitivity to
cathecolamine (halothane)

General Anesthetics
• Halothane- hepatotoxic
• Enflurane and sevoflurane- nephrotoxic
• Thiopental- commonly sued in the induction of anesthesia
• Propofol (2,6-diisopropylphenol)
• Ketamine- dissociative anesthetic, related to PCP

Local Anesthetics
MOA: BLOCKS Na channels
- Produce reversible loss of sensation
- They do not produce a loss of consciousness

Chemistry
- Hydrophylic aminogroup linked through an ester or amide connecting - group to
a lipophilic armatic moiety

Cocaine- was first isolated in 1860 by Niemann

 Lidocaine- Prototype anesthetic agent

Esters
-Procaine
-Chlorprocaine
-Tetracaine
-has shorter duration of action since they are easily hydrolyzed by plasma esterases

Amides
-Mepivacaine
-Lidocaine
-Edtidocaine
-Prilocaine
-metabolized in the liver and has longer duration of action

Adverse effects
- high plasma concentrations can cause excitation, dizziness, tinnitus, disorientation
and muscle twitching
- Cardiovascular effects include myocardial depression, hypotension, decreases
cardiac output, heart block, bradycardia, ventricular arrhythmia and cardiac
arrest.

Assessment A chapter examination regarding the topic discussed.

SUBJECT PHARMACOLOGY 1 TOPIC Analgesics-1
IG NUMBER IG-PHA-325LC WEEK NO 11
TERM MIDTERM SESSION 19 OF 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This topic is intended to discuss the pharmacology of drugs’ use in pain management.
Session
1. To present the pathophysiology of pain
Objectives 2. To identify the drugs used in pain management
3. To elaborate the mechanisms of action of the different classes of drugs used in
pain mangement
4. To discuss the adverse effects associated with the drugs

1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

Materials 2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary , Latest edition

Lesson PAIN MANAGEMENT

Outline
Pain
- An unpleasant sensory and emotional experience, associated with, or described in
terms of actual, or potential tissue damage.
- It is derived from the latin word peone and Greek word poine meaning “penalty” or
“punishment.”
- Aristotle, who considered pain a feeling and a passion of the soul, advanced the
punishment theory.

Pathophysiology
• AFFERENT PAIN TRANSMISSION
A. Peripheral Stimulation
- The first step leading to pain is the activation of nociceptors
- Bradykinins, hydrogen, potassium, prostaglandins, histamine, leukotrienes and
serotonin sensitisize nociceptors.
- Nociception leads to action potentials that are transmitted along nerve fibers to
the spinal cord.
- Somatostatin, CCK,and substance P have been identified as possible
neurotransmitters in afferent nociceptive neurons.
- Substance P plays a role in enhancing the effectiveness of nociceptive
neurotransmitters that promote pain.
- Substance P blockade by capsaicin significantly reduces pain transmission.
- Nociceptive transmission takes place in the A-delta or C-afferent nerve fibers.
- Stmulation of the A-delta fibers evokes sharp, acute, well-localized pain, while
stimulation of C-fibers produces dull, aching and poorly localized pain

B.Gate Control Theory

- Afferent, nociceptive pain fibers synapse at the dorsal horn of the spinal cord
along with other non-pain-transmitting neurons.
- Perception of pain is a complex summation of nociceptive and nonnociceptive
neuronal stimulation
- Melzack and Wall first explained this theory.
C. SPINAL CORD TRANSMISSION
- Pain reaches brain through ascending fiber tracts.
- The spinothalamic tract is divided into two ascending pathways: Lateral and
 ventral.
- The lateral pathway is associated with sharp, localized pain and is responsible for
spatial and temporal discriminative aspects of nociception.
- The ventral pathway makes possible for the perception of aching, dull,
nonlocalized pain and the reflexes responsible for aversion motivation.
• PAIN MODULATION
- First evidence that brin modulates pain is anlagesia produced by selected
electrical stimulation of animal brains, with subsequent similar results in patients
with intractible clinical pain.
- The opiate receptors are found in the ascending and descending pain pathways
and in portions of the brain believed to be essential in pain modulating system.
- 1975- two pentapeptides (Met and Leu-enkephalin) were discovered with actions
similar to Morphine.
- Met and Leu-enkepalins interact with opiate receptors to form a part in the
endogenous opiate system.
- Three classes of opioid peptides were known: enkephalins, dynorphins and beta-
endorphins.
- Three major classes of opioid receptors: mu, kappa and delta
- Other neurotransmitters that play a role in nociception are NE and 5-HT.

Opiate Receptor Effects

Opiate Receptor Function
Mu Analgesia
Respiratory depression
Miosis
Reduced Gastric motility
Sedation
Euphoria
Analgesia

Kappa Analgesia
Less respiratory depression than mu
Less intense miosis than mu
Sedation
Reduced gastric motility
Dysphoria
Psychotomimetic effects

Delta Analgesia

- Algodynia- pain without nociception

- Neuropathic pain
- Phantom limb pain- pain in an amputated limb

CLINICAL PRESENTATION
• Pain with a known source is often localized, well described, and relieved with proper
analgesic therapy. Whereas, pain with no obvious origin is odten nonlocalized, ill
defined and not easily treated with conventional analgesics.

ACUTE versus Chronic Pain

• Acute pain
- a useful physiologic process that warns an individual of disease states and
potentially harmful situations
- When pain is not effectively treated, the stress and concurrent reflex reactions
often cause hypoxia, hypercapnia, hypertension, diaphoresis, mydriasis, excessive
cardiac activity, and emotional difficulties.
 - Lasts less than 30 days and occurs following muscle strains and tissue injury,
such as trauma or surgery.
- It is usually self-limiting, decreasing with time as the injury heals.
• Chronic Pain
- Four subclasses of chronic pain
a. pain that persists beyond normal healing time
b. pain related to chronic disease
c. pain without identifiable organic cause
d. pain with both acute and chronic pain associated with cancer
- Chronic pain patients may develop tolerance and dependence with analgesics,
trouble sleeping, and more readily react to environmental changes that readily
intensify the pain response.
• Breakthrough pain
- intermittent and transitory increase in pain that occurs at a greater intensity over
baseline chronic pain.

PRINCIPLES OF MANAGEMENT
1. Comprehensive Pain Management should determine the characteristics of the
patient’s pain complaint, clinical status and pain management history
a. Assessment of pain complaint should include chronology and symptomatology
of the presenting complaint such as location, onset, duration, intensity, quality,
provocative factors, temporal qualities, severity and pain history.
b. Assessment of clinical status should include the extent of underlying trauma or
disease.
c. Assessment of pain includesdrug allergies, analgesic response, onset, duration
and side effects.
2. Appropriate Pain Management
a. The primary pain goal is to improve patient comfort
b. For acute pain management, improved comfort can aid the healing and
rehabilitation processes
c. For chronic pain, the objective is to break the pain cycle.

NARCOTIC ANALGESICS
- include the opioid drugs. Because of their abuse potential, opioids are classified as
controlled drugs.

Mechanism of action
- endogenous opiates afford the body self-pain relieving mechanisms. These
endogenous peptides include the endorphins, enkephalins and dynorphins.
- Exogenous opiates are classified as agonists, antagonists and mixed opiates.
- The specific mechanism of opiate agonist is alteration of the effects of nociceptive
neurotransmitters, possibly nE and 5-HT.

Clinical Uses
- management of moderate to severe painof somatic or visceral origin
- the appropriate route of administration is individualized.
- Oral adminstration is preferred particularly for patients with chronic, stable pain.
- Intramuscular and subcutaneous are very commonly used in the post operative
period
- Intravenous for stable, chronic pain
- Epidural and intrathecal administrations are used for acute postoperative pain and
early management of chronic cancer pain.
- Rectal route for patients who cannot take oral narcotics
- Transdermal route is an alternative for patients with chronic pain and cannot
afford to take oral narcotics

Adverse Effects
 - constipation
- nausea and vomiting
- sedation
- respiratory depression
- anticholinergic effects
- hypersensitivity
- CNS excitation

Drug Interactions
a. additive effects with CNS depressants, alcohol, BZD
b. Meperidine can cause severe excitation, sweating, rigidity and hypertension in
patients taking MAOIs.

Indications
a. Meperidine is used in severe pain. May precipitate tremors, myoclonus and
seizures
b. Fentanyl is used in severe pain
c. Methadone is effective in severe chronic pain, sedation can be a major problem
d. Propoxyphene is effective in moderate pain, it has weak analgesic properties and
most effective when used with nonnarcotic analgesics
e. Pentazocine is the 3rd line agent for modaerate to severe pain. May precipitate
withdrawal in opiate-dependent patients
f. Butorphanol and nalbuphine is the 2nd line agent for moderate to severe pain
g. Tramadol-maximum dose is 400mg/day
h. Codeine is used in moderate pain, has weak analgesic properties.
Morphine is the drug of choice in acute severe pain.
Assessment
A short exam regarding pain mangement next meeting.
SUBJECT PHARMACOLOGY 1 TOPIC Analgesics-2
IG NUMBER IG-PHA-325LC WEEK NO 11
TERM MIDTERM SESSION 20 OF 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This topic is intended to discuss the pharmacology of drugs’ use in pain management.
Session

Objectives 1. To enumerate the Non-steroidal drugs

2. elaborate the mechanisms of action of the different classes of drugs used in
pain mangement
3. To discuss the adverse effects associated with the drugs

Materials 1. Stedman’s Concise Medical Dictionary , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition

Lesson ANALGESICS
Outline II- NONNARCOTIC ANALGESICS
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
A. Overview
1. The inflammatory response is complex, involving the immune system and the
influence of various endogenous agents, including prostaglandins, bradykinin,
histamine, chemotactic factors, and superoxide free radical formed by the
action of lysozomal enzymes.

2. Aspirin, other salicylates, and newer drugs with diverse structures are referred
to as NSAIDs to distinguish them from the anti-inflammatory glucocorticoids.
NSAID are used to suppress the symptoms of inflammation associated with
rheumatic disease. Some are also used to relieve pain and fever.

B. Mechanism of actions
1. Anti-inflammatory effect
a. The anti-inflammatory effect of Nsaids is due to the inhibition of the enzyme
prostaglandin H synthase (cyclooxygenase, or COX), which converts arachidonic
acid to prostaglandins, and to TXA2 and prostacyclin. Most of the current
NSAIDs inhibit both COX-1 and COX-2 to about the same extent; compounds
more specific for COX-2 are in clinical trials.
b. Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific
serine residue. This is an important distinction compared to other NSAIDs,
which reversibly inhibit COX-1 and COX-2.
c. NSAIDs have no effect on lipoxygenase and therefore do not inhibit the
production of leukotrienes.
c. Additional anti-inflammatory mechanisms may include interference with the
potentiative action of other mediators of inflammation, modulation of T-cell
function, stabilization of lysosomal membranes, and inhibition of chemotaxis.

2. Analgesic effect
a. The analgesic effect of NSAIDs is thought to be related to the peripheral
inhibition of prostaglandin, but it may also be due to the inhibition of pain
stimuli at a subcortical site.
 b. NSAIDs prevent the potentiating action of prostaglandins on endogenous
mediators of peripheral nerve stimulation.
3. Antipyretic effect. The antipyretic effect of NSAIDs is believed to be related to
inhibition of the interleukin-1- and interleukin-6-induced production of prostaglandins
in the hypothalamus and the resetting of the thermoregulatory system, leading to
vasodilation and increased heat loss.

Therapeutic uses

1. Inflammation
a. NSAIDs are first-line drugs used to arrest inflammation and the accompanying pain
of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile
arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter’s syndrome,
and dysmennorhea. Pain and inflammation of bursitis and tendonitis also response to
NSAIDs.

b. NSAIDs do not significantly reverse the progree of rheumatic disease, but rather,
they slow destruction of cartilage and bone and allow patients increased mobility and
use of their joints.

c. These agents are administered chronically in doses well above those used for
analgesia and antipyresis and, at those dosages, are more likely to cause adverse
druf effects. Drug selection is generally dictated by the patient’s ability to tolerate the
adverse effects, and the cost of the drugs.

d. Anti-inflammatory effects may develop only after several weeks of treatment.

2. Analgesia. NSAIDs alleviate mild-to-moderate pain. They are less effective than
opioids, and they are more effective against pain associated with integumental
structures (Pain of muscular and vascular origin, arthritis, and bursitis) than with that
associated with the viscera.

3. Antipyresis. NSAIDs reduce elevated body temperature with little effect on normal
body temperature.

4. Miscellanous uses. Aspirin reduces the formation of thrombi and is used

prophylactically to reduce recurrent transient ischemia, unstable angina, and the
incidence of thrombosis after coronary artery bypass grafts.

- Aspirin (acetylsalicylic acid) and nonacetylated salicylates. These agents include

sodium salicylate, magnesium salicylate, choline salicylate, sodium thiosalicylate,
sulfasalazine (Azulfidine), mesalamine (Asacol), and salsalate.

Pharmacologic properties
1. Salicylates are weak organic acids; aspirin has a pK of 3.5
2. These agents are rapidly absorbed from the intestine as well as from the
stomach, where the low pH favors absorption. The rate of absorption is increased
with rapidly dissolving or predissolved dosage forms.
3. Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid
and the active metabolite salicylic acid. Salicylic acid is more slowly oxidized to
gentisic acid and conjugated with glycine to salicyluric acid and to ether and an
ester glucuronides.
4. Salicylates have a t1/2 of 3-6 hours after acute administration. Chronic
administration of high doses or toxic overdose increases the t1/2 to 15-30 hours
because the enzymes for glycine and glucuronides conjugation became saturated.
5. Unmetabolized salicylates are excreted by the kidney. If the Urine pH is increased
above 8, clearance is increased approximately fourfold as a result of decreased
 reabsorption of the ionized salicylate from the tubules.

Therapeutic uses
1. salicylates are used to threat rheumatoid arthritis, juvenile arthritis, and
osteoarthritis, as well as other inflammatory disorders. 5-amino salicylates can be
used to treat Crohn’s disease.
2. Salicylic acid is used topically to treat plantar warts, fungal infections, and corns;
use is based on the destruction of keratinocytes and dermal epithelia by the free
acid.

Adverse effects
1. Gastrointestinal effects
a. Gastrointestinal effects are the most common adverse effects of hig-dose
aspirin use; these effects may include nausea, vomiting, diarrhea or
constipation, dyspepsia, epigastric pain, bleeding and ulceration.
b. These gastrointestinal effects are thought to be due to a direct chemical effect
on gastric cells or a decrease in the production and cytoprotective activity of
prostaglandins, which leads to gastric tissue susceptibility to damage by
hydrochloric acid.
c. The gastrointestinal effects may contraindicate aspirin use in patients with an
active ulcer. Aspirin may be taken with prostaglandins to reduce gastric
damage.
d. Substitution of enteric coated or timed release preparations, or the use of
nonacetylated salicylates, may decrease gastric irritation. Gastric irritation is not
prevented by using buffered tablets.

2. Hypersensitivity (intolerance)
a. Hypersensitivity is relatively common with the use of aspirin; hypersensitivity
results in rash, bronchospasm, rhinitis, edema, or an anaphylactic reaction with
shock, which may be life-threatening. The incidence of intolerance is highest in
patients with asthma, nasal polyps, recurrent rhinitis, or urticaria. Aspirin should
be avoided in such patients.
b. Cross-hypersensitivity may exist to other NSAIDs and to the yellow dye
tartrazine, which is used in many pharmaceutical preparations.
c. Hypersensitivity is not associated with sodium salicylate or magnesium
salicylate.
d. The use of aspirin and other salicylates to control fever during viral infections in
children and adolescents is associated with an increased incidence of Reye’s
syndrome, an illness characterized by vomiting, hepatic disturbances, and
encephalopathy that has a 35& mortality rate. Acetaminophen is recommended
as a substitute for children with fever of unknown etiology.
3. Miscellaneous adverse effects and contraindications
a. salicylates occasionally decrease the glomerular filtration rate, particularly in
patients with renal insufficiency.
b. Salicylates occasionally produce mild hepatitis, usually asymptomatic,
particularly in patients with systemic lupus erythematosus, juvenile, or adult
rheumatoid arthritis, or rheumatic fever.
c. These agents prolong bleeding time. Aspirin irreversibly inhibits platelet type
1 and type 2 cyclooxygenase and TXA2 production, suppressing platelet
adhesion and aggregation. The use of salicylates is contraindicated in patients
with bleeding disorders, such as hypothrombinemia, hemophilia, hepatic
disease, and vitamin K deficiency and use should be avoided in patients
receiving anticoagulants such as coumarin and heparin.
d. Salicylates are not recommended during pregnancy; they may induce
postpartum hemorrhage and lead to premature closure of the fetal ductus
arteriosus.
Drug interactions
1. The action of anticoagulants may be enhanced by their displacement by aspirin
from binding sites on serum albumin. Aspirin also displaces tolbutamide,
phenytoin, and other drugs from their plasma protein binding sites.
2. The hypoglycemic action of sulfonylureas may be enhanced by displacement from
their binding sites on serum albumin or by inhibition of their renal tubular secretion
by aspirin.
3. Usual analgesic doses of aspirin decrease renal excretion of sodium urate and
antagonize the uricosuric effect of sulfinpyrazone and probenecid; aspirin is
contraindicated in patients with gout who are taking uricosuric agents.
4. Antacids may alter the absorption of aspirin.
5. Aspirin competes for tubular reabsorption with penicillin G and prolongs its half-
life.
6. Corticosteroids increase renal clearance of salicylates.
7. Alcohol may increase gastrointestinal bleeding when taken with aspirin.

Toxicity
1. In adults, salicylism occurs as initial sign of toxicity after aspirin or salicylate
oversdose or poisoning.
2. In children, the common signs of toxicity include hyperventilation and acidosis, with
accompanying lethargy and hyperpnea.
3. Disturbance of acid base balance results in metabolic acidosis in infants and young
children and in compensated respiratory alkalosis in older children and adults.
Salicylate toxicity initially increases the medullary response to carbon dioxide, with
resulting hyperventilation and respiratory alkalosis. In infants and young children,
increases in lactic acid and ketone body production result in a metabolic acidosis.
With increased severity of toxicity, respiratory depression occurs, with
accompanying respiratory acidosis.
4. The uncoupling of oxidative phosphorylation by aspirin results in hyperthermia and
hypoglycemia, particularly in infants and young children. Nausea, vomiting,
tachycardia, hyperpnea, dehydration and coma may develop.
5. Treatment includes correction of acid base disturbances, replacement of electrolytes
and fluids, cooling, alkalinization or urine with bicarbonate to reduce salicylate
reabsorption, forced diuresis and gastric lavage or emesis.

Other nonsteroidal anti-inflammatory drugs

Overview
1. Like aspirin, these agents are used for the treatment of inflammation associated
with rheumatic and nonrheumatic diseases.
2. Nonsteroidal anti-inflammatory drugs are absorbed rapidly after oral
administration. These agents are extensively bound to plasma proteins, especially
albumin. They cause drug interactions due to the displacement of other agents,
particularly anticoagulants, from serum albumin; these interactions are similar to
those seen with aspirin.
3. Nonsteroidal anti-inflammatory drugs are metabolized in the liver and excreted by
the kidney; the half-lives of these agents vary greatly. The required frequency
administration may influence drug choice because of possible problems with
compliance.
4. These agents commonly produce gastrointestinal disturbances; they demonstrate
cross-sensitivity with aspirin and with each other. Other adverse effects, such as
hypersensitivity, are generally the same as for aspirin; the cautions and
contraindications are also similar to those for aspirin.
5. Nonsteroidal anti-inflammatory drugs are associated with non-dose-related
instances of acute renal failure and nephritic syndrome, and they may lead to renal
toxicity in combination with angiotensin-converting enzyme (ACE) inhibitors.
Indomethacin, meclofenamate, tolmetin and phenylbutazone are generally more
toxic than other NSAIDs.
 a. ibuprufen (Motrin, Advil), naproxen (Naprosyn, Aleve), fenoprofen (Nalfon), and
ketoprofen (Orudis)
- These agents are propionic acid derivatives.
- There is no reported interaction of ibuprofen or ketoprofen with anticoagulants;
fenoprofen has been reported to induce nephrotoxic syndrome.
b. Sulindac (Clinoril), tolmetin (Tolectin), and ketorlac (Toradol).
1. Sulindac and tolmetin are pyrrole acetic acid derivatives. Sulindac is a
prodrug that is oxidized to a sulfone and then to the active sulfide, which
has a relatively long t1/2 (16 hours) due to enterohepatic cycling.
2. Tolmetin has a minimal effect on platelet aggregation; it is associated with
a higher incidence of anaphylaxis than other NSAIDs. Tolmetin has a
relatively short t1/2 (1 hour).
3. Ketorlac is a potent analgesis with moderate anti-inflammatory activity that
can be administered intravenously or topically in an ophthalmic solution.
c. Indomethacin (Indocin)
1. Indomethacin is the drug of choice for treatment of ankylosing spondylitis
and Reiter’s syndrome; it is also used for acute gouty arthritis.
2. Indomethacin is used also to speed the closure of patent ductus arteriosus
in premature infants; it inhibits the production of prostaglandins that
orevent closure of the duct.
3. Indomethacin is not recommended as a simple analgesic or antipyretic
because of the potential for severe adverse effects.
4. Bleeding, ulceration, and other adverse effects are more likely with
indomethacin than with most other NSAIDs. Headache is a common
adverse effect; tinnitus, dizziness, or confusion also occasionally occurs.
d. Piroxicam (Feldene)
1. Piroxicam is an oxicam derivative of enolic acid.
2. Piroxicam has t1/2 of 45 hours.
3. Like aspirin and indomethacin, bleeding and ulceration are more likely with
piroxicam than with other NSAIDs.
e. Meclofenamate (Meclomen) and mefenamic acid (Ponstel)
1. Meclofenamate and mefenamic acid have t1-2 of 2 hours.
2. A relatively high incidence of gastrointestinal disturbances is associated with
these agents.
f. Phenylbutazone (Azolid, Butazolidin)
1. Phenylbutazone is a pyrazolone derivative.
2. Phenylbutazone is metabolized to the active oxyphenbutazone and to a
uricosuric compound.
3. This agent presents significant risk of blood dyscrasias, including
agranulocytosis and aplastic anemia; there is no reported interaction with
anticoagulants.
g. Nabumetone (Relafen)
1. Nabumetone is another chemical class of NSAIDs, but it has similar effects.
2. Compared to NSAIDs, nabumetone is associated with reduced inhibition of
platelet function and reduced incidence of gastrointestinal bleeding.
h. Other NSAIDs. Other NSAIDs include flurbiprofen (Ansaid), diclofenac
(Voltaren), and etodolac (Lodine). Flurbiprofen is also available for topical
ophthalmic use.

Therapeutic effects:
a. The peripherally acting, nonnarcotic analgesics have several effects in common:
1. they are antipyretic
2. they are anti-inflammatory(except acetaminophen)
3. there is a ceiling effect to analgesia
4. they do not cause tolerance
5. they do not cause physical or psychological dependence
b. The efficacy of nonnarcotics is compared to aspirin. Several NSAIDs have shown a
 superior effect to 650 mg of aspirin:
1. Diflunisal
2. Ibuprofen
3. Naproxen
4. Ketoprofen

Clinical Uses:
a. Generally, non-narcotic analgesics are used orally to manage mild to moderate
pain.
b. The NSAID ketorolac is administered intramuscularly and is useful in moderate to
severe pain, particularly in cases of drug addicts, excessive narcotic sedation and
respiratory depression.
c. Patients may vary in their response and tolerance to non-narcotic analgesics.
d. Several drugs such as diflunisal, naproxen, celecoxib, valdecoxib, leflunomide and
etanercept have long half-lives and, therefore,may be administered less frequently.
Rofecoxib, with a 17-hour half-life may be administered once daily

Adverse Effects:
a. Gastrointestinal effects: Most nonnarcotic analgesics cause GI symptoms
secondary to prostaglandin inhibition. Etanercept has not been associated with GI
side effects, whereas leflunomide has been associated with nausea and diarrhea.
1. Dyspepsia, ulceration, bleeding and perforation may occur
2. Patients most predisposed to severe GI effects include the elderly, those with
history of ulcers or chronic disease, and those who smoke or use alcohol
3. To minimize GI effects, the lowest possible analgesic dose should be used.
Aspirin, available as enteric-coated may minimize GI upset. Combination therapy
with GI protectant may be needed.
b. Hematological effects. Most nonnarcotic analgesics inhibit platelet aggregation.
The effect is produced by the reversible inhibition of prostaglandin synthase.
Aspirin is an irreversible inhibitor. Acetaminophen lack anti-platelet activity. Use of
anticoagulants is relatively containdicated in combination with aspirin or NSAIDs.
c. Renal effects. NSAIDs produce renal dysfunction. Selective COX-2 inhibitors are
not devoid of this effect.
- the mechanism of NSAID-induced renal dysfunction includes prostaglandin
inhibition, interstitial nephritis, impaired renin secretion, and enhanced tubular
water/sodium reabsorption.
- It is manifested by oliguria with sodium and water retention. This effect is
reversed upon discontinuation of NSAID therapy.
d. Miscellaneous effects
- Acetaminophen- hepatotoxicity at normal doses in patients with liver
disease and are chronic alcoholics
- Leflunomide- transient elevations in liver function tests, weight loss,
alopecia, rash an anemia. It is a category X drug.
- Aspirin- hypersensitivity reactions
- Etanercept- sepsis and reactions at injection sites
- Celecoxib- the only selective COX-2 inhibitor contraindicated with
sulfonamide allergy
Drug Interactions
a. Oral anticoagulants. Aspirin should be avoided in anticoagulated patients. Aspirin
inhibits platelet function and can cause gastric mucosal damage. Choline
magnesium trisalicylate or acetaminophen should be used if a nonnarcotic is needed
in an anticoagulated patient.
b. Methotrexate. Salicylates may enhace toxicity of methotrexate. The primary
mechanism is blockade of methotrexate renal tubular secretion by salicylates
resulting to pancytopenia or hepatotoxicity.

Assessment A short exam regarding pain mangement next meeting.

SUBJECT PHARMACOLOGY 1 TOPIC Schizoprenia-1
IG NUMBER IG-PHA-325LC WEEK NO 13
TERM FINALS SESSION 21 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson and the succeeding topics are intended to introduce the pharmacology of
Session drugs that act on the central nervous system. In this lesson, the pharmacology of the
drugs used in the treatment of schizoprenia would be introduced.

Objectives 1. To discuss Schizoprenia

2. To enumerate the drugs that are used in the treatment of Schizoprenia
3. To discuss the mechanisms of action of drugs that are used in the treatment of
schizoprenia
4. To enumerate the adverse effects associated with the use of anti psychotics

Materials 1. Pharmacotherapy: A Pathophysiologic approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.

Lesson Introduction to Central Nervous System

Outline
Drugs acting on Central Nervous System
How is schizoprenia being characterized?
What are the clinical presentations of schizoprenia?
How is schizoprenia being diagnosed?
What are the agents used in the treatment of schizoprenia?
What are the different theories concerning schizoprenia?
What are the adverse effects associated with anti-psychotic drugs?

SCHIZOPRENIA
• A disorder represented by a heterogenous syndrome of disorganized and bizarre
thoughts, delusions, hallucinations, inappropriate affect, and impaired social
functioning.
PATHOPHYSIOLOGY
Multifactorial, multiple pathophysiologic abnormalities may play a role in producing
the similar but varying clinical phenotypes.

A. NEUROTRANSMITTER CHANGES
• The most common pathophysiologic theories associated with the etiology of
schizoprenia have involved the dopaminergic system.
• Antagonism of DA receptors lead to schizoprenia
• Homovanillic acid (HVA)- concentrations in the CSF are correlated with
dopaminergic turnover in the synapse, and therefore HVA formation. A
hyperactive DA system should result in increased DA release from the presynaptic
termianl and increased metabolite formation.
• Da hypothesis may be more applicable to “neuroleptic-responsive psychosis.”
• Glutamatergic dysfuction has been suggested as the etiology in schizoprenia.
• The glutamatergic system is one of the most widespread excitatory
neurotransmitter systems in the brain.
• Dopaminergic innervation from the ventral striatum decreases the limbic system’s
inhibitory activity; thus, dopaminergic stimulation increases arousal.
• Glutamatergic deficiency produces symptoms similar to those seen in
schizoprenia.
• Serotonergic receptors are present on Daergic axons, and it is known that
stimulation of these receptors will decrease DA release, at least in the striatum.
• Atypical antipsychotics with potent 5-HT2 receptor antagonist effects have been
shown to reverse worsening of symptomatology induced by 5-HT agonist in
schizoprenic patients.
Increased concentrations of NE have been observed in limbic structures of patients
with chronic paranoid schizoprenia, but not with other subtypes.
• The dysregulation hypothesis maintains that aberrant homeostatic control
mechanisms cause erratic neurotransmission; that is, the homeostatic
mechanisms that control the relationships among neurotransmitter syntheis,
release, reuptake, metabolism, activity at receptors, and second messenger
systems are defective. This lack of hemeostais is manifested in dysfunction of
several processes including basal neurotransmission, biological rhythm, and
return to basal rate after pertubations on the system.
• The primary pathophysiologic abnormality in schizoprenia may occur in one of the
neurotransmitters(dopamine, glutamate, serotonin), with permissive properties of
other neurotransmitters.
Dopaminergic Tracts and Effects of Dopamine Antagonists

1. Nigrostriatal Tract
a. Origin. Substancia nigra (A9 area)
b. Innervation. Caudate nucleus, putamen
c. Function. Extrapyramidal system, movement
d. Dopamine Antagonist effect. Movement disorders
2. Mesolimbic Tract
a. Origin. Midbrain ventral tegmentum (A10 area)
b. Innervation. Limbic areas (amygdala, olfactory tubercle, septal nuclei), cingulate
gyrus
c. Function. Arousal, memory, stimulus processing, motivational behavior
d. Dopamine Antagonistic effect. Relief of psychosis
3. Mesocortical Tract
a. Origin. Midbrain ventral tegmentum (A10 area)
b. Innervation. Frontal and prefrontal lobe cortex
c. Function. Cognition, communication, social function, response to stress
d. Dopamine Antagonistic effect. Relief of psychosis
4. Tuberoinfundibular
a. Origin. Hypothalamus
b. Innervation. Pituitary gland
c. Function. Regulates prolactin release
d. Dopamine Antagonistic effect. Increased prolactin secretion

B. STRUCTURAL CHANGES
• Increased ventricular size, particularly in the third and lateral ventricles.
• Decrease in brain size
• Decreased cortical thickness
• Increased neuronal density
C. GENETICS
• If both parents have schizoprenia, the risk of producing a schizoprenic offspring
increases to approximately 40%
D. NEURODEVELOPMENTAL CHANGES
• This model proposes that genetic predisposition exists for schizoprenia and that
an unknown in utero disturbance occurs, probably in the second trimester of
pregnancy.
• Schizoprenic lesions are characterized by abnormalities in cell shape, position,
symmetry, connectivity and dysfunctional brain circuits.
• Gliosis, or proliferation of glial cells, is thought to occur as compensatory change
 in degenerative brain disorders.

CLINICAL PRESENTATION
Schizoprenia is the most common form of functional psychosis. It is a chronic disorder
of thought and affect with the individual having a significant disturbance in
interpersonal relationships and ability to function in society on a daily basis.
Characteristic symptoms: Two or more of the following, each persisting for a
significant portion of at least a 1-month period:
1.Delusions
2.Hallucinations
3.Disorganized speech
4.Grossly disoganized or catatonic behavior
5.Negative symptoms

Note: Only one criterion is required if delusions are bizarre, if hallucinations consist
of a voice keeping a running commentary on the person’s behavior, or if there are
two or more voices conversing with each other.

Duration: Continuous signs of the disorder for at least 6 months. This must include at
least 1 month of symptoms fulfilling criterion. This 6 months may include prodromal
or residual symptoms.

Schizoprenia Symptom Clusters

Positive Negative Disorganized
Hallucinations Affective flattening Disorganized speech
Delusions Alogia Disorganized behavior
Anhedonia Poor attention
Avolition

DESIRED OUTCOME
• Pharmacotherapy is the mainstay in the treatment of schizoprenia, and it is
essentially impossible in most patients to implement effective psychosocial
rehabilitation programs in the absence of antipsychotic treatment.

ANTI-Psychotic Agents

HISTORY
Reseprine and Chlorpromazine- first drugs found to be useful in schizoprenia.
PHARMACOLOGY
Mechanisms of Action of Antipsychotics
• Strongly block postsynaptic D2 receptors in the central nervous system, especially
in the mesolimbic frontal system
• Change the amount of homovanillic acid(HVA), a metabolite of dopamine in the
cerebrospinal fluid, plasma and urine
• Atypical antipsychotics do not only block dopamine receptors but show strong
antagonistic effect at serotonin receptors.
• Typical or Tradition AP medications are putative dopaminergic antagonists, with
an affinity for D2 receptors that is greater than fo D1.
• Typical APs affect other neurotransmitter receptor systems, including blockade of
muscarinic, alpha1 adrenergic and histaminic receptors.
• As a rule, the lower potency APs are less specific for DA receptors and block other
receptors as well.

ATYPICAL ANTIPSYCHOTICS
MOA: Exact mechanisms are unknown. The mechanisms may be related to one or
more of the following pharmacodynamic effects: relative D1, D4 and D5 specificity,
relative selectivity for limbic dopaminergic receptors; 5-HT2, 5-HT6 and 5-HT7
antagonism; or alpha-1 adrenergic antagonism.
• Blockade of 5-HT2 receptors on presynaptic neurons on the striatum may lead to
increased Dopamine release, and therefore, less EPS.
• Atypical antipsychotics, with the exception of clozapine(CLZ) and sertindole
because of the associated side effects, have become the agents of choice in the
pharmacologic treatment of schizoprenia.
• Olanzapine(OLZ), Risperidone(RSP), quetiapine, sertindole and ziprasidone- have
superior efficay in the treatment of negative symptoms.
• Produce fewer or no acutely occurring extrapyramidal effects.
• They are described to be more effective, produce no tardive dyskinesia and does
not have much effect on serum prolactin.
• Clozapine- the prototypical agent
• Risperdone- low incidence of EPS at low to moderate doses. Effectivity is uperior
compared to haloperidol in the treatment of the negative symptoms.
• Olanzapine- has uperior efficacy in the treatment of the negative symptoms and
has very low incidence of extrapyramidal side effects.
• Quetiapine- minimal effect on negative symptoms
• Sertindole/Ziprasidone- has superior efficacy compared to typical antipsychotics,
with less Eps when used in doses 12 to 20 mg daily.
Typical/Traditional Antipsychotics

MOA: Putative Dopamiergic antagonists, with greater affinity to D2 receptors than D1.

• The primary therapeutic effects are thought to occur in the limbic system,
including ventral striatum, whereas, EPS are thought to be related to DA blockade
in the dorsal striatum.
• Tolerance develops but are less common.
• In the tuberoinfundibular system, APs block prolactin inhibitory factor, which is
DA acting at D2 sites.
• Side effects include dry mouth, constipation, sinus tachycardia, and orthostatic
hypotension, seen more commonly on low-potency typical APs.

A. Phenothiazines
- must have a nitrogen-containing substituent on the nitrogen-containing side-
chain substituent on the ring nitrogen which is responsible for its antipsychotic
property
- Phenothiazines in which the ring and side-chain nitrogen are separated by a
two-carbon chain have only antihistaminic or sedative property.
a. Alipathic (Chlorpromazine, CPZ) and piperidine (Thioridazine) derivatives are
the least potent
b. Piperazine derivatives are more effective even at lower doses. This group
includes trifluoperazine, perphenazine and fluphenazine.
B. Thioxanthenes
- exemplified by thiothixene
- slightly less potent than phenothizine analogues
- lack the ring nitrogen of phenothiazines and have a side chain attached to the
double bonds.
C. Butyrophenones
- chemically unrelated to phenothiazines but have similar activity
- haloperidol is the most widely used
- diphenylbutylpiperidines are closely related compounds
• they are more potent and have fewer autonomic effects.
Effects of Receptor Blockade

Receptor Blockade Adverse Effect

Histamine Sedation
Weight gain
Potentiation of CNS-depressant drugs

Muscarinic Urinary retention

Cognition and memory effects
Sinus tachycardia
Dry mouth
Blurred vision
Constipation
Alpha1-adrenergic Orthostatic hypotension
Reflex tachycardia
Potentiation of antihypertensives
Dopamine-2 Extrapyramidal effects
Prolactin elevation
Serotonin 5-HT2 Orthostatic hypotension
Sedation
Weight gain

Muscarinic Urinary retention

Cognition and memory effects
Sinus tachycardia
Dry mouth
Blurred vision
Constipation
Alpha1-adrenergic Orthostatic hypotension
Reflex tachycardia
Potentiation of antihypertensives
Dopamine-2 Extrapyramidal effects
Prolactin elevation
Serotonin 5-HT2 Orthostatic hypotension
Sedation
Weight gain

A short quiz regarding anti-psycotic drugs next meeting.

SUBJECT PHARMACOLOGY 1 TOPIC Schizoprenia-2
IG NUMBER IG-PHA-325LC WEEK NO 13
TERM FINALS SESSION 22 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This subtopic of antipsychotics is intended to discuss the pharmacokinetics and
Session physiologic effects of agents that are used in the treatment of schizoprenia.

Objectives 1. To discuss the pharmacokinetics of antipsychotics

2. To discuss the effects of antipsychotics to different organ systems
3. To discuss other therapeutic indications of antipsychotics

Materials 1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.

Lesson Pharmacokinetics
Outline A. Absorption and Distribution
• Readily but incompletely absorbed and undergoes significant first-pass
metabolism
• Oral doses of chlorpromazine and thioridazine- 25 to 35% bioavailable
• Oral dose of haloperidol- 65% bioavailable
• Most antipsychotics are highly lipid-soluble and protein-bound
• They have large volumes of distribution since thay are sequestered in lipid
compartments of the body and have high affinity for selected neurotransmitter
receptors in the CNS, and have generally much longer clinical duration of action
than would be estimated fromtheir plasma half-lives.
B. Metabolism
• Most agents are completely metabolized by a variety of processes.
• Mesoridazine- major metabolite of thioridazine, which is more potent than the
parent compound and accounts for most of the effect.
C. Excretion
• They are excreted unchanged, because they are almost completely metabolized
to polar substances.

Dopamine receptors and their effects

• AT present, five different dopamine receptors have been described, consisting of
two separate families, the D1-like and the D2-like receptor subgroups.
• D1 receptor- coded by a gene in chromosome 5, increases cAMP by activation of
adenylyl cyclase, and is located in the putamen, nucleus accumbens and olfactory
tubercle.
- D5- the 2nd member of the family and is coded on chromosome 4. It also
increases cAMP, and is found in hippocampus and hypothalamus.
• D2 receptor- coded on chromosome 11, decreases cAMP and inhibits calcium
channels opening potassium channels. It is found both pre and post-synaptically
on neurons in the caudate-putamen, nucleus accumbens and olfactory tubercle
- D3- coded at gene 11, decreases cAMP, and is located in the frontal cortex,
medulla and midbrain.
- D4- the newest member, also decreases cAMP.
• Aripiprazole- partial agonist at D2 and 5-HT1a receptors
• Selective D3 antagonists- may be used therapeutically but none are available.
Differences Among Antipsychotic Drugs
• Chlorpromazine and thioridazine- blocks alpha1 adrenoceptors more potently than
 D2 receptors. They also block 5-HT2 receptors relatively strongly. Low affinity to
D1 receptors.
• Perphenazine/Haloperidol- act mainly on D2 receptors, mild effects on 5-HT2 and
alpha1 receptors and negligible effects on D1 receptors.
• Pimozide-almost exclusively D2 receptor antagonist
• Clozapine- more affinity to D4, 5-HT2, alpha1 and histamine H1 receptors than to
either D2 or D1 receptors.
• Risperidone- equally potent in blocking D2 and 5-HT2 receptors.
• Olanzapine- more potent antagonist at 5-HT2 receptors, with lesser and
approximately equal potency at D1, D2 and alpha1 receptors.
• Quetiapine- lower potency with similar antagonism of 5-HT2, D2, alpha1 and
alpha2 receptors.
• Olanzapine/Quetiapine- potent inhibitors of histamine H1 antagonist.
• Aripiprazole- partial agonistic effects at D2 and 5-HT1a receptors.

Psychological effects
• Most agents cause unpleasant subjective effects in nonpsychotic individuals; the
combination of sleepiness, restlessness, and autonomic effects create experiences
unlike those associated with more familiar sedatives or hypnotics.

Neurophysiologic effects
• Hypersynchrony may be focal or unilateral

Extrapyramidal system Effects

A. Dystonia-state of abnormal tonicity. “muscle spasm”
- may be dramatic, frightening and painful
- manifested by trismus, glossospasm, tongue protrusion, pharyngeal-laryngeal
dystonia, blepharospasm, oculogyric crisis, torticollis, and retrocollis
- Two pathophysiologic theories for dystonia:1) DA release from the presynaptic
receptors transiently increases in compensatory response to DA blockade, and
2) heightened sensitivity of post synaptic DA receptor, such that DA release has
an enhanced effect.
B. Akathisia- inability to sit still and is being functionally motor restless.
- it is frequently accompanied by dysphoria
- can be managed with BZD and beta-blockers with increasing frequency
- can result to violence and suicide
C. Pseudoparkinsonism- AP-induced EPS.
- Four cardinal symptoms: 1) akinesia, bradykinesia, decreased motor activity,
micrographia, slowed speech, decreased arm swing
- 2) tremor, pill-rolling type, predominant at rest
- 3) cogwheel rigidity
- 4) slow and shuffling to festinating gait.
- Perioral tremor
- It can be managed with anti-cholinergics and amantadine
D. Tardive dyskinesia- characterized by abnormal involuntary movements occurring
late in onset in relation to initiation of AP therapy.
- it is manifested by blinking, brow arching, grimacing, upward deviation of the
eyes, and lip smacking, with restless choreiform and distal athetosis.
- No reports of TD were observed with CLZ.

• Sedation- usually occurs with CPZ, TRD, mesoridazine and CLZ

• Seizures- APs lower the seizure threshold through GABA depletion.

- changes in CNS permeability lead to enhanced conduction of a discharge,
disruption of DA-acetylcholine balance, or the activation of a latent seizure
focus.
- Highest potential seizure risk by an AP drug is with the use of CPZ or CLZ
 - Molindone, TRD, HPD, and FPZ are associated with the lowest seizure potential
• Thermoregulation- Poikilothermia, the body temperature adjusting to ambient
temperature, can be a serious side effect of AP at temperature extremes.
- hyperpyrexia can be a danger in hot weather during exercise. Inhibition of
sweating, a result of Ach properties impairing the peripheral mechanisms of
heat dissipation, can contribute to this problem, which can lead to heat stroke.
- It is more commonly observed with the use of lo potency APs.
• Neuroleptic Malignant Syndrome- may occur in patients receiving high-potency,
injectable, or depot APs, and in patients who are dehydrated, with physical
exhaustion, or organic mental disorders.
- it has been reported with the use of atypical antipsychotics, clozapine and with
typical APs.
- Possible mechanisms of NMS include disruption of the central thermoregulatory
processes or excess production of heat secondary to skeletal muscle
contractions.
- The differential diagnosis includes heat stroke, lethal catatonia, anesthetic-
associated malignant hyperthermia, Ach toxicity and MAOI drug interactions.
- Cardinal signs and symptoms: 1) hyperpyrexia, 2) altered level of
consciousness, 3) autonomic dysfunction, 4) rigidity
- Can be managed using 1) bromocriptine- reverses DA blockade, reduces rigidity
and fever; 2) amantadine; 3) Dantrolene- skeletal muscle relaxant, with effects
on temperature, heart, respiratory rate; 4) Ach and BZD

Endocrine effects
• Amenorrhea-galactorrhea, false positive pregnancy tests, and increased libido
have been reported in women, whereas, men have experienced decreased libido
and gynecomastia.

Cardiovasular effects
• Orthostatic hypotension and high resting pulse rate frequently result from use of
the high-dose phenothiazines.
• Mean arterial pressure, peripheral resistance and stroke volume are decreased,
and heart rate is increased.
• Abnormal ECG with thioridazine. Changes include prolongation of the QT interval,
and abnormal St segment and T waves, the latter being rounded, flattened or
notched.
• Prolonged Qt interval with increased risk of arrhythmias- Sertindole
• Ziprasidone- risk of QT prolongation

Ophthalmologic Effects
• Impairment in visual accommodation results from paresis of ciliary muscles, an
Ach effect
• Photophobia
• May be managed using pilocarpine
• CPZ-opaque deposits in cornea and lens
• TRD- retinitis pigmentosis
Hematologic effects
• Transient leukopenia
• CLZ-agranulocytosis

Genitourinary system
• TRD-erectile dysfunction and impotence
• OLZ/quetiapine- can be used to prevent sexual dysfunction
• Sertindole- reduced ejaculatory volume

Dermatologic system
• Allergic reaction are rare
 • Phenothiazine- absorbs UV light and energy, resulting in the formation of free
radicals, which can have damaging effects on skin.
• Blue-gray or purplish skin coloration with lens/corneal pigmentation-CPZ

INDICATIONS
• Schizoprenia is the primary indicationfor these drugs
• They are also indicated for schizoaffective disorders
• The manic episode in the bipolar disorder often requires treatment with
antipsychotic drugs, though lithium or VPA, supplemented with high-potency
BZD may suffice in milder cases.
• Olanzapine- acute phase of mania; shows antidepressant effect in schizoprenia
• Tourette’s syndrome
• Senile dementia of the Alzheimer type
• With antidepressants- to control agitation or psychosis in depressed patients
• OLZ, RSP, Quetiapine, Aripiprazole- better tolerated compared to other agents
• Ziprasidone- may be used in some cases of anxiety.

Non-psychiatric indications
• Antipsychotics, except thioridazine- have strong antiemetic property due to their
ability to block the dopamin receptor both centrally(CRTZ) and
peripherally(stomach).
• Prochlorphenazine and benzquinamide- marketed solely as antiemetics
• Phenothiazines with shorter side chains- have H1 receptor blocking abilities
preventing pruritus. In the case of promethazine, as preoperative sedatives.
• Droperidol(butyrophenone) + fentanyl= neurolepthanesthesia

DRUG INTERACTIONS
• With Lithium- safe, but irreversible encepalopathies were reported.
• With cigarette smoking- increased AP clearance
• With ACE inhibitors- additive hypotensive effects

Assessment Short Quiz regarding the topic discussed will be given the following meeting
SUBJECT PHARMACOLOGY 1 TOPIC MOOD DISORDERS-1
IG NUMBER IG-PHA-325LC WEEK NO 14
TERM FINALS SESSION 23 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the pharmacology of drugs used in the treatment of
Session mood disorders.

Objectives 1. To discuss mood disorders

2. To enumerate the classes of drugs used in the management of mood disorders
3. To discuss the principles involved in the management of mood disorders
4. To enumerate the adverse effects of drugs used in the management of mood
disorders

Materials 1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary , Latest edition.

Lesson MOOD DISORDERS

Outline
What are the major subclassifications of affective disorders?
What are the theories postulated about Mood disorders?
What are the classifications of drugs used in the management of mood disorders?
What are the adverse effects associated with the use of the drugs?

• Affective disorders
• Characterized into two major disturbance in mood:
- Bipolar
- Depressive
• Mood- defined as pervasive and sustained emotion that in extreme, markedly
affects the person’s perception of the world and the ability to adequately function
in the society.
• Bipolar disorders refer to patients who have episodes of mania and/or hypomania
usually alternating with depression episodes.
• Patients with depressive disorders do not have episodes of mani or hypomania.

Two Types of Depressive Disorders

• Dysthymic disorder is a chronic disturbance of mood combined with at least two
other symptoms sucha s appetite or sleep disturbance, low energy, low self-
esteem, hopelessness, poor concentration and indecisiveness. Also, the patient
has experienced a depressed mood more days than not, for at least 2 years.
• Depression is associated with a high level of functional disability and increased
use of out-patient medical services. The most frequent complication of depression
is suicide.

EPIDEMIOLOGY
• Depression is two or three times as frequent in females than in males.
• It can occur at any age, but major incidence occurs at ages between 25-44 years
old.
• Depressive disorders and suicide tend to cluster in families, and first-degree
relatives of patients with depression are one and a half to three times more likely
to develop depression than normal subjects.
ETIOLOGY
• Alterations in brain monoamine neurotransmitters: Norepinephrine, serotonin and
dopamine play a major role in depressive disorders.
• Other factors include stressful events, medical illness an monoamine-depleting
drugs(reserpine).

PATHOPHYSIOLOGY

A. BIOGENIC AMINE HYPOTHESIS

• Most effective antidepressants increase the availability of certain monoamines at
selected brain synapses
• Reserpine, an antihypertensive drug known to deplete neuronal storage granules
of serotonin, norepinephrine and dopamine precipitates depression.
• Inadequate transmission, mostly of NE, leads to depression.
B. PERMISSIVE HYPOTHESIS
• It states that decreased serotonin levels permit the expression of affective state,
but NE governs the type.
• Decrease levels of NE cause depression and elevated levels lead to mania
• ACCording to this hypothesis, correcting the deficiency in the 5-Ht activity
corrects the affective disease.
C. THEORIES OF POSTSYNAPTIC CHANGES IN RECEPTOR SENSITIVITY
• mid 1970’s- it was recognized that chronic, but not acute, administration of
antidepressants to animals caused desensitization of NE-stimulated CAMP
synthesis. It was also observed that for most antidepressants, down-regulation of
beta-adrenergic receptors accompanies this desensitization.
D. DYSREGULATION HYPOTHESIS
• Incorporates the diversity of antidepressant activity with the adaptive changes
occurring in receptor sensitization over several weeks.
• It was hypothesized that effective antidepressant agents restore efficient
regulation to the dysregulated neurotransmitter system.
E. 5-HT/NE LINK HYPOTHESIS
• Maintains that both the serotonergic and noradrenergic systems need to be
functional for an antidepressant effect to be exerted.
• It is also consistent with the rationale of the postsynaptic alteration theory of
depression, which emphasizes the importance of beta-adrenergic receptor down-
regulation for achieving an anti-depressant effect.
• It has been proposed that both NE and serotonin are necessary for homologous
desensitization of central beta-adrenergic receptors by antidepressants.
F. ROLE OF DOPAMINE IN DEPRESSION
• Elevation of dopamine neurotransmission in the nucleus accumbens may
represent a final common pathway for at least part of mechanism of action of
antidepressant medications.
G. BIOLOGIC MARKERS
• A large number of patients with minor depression have a neuroendocrine
abnormality, including hypersecretion of cortisol, lack of cortisol suppression after
dexamethasone administration, or an abnormal or diminsished thyroid-stimulating
hormone response to the administration of thyrotropin releasing factor.
• Dexamethasone suppression test (DST)- is the most specific measure of
hypothalamic-pituitary-adrenal axis overactivity.
• Failure of dexamethasoe to suppress plasma cortisol concentration indicates
overactivity or dysregulation of the HPA axis, and in depressed patients this
reflects a vulnerability to commit suicide.

CLINICAL PRESENTATION
• Major depressive disorder is characterized by one or more episodes of major
depression.
• A major depression is characterized by five or more of the following symptoms for
 2 weeks and represent a change in functioning, characterized by either depressed
mood or loss of interest/pleasure:
1. Depressed mood, most of the day, nearly everyday
2. Markedly diminished interest or pleasure in all, or almost all of activities
3. Significant weight loss or weight gain, or decrease or increase in appetite
4. Insomnia or hypersomnia nearly everyday
5. Observable psycomotor agitation or retardation everyday
6. Fatigue or loss of energy nearly everyday
7. Feelings of worthlessness or inappropriate guilt
8. Alogia
9. Recurrent thoughts of death and suicidal ideation

TREATMENT

Goals of Treatment:
a. to reduce symptoms of depression
b. to facilitate the person’s return to a premorbid level

General Approach
• Melancholic depression is characterized by a nearly complete absence of capicity
for pleasure, diurnal mood swings, early morning awakening, psychomotor
disturbances, excessive guilt and weight loss.
• A preferential response to Monoamine Oxidase Inibitors has been reported in
patients with atypical depression.
• Atypical depression is manifestion by any two or more of the following symptoms:
4. Weight gain or increase in appetite
5. Hypersomnia
6. Heavy feelings in arms and legs
7. Interpersonal rejection sensitivity
• Psychotically depressed individuals generally require either ECT or combination
therapy with an antidepressant plus an antipsychotic agent.

NON-Pharmacologic Therapy
• Psychotherapy is employed whenever the patient is able and willing.
• Psychotherapy alone is not recommended for the acute treatment of patients with
severe and/or psychotic major depressive disorder.
• Electroconvulsive Therapy (ECT) is a safe and very effective treatment for certain
severe mental illnesses. It is apllied when rapid response is needed.
• ECT is effective for all subtypes of major depressive disorder as well as other
selected psychiatric illnesses.
• Adverse effects of ECT include cognitive dysfunction, cardiovascular dysfunction,
prolonged apnea, treatment-emergent mania, headache, nausea and muscle
aches. Cognitive changes include confusion immediately after the seizure, and
retrograde and anterograde memory disturbance. Most cognitive disturbances are
transient.
• The light therapy is generally well-tolerated with minor visual complaints. Patients
undergoing light therapy should undergo periodic eye examinations.

Pharmacologic Therapy
Antidepressants can be classified in several ways. One approach is by hemical
structure, and another is by presumed mechanism of antidepressant activity.

A. MIXED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS

• Amitriptyline and imipramine are the most extensive studied TCAs
• Comparison betwee Secondary TCAs (desipramine and nortriptyline) to Tertiary
TCAs (amitriptyline and imipramine) found no clinically important difference in
efficacy; however, the secondary amines were more potent.
• Are effective in the treatment of all depressive subtypes especially the severe
melancholic type.
• They potentiate the activity of serotonin and norepinephrine by blocking their
uptake.
• Anticholinergic, neurologic and cardiovascular adverse effects are frequently
observed.
• Venlafaxine- potent inhibitor of of 5-HT and NE reuptake and a weak inhibitor of
dopamine reuptake. It has no affinity for muscarinic, histaminergic and alpha1-
adrenergic receptors.
- a potent inhibitor of serotonin reuptake and a weaker inhibitor of NE
- AT high doses it produces mild to moderate increases of heat rate and blood
pressure attributable to NE reuptake inhibition.
• Maprotiline and amoxapine- inhibitor of NE reuptake with less effect on serotonin
reuptake
• Maprotiline-associated with a higher incidence of seizures than is imipramine and
amitriptyline.
• Amoxapine- less sedating and blocks cholinergic receptors. Thus, associated with
anticholinergic effects.
- A heterocyclic drug
- metabolite of the drug loxapine
- a second-generation agent
- dopamine antagonism often leads to akathisis, parkinsonism, amenorrhea-
galactorrhea syndrome and tardive dyskinesia.
B. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
• Adminstered to patients who fail to respond to TCAs
• Fluoxetine- the first SSRI to reach general clinical use
• Serotonin syndrome- a dangerous pharmacodynamic interaction between a SSRI
and MAOI that leads to inhibition of reuptake after release resulting to the
accumulation of serotonin at the synapses. It is sometimes fatal, and
manifestations include hyperthermia, muscle rigidity, myoclonus and rapid
changes inmental status and vital signs.
• Paroxetine and sertraline- have shorter half-lives and potent inhibitors of P450
enzymes.
C. TRIAZOLOPYRIDINES
• Trazodone and nefazodone have dual actions on serotonergic neurons, acting as
both 5-HT2 antagonist and 5-HT-reuptake inhibitor. They appear to enhane 5-
HT1a mediated neurotransmission. They have negligible affinity for cholinergica nd
histaminergic receptors.
• Nefazodone- has low affinity for alpha1-adrenergic receptors.
closely related to trazodone but is less sedating.
- It produces fewer adverse sexual effects than SSRI and
is a potent inhibitor of the CYP3A4.
• They are effective in treating major depression.
D. AMINOKETONE
• Bupropion- only marketed aminoketone antidepressant
• It has no appreciable effect on the reuptake of 5-HT, and its most potent
neurochemical actionis blockade of dopamine uptake.
E. MIXED SEROTONIN/NOREPINEPHRINE EFFECTS
• Mirtazapine- a tetracyclic antidepressant that enhances central noradrenergic and
serotonergic activity through the antagonism of central presynaptic alpha2-
adrenergic autoreceptors and heteroceptors.
- a drug derived from mianserin with a potent antihistaminic with greater
sedating effects than the other second- and third-generation antidepressants.
- Associated with weight gain
- It was hypothesied that it acts by antagonizing 5-HT2 and alpha-adrenoceptor.
- It is beneficial to patients who can tolerate its sedative effects and do not
respond well to SSRIs or cannot tolerate the sexual or adverse effects of other
 antidepressants.
F. MONOAMINE OXIDASE INHIBITORS
• MAO-A is the amine oxidase primarily responsible for norepinephrine, serotonin
and tyramine metabolism.
• MAO-B is more selective for dopamine.
• The MAOIs increase the concentrations of NE, 5-HT and DA within the neuronal
synapse, through the inhibition of the mAO enzyme.
• Clinical features that predict preferential response to MAOIs include mood
reactivity, irritabilit, hypersomnia, hyperphagia, psychomotor agitation, and
hypersensitivity to rejection, the defining features of atypical depression.
• Phenelzine and Tranylcypromine inhibit both of these isoenzymes of MAO.
• Moclobemide- selective and irreverible MAO A inhibitor.
• The selective MAO-B inhibotr, selegiline, loses selectivity at antidepreassant
dosage. Because of its action is on enzyme that metabolizes dopamine, it is more
useful in the treatment of Parkinson’s disease.

ADVERSE EFFECTS

Tricyclic Antidepressants and Other Heterocyclics

• Since TCAs affect several neurotransmitters and produce a wide range of
pharmacologic actions, this group of drugs is also associated with a variety of
unwanted effects.
• The most common side effects observed are: dry mouth, constipation, blurred
vision, urinary retention, dizziness, tachycardia, memory impairment, and at
higher dose, delirium due to cholinergic receptors blockade.
• Anticholinergic effects and sedation are more severe during therapy with tertiary
amine TCAs than with secondary amine TCAs.
• Orthostatic hypotension- potentially serious side effect attributable to the affinity
of TCAs for adrenergic receptors. It may be symtomatic resulting in syncope,
especially in the elderly due to incresaed risk of falls and subsequent fractures.
• Patients are advised to rise slowly from a supine position, and prolonged bedrest
should be avoided because of deconditioning and volume-contracting effect.
Tilting the head of the bead upward can be helpful for some patients.
• Adequate ambulation and hydration along with proper drug selection, gradual
dose increases, and patient education can minimize the risk of symptomatic
orthostatic hypotension.
• TCAs also cause cardiac conduction delays and may even induce heart block in
patients with a preexistingconduction disease.
• TCAs can cause severe arrhythmias.
• Abrupt withdrawal of TCAs is associated with symptoms suggestive cholinergic
rebound(eg, dizziness, nausea, diarrhea, insomnia nd restlessness), especially if
daily dose exceeds 300 mg.
• Clomipramine- a tertiary amine TCA with 5-HT reuptake inhibiting properties and
is approved only for obsessive-compulsive disorder.
• Amoxapine- demethylated metabolite of loxapine, has intermediate sedative and
anticholinergic property. It is associated with unwanted effects such as
pseudoparkinsonism, dystonia, akathisis, and tardive dyskinesia because of its
postsynaptic DA receptor blocking ability.
• Maprotiline- a tetracyclic drug, blocks reuptake of NE with little effect on 5-HT. IT
has intermediate sedative and anticholinergic effects and may cause less
orthostatic hypotension than imipramine. Some patients experience
exanthematous rash. It is contraindicated to patients with co-existing and history
of seizure disorders.

VENLAFAXINE
• The most commonly reported unwanted effects include nausea, constipation,
somnolence, dry mouth, dizziness, nervousness, sweating, asthenia, abnormal
 ejaculation/orgasm, and anorexia.
• The effects are dose-related.
• It may also cause diastolic hypertension. Blood pressure should be monitored.

Selective Serotonin Reuptake Inhibitors

• This group incudes citalopram, sertraline, paroxetine and fluvoxamine.
• Fluvoxamine- approved for the treatment of obsessive-compulsive disorder.
• They produce fewer anticholinergic and cardiovascular adverse effects than TCAs
and they are not associated with weight gain.
• The main adverse effects, which are generally mild and short-lived, are
gastrointestinal symptoms (nausea, vomiting, diarrhea), sexual dysfunction in
both males and females, headache, insomnia nd fatigue.
• The occurrence of anxiety is most frequently observed with the use of fluoxetine.

TRIAZOLOPYRIDINES
• Trazodone and nefazodone- produce minimal anticholinergic effects or 5-HT
agonist side effects, but can cause orthostatic hypotension.
• Trazodone- sedation, cognitive slowing, and dizziness are the most frequent dose-
limiting side effects. Priapism is observed in some patients.
• Nefazodone- light-headedness, dizziness, orthostatic hypotension, somnolence,
dry mouth, nausea and asthenia

AMINOKETONE
• Bupropion- nausea, dizziness, tremor, insomnia, vomiting, constipation, dry
mouth and skin reactions. Dose-dependent toxicity is manifested by seizures.

MIXED SEROTONIN/NOREPINEPHRINE EFFECTS

• Mirtazapine- somnolence, weight gain, dry mouth and constipation. Rare effects
include agranulocytosis and liver function test (LFT) elevation.

MONOAMINE OXIDASE INHIBITORS

• Postural hypotension is more likely to occur with phenelzine than
tranylcypromine. It may be minimized through dosage scheduling.
• Anticholinergic effect especially dry mouth and constipation are common, but are
milder compared with TCAs.
• Phenelzine- a hydrazine, has mild to moderate sedating effects. It is associated
with hepatocellular damage and weight gain.
• Tranylcypromine- stimulant and insomnia may occur. Dose-related impotence and
anorgasmia in males and orgasmic inhibition in females have been reported. In
addition, fever, myoclonic jerking, and brisk deep tendon reflexes may occur. It is
used in treating aptients with a history of liver disease.
• Hypertensive crisis may culminate in cerebrovascular accidents and death.
Symptoms of hypertensive crisis include occipital headache, stiff neck, nausea,
and vomiting, sweating and sharply elevated blood pressure.
• Patients should be educated regarding dietary and medication restrictions.

Pharmacokinetics
• Generally, TCAs are rapidly absorbed after oral administration. Bioavailability is
low as a result of the first-pass effect. They have a large volume of distribution
and concentration in the brain and cardiac tissues in laboratory animals. The
major metabolic pathways are demethylation, aromatic and alipathic
hydroxylation, and glucoronide conjugation.
• Fluoxetin has an elimination half-life of 2 to 3 days. The single-dose half-life of
norfluoxetine, the active metabolite is 7 to 9 days. Paroxetine and sertraline have
half-lives of 24 hours.
• Sertraline- has an active metabolite but it contributes minimally to pharmacologic
effects.
• Citalopram- half-life is 30 hours
• The SSRIs except fluvoxamine and citalopram, are extensively bound to plasma
proteins (94-95%).
• Mirtazapine-undergoes biotransformation via demethylation and hydroxylation
followed by glucoronide conjugation. CYPIA2 and CYPIID6 are responsible for the
formation of hydroxyl metabolite, while the CYPIIA4 may be responsible for the
formation of the N-desmethyl and N-oxide metabolite.

Antidepressant Clinically Important Metabolite

I. Tricyclic Antidepressant
A. Tertiary Amines
a. Amitriptyline Nortriptyline, 10-Hydroxynortriptyline
b. Clomipramine
c. Doxepin Desmethyldoxepine
d. Imipramine 2-hydroxyimipramine,desipramine, 2-
hydroxydesipramine
e. Trimipramine None
B. Secondary amines
a. Desipramine 2-hydroxydesipramine
b. Nortriptyline 10-hydroxynortriptyline
c. Protriptyline None
II. Dibenzoxazepine
Amoxapine 8-hydroxyamoxapine
III. Tetracyclic
Maprotiline Desmethylmaprotiline
Mirtazapine
IV. Triazolopyridines
Nefazodone Meta-chlorophenylpiperazine,
hydroxynefazodone, triazoledione
Trazodone Meta-chlorophenylpiperazine,
V. Aminoketone
Bupropion Bupropion theoamino alcohol,
bupropion morphinol
VI. MAOI
Phenelzine
Tranylcypromine
VII. SSRI
Citalopram Demethyl and didemethylcitalopram
Fluoxetine Norfluoxetine
Fluvoxamine
Paroxetine
Sertraline N-desmethylsertraline
VIII. 5-HT/NE Reuptake Inhibitor
Venlafaxine O-desmethylvenlafaxine

Altered Pharmacokinetics
• Factors that influence TCA plasma concentrations:
A. Disease states, genetics, age, cigarette smoking, and concurrent drug
administration.
B.Renal failure does not alter nortriptyline concentration but allows accumulation
of metabolite resulting to enhanced sensitivity to the drug
C. TCA plasma concentrations are increased in elderly patients
• Factors affecting half-lives of SSRI:
A. Liver cirrhosis increases half-lives of fluoxetine and norfluoxetine
B.Hepatic diseases provide a twofold increase in the plasma concentration of
paroxetine
 C. Half-life of sertraline is 2.5 times greater in patients with mild stable cirrhosis.
D. With renal impairment, two to four-fold increase in paroxetine plasma
concentrations was observed.
E. Plasma concentrations increase with age.
• Factors that affect the AUC of Triazolopyridines:
A. Liver cirrhosis increases AUC of nefazodone and trazodone
• Factors affecting concentrations of Aminoketones:
A. Accumulation of metabolites of bupropion was observed among patients with
liver cirrhosis.

DRUG INTERACTIONS
A. Tricyclic Antidepressants
• TCAs are metabolized in the liver through the cytochrome P450 system, they may
interact with other drugs that modify hepatic enzyme activity or hepatic blood
flow.
• They can displace other drugs bound to proteins.
• They can reverse the hypotensive effects of certain sympatholytic
antihypertensives (guanethidine, methyldopa, clonidine) because of inhibition of
presynaptic uptake of antihypertensive or desensitization of the alpha2-adrenergic
receptor.
• TCAs may increase the vasopressor response to direct-acting sympathomimetics
such as NE, epinephrine and phenylephrine
• TCAs decrease the vasopressor response to indirect-acting sympathomimetics.
• Adverse effects would be additive with anticholinergic, sedative or hypotensive
drugs.
• MAOIs and TCAs may be coadministered safely in refractory patients with
apparent increased efficacy compared with monotherapy. However, severe
reactions and fatalities have occurred including hypertensive crises, hyperpyrexia,
excitation, and convulsion.
B. Selective Serotonin Reuptake Inhibitors
• The very slow elimination of fluoxetine makes it critical to ensure a 5-week
washout after fluoxetine discontinuation before starting a MAOI.
• Serotonin syndrome may occur upon administration with MAOI.
• Fluoxetine + Warfarin = increased risk of bleeding
• Fluoxetine + Carbamazepine/Phenytoin = increased anticonvulsant properties
• Fluoxetine + TCA = increased plasma concentration of TCA
• Paroxetine + Warfarin = increased bleeding time
• Sertralin + Warfarin = increased bleeding time
• Sertraline + Sec. Amine TCA /Carbamazepine = increased concentrations of TCA
and carbamazepine
• Cimetidine + Citalopram = reduced oral clearance of citalopram by 29%
• Citalopram + Fluvoxamine = increased plasma concentrations of citalopram
C. Other Agents
• Mirtazapine + MAOI = should not be permitted

Dosing and Administration

• TCA- initial dose is 50 mg at bedtime
• SSRI- 10 to 20 mg (fluoxetine), 20 mg (paroxetine), 50 mg (sertraline) and 20
mg (citalopram)
• Bupropion- 100 mg twice daily
• Phenelzine- 15 mg in the morning, increased by 15 mg every third day up to 60
mg daily
• Venlafaxine- 75 mg daily in two or three divided doses(initially)
• Nefazodone- 100 mg twice daily
• Mirtazapine- 15 mg daily as single dose at bedtime
 • Desipramine/Nortriptyline- 10 to 25 mg daily

Refractory Patients
• The majority of treatment-resistant depressed patients are likely the result of
inadequate therapy (relative resistance)
• Three primary pharmacologic approaches:
6. Current antidepressant may be stopped and a trial with an unrelated agent
may be initiated
7. The current antidepressant may be augmented by administration of lithium,
liothyronine, CBZ, VPA
8. Use concurrently two different classes of antidepressants
• Never coadminister MAOI with SSRI

EVALUATION OF THERAPEUTIC OUTCOMES

• Psychometric tests should be conducted
• An assessment of compliance should be made at every visit.

Assessment A chapter examination regarding mood disorders will be given the following meeting.
SUBJECT PHARMACOLOGY 1 TOPIC MOOD DISORDERS-2
IG NUMBER IG-PHA-325LC WEEK NO 14
TERM FINALS SESSION 24 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the pharmacology of agents used in the management
Session of bipolar disorders.

Objectives 1. To discuss bipolar disorders

2. To enumerate the classes of agents used in the management of bipolar disoders
3. To discuss the principles in the mangement of bipolar disorders
4. To enumerate the adverse effects associated with the agents used in the
amngement of bipolar disorders

Materials 1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed.

Lesson BIPOLAR DISORDER or MANIC-DEPRESSIVE DISORDER

Outline
What are the manifestations of bipolar disorders?
What are the pharmacologic classes of drugs used in the treatment of bipolar
disorders?
What are the principles underlying the management of bipolar disorders?
What are the adverse effects of the agents used in the treatment of bipolar
disorders?

• It was previously known as manic-depressive disorder

• It is a cyclical disorder characterized by recurrent fluctuations in mood, energy,
and behavior encompassing the extremes of human experience.
• It is differentiated from recurrent major depression in the presence of manic,
hypomanic, or mixed episode during the course of illness.

EPIDEMIOLOGY
• Onset of mania after age 50 is rare, its prevalence increases during late
adolescence into early adulthood (15-30 y/o)
Etiology
A. GENETICS
- it has higher genetic risk than major depressive orders
- X chromosome may contribute susceptibilty to bipolar disorders
B. SECONDARY MANIA
- in this case, medications causing mania, agitation, or insomnia should be
discontinued

PATHOPHYSIOLOGY

A. NEUROTRANSMITTER THEORIES
- The monoamine hypothesis suggests a functional alterations of
neurotransmitters- NE, DA and 5-HT
- Excess catecholamines are associated with mania
- Deficiencies in neurotransmitters result to depression
- PERMISSIVE SEROTONIN HYPOTHESIS- low central 5-HT activity in both mania
and depression; 5-Ht plays a critical role in modulating CNS activity.
 - Lithium-facilitates the release of 5-HT and increases postsynaptic 5-HT receptor
activity.
- L-tryptophan and fenfluramine(block 5-HT reuptake and enhances 5-HT
release) have been used with other antimanic agents to enhance efficacy.
- One hypothesis of the switch phenomenon from depression to mania involves
the balance of NE to DA. When NE activity is decreased, the DA activity
predominates, and this may switch hypomania to mania.
- Increased dopaminergic activity plays a role in causing hyperactivity and
psychosis associated with the severe stages of mania, and reduced DA activity
may cause depression. In this case, lithium decreases beta-adrenoceptor
number and blocks DA receptor sensitivity.
- Clonidine- an alpha2 agonist decreases NE release and has been used as an
adjuctive agent for agitation and insomnia.
- Antidopamine medications find their application in the acute manic phase of
illness.
- Antidepressants that augment NE, DA, 5-HT activity have been used to treat
bipolar disorders; however, these agents may cause switching to mania.
- GABA-the main inhibitory neurotransmitter in the brain, is involved in the
inhibition of NE and DA. It was hypothesized that the concentration of GABA is
deficient in cases of mood disorders. Several antimania drugs such as Lithium,
CBZ, VPA, clonazepam, and lorazepam enhance GABAergic activity.
- Glutamate- an excitatory neurotransmitter can be decreased by CBZ and
lamotrigine, and topiramate acts a glutamate-receptor antagonist.
- Acetylcholine deficiency or cholinergic-adrenergic imbalance- choline interacts
with catecholamines between IP and IP-choline secondary messenger systems.
In such cases, lithium increases RBC levels of choline, and choline
supplementation has been used in combination with lithium to treat rapid-
cycling bipolar patients.

B. SENSITIZATION AND KINDLING THEORIES

- Recurrences of illness may result in behavioral sensitivity and electrophysiologic
kindling.
- Anticonvulsants such as VPA and CBZ have antikindling properties and are
effective in rapid cyclers and mixed states.
- ECT can also inhibit kindling.

C. NEUROENDOCRINE THEORIES
- Involves the hypothalamic-pituitary-thyroid axis
- Excessive thyroid activity may precipitate a manic episode by potentiating beta-
adrenergic activity
- Thyroid hormones are used to hasten the response of antidepressant activity
and to convert nonresponders to responders.
- Thyroid supplementations have been used to treat refractory rapid-cycling
bipolar disorders including episodes of mania and hypomania.
- Lithium blocks the release of thyroid hormones and CBZ decreases thyroid
indices.

D. MEMBRANE AND CATION HYPOTHESIS

- Abnormal calcium and sodium homeostasis causes mood fluctuations in bipolar
disorder.
- Extracellular and intracellular calcium concentrations affect the excitability of
neuronal firing and may cause “switches” from depression to mania.
- Several antimanic drugs have calcium antagonistic effects, including lithium,
calcium channel blockers, and phenothiazine antipsychotics
- Calcium channel blockers decrease intracellular calcium, block 5-HT, DA and
endorphin activity, alter sodium-calcium exchangers, and act as anti-
convulsants.
 - CBZ decreases serum sodium and calcium concentrations and blocks calcium
influx through the NMDA-glutamate receptor.
- Lamotrigine blocks sodium channels, which decrease presynaptic glutamate
release and has an effect on calcium channels
- Lithium decreases calcium transport intracellularly, interferes with calcium
uptake of platelets, alters calcium-sodium active transport system, increases
renal tubular reabsorption of calcium, and increases serum calcium and PTH
concentrations.

E. SECONDARY MESSENGER SYSTEM THEORIES

- Involvement of cAMP and IP systems
- CAMP is involved in the regulation of neuronal excitability and plays an
important role in bipolar disorder.
- G-proteins regulate adenylyl cyclase activity and IP responses, modulate
sodium-proton exchange and potassium-calcium channels, and activate
phospholipases
- Reduced erythrocyte Na/K-atpase activity is a marker of bipolar disorder.
ATPase maintains ionic gradient across cell membranes and respons to
neurotransmitter activation.
- If ATPase activity is reduced, another second messenger involving IP may be
more active, resulting in excessive release of monoamine neurotransmitters.
- Lithium exerts major effects on G-protein functioning, which is involved in
regulating mood, appetite and wakefulness. Lithium blocks the enzyme inositol-
1-phosphatase, which decreases the neurons’ ability to restore normal PIP 2
concentrations. By affecting this system, lithium reduces the responsiveness of
neuons to muscarinic, dopaminergic, serotonergic, alpha-adrenergic and other
stimuli. It also inteferes with the adenylyl cyclase-catalyzed conversion of ATP
to cAMP.
- CBZ- decreases basal cAMP levels and attenuates stimulated cAMP production.
- Chronic lithium and VPA- downregulate kinase C isoenzymes, which plays a role
in regulating presynaptic and postsynaptic neurotransmission.

F. BIOLOGIC RHYTHMS HYPOTHESIS

- Abnormalities of circadian rhythms have been reported in bipolar patients, such
as alterations in the suppression of the rhytmical hormone melatonin(a
metabolite of 5-HT) due to abnormalities in light sensitivity.
- Changes in sleep-wake or light-dark cycle have precipitated episodes of mania
or depression.
- Bright light therapy has been used for the treatment of winter depression amd
may precipitate hypomanic, manic or mixed episodes.
- Abnormalities in sleep biologic rhythms are implicated in the pathogenesis of
bipolar disorder.

CLINICAL PRESENTATION

1. MAJOR DEPRESSIVE EPISODE

- defined by discrete periods of depressed mood or loss of interest or pleasure in
life for greater than two weeks
- in bipolar depression, patients often have changes in sleep patterns, low
energy, psychomotor retardation, cognitive impairment, decreased sexual
activity, slowed speech, carbohydrate craving and weight gain.
- It is characterized by greater than 2-week period or either depressed mood or
loss of interest or pleasure in normal activities; associated with at least 5 of the
following symptoms:
a. depressed, sad mood, irritable
b. decreased interest and pleasure in normal activities
c. decreased appetiet, weight loss
 d. insomnia or hypersomnia
e. psychomotor retardation or agitation
f. decreased energy or fatigue
g. feelings of guilt or worthlessness
h. impaired concentration and decision making
i. suicidal thoughts or attempts

2. MANIC EPISODE
- defined by a distinct period when the mood is abnormally and peristently
elecated, expansive or irritable and is accompanied by impairment in judgment,
and in social and occupational functioning. Acute mania begins abruptly, and
symptoms escalate over several days.
- Seasonal changes, stressors, sleep deprivation, antidepressants, bright light, or
Ect can precipitate a manic episode.
- It is characterized by euphoria, unrealistic grandiosity, flight of ideas, faster
speech, increased energy, psychomotor excitement, decreased need for sleep,
anger orirritability, heightened perceptual acuity and impulsivity.
- The first clue of a manic attack is a decrease in sleep; followed by short
attention span and flight of ideas.
- To consider a manic episode, there should be a persistent elevated mood
(greater than 1 week) with at least three of the following symptoms:
a. inflated self-esteem
b. decreased need for sleep
c. increased talking
d. racing thoughts
e. distractible
f. agitation
g. excessive involvement in pleasurable activities

3. HYPOMANIC EPISODE
- less severe form of mania in which the patient’s mood is elevated, expansive, or
irritable.
- During this episode, aptient may be more productive and creative
- Patients usually find this episodevery desirable because they have heightened
sense of well being, happiness, exhilaration, feel more powerful and productive,
and have increased energy.
- At least four days of abnormal and persistent mood elevation associated with
three of the following symptoms:
a. grandiosity
b. decreased need for sleep
c. increased talking
d. flight of ideas
e. poor attention
f. increased activity

4. MIXED
- bipolar disorder is a dynamic and constantly changing illness, so that
manifestations of either phase may occur simultaneously.
- Known as dysphoric mania
- Possess the criteria for both manic and depressive episode occurring nearly
evryday for at least 1-week.

2. RAPID CYCLING
- characterized by greater than four major depressive or manic episodes in 12
months.
Goals of Therapy
a. to resolve bipolar symptoms
b. to prevent future episodes
c. to minimize adverse drug effects
d. to comply with the treatment
e. to avoid stressors that may precipitate an acute phase
f. to decrease the risk of relapse after an episode has been controlled

General Approach to Treatment

Three main mood stabilizers are used for the acute and maintenance treatment of
bipolar disorder:
1. Lithium- acute and prophylactic treatment of bipolar disorder.
2. Divalproex sodium- converted to VPA in the stomach
3. CBZ- not FDA approved for bipolar disorder

• Acute manic episodes can be treated with lithium, CBZ, or VPA along with
adjunctive BZD for anxiety and insomnia.
• Severe manic episodes associated with psychosis and agitation require
antipsychotics alone or with BZDs for sedation along with lithium, CBZ, or VPA
until mania subsides.
• Monotherapy is preferred for long-term maintenance; however, combinations of
drugs may be necessary for patients with mixed episodes, rapid cycling, or those
with partial or nor response to monotherapy.
• Possible combinations include lithium and CBZ, lithium and VPA. The concomitant
use of multiple drugs may be needed to stabilize refractory patients or continuous
cyclers (lithium and CBZ with clonazepam, VPA and antipsychotic with BZD).
• Rapid discontinuation of effective prophylaxis with lithium therapy has been
associated with an increased risk of relapse and possibly a more severe and
nonresponsive type of disorder, gradual tapering should be done.

PHARMACOLOGIC THERAPY

Drug Treatments of First Choice

• Lithium- drug of choice for bipolar disorder
• VPA/CBZ- first-line mood stabilizers, found to be more effective in several mood
subtypes
• Gabapentine, lamotrigine and calcium-channel blockers- under investigation as
mood stabilizers and may be considered alternative for patients who cannot
tolerate lithium, CBZ or VPA.

Lithium
• 1970- Lihium carbonate was approved for the treatment of mania
• 1974- approved for bipolar disorder
• Long-term lithium therapy may be more effective in patients with fewer prior
episodes, with a history of euthymia or good functioning between episodes, and
with a family history of bipolar illness with a positive response to lithium.
• Less effective for severe mania with psychotic features, mixed episodes, rapid or
continuous cycling, alcohol and drug abuse, and in organic-induced mood states.

Divalproex sodium (DVPX), Sodium valproate, or Valproic acid

• VPA- a branched-chain fatty acid, originally was marketed as anticonvulsant
• DVPX- approved on 1995 for the treatment of mania, may be more effective than
lithium in some bipolar subtypes.
• Antimanic effects can be augmented with lithium, CBZ, antipsychotics, or BZDs.
• VPA also has anntianxiety, antipanic, antimigraine, and antiaggressive effects.
Carbamazepine
• Marketed as an anticonvulsant, paroxysmal pain syndromes, and trigeminal
neuralgia, has acute antimanic, antidepressant, and prophylactic effects
comparable with lithium in bipolar disorders.
• More effective than lithium in severe mania, rapid recycling and in mixed episodes

ALTERNATE DRUG TREATMENTS

• Antipsychotics
- acute manic episodes may be treated with a mood stabilizer, an antipsychotic,
or a combination of the agents for an additive or synergistic effects.
- Low potency agents(chlorpromazine and thrioridazine) are more sedating and
cause more orthostatic hypotension, but have the advantages of causing fewef
EPS effects.
- High potency agents and moderate-poetency agents cause less sedation and
fewer blood pressure changes but have increased risk of causing EPS.
- Newer antipsychotic agents that block D2 and 5-HT2 receptors (clozapine,
olanzapine, quetiapine, RSP) cause fewer EPS and have been combined with
mood stabilizers for treatment-resistant patients.
- Clozapine appears to be effective in more refractory bipolar disorder, including
rapid cyclers, but requires weekly WBC to monitor for agranulocytosis.
- RSP with mood stabilizers are effective in acute mania with psychotic features.
• Benzodiazepines
- facilitates GABAergic transmission
- they are used in conjuction with lithium, CBZ and VPA for acute mania
- they are not effective when used prophylactically.
- Should be gradually tapered to avoid withdrawal symptoms.
• Antidepressants
- Bupropion and SSRIs are first-line antidepressants
- MAOIs and venlafaxine are second-line agents for the treatment of moderate or
severe bipolar depression
- Trazodone, is an adjunctive treatment for insomnia
• Calcium channel antagonist
- Verapamil, nifedipine and nimodipine are alternative mood stabilizers if
patientscannot be treated with lithium, CBZ, or VPA
- The most common adverse effects of calcium channel antagonists are
bradycardia nd orthostatic hypotension.
- Associated with low teratogenic effects
• Alternative anticonvulsants
- Lamotrigine- adjunct therapy for partial seizures and inhibits release of
glutamate, an excitatory amino acid.
- Lamotrigine is well-tolerated and has fewer side effects.
- Gabapentin- adjunct for focal seizures with and without secondary
generalization, has a structure similar to GABA, but it does not bind to GABA
receptor.
- It is associated with GI upset, somnolence and dizziness, although it is usually
well tolerated.

DRUG CLASS INFORMATION

• Lithium
- a monovalent cation and competes with other monovalent and divalent cations
in body tissues and at receptor sites.
- Neuropharmacologic effects of lithium include blockade of the dopamine-
receptor suspersensitivity, decreases beta-adrenoceptor stimulation of
adenylate cyclase, and increases of 5-HT, acetylcholine and GABA function.
- It decreases neurotransmitter activity by acting at the postsynaptic secondary
messenger system
 - It decreases receptor-G-protein coupling and decreases phosphoinositide
metabolism
- It is rapidly absorbed, no protein binding, is not metabolized and is excreted
unchaged in the urine and other body fluids.
- Side effects are innocuous and transient. Include SA block, T-wave flattening,
QRS widening, acne, exfoliative dermatitis,hair loss, rash and psoriasis. It is also
associated with hyperparathyroidism, hypothyroidism and weight gain.
- It is extremely toxic if taken in large doses.
- Lithium toxicity is manifested by: fine hand tremor, GI upset, fatigue, confusion,
lethargy, ataxia, dysarthria, nystagmus, emesis, increased deep-tendon
reflexes, muscle fasciculations.

• Valproic acid
- The exact mechanism is unknown but may be related to the inhibition of GABA
metabolism, stimulation of GABA synthesis and release, and augmentation of
postsynaptic inhibitory effect of GABA.
- It has lower incidence of adverse effects and generally well tolerated.

• Carbamazepine
- a dibenzazepine derivative, structurally related to TCAs.
- Blocks reuptake of NE, decreases NE release, increases Ach in striatum,
decreases DA and GABA turnover, bluck calcium influx through the NMDA-
glutamate receptor, and decreases the activity of adenylate cyclase.
- The most common adverse effects is associated with CNS toxicity.
- Neurologic side effects include drowsiness, vertigo, blurred vision, diplopia,
nystagmus, dysarthria, confusion and headache.
- Leukopenias were observed
Assessment
A chapter examination reagrding bipolar disorders next meeting.
SUBJECT PHARMACOLOGY 1 TOPIC ANXIOLYTICS
IG NUMBER IG-PHA-325LC WEEK NO 15
TERM FINALS SESSION 25 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the pharmacology of drugs used in the treatment of
Session Anxiety that includes anxiolytics and sedative-hypnotics.

Objectives 1. To present anxiety disorders

2. To enumerate the subclasses of anxiolytics
3. To discuss the mechanisms of action of anxiolytics
4. To enumerate the subclasses of sedative-hypnotics
5. To discuss the mechanisms of action of sedative-hypnotics
6. To enumerate the adverse effects asscociated with the use of the following
agents.

Materials 1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed

Lesson ANXIOLYTICS AND SEDATIVE HYPNOTICS

Outline
How are anxiety disorders presented?
What are the different subtypes of anxiety disorders?
What are the mechanisms of action of anxiolytic drugs?
What are the adverse effects associated with the use of anxiolytics?

PRESENTATION OF ANXIETY DISORDERS

Definition
• Anxiety is an emotional state commonly caused by the perception of real or
potential danger that threatens the security of an individual

Epidemiology
• Generally, anxiety disorders are group of heterogenous illnesses that develop
before age 30 and are more common in women and those with a family history of
anxiety and depression.
• Anxiety disorders are chronic in nature, patients are rarely completely symptom-
free.

ETIOLOGY
• Evaluation of anxious patients require a complete physical and mental status
examination, appropriate laboratory tests, toxicologic screen, and a thorough
knowledge of the patients’ medical, psychiatric and drug history.

Common Medical Diseases Associated with Anxiety

-Anxiety symptoms are an inherent part of the initial clinical presentation in several
medical disorders, thus complicating the distinction between anxiety disorders and
medical disorders.

• Cardiovascular- Angina, arrhythmia, hypertension, mitral valve prolapse,

myocardial infarction
• Endocrine and Metabolic- Anemia, Cushing’s disease, hyperthyroidism,
hypothyroidism, hypoglycemia, hypokalemia, insulinoma, pheochromocytoma
• Gastrointestinal- Colitis, irritable bowel syndrome, peptic ulcer
• Neurologic- Akathisia, essential tremor, seizures, migraine, pain, Parkinson’s
disease
• Repiratory- Asthma, chronic obstructive lung disease, hyperventilation,
pneumonia, pulmonary embolus

Psychiatric Diseases associated with Anxiety

-Anxiety may be a concomitant symptom of several major psychiatric illnesses.
Symptoms are extremely common in patients with mood disorders, schizoprenia,
delirium, dementia and substance use disorders.

Drug-Induced Anxiety
• Two major drug classes that cause anxiety symptoms:
1. CNS stimulants
2. CNS depressants

• Manifestations occur at a dose-dependent manner, but ingestion of minimal

amounts may result in marked anxiety, including panic attacks in some
individuals.

PATHOPHYSIOLOGY

-Anxiety may result from alterations associated with multiple brain structures and
abnormal function in several neurotransmitter systems including norepinephrine(NE),
gamma-amino butyric acid(GABA), and serotonin(5-HT).
-The key brain structures that play an important role in anxiety states are:
- Amygdala, for assessment of fear and response to danger
- Locus ceruleus, located in the brainstem, is the primary site for NE-containing
site in the brain
- Hippocampus, integrates and consolidates traumatic memory and, along with
entorhinal cortex, contextual fear conditioning.
- Hypothalamus, the principal site for integrating neuroendocrine and autonomic
responses to threat.

NEUROCHEMICAL THEORIES

NORADRENERGIC MODEL
• The autonomic nervous system of anxious patients is hypersensitive and
overreacts to various stimuli with peripheral autonomic hyperactivity.
• Chronic, central noradrenergic overactivity down-regulates alpha2 receptors in
patients.
• Alpha2 receptors are hyperactive in some patients with panic disorder.
• Drugs with anxiogenic effects stimulate locus ceruleus firing and increase
noradrenergic activity.
• Drugs with anxiolytic or antipanic effects inhibit locus ceruleus firing, decrease
noradrenergic activity and block the effect of anxiogenic drugs.

BENZODIAZEPINE RECEPTOR MODEL

The BZ receptor is functionally and structurally linked to the GABA type A receptor a
chloride ion channel- GABA-BZ receptor complex.
• Gamma Amino Butyric Acid- the major inhibitory neurotransmitter of the CNS,
involved in nerve transmission in nearly one-third of brain impulses.
• The GABA system has a strong regulatory or inhibitory effect on 5-HT and NE
systems.
• As GABA binds to its receptor, the adjacent chloride channel opens and permits
 the influx of negatively charged chloride ions, resulting in hyperpolarization of the
cell membrane and causes a decrease in neuronal excitability.
• Abnormal sensitivity to the antagonism of the BZ receptor was demonstrated in
panic disorder patients.
• In patients with Generalized anxiety disorder, down-regulated BZ receptors and
low levels of peripheral lymphocyte and platelet BZ receptors that reverted to
normal upon treatment were reported.

SEROTONIN MODEL
• Serotonin is primarily an inhibitory neurotransmitter that is used by the neurons
originating in the raphe nuclei of the brainstem and projecting diffusely in the
brain.
• The diverse actions of serotonin were attributed to its 14 receptor subtypes.

PEPTIDE THEORY
• Cholecystokinin is an abundant peptide with receptors located through out the
CNS and high densities in the hypothalamus, limbic system, basal ganglia, cortex
and brainstem.
• CCk increases the activity of catecholamines in the locus ceruleus and co-exists
with GABA-producing neurons.

CLINICAL PRESENTATION
The DIAGNOSTIC and STATISTICAL MANUAL OF MENTAL DISORDERS, fourth edition
classifies anxiety disorders into several categories:

A. Generalized anxiety disorder

B. Panic disorder
With or without agoraphobia
C. Agoraphobia without a panic disorder history
D. Phobic disorders
Social phobia
Specific phobia
E. Obsessive-Compulsive disorders
F. Posttraumatic stress disorder
G. Acute Stress disorder

Generalized Anxiety Disorder

• The diagnostic criteria require persistent symptoms for at least 6 months.
• The essential feature is unrealistic or excessive anxiety and worry about a
number of events or activities.
• GAD has a gradual onset, usually in the early 20’s, but may be precipitated in the
later life by severe psychological stressors.
• The majority of GAD patients will eventually develop another mental disorder.

Diagnostic Criteria for GAD

1. Excessive anxiety and worry, occurring more days than not for at least 6 months,
about a number of events or activities.
2. Difficulty to control worry
3. Anxiety and worry, associated with three of the following symptoms:
a. restlessness
b. fatigue
c. difficulty in concentrating
d. irritability
e. muscle tension
f. sleep disturbance
4. Constant worries causing significant distress, and significant impairment in social,
occupational, or other important areas of functioning.
5. Excessive anxiety and worry not caused by a drug substance.

PANIC DISORDER
• It begins as a series of spontaneous, unexpected panic attacks, involving an
intense, terrifying fear, similar to that caused by life-threatening danger.
• The unexpected panic attacks are followed by at least one month of persistent
concern about having another panic attack, or a significant behavioral change
related to attacks.
• It usually lasts for no more than 20 to 30 minutes, with the peak intensity of
symptoms within the first 10 minutes.

Diagnostic Criteria for Panic Attacks

• At least for of the following symptoms developed abruptly and reached a peak
within 10 minutes:
1. Palpitations or tachycardia
2. Sweating
3. Trembling or shaking
4. Sensations of shortness of breath or smothering
5. Feeling of choking
6. Chest pain or discomfort
7. Nausea or abdominal distress
8. Dizziness, unsteadiness, lightheadedness
9. Derealization or depersonalization
10. Fear of losing control
11. Fear of dying
12. Paresthesia
13. Chills or hot flushes

SOCIAL PHOBIA
• The essential feature is a marked and persistent fear of social performance
situations in which embarrassment may occur
• Exists in two distinct forms:
1. Generalized- related to most social situations
2. Discrete-related to performance and is specific for one or two situations
• The fear and avoidance of the situation must interfere significantly with the
person’s daily functioning.

SPECIFIC PHOBIA
• A marked and persistent fear of a circumscribed object or situation.

TREATMENT
I. Generalized Anxiety Disorder
A. Goals of Therapy:
1. to reduce the severity, duration and frequency of the anxiety symptoms
2. to improve the patient’s overall functioning
3. to prevent anxiety symptoms
4. to improve quality of life

B. Nonpharmacologic Therapy
1. Short-term counseling
2. Stress management
3. Psychotherapy- for encouragement
4. Meditation
5. Exercise
6. Avoidance from caffeine, nonprescription stimulants and diet pills

C. Pharmacologic Therapy
BENZODIAZEPINES
• Drugs of Choice for treating GAD
• The BZ’s are the most effective and safe medication for the amelioration of
anxiety symptoms.
• All BZ’s are equally effective anxiolytics.
• Estazolam, flurazepam, temazepam, quazepam, and triazolam are used
therapeutically as sedative-hypnotics.
• Clonazepam is marketed as antipanic and anticonvulsant
• Midazolam is labeled for preoperative sedation
• Alprazolam is indicated for the traetment of panic disorder with or without
agoraphobia, as well as GAD.

Mechanism of Action:
• Potentiation in the inhibitory effect of GABA.
• Activation of the benzodiazepine receptor in the presence of GABA increases the
frequency of the chloride ion channel opening and increases in the influx of
chloride ions in the neuronal cell.
• The resultant negatively charged, hyperpolarized membrane prevents further
depolarization by excitatory neurotransmitters.

Pharmacokinetics
• Differences in lipid solubility influence pharmacokinetic properties.
• Diazepam and clorazepate are rapidly absorbed and quickly distributed in the CNS
because of their high lipophilicities.
• Onset of action of chlordiazepoxide is much slower because of decreased
lipophilicity, slower absorption and delayed passage into the CNS.
• In comparison with diazepam, lorazepam and oxazepam are relatively less
lipophilic and have a slower onset of effect. They have smaller volumes of
distribution and a resultant longer duration of action.
• Oxazepam absorption is slow and peak levels are not obtained until 2 to 4 hours
after single dose.
• Benzodiazepines with slow absorption rates are not recommended for acute relief
of anxiety symptoms.
• Diazepam and Chlordiazepoxide- not administered through IM route.
• Lorazepam-provides rapid, reliable and complete absorption when administered
intramuscularly; preparation requires refrigeration.
• Many benzodiazepines are converted to N-desmethyldiazepam(N-DMDZ), an
active metabolite with a long elimination t1/2 of 36 to 200 hours.
• N-DMDZ is further oxidized to oxazepam, then conjugated, and excreted.
• Clorazepate is a prodrug and possesses no anxiolytic effects until metabolized to
N-DMDZ. Absorption is pH-dependent.
• Alprazolam, Lorazepam, Oxazepam- short t1/2

Adverse Effects
• CNS depression- most common AE.
- drowsiness
- sedation
- psychomotor impairment
- ataxia
• Transient mild drowsiness
• Disorientation, confusion, irritability, aggression and excitement
• Tolerance
• Anterograde amnesia

Dependence and Withdrawal

• Chronicity of illness often leads to dependence.
• Benzodiazepine dependence is a physiologic phenomenon demonstrated by the
appearance of a predictable abstinence syndrome upon abrupt discontinuation of
therapy resulting in a less inhibited CNS.

Benzodiazepine Discontinuation
• Withdrawal symptoms may persist for days to weeks.
• Common symptoms of withdrawal include:
1. anxiety
2. insomnia
3. restlessness
4. agitation
5. muscle tension
6. irritability
• Less frequently occurring symptoms:
1. nausea
2. malaise
3. coryza
4. blurred vision
5. diaphoresis
6. nightmares
7. hyperreflexia
8. ataxia
• Rarely occurring symptoms:
4. Tinnitus
5. Confusion
6. Paranoid delusions
7. Hallucinations
8. Seizures
9. Psychosis
• The onset of withdrawal symptoms in patients ingesting benzodiazepines with
short-elimination half-lives occurs much earlier than those with long-elimination
half-lives.
• If BZ therapy exceeds 6 weeks, a slow dosage taper over several weeks is
recommended.
• To treat withdrawal symptoms:
a. Diazepam-can be initiated as loading dose(40% of daily consumption),
followed by a daily tapering of 10%.
b. Clonazepam-an alternative agent
c. Phenobarbital-for mixed Bz and alcohol dependence.

Drug Interactions
• Alcohol + BZ – additive effect; lowers the therapeutic index of BZ
• CNS depressants + BZ – potentiation of adverse sedative effects
• Lorazepam + Clozapine – Respiratory suppression and death
• Cimetidine + BZ – inhibition of BZ metabolism
• Nefazodone/Fluvoxamine- increased alprazolam concentrations.

Dosing and Adminstration

• Therapy is initiated using low doses
• The duration should not exceed 4 to 6 months generally.

BUSPIRONE THERAPY
• An azapirone anxiolytic
• Possess no anti-convulsant , muscle relaxant, hypnotic, motor impairment and
dependence properties.
Mechanism of Action:
• Anxiolytic mechanism is unknown
• As a serotonin partial agonist, it binds presynaptically to the receptors in the
dorsal raphe and postsynaptically to receptors in hippocampus and cortical brain
areas.
• It also possesses both dopamine agonist and indirect dopamine antagonist
properties.

Pharmacokinetics
• After an oral dose, it is rapidly and completely absorbed, and undergoes
extensive first-pass metabolism.
• It is 95% protein bound.
• Mean elimination half-life is 2.1 to 2.7 hours
• It is eliminated primarily by oxidative metabolism and is converted into both
active and inactive metabolites.

Adverse Effects
• Lack of sedative properties
• Dizziness, nausea, headaches, nervousness and dysphoria

Drug Interactions
• Buspirone + Cyclosporine/haloperidol – increased levels of cyclosporine and
haloperidol
• Buspirone + MAOI – elevated blood pressure
• Buspirone + Disulfiram – mania
• Buspirone + Clomipramine – hypertension and anxiety

Dosing and Administration

• The usual therapeutic dose is 20 to 30 mg/d, with a maximum dose of 60 mg/d.
• The onset of anxiolysis is not immediate, requiring a week or more before clinical
effects are observed.
• It has minimal sedating properties and is not useful in clinical situations requiring
immediate anxiolytic effects or for situations requiring as-needed anxiolytic
therapy.
• It is an alternative for GAD patients who cannot tolerate the sedating effects and
psychomotor impairment of BZs.
• The agent of choice in the management of chronic, persistent anxiety.
• It is not cross-tolerant with BZs and will not treat or prevent symptoms of BZ
withdrawal.
• BZ dose should be tapered before switching to buspirone.
• It is an appropriate choice for anxious patients with a history of alcohol or drug
abuse.

ADRENERGIC BLOCKING AGENTS

• Propranolol and other beta-blockers may be useful in patients with prominent
cardiovascular symptoms of anxiety.
• They are less effective anxiolytics than BZs, and their usefulness may be
restricted to those anxiety patients with physical symptoms, especially
cardiovascular complaints, have not adequately responded to BZ therapy.
• Propranolol,10 mg bid should be used initially and gradually titrated to anxiolytic
response.
• Discontinuation should be gradual to avoid rebound anxiety and cardiovascular
effects.

ANTI-Depressants
• Not the first line of agents for GAD because of their adverse effects.
• Imipramine and Trazodone- effective in GAD after 3 to 8 weeks of therapy.
 • Low doses of SSRI’s are found to be effective to some patients.
• They are used as alternatives for individuals with contraindications to
benzodiazepine use or those with concomitant depressive symptoms.
• They are also used as adjuncts in the treatment of patients with a partial response
to BZ’s or buspirone.

Assessment A short quiz about the topic discussed next meeting.

SUBJECT PHARMACOLOGY 1 TOPIC ANXIETY-2
IG NUMBER IG-PHA-325LC WEEK NO 15
TERM FINALS SESSION 26 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the pharmacology of drugs used in Panic disorder- a
Session subtype of anxiety disorder.

Objectives 1. To present panic disorder

2. To enumerate the classes of drugs used in the treatment of panic disorder
3. To discuss the mechanisms of action of drugs used in the treatment of panic
disorder
4. To enumerate the unwznted effects associated with the use of the following
agents

1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

Materials 2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed

PANIC DISORDER
Lesson
Outline What are the characteristics of a panic disorder?
What are the pharmacologic classes of drugs used in the threatment of panic
disorder?

Goals of Therapy
a. to completely resolved panic attacks
b. to markedly reduce anticipatory anxiety
c. to avoid phobic attacks
d. to maintain clinical response that allows patient to resume normal activities

Nonpharmacologic Therapy
• Patients should avoid substances that may precipitate panic attacks including
caffeine, drugs of abuse, and non-prescription stimulants

Pharmacologic Therapy
• Panic disorder is effectively treated with several drugs including the TCA
imipramine, the BZ alprazolam, the MAOI phenelzine, and SSRIs.
• Alprazolam, clonazepam, sertraline and paroxetine are approved for panic
disorders.
• SSRIs are emerging as first-line agents because of their improved tolerability.
• SSRIs and Clomipramine are found to be more effective than imipramine and
alprazolam.
• In patients whose illness is complicated by a history of alcohol or drug abuse,
benzodiazepines should be cautiously used, and a TCA, SSRI, or MAOI would be
more appropriate.
• Concomitant benzodiazepine and SSRI therapy for 1 to 3 weeks may be
indicated in persons with severe symptoms of anticipatory anxiety.

ANTI-DEPRESSANTS

A. TRICYCLIC ANTIDEPRESSANTS
• Imipramine effectively blocks panic attacks within 3 to 5 weeks; however,
maximal improvement does not occur until 6 to 10 weeks.
• Approximately 20-30% of patients experience stimulatory side-effects including
insomnia, jitterness, irritability and unusual energy.
• Imipramine and Clomipramine-most widely studied
• Desipramine and nortriptyline- possibly effective
• TCAs possess stimulatory effects, anticholinergic effects, orthostatic hypotension,
delayed onset of antipanic effects, and toxicity in an overdose.
• For patients who cannot tolerate the anticholinergic effects of TCAs, a switch to
an SSRI may be helpful.
• Weight gain is associated with long-term therapy

B. SELECTIVE SEROTONIN REUPTAKE INHIBITORS

• Commonly used drugs for panic disorders.
• Fluvoxamine, fluoxetine and sertraline- effective for panic disorders
• The effect is delayed for 3-5 weeks.
• Adverse effects include insomnia, jitterness, restlessness, and agitation.
• Transient gastrointestinal disturbances occur frequently.
• Sexual dysfunction is problematic

C. MONOAMINE OXIDASE INHIBITORS

• This group of drugs is reserved for refractory or difficult patients.
• The antipanic effect of phenelzine is delayed for 3 to 5 weeks, and the antiphobic
effect does not occur for 6 to 10 weeks.

D. Other Agents
• Trazodone and maprotiline- effective for panic disorders
• Nefazodone- reduces panic symptoms in patients with comorbid depression
• Bupropion is ineffective in treating panic symptoms
• Venlafaxine- also helpful in preventing panic attacks

E. BENZODIAZEPINES
• Clonazepam and high-dose Alprazolam – effective in preventing panic attacks
• Diazepam and lorazepam – effective at high doses
• Therapeutic response to these agents occurs in 1 to 2 weeks, with further
improvement occuring at 4 to 6 weeks.
• Alprazolam- ideal for patients who need immediate relief.

DOSING AND ADMINISTRATION

Acute Phase
• The main goal of therapy in this phase is to reduce symptoms.
• The duration of this phase generally is 1 to 3 months depending on the choice of
medications.
• The guiding principle in the treatment of panic disorders is to start at adequately
low dose and to treat for an appropriate period of time.
• The duration of acute phase with antidepressants requires a minimum of 8 to 12
weeks.
• Low initial doses of SSRIs are recommended to avoid stimulatory side effects.
- The starting dose of paroxetine is 10 mg with dosage increase of 10mg
weekly; target dose is 40 mg
- Starting doses for fluoxetine are 2.5 to 5 mg/d to a dosage range of 10-20
mg/d by the end of 2 weeks.
- Fluvoxamine 25 to 50 mg/d was increased to 150mg/d in divided doses
- Sertraline initiated at 12.5 or 25 mg/d and titrated to 100 to 200 mg/d is
effective in panic disorder

• Phenelzine
- starting dose is 15 mg/d after evening meal every 3 to 4 days until 60 mg/d is
 reached
- fluoxetine must be stopped 5 weeks before phenelzine can be started
- if taken after meals, orthostatic hypotension is less likely to occur.
- Anti-cholinergic effects are less severe than with TCAs.
- Unpleasant side effects subside after 3 weeks
- Hypertensive crisis following an ingestion of tyramine-containing foods or
sympathomimetic drugs is the most serious, potentially life-threatening
adverse effect manifested by severe headache with flushing accompanied by
heavy “thumping” of the myocardium.

• The duration of acute phase with BZs is approximately 1 month because response
is rapid and occurs within 1 to 3 weeks.

Continuation Phase
• The goals of therapy during this phase are to complete and extend the treatment
response obtained in the acute phase, especially with regards to phobic
avoidance.
• This phase may last for 2 to 4 months.

Maintenance Phase and Discontinuation

• The duration of this phase is from 3 to 12 months.
• Patients taking alprazolam and imipramine for up to 8 months maintained
antipanic efficacy without dosage increase since tolerance hardly develops.
• Patients are advised not to discontinue the medication unless authorized by the
physician.

Assessment A short quiz regarding the topic discussed will be given next meeting
SUBJECT PHARMACOLOGY 1 TOPIC PARKINSON’S-1
IG NUMBER IG-PHA-325LC WEEK NO 16
TERM FINALS SESSION 27 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson intends to discuss the pathophysiology of Parkison’s disease and the
Session pharmacology of drugs used in the management of Parkinson’s disease

Objectives 1. To present the pathophysiology of Parkinson’s disease

2. To enumerate the classes of drugs used in the treatment of Parkinson’s disease
3. To discuss the mechanisms of action of anti-Parkinsonism agents
4. To enumerate the adverse effects associated with the use of anti-Parkinsonism
drugs

Materials 1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed

Lesson PARKINSON’S DISEASE

Outline
DISEASE STATE AND PATHOLOGY

Definition. Parkinson’s disease is a slowly progressive degenerative neurological

disease characterized by tremor, rigidity, bradykinesia (sluggish neuromuscular
responsiveness), and postural instability. Dr. James Parkinson first described
Parkinson’s disease in 1817 as “shaking palsy.”

Incidence
1. It has a prevalence of 1 to 2 per 1000 of the general population and 2
per 100 among people older than 65 years.
2. Onset generally occurs between age 50 and 65; usually occurs in the 60s.

Pathogenesis. Parkinson’s disease is a neurodegenerative disease associated with

depigmentation of the substantia nigra and the loss of dopaminergic input to the basal
ganglia (extrapyramidal system); it is characterized by distinctive motor disability. The
basal ganglia are responsible for initiating, sequencing, and modulating motor activity.

1. In healthy individuals, dopamine is produced by neurons that project from the

substantia nigra to the neostriatum (which include caudate and putamen) and
globus pallidus. In these areas, dopamine acts as an inhibitory neurotransmitter.
2. Lewy bodies are widespread but occur especially in the basal ganglia, brain stem,
spinal cord, and sympathetic ganglia.
3. In Parkinson’s disease, the loss of dopamine-producing neurons in the substantia
nigra results in an imbalance between dopamine, an inhibitory neurotransmitter,
and the excitatory neurotransmitter acetylcholine. Alterations in the
concentrations of other neurotransmitters, such as norepinephrine, serotonin, and
γ-aminobutyric acid (GABA), are also involved in the pathophysiology of
Parkinson’s disease.

Etiology. Several forms of Parkinson’s disease have been recognized.

Primary (idiopathic) Parkinson’s disease
 a. This is also called classic Parkinson’s disease or paralysis agitans.
b. The cause is unknown, and while treatment may be palliative, the disease is
incurable.
c. Most patients suffer from this type of parkinsonism.
d. Hypotheses of neuronal loss in idiopathic Parkinson’s disease are:

1. Absorption of highly potent neurotoxins, such as carbon monoxide,

manganese, solvents, and N-methyl-4-phenyl-1,2,3,6-tetrahydropiridine
(MPTP), which is a product of improper synthesis of a synthetic heroin-
like compound. Exposure to these agents, alone or in combination with
the neuronal loss of age may be the cause of Parkinson’s disease.

2. Exposure to the free radicals. Normally, dopamine is catabolized by

monoamine oxidase (MAO). Hydrogen peroxide and production of free
radicals – both toxic to cells – are products of catabolism. Protective
mechanisms, enzymes, and free radical scavengers, such as vitamins E
and C, protect cells from damage. It is proposed that either a decrease
in these protective mechanisms or an increase in the production of
dopamine cause a destruction of the neurons by free radicals.

Secondary parkinsonism – from a known cause

a. Only a small percentage of cases are secondary, and many of these are curable.
b. Secondary parkinsonism may be caused by drugs, including dopamine
antagonists, such as:
1. Phenothiazines (e.g., chlorpromazine, perphenazine)
2. Butyrophenones (e.g., haloperidol)
3. Reserpine
c. Poisoning by chemicals or toxins may be the cause; these include:
1. Carbon monoxide poisoning
2. Heavy metal poisoning, such as that by manganese or mercury
3. MPTP, a commercial compound used in organic synthesis and found (as a side
product) in an illegal meperidine analogue.
d. Infectious causes include:
1. Encephalitis (viral)
2. Syphilis
e. Other causes include:
1. Arteriosclerosis
2. Degenerative diseases of the central nervous system (CNS), such as
progressive supranuclear palsy
3. Metabolic disorders, such as Wilson’s disease

Signs and symptoms

1. Tremor
a. Tremor may be the initial complaint in some patients. It is most evident at
rest (resting tremor) and with low-frequency movement. When the thumb and
forefinger are involved, it is known as the pill-rolling tremor. Before pills were
made by machine, pharmacists made tablets (pills) by hand.
b. Some patients experience action tremor (most evident during activity), which
can exist with or before the resting tremor develops.
2. Limb rigidity is present in almost all patients. It is detected clinically when the
arm responds with a ratchet-like (i.e., cogwheeling) movement when the limb is
moved passively. This is owing to a tremor that is superimposed on the rigidity.
3. Akinesia or bradykinesia. Akinesia is characterized by difficulty in initiating
movements, and bradykinesia is slowness in performing common voluntary
movements, including standing, walking, eating, writing, and talking. The lines of
the patient’s face are smooth, and the expression is fixed (masked face) with little
evidence of spontaneous emotional responses.
4. Gait and postural difficulties. Characteristically, patient walk with a stooped,
flexed posture; a short, shuffling stride; and a diminished arm swing in rhythm
with the legs. There may be tendency to accelerate or festinate.

STAGES OF PARKINSON’S DISEASE

Stage 0: No clinical signs evident
Stage I: Unilateral involvement, including the major features of tremor,
rigidity, or bradykinesia; minimal functional impairment
Stage II: Bilateral involvement but no postural abnormalities
Stage III: Mild to moderate bilateral disease, mild postural imbalance, but still
ability to function independently
Stage IV: Bilateral involvement with postural instability; patient requires
substantial assistance
Stage V: Severe disease; patient restricted to bed or wheelchair unless aided.

5. Changes in mental status. Mental status changes, including depression (50%),

dementia (25%), and psychosis, are associated with the disease and may be
precipitated or worsened by drugs.

6. Unified Parkinson’s disease rating scale (UPDRS)

a. To evaluate the clinical efficacy of antiparkinson drugs and to monitor disease
progression, most investigators have used the UPDRS.
1. The disadvantages associated with the use of scales for rating the functional
and motor disabilities of patients with Parkinson’s disease include the
potential of interrater variability and imprecision due to semiquantitative
scoring.
2. The result of testing highly dependent on the stage of the disease, whether
the patient is being evaluated during an on- or off- period, and the relative
distribution of the improvement across all the items evaluated.
b. Part I of the UPDRS is an evaluation of mentation, behavior, and mood
c. Part II is a self-reported evaluation of the activities of daily living (ADL) and
includes speech, swallowing, handwriting, ability to cut food, dressing, hygiene,
falling, salivating, turning in bed, and walking.
d. Part III is a clinician-scored motor evaluation
1. Patients are evaluated for speech, rest-tremor facial expression and
mobility, action or postural tremor of hands, rigidity, finger taps, hand
movements, rapid alternative pronation-suppination movement of hands,
legs agility, ease of arising from a chair, posture, postural stability, gait and
bradykinesia.
2. Each item is evaluated on a scale of 0-4.
a. A rating of 0 on the motor performance evaluation scale indicates
normal performance.
b. A rating of 4 on the motor performance evaluation scale indicates
severely impaired performance.
e. Part IV is the Hoehn and Yahr staging of severity of Parkinson’s disease.
f. Part V is the Schwan and England ADL scale.

Diagnosis
1. Diagnosis depends on clinical findings.
2. Tests (including imaging) are most often used to rule out an etiology of
secondary Parkinson’s disease.
3. New technologies [e.g., positron emission tomography (PET) scan] are used to
visualize dopamine uptake in the substantia nigra and basal ganglia. The PET
scan measures the extent of neuronal loss in these areas, but it is not yet widely
available.
4. A specific form of single-photon-emission computed tomography (SPECT) could
 be helpful for diagnosis of Parkinsonian syndromes and non-parkinsonisms,
particularly essential tremor.

Treatment
1. Nondrug treatment
a. Exercise is an important adjunctive therapy and is most beneficial. Although
exercise does not help with the symptoms of Parkinson’s disease, regular
focused exercise, stretching, and strengthening activities can have a positive
effect on mobility and mood.
b. Nutrition. Patients with Parkinson’s disease are at increased risk of poor
nutrition, weight loss, and reduced muscle mass. Examples of the beneficial
effects of proper nutrition in this group of patients include:
1. Sufficient fiber and fluid intake help prevent constipation associated with
Parkinson’s disease and the medications used to treat the disease.
2. Calcium supplementation helps to maintain the existing bone structure.
3. Excessive dietary protein in the late stages of the disease causes erratic
responses to levodopa therapy.
4. A large body of literature supports the pathophysiological role of antioxidants
in the relief of oxidative stress in Parkinson’s disease. High doses of
antioxidants and α-tocopherol or vitamin E are recommended in this group
of patients.
2. Drug therapy for symptomatic relief. Treatment is divided into two generalized
categories: symptomatic therapies and preventive or protective measures.
Neuroprotective strategies are used to slow the development and progression of
the disorder.

Neuroprotective Treatment
1. MAO B such as selegiline and tocopherol (vitamin E) acts as a scavenger of free
radicals.
2. Dopamine agonists serve as scavengers of free radicals and decrease dopamine
turnover, which reduces oxidative stress. During early development of the
disease, there are increases in oxidative stress. Four classes of drugs are
available:
a. Anticholinergics (for resting tremor)
b. Precursor of dopamine agonists (e.g., carbidopa/levodopa)
c. Direct-acting dopamine agonists (e.g., bromocriptine, pergolide)
d. Indirect-acting dopamine agonists
1. Decrease reuptake (e.g., amantadine)
2. Decrease metabolism (e.g., selegiline)
3. Drug therapy for treating associated symptoms
a. Tricyclic antidepressants are used to treat depression. They exhibit some
dopaminergic and anticholinergic effects.
b. β-Blockers, especially propanolol with its high lipophilicity, benzodiazepines,
and primidone, are medications used for action tremor. Usually patients
show a clinical response in low doses.
c. Antihistamines. Diphenhydramine hydrochloride has some mild
anticholinergic effects and is used for symptomatic release of mild tremor;
because of its adverse reaction in the CNS, it should be used with caution in
the elderly.

4. General principles of drug therapy

a. If a patient does not respond to an agent in one class, another class should
be tried. The two dopamine agonists, bromocriptine and pergolide, are two
exceptions. Studies show that some patients respond to one agent when
they fail to respond to another. This could be because of their different
potencies or the limited information available in pergolide.
 b. Therapy should be started with a low dose and titrated up. Response usually
is seen within a few days after starting therapy.
c. If a second agent is added to the drug therapy, the dose of the first
medication should be decreased to minimize side effects.
d. Drug therapy should never be discontinued suddenly because withdrawal may
exacerbate the symptoms.

5. Definitions concerning drug therapy

a. Dyskinesias/dystonia are typically oral-facial movements, grimacing, or jerky
and writing movements of the trunk and extremities. They are always
reversible with antiparkinsonian medications, and they decrease or diminish
with dose reduction. Symptoms of Parkinson’s disease may reappear by
reducing the dose, and it is the clinical judgement of the physician of the
preference of the patient whether to continue with the drug regimen or
tolerate the side effects. There are three types of dyskinesias/dystonia: peak
dose dyskinesia, biphasic dyskinesias, and off-period dystonia. All could
benefit from sustained release preparations.
1. Peak dose dyskinesia
a. Could be corrected with sustained-release preparations
b. Decrease L-dopa dose, or add COMT inhibitor.
c. Add amantadine.
d. Perform surgery.
2. Biphasic dyskinesias
a. Could be corrected with sustained-release preparations
b. Decrease L-dopa dose and increase dopaminergic dose. If symptoms are
still present, a COMT inhibitor should be added.
c. Amantadine may be helpful
3. Off-period dystonia
a. Decrease L-dopa dose
b. Increase dopaminergic dose

b. On-off effect describes oscillations in response (at the receptor site) and sudden
changes in mobility from no symptoms to full parkinsonian symptoms in a matter
of minutes. No direct relationship between the on-off effect and drug levels has
been found. Usually, a second drug is added to the therapy regimen to correct
the effect. Reducing the dose of one drug and adding a second drug may also
be helpful.

c. End-dose effect, known also as the wearing-off effect, occurs at a latter part of
the dosing interval; it happens after a few years of L-dopa therapy. Reduce the
single L-dopa dose and spread the total L-dopa dose over a larger number of
single doses. Change to a dopamine agonist and use a sustained-release
formulation of L-dopa.

d. Drug holiday. Long-term levodopa use results in downregulation of dopamine

receptors. A drug holiday allows striatal nigra dopamine receptors to be
resensitized, although controversy exists regarding the consequences and the
outcome of his “holiday.”

6. Physical rehabilitation restores patients’ physical function and independence

through physical and occupational therapy. These will help patients with
managing big and small muscle groups by focusing on maintaining coordination,
dexterity, flexibility, and range of motions.

7. Psychological rehabilitation provides support for patients and their families. Keep
in mind that patients with Parkinson’s disease have a high incidence of depression
and that, in later stages of the disease, they develop dementia.
 8. Secondary effects of Parkinson’s disease include:
a. Cardiovascular effects, including orthostatic hypotension and arrhythmia
b. Gastrointestinal effects, including constipation and hypersalivation
c. Genitourinary effects, including increased urinary frequency and impotence
d. Central nervous system effects, including hallucinations, depression, and
psychosis

9. Parkinson’s disease late disabilities can be divided into two groups.

a. Levodopa-related disabilities, which include motor fluctuation, dyskinesia,

neuropsychiatric toxicity, and reduced response.
b. Non-levodopa related disabilities, which include cognitive impairment,
instability resulting in more frequent falls, gait disturbance, incontinence,
dysphagia, and speech disturbance.
c. Parkinson’s disease late disabilities and management therapies include:
1. Motor fluctuation. Altering the levodopa dosage and timing, alternative
means of levodopa administration, delivery, and absorption,; using direct-
acting dopamine agonists or experimental agonists; altering metabolism
of dopamine and levodopa parental agonists; using glutamate
antagonists; and performing functional neurosurgery.
2. Miscellaneous late disabilities and management therapies include:
a. Urinary urgency: oxybutynin
b. Urinary retention: apomorphine
c. Constipation: fiber, polyethylene glycols
d. Tenesmus: clonazepam, apomorphine
e. Hypersalivation: antihistamine, anticholinergic
f. Dysphagia: liquid levodopa
g. Sweating crises: β-blockers, anticholinergic agents
h. Daytime sleepiness: selegiline
i. Nightmares: amtriptyline, clonazepam
j. Panic attacks and depression: liquid levodopa,
amitriptyline
k. Orthostatic hypotension: domperidone, desmopressin
l. Dysphonia: reduce levodopa dosage, speech therapy
m. Pain: amitriptyline, fluvoxamine
Assessment
A short quiz regarding the topic next meeting.
SUBJECT PHARMACOLOGY 1 TOPIC PARKINSON’S-2
IG NUMBER IG-PHA-325LC WEEK NO 16
TERM FINALS SESSION 28 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This subtopic of Parkinson’s disease is intended to discuss the pharmacology
Session individual drugs used in the management of Parkinson’s disease.

Objectives 1. To discuss the classes of drugs used in the management of Parkinson’s disease
2. To discuss the mechanisms of action of the agents for Parkinson’s disease
3. To enumerate the adverse effects associated with the use of the drugs

Materials 1. Pharmacotherapy: A Pathophysiologic Approach , Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Comprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed

Lesson INDIVIDUAL DRUGS

Outline A. Anticholinergic agents are used for mild symptoms, predominantly tremors.
1. Mechanism of action. This class of drugs blocks the excitatory
neurotransmitter cholinergic influence in the basal ganglia. These drugs are
more effective for tremor and rigidity than for bradykinesia and less effective
for postural imbalance.

2. Administrations and dosage

3. Precautions and monitoring effects

a. Anticholinergics should be used with caution in patients with obstructed
gastrointestinal (GI) or genitourinary (GU) tracts, narrow-angle glaucoma,
or severe cardiac disease. Physicians should be notified if a rapid
heartbeat or eye pain is experienced. (Frequent ophthamological visits are
recommended)
b. The sedative side effects of antihistamines may be beneficial in some
patients.
c. Alcohol and other CNS depressants should be used with caution.
d. Adverse effects of anticholinergic therapy include the following:
1. Peripheral anticholinergic effects include dry mouth (hard candies may
be helpful); decreased sweating, resulting in decreased tolerance to
heat; urinary retention; constipation (stool softeners may be helpful);
increased intraocular tension and nausea. Because of patients’
decreased tolerance to heat, these agents should be used with caution
in hot weather. They should also be taken with food to minimize GI
upset.
2. CNS effects include dizziness, delirium, disorientation, anxiety,
agitation, hallucinations and impaired memory. The incidence of CNS
effects increases in elderly individuals.
3. Cardiovascular effects include hypotension and orthostatic hypotension.

4. Significant interactions
a. Side effects may be potentiated by other drugs with anticholinergic activity
such as antihistamines, antidepressants, and phenothiazines.
b. Anticholinergic agents increase digoxin levels.
c. When anticholinergic agents are taken with haloperidol, the following occurs:
1. Schizophrenic symptoms may increase.
 2. Haloperidol levels may decrease.
3. The severity of (not the risk of) tardive dyskinesia may increase.
d. When phenothiazines are taken with anticholinergic drugs, the effects of the
phenothiazines decrease and the anticholinergic symptoms increase.
e. Patients in high doses of anticholinergics combined with levodopa should be
watched for decreased levodopa activity because of a delayed gastric
emptying time.

B. Dopamine precursor. Levodopa/carbidopa is the most effective drug for

managing Parkinson’s disease; however, prolonged use decreases its therapeutic
effects (there is a decline in efficacy after 3-5 years) and increases adverse drug
reactions. Dopamine does not cross the blood-brain barrier; therefore, a
precursor is used. Peripheral conversion of levodopa to dopamine causes adverse
reactions like nausea, vomiting, cardiac arrhythmias, and postural hypotension.
To decrease the peripheral conversion and peripheral adverse effects, a
peripheral dopa decaryboxylase inhibitor (carbidopa) is added to levodopa.

1. Mechanism of action
a. Levodopa is converted to dopamine by the enzyme dopa decarboxylase, which
elevates CNS levels of dopamine.
b. The sustained-release formulation is designed to release the drug over 4-6
hours, thereby inhibiting variation in plasma concentration and decreasing
motor fluctuation “off” time, or to improve overall dose response in patients
with advanced disease.

2. Administration and dosage

a. It is necessary to give at least 100 mg daily of carbidopa to decrease the
incidence of the peripheral conversion of levodopa and GI side effects (e.g.,
nausea) and increase the bioavailability of levodopa for the CNS.
b. If carbidopa is given in a separate dosage form, the dose of levodopa can be
decreased by 75%.
c. If patients still complain of GI side effects after combination
levodopa/carbidopa, plain carbidopa can be given.
d. Sustained-release preparations are approximately 30% less bioavailable as
compared with levodopa/carbidopa. Because of this lower bioavailability, the
daily dosage should be higher. If a patient is receiving a standard preparation
and needs to be converted to the sustained-release dose, approximately 10%
more levodopa should initially be added to the daily dosage and at least 3 days
should pass between increased dosages; then gradually increase the levodopa
dose up to 30% of standard preparation.
e. With the sustained-release preparation, the peak plasma concentration is lower
and the trough plasma concentration is higher.
f. The sustained-release preparation could be divided in half at the scored point
only. The tablet should not be chewed or crushed.
g. When carbidopa is given to patients being treated with levodopa, give the two
drugs at the same time, starting with no more than 20% - 25% of the
previous daily dosage of levodopa and initiating therapy with carbidopa and
levodopa.
h. Long-term treatment could lead to motor fluctuation and dyskinesias,
especially at high doses.

3. Precautions and monitoring effects

a. Levodopa must be used with caution in patients with narrow-angle glaucoma.
b. Levodopa may activate a malignant melanoma in patients with suspicious
undiagnosed skin lesions or a history of melanoma.
c. The efficacy of levodopa declines with long-term therapy by desensitizing the
receptors or because of the decreased number of receptors, resulting from
 the progression of the disease.
d. Adverse drug reactions
1. GI effects include anorexia, nausea and vomiting, and abdominal distress.
Levodopa should be taken with food to minimize stomach upset.
2. Cardiovascular effects include postural hypotension and tachycardia.
3. Musculoskeletal effects include dystonia or choreiform muscle movement.
4. CNS effects include confusion, memory changes, depression,
hallucinations, and psychosis. Physicians should be notified if any of
these symptoms occur.
5. Hematological effects include hemolytic anemia, leukopenia, and
agranulocytosis (rare).
4. Significant interactions
a. Antacids cause rapid and complete intestinal levodopa absorption (by
decreasing gastric empting time).
b. Hydantoin decreases the effectiveness of levodopa.
c. Methionine increases the clinical signs of Parkinson’s disease.
d. Metoclopramide increases the bioavailability of levodopa, which decreases the
effects of metoclopramide on gastric empting and on lower esophageal
pressure. As a dopamine blocker, it may also precipitate parkinsonian
symptoms.
e. False-positive results are seen with the Coomb’s test.
f. The uric acid test increases with the calorimetric method but not with the
uricase method.
g. Hypertensive reactions may occur if levodopa is administered to patients
receiving MAO inhibitors and furazolidone. MAO inhibitors must be
discontinued 2 weeks before starting levodopa.
h. Administering papaverine may decrease the effect of levodopa
i. Tricyclic antidepressants decrease the rate and extent of absorption of
levodopa; hypertensive episodes have been reported when levodopa is
combined with tricyclic antidepressants.
j. Food decreases the rate and extent of absorption and transport to the CNS
across the blood brain-barrier. A protein-restricted diet may also help to
minimize the “fluctuations” (i.e., the decreased response to levodopa) at the
end of each day or at various times of the day.

C. Direct-acting dopamine agonists are classified as ergot derivatives such as

bromocriptine and pergolide and the non-ergolines such as pramipexole and
ropinirole.
• Mimic dopamine agonist and reduce motor fluctuations.
• Half-life of drugs in this class varies and also varies among patients.
• Are not metabolized by the oxidative pathway and do not produce free-radical
metabolites
• May have a direct antioxidative effect
• Take longer than L-dopa to reach effective doses and require supplementary L-
dopa for relief of symptoms after a varying period of time.
• Common side effects are nausea and psychiatric side effects similar to L-dopa
such as hallucinations and delusions; dyskinesias are less common.
• Other adverse effects are headache, nasal congestion, erythromelalgia, pleural
and retroperitoneal fibrosis, pulmonary infiltrates, and vasospasm (except with
new, non-ergot derivatives such as ropinirole).
• Annual chest radiographs have been recommended in patients on high-dose
therapy with bromocriptine or pergolide to detect pleuropulmonary changes.
• New dopaminergic agonists (not ergot derivatives) cause postural hypotension,
sleep disturbances, peripheral edema, constipation, nausea, dyskinesias, and
confusion.
Bromocriptine

a. Mechanism of action. Bromocriptine is responsible for directly stimulating

postsynaptic dopamine receptors; it is most commonly used as an adjunct to
levodopa therapy in patients:
1. With a deteriorating response with levodopa
2. With a limited clinical response to levodopa secondary to an inability to
tolerate higher doses
3. Who are experiencing fluctuations in response to levodopa

b. Administration and dosage

1. Initially, patients are given one-half of a tablet twice daily, which is then
increased to one tablet twice daily every 2-3 days.
2. Patients’ responses are extremely variable. Many patients show a dopamine
antagonist response at both low and high doses, with the desirable agonist
response in the midrange.
3. Because postural hypotension may result from the first few doses of
bromocriptine, the first dose should be administered with the patient lying
down, and sudden changes in posture should be avoided.

c. Precautions and monitoring effects

1. Bromocriptine may cause a first-dose phenomenon that can trigger sudden
cardiovascular collapse. It should be used with caution among patients with
a history of myocardial infarction or arrhythmias.
2. Early in therapy, dizziness, drowsiness, and fainting may occur, so patients
should be cautious about driving or operating machinery. A physician should
be notified if these symptoms appear.
3. Cardiac dysrhythmias. Patients on bromocriptine were found to have
significantly more episodes of atrial premature contractions and sinus
tachycardia.
4. Other adverse effects
a. GI effects, including anorexia, nausea, taking bromocriptine with food
may decrease vomiting, and abdominal distress.
b. Cardiovascular effects include postural hypotension (to which tolerance
develops) and tachycardia. Blood pressure must be monitored,
particularly for patients taking antihypertensive medication.
c. Pulmonary effects, including reversible infiltrations, pleural effusions, and
pleural thickening, may develop after long-term treatment, so pulmonary
function should be monitored in patients treated longer than 6 months.
d. CNS effects, including confusion, memory changes, depression, and
hallucinations, as well as psychosis may be exacerbated by
bromocriptine; thus, patients with psychiatric illnesses must be
monitored.

d.Significant interactions
1. A combination of antihypertensive drugs and bromocriptine could decrease
blood pressure.
2. Dopamine antagonists increase the effect of bromocriptine.

Pergolide
a. Mechanism of action. Pergolide is a semisynthetic ergosine derivative. In
Parkinson’s disease, it exerts its effect by directly stimulating postsynaptic dopamine
receptors in the nigrostriatal system.
1. It is 1000 times more potent than bromocriptine on a milligram basis.
2. It inhibits the secretion of prolactin, increases the serum concentration of
growth hormone, and decreases the serum concentration of luteinizing
hormone.
 3. It is most commonly used as adjunctive treatment to levodopa/carbidopa
b. Administration and dosage
c. Precautions and monitoring effects
1. Hypersensitivity reactions to pergolide and other ergot derivatives can occur.
2. Caution must be used with patients who are at high risk for ventricular
arrhythmia, especially when doses higher than 3 mg/day are used.
3. Cardiac dysrhythmias. Adverse effects are similar to those experienced with
bromocriptine.
4. CNS effects include dyskinesia, hallucinations, somnolence, and insomnia.
5. GI effects include nausea, constipation, diarrhea, and dyspepsia.
6. Cardiovascular effects include premature atrial contractions and sinus
tachycardia (alone or in combination with levodopa).
7. Miscellaneous effects include transient elevations of aspartate
aminotransferase, alanine aminotransferase, and alkaline phosphatase, and
pleural thickening.

Significant interactions
1. Because pergolide is 90% protein bound, it must be used with caution with
other highly protein-bound drugs.
2.Antipsychotic agents (e.g., phenothiazines, haloperidol, metoclopramide)
combined with dopamine agonists decrease the dopamine action and decrease
the dopamine action and decrease the therapeutic action of the antipsychotic
agent.

D. Indirect-acting dopamine agonists

1. Selegiline
a. Mechanism of action
1. MAO catabolizes various catecholamines (e.g., dopamine, norepinephrine,
epinephrine), serotonin, and various exogenous amines (e.g., tyramines) found in
foods (e.g., aged cheese, beer, wine, smoked meat) and drugs. Lack of MAO in
the intestinal tract causes absorption of these amines, creating a hypertensive
crisis. MAO type A is predominantly found in the intestinal tract, and MAO type B
in the brain. They differ in their substrate specificity and tissue distribution. This
specificity decreases with selegiline higher than 30-40 mg/day.
2. Selegiline is a selective inhibitor of MAO type B, which prevents the breakdown of
dopamine selectively in the brain at recommended doses.
3. Selegiline is most commonly used as an adjunct with levodopa/carbidopa when
patients experience a “wearing-off” phenomenon; it decreases the amount of
“off” time and decreases the dose needed of levodopa/carbidopa by 10%-30%.
4. Results of some studies show that selegiline delays the time before treatment
with a more potent dopaminergic drug like levodopa is needed; the proposed
mechanism of action is that an oxidation mechanism contributes to the
emergence and progression of Parkinson’s disease.
b. Administration and dosage. Exceeding the recommended dose of 10 mg/day
increases the risk of losing MAO selectivity. The precise selectivity dose is
unknown but seems to be above 30-40 mg/day.
c. Precautions and monitoring effects
1. Hypertensive crisis
2. Levodopa-associated side effects may be increased because the increased
amounts of dopamine react with supersensitive postsynaptic receptors. Reducing
the dose of levodopa/carbidopa by 10%-30% may decrease levodopa side
effects.
3. Patients should be educated about foods and drugs containing tyramine and
the signs and symptoms of hypertensive reactions.
4. CNS effects include dizziness, confusion, headache, hallucinations, vivid
dreams, dyskinesias, behavioral and mood changes, and depression. Patients
 with experience insomnia should avoid taking the drug late in the day.
5. Cardiovascular effects include orthostatic hypotension, hypertension,
arrhythmia, palpitations, sinus bradycardia, and syncope.
6. GI effects include nausea and abdominal pain and lead to GI bleeding, weight
loss, poor appetite, and dysphagia.
7. GU effects include slow urination, transient nocturia, and prostatic
hypertrophy.
8. Dermatological effects include increased sweating, diaphoresis, and
photosensitivity.
9. Hepatic effects include mild and transient elevations in liver function tests.

d. Significant interactions. Mao inhibitors are contraindicated with meperidine and

other opioids. Because the mechanism of action is unknown, administration with
opioids should be avoided.

e. Death has occurred following initiation of selegiline shortly after discontinuation of

fluoxetine. At least 5 weeks should elapse between discontinuation of fluoxetine
and initiation of selegiline.

2. Amantadine
a. Mechanism of action. Amantadine is an antiviral agent (used to prevent
influenza).
1. Amantadine increases dopamine levels at postsynaptic receptor sites by
decreasing presynaptic reuptake and enhancing dopamine synthesis and release.
2. It may also have some anticholinergic effects. It decreases tremor, rigidity,
and bradykinesia.
3. It can give in combination with levodopa as Parkinson’s disease progresses.
4. Clinical effects of amantadine can be seen within the first few weeks of
therapy, unlike the other antiparkinsonian medications (e.g., carbidopa/levodopa),
which need weeks to months to show their full clinical effects.
b. Administration and dosage
1. Amantadine should be started at 100 mg/day. This may be increased to 200-300
mg/day as a maintenance dose.
2. Patients experiencing a decline in response may benefit from the following:
a. Discontinuing the drug for w few weeks, then restarting it.
b. Using the drug episodically, only when the patients’ condition most needs a
therapeutic boost.
3. Amantadine is also available in liquid form for patients with dysphagia.

c. Precautions and monitoring effects

1. Amantadine should be used with caution to patients with renal disease,
congestive heart failure (CHF), peripheral edema, history of seizures, and mental
status changes. It may be necessary to modify dosages to patients with renal
failure.
2. Tolerance usually develops within 6-12 months. If tolerance occurs, another drug
from a different class can be added, or the dose may be increased.
3. Patients should be informed about the side-effect profile.
a. Peripheral anticholinergic effects
b. CNS effects include seizures
c. Cardiovascular effects. Patients may develop CHF. Periodic blood pressure
monitoring and electrocardiograms (ECGs) are necessary in patients with
myocardial infarction and arrhythmias
d. Dermatological effects include livedo reticularis, a diffuse rose-color mottling
of the skin, which is reversible upon discontinuation of the drug.
e. Hematological effects. Periodic complete blood counts (CBCs) should be
done for patients with long-term therapy.
4. Renal function impairment. Dose adjustment is necessary in patients with renal
 function impairment.

Significant interactions
1. Amantadine increases the anticholinergic effects of anticholinergic drugs,
requiring a decrease in the dosage of the anticholinergic drug.
2. Hydrochlorothiazide plus triamtrene decreases the urinary excretion of
amantadine and increases its plasma concentrations.

E. Non-ergot dopamine agonists

1. Pramipexole and ropinirole are indicated for both early and advanced stages of
Parkinson’s disease.
2. Both selectively bind to dopamine receptors and activate the D 2 receptors but
have little or no affinity to the D1 receptor. They have greater affinity for the D3
receptor than for the D2 receptor. The incidence of adverse events (such as
pleuropulmonary fibrosis and retroperitoneal fibrosis, coronary vasoconstriction,
erythromelalgia, and Raynaud’s phenomenon), is low compared to nonselective
dopamine agonists.
3. Non-ergot dopamine agonists have a low potential for the development of motor
fluctuations and dyskinesia.

a. Pramipexole
1. Mechanism of action
a. D2 subfamily of dopamine receptors. Pramipexole fully stimulates the
dopamine receptors to which it binds. Its action may be related to its
capacity to function as an antioxidant and oxygen free-radical scavenger.
b. Pramipexole also has antidepressant activity in moderate depression, which
may be related to its preferential binding to the dopamine D 1-receptor
subtype.
c. Long-acting dopamine agonists appear to have a lower risk of inducing
abnormal movements. Their use as initial treatment in early Parkinson’s
disease seems warranted, particularly for those with disease onset at a
younger age.

2. Administration and dosage

a. Initial treatment: starting dose of 0.375 mg daily given in three divided
doses.
b. Do not increase more frequently than every 5-7 days
c. Maintenance treatment: 1.5-4.5 mg daily in three divided doses with or
without levodopa
d. When given in combination with levodopa, consider reduction of levodopa
dose by an average of 27% from baseline.
e. Titrate slowly to balance benefits and side effects, such as dyskinesia,
hallucinations, somnolence, and dry mouth.
f. May be taken with food to reduce the occurrence of nausea. Food
decreases the rate of absorption but not the extent of absorption.
g. Dosage adjustment is necessary in patients with renal function impairment.
h. Weak protein bound 15%
i. Not extensively metabolized. More than 90% of the dose is excreted
unchanged in urine.
j. Dose needs to be decreased by 25% in the elderly.

3. Precautions and monitoring effects

a. Dose reduction necessary in patients older than 65 years, and in patients
with renal function impairment or failure.
b. Symptomatic hypotension
i. Dopaminergic agents appear to impair the systemic regulation of blood
 pressure, which results in orthostatic hypotension.
ii. Monitoring and education of the patient is necessary, especially during
dose-escalation periods.
c. Hallucinatory effects are increased in patients over 65 years of age with
early or advanced stages of Parkinson’s disease.
d. Other effects include nausea, insomnia, constipation, dizziness, somnolence,
GI side effects, and visual hallucinations.

4. Significant interactions
a. Cimetidine reduces renal clearance of pramipexole
b. No interaction with selegiline, probenicid, or domperidone
c. When combined with levodopa, the dosage of levodopa must be decreased
by 27%.

b.Ropinirole
1. Mechanism of action is similar to pramipexole.

2. Administration and dosage

a. Initial treatment: 0.25 mg three times daily
b. Titrate weekly increments.
c. After week 4, if necessary, daily dosage may be increased by 1.5 mg/day on
a weekly basis up to 9 mg/day, to a total of 24 mg/day.
d. Discontinue gradually over a 7-day period. Decrease the frequency of
administration from three times to two times daily for 4 days, and then once
daily for the remainder of the week.
e. When given in combination with levodopa, consider reduction of levodopa
dose.
f. May be taken with food to reduce the occurrence of nausea. Food decreases
the rate of absorption, but not the extent of absorption.
g. Metabolized by the liver (CYP1A2), and first-pass effect.
h. Smoking induces the liver metabolism
i. 30%-40% protein bound

3. Precautions and monitoring effects

a. Syncope. Bradycardia is observed in patients treated with ropinirole. Most
cases occur within the first 4 weeks of therapy and are usually associated with
a recent increase of dose.
b. Binds to melanin-containing tissues like the eyes and skin.
c. Symptomatic hypotension
i. Dopaminergic agents appear to impair the systemic regulation of blood
pressure, which results in orthostatic hypotension.
ii. Monitoring and education of the patient is necessary, especially during
dose-escalation periods.
d. Hallucinatory effects are increased in patients over 65 years of age with early
or advanced stages of Parkinson’s disease
e. Other side effects include nausea, dizziness, somnolence, headache, fatigue,
and abdominal vision.
Significant interactions
a. Smoking induces the liver metabolism, but the affect of smoking on clearance
of ropinirole has not been studied.
b. There is no interaction between levodopa, theophylline, digoxin, or
domperidone.
c. Estrogens decrease the clearance of ropinirole by approximately 36%.
d. Ciprofloxacin increases ropinirole area under the curve by 84% and maximum
plasma concentrations by 60%
4. Catechol-O-methyltransferase (COMT) inhibitors
a. Tolcapone
1. Mechanism of action
a. Tolcapone is a selective and reversible inhibitor of COMT and is used as
an adjunct to levodopa/carbidopa therapy.
b. Tolcopone inhibits COMT both peripheral and centrally
c. COMT is the main enzyme responsible for peripheral and central
metabolism of catecholamines, including levodopa. Addition of a COMT
inhibitor results in the doubling of the elimination half-life of levodopa
and in increased oral bioavailability of levodopa 40%-50%.
d. Tolcapone is indicated as an adjunct therapy to carbidopa/levodopa
therapy.
2. Administration and dosage
a. Starting dose of 100-200 mg, three times daily.
b. Usually daily dose of 200 mg, three times daily
c. If patient fails to show expected benefit after 3 weeks of treatment,
discontinue drug because of associated risk of liver failure. Rapid
withdrawal or abrupt reduction dose could lead to hyperpyrexia and
confusion symptoms such as high fever and severe rigidity similar to
those in neuroleptic malignant syndrome.
3. Precautions and monitoring
a. Liver toxicity. High risk of fatal liver failure has been reported with
tolcapone. Discontinue use if substantial benefit is not seen within 3
weeks of commencement of therapy.
b. Do not use in patients with liver disease or in patients who have two ALT
or AST values greater than the upper limit of the normal.
c. Advise patient regarding self-monitoring for liver disease (i.e., clay-
colored stool, jaundice, fatigue, appetite loss, or lethargy).
d. Monitor AST and ALT every 2 weeks for the first year, then every 4
weeks for the next 6 months and every 8 weeks thereafter.
e. MAO and COMT are two major enzyme systems involved in the
metabolism of catecholamines; combination of tolcapone with a non-
selective MAO inhibitor will result in inhibition of the pathway responsible
for normal catecholamine metabolism.
f. Tolcapone can be taken concomitantly with a selective MAO-B inhibitor,
such as selegiline.

4. Other side effects

a. Orthostatic hypotension. Tolcapone enhances levodopa bioavailability,
and therefore may increase the occurrence of orthostatic hypotension.
b. Diarrhea usually manifests within 6-12 weeks after administration of
tolcapone, but can develop as early as 2 weeks after administration.
Diarrhea normally resolves after discontinuation of the drug.
c. Confusion, insomnia, and excessive dreaming sometimes accompany
hallucinations. Hallucinatory effects usually occur after initiation of
tolcapone and are usually resolved by decreasing the dose of levodopa.
d. Tolcapone may potentiate the dopaminergic side effect of levodopa and
may cause or exacerbate preexisting dyskinesia. Decreased doses of
levodopa may or may not alleviate the symptoms.
e. Severe cases of rhabdomyolysis have been reported, which present as
fever, alternation of consciousness, and muscular rigidity.
f. Others. Dyspepsia, abdominal cramping, mild paresthesia of the legs,
and temporary discoloration of urine has also been noted but are not
considered clinically important.
g. Drug interactions. Although no drug interaction studies have been
conducted, concurrent use of tolcapone and drugs that are metabolized
by the COMT system (i.e., methyldopa, dobutamine, apomorphine)
 should be monitored. Tolcapone also has affinity for the CYP2C9
isoenzyme, similar to warfarin.

b. Entacapone
1. Mechanism of action
a. Entacapone is a selective and reversible inhibitor of COMT and permits
additional levodopa to reach the brain. It does not have any anti-parkinson
effect of its own.
b. It acts only peripherally by inhibiting COMT.
c. It improves the duration of “on” time and decreases the duration of “off”
time.
d. It is indicated as an adjunct to those on levodopa/carbidopa therapy who
experience the signs and symptoms of end-of-dose “wearing-off.”
2. Administration and dosage
a. 200 mg with each dose of L-dopa up to 8 times daily with a maximum dose
of 1600 mg daily.
b. Rapid withdrawal could lead emergency signs and symptoms of Parkinson’s
disease such as hyperpyrexia and confusion (symptoms resembling
neuroleptic malignant syndrome).
3. Precautions and monitoring effects
a. MAO. COMT and MAO are two major enzymes in the metabolism of the
catecholamines. Do not use together.
b. Drugs metabolized by COMT. Drugs that are metabolized by this pathway,
such as isoproterenol, epinephrine, norepinephrine, dopamine, and
dobutamine, as well as methyldopa may interact and may result in increased
heart rate, arrhythmias, and an excessive increase in blood pressure.
c. Hepatic function impairment. The majority of the drug is metabolized by the
liver; therefore, use caution in patients who have liver function abnormalities.
d. Fibrotic complication. Cases of retroperitoneal fibrosis, pulmonary infiltrates,
pleural effusion, and pleural thickening have been reported. These
complications may resolve when the drug is discontinued, but complete
resolution may not always occur.
e. Biliary excretion: Enatacapone is excreted by bile; therefore, use caution with
drugs known to interfere with biliary excretion, such as probenecid,
erythromycin, and ampicillin.
4. Other side effects. Dyskinesia/hyperkenesia, nausea, urine discoloration
(brownish-orange), diarrhea, and abdominal pain.
5. Drug interactions. May interact with drugs that are metabolized by the liver
cytochrome P450.

SURGICAL TREATMENT. All surgeries require needle insertion into the brain, which in
turn increases the risk of hemorrhage.

A. Globus pallidus internus (Gpi) pallidotomy

1. Definition. A pallidotomy entails the surgical resection of parts of the globus
pallidus.
2. Advantage. Improves contralateral dyskinesia.
3. Disadvantage. Increased risk of damage to other parts of the brain, including
optic nerve and internal capsule, and risk of emotional, behavioral, and
cognitive deficits.
B. Deep brain stimulation
1. Definition. High-frequency stimulation that induces functional inhibition of
target regions of the brain by implanting an electrode into a target site and
connecting the lead to a subcutaneously placed pacemaker.
2. Advantage. No destructive lesion is formed. Stimulation parameters can be
readjusted at any time to improve efficacy or decrease adverse events.
 3. Disadvantage. Side effects associated with equipment (such as lead breaks,
infection, skin erosion, mechanical malfunction, and need for battery
replacement). Other side effects include paresthesia limb dystonia, ataxia,
intracerebral hemorrhage, seizure, and confusion.

C. Fetal nigral transplantation

1. Definition. Implantation of embryonic dopaminergic cells into the denervated
striatum to replace degenerated neuronal cells.
2. Advantage. Implanted cells all survive, and innervation of the striatum is
accomplished in an organotypic manner. Does not necessitate making a
destructive lesion.
3. Disadvantage. Optimal transplant variables and target site not defined.
Assessment
A short exam regarding the topic discussed will be given the following meeting
SUBJECT PHA 325 TOPIC ANTI-SEIZURES
IG NUMBER IG-PHA-325LC WEEK NO 17
TERM FINALS SESSION 29 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to present seizure disorders and the pharmacology of anti-seizure
Session and anti-convulsant agents.

Objectives 1. To present seizure disorders

2. To enumerate the classes of drugs used in the treatment of seizure disorders
3. To elaborate the mechanisms of action involved
4. To discuss the different adverse effects associated with use of anti-seizure agents

Materials 1. Pharmacotherapy: A Pathophysiologic Approach, Latest edition

2. Basic and Clinical Pharmacology , Latest edition
3. Acomprehensive Pharmacy Review , Latest edition
4. Stedman’s Concise Medical Dictionary 2nd ed

Lesson SEIZURE DISORDERS

Outline
SEIZURES – characterized by an excessive, hypersynchronous discharge of cortical
neuron activity, which can be measured by the ELECTROENCEPHALOGRAM
(EEG).
- there are disturbances in consciousness, sensory motor systems,
subjective well-being, and objective behavior.
- It is usually brief, with a beginning and an end, and may produce
postseizure impairment.

EPILEPSY – a chronic seizure disorder, or group of disorders, characterized by

seizures that usually recur unpredictably in the absence of a consistent
provoking factor.
- derived from the Greek word meaning “to seize upon” or “taking hold of.”
- first described by Hughlings Jackson as an intermittent derangement of
the nervous system due to a sudden, excessive, disorderly discharge of
cerebral neurons.

CONVULSIONS – violent, involuntary contractions of the voluntary muscles.

* A patient may have epilepsy or a seizure disorder without convulsions.

INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES

I. PARTIAL SEIZURES – most common seizure type, occurring in approximately 80% of

epileptic patients.
- clinical and EEG changes indicate initial activation of a system of neurons limited to
part of one cerebral hemisphere that may spread to other or all brain areas.
- manifestations of the seizures depend on the site of the epileptogenic focus in the
brain.

CONSCIOUSNESS – defined as the degree of awareness and responsiveness

of the patient to externally applied stimuli.
CLASSIFICATION OF PARTIAL SEIZURES

• SIMPLE PARTIAL SEIZURES – generally do not cause loss of consciousness.

- SIGNS AND SYMPTOMS: primarily motor, sensory, somatosensory, autonomic or
behavioral.
- the signs and symptoms may help pinpoint the site of abnormal brain discharge
(e.g., localized numbness and tingling reflects a dysfunction in the sensory cortex,
located in the parietal lobe).
➢ MOTOR SIGNS: convulsive jerking, chewing motions and lip smackling.
➢ SENSORY AND SOMATOSENSORY MANIFESTATIONS: paresthesias and auras.
➢ AUTONOMIC SIGNS: sweating, flushing and pupil dilation.
➢ BEHAVIORAL MANIFESTATIONS: sometimes accompanied by impaired
consciousness, include déjà vu experiences, structured hallucinations, and
dysphasia.
• COMPLEX PARTIAL SEIZURES – accompanied by impaired consciousness; however
in some cases, the impairment precedes or follows the seizure.

MANIFESTATIONS
- Purposeless behavior is common.
- The affected person may have a glassy stare, may wander about aimlessly, and
may speak unintelligibly.
- Psychomotor (temporal lobe) epilepsy may lead to aggressive behavior (e.g.,
outbursts of rage or violence).
- Postictal confusion usually persists for 1-2 minutes after the seizure ends.
- Automatism (e.g., picking at clothes) is common and may follow visual, auditory
or olfactory hallucinations).

II. GENERALIZED SEIZURES – diffuse, affecting both cerebral hemispheres.

- clinical and EEG changes indicate initial involvement of both hemispheres.
- consciousness may be impaired, and this impairment may be initial manifestation.
- motor manifestations are bilateral.
- the ictal EEG patterns initially are bilateral and presumably reflect neuronal
discharge, which is widespread in both hemispheres.

TYPES OF GENERALIZED SEIZURES

• IDIOPATHIC EPILEPSIES – have an age-related onset, typical clinical and EEG

characteristics, and a presumed genetic etiology.
• SYMPTOMATIC EPILEPSIES – considered the consequence of a known or suspected
underlying disorder of the central nervous system.
• CRYPTOGENIC EPILEPSIES – refers to a disorder whose cause is hidden or occult; it
is presumed to be symptomatic, but the etiologic factors are unknown. It is age-
related, but often does not have well-defined clinical and EEG characteristics.

SIGNS AND SYMPTOMS OF GENERALIZED SEIZURES

➢ABSENCE (petit mal) SEIZURES – present as alterations of consciousness

(absences) lasting 10-30 seconds.
- Staring (with occasional eye blinking) and loss or reduction in postural tone is
typical. If the seizure takes place during conversation, the individual may break
off in midsentence.
- Enuresis and other autonomic components may occur during absence seizures.
- Some patients experience 100 or more absences daily.
- Onset of this seizure type occurs from ages 3-16 years; in most patients,
absence seizures disappear by age 40.
➢MYOCLONIC (bilateral massive epileptic myoclonus) SEIZURES – present as
involuntary jerking of the facial, limb, or trunk muscles, possibly in rhythmic
 manner.
➢CLONIC SEIZURES – characterized by sustained muscle contractions alternating
with relaxation.
➢TONIC SEIZURES – involve sustained tonic muscle extension (stiffening).
➢GENERALIZED (grand mal) TONIC-CLONIC SEIZURES – cause sudden loss of
consciousness.
- The individual becomes rigid and falls to the ground. Respirations are
interrupted. The leg extended, and the back arches; contraction of the
diaphragm may induce grunting. This tonic phase lasts for about 1 minute.
- A clonic phase follows, marked by rapid bilateral muscle jerking, muscle
flaccidity, and hyperventilation. Incontinence, tongue biting, tachycardia, and
heavy salivation sometimes occur.
- During the postictal phase, the individual may experience headache, confusion,
disorientation, nausea, drowsiness, and muscle soreness. This phase may last
for hours.
- Some epileptics have serial grand mal seizures, regaining consciousness briefly
between attacks. In some cases, grand mal seizures occur repeatedly with no
recovery of consciousness between attacks (status epilepticus).
➢ ATONIC SEIZURES (drop attacks) – characterized by a sudden loss of postural tone
so that the individual falls to the ground. They occur primarily in children.

ETIOLOGY
Some seizures arise secondary to other conditions. However, in most cases,
the cause of the seizure is unknown.

• PRIMARY (idiopathic) SEIZURES – have no identifiable cause.

- this type affects about 75% of epileptics
- the onset of primary seizures typically occurs before age 20.
- birth trauma, hereditary factors, and unexplained metabolic disturbances have
been proposed as possible causes.

• SECONDARY SEIZURES (symptomatic or acquired seizures) – occur secondary to an

identifiable cause.
- disorders that may lead to secondary seizures include:
(1) Intracranial neoplasms
(2) Infectious diseases (meningitis, influenza, toxoplasmosis, mumps, measles,
syphilis)
(3) High fever (in children)
(4) Head trauma
(5) Congenital diseases
(6) Metabolic disorders (hypoglycemia, hypocalcemia)
(7) Alcohol or drug withdrawal
(8) Lipid storage disorders
(9) Developmental abnormalities
- age at seizure onset is associated with specific etiologies.
PROBABLE CAUSES OF RECURRENT SEIZURES BY AGE GROUP

AGE AT SEIZURE ONSET PROBABLE CAUSE OF SEIZURE

Birth – 1 month Birth injury or anoxia, congenital hereditary disease,

and metabolic disorders
1 – 6 months As above, plus infantile spasms
6 months – 2 years Infantile spasms, febrile convulsions, birth injury or
anoxia, meningitis and head trauma
3 – 10 years Birth injury or anoxia, meningitis, cerebral vessel
 thrombosis, and idiopathic epilepsy
10 – 18 years Idiopathic epilepsy and head trauma
18 – 25 years Idiopathic epilepsy, trauma, neoplasm, and
withdrawal from alcohol or drugs.
35 – 60 years Trauma, neoplasm, vascular disease, and withdrawal
from alcohol or drugs
Over 60 years Vascular disease, neoplasm, degenerative disease,
and trauma

PATHOPHYSIOLOGY
Seizures reflect a sudden, abnormal, excessive neuronal discharge in the
cerebral cortex. Any abnormal neuronal discharge could precipitate a seizure.

• NORMAL FIRING OF NEURONS – usually originate from the gray matter of one or
more cortical or subcortical areas, requires the following elements:

➢ VOLTAGE-DEPENDENT ION CHANNELS – involved in action-potential propagation

or burst generation.

➢ NEUROTRANSMITTERS – control neuronal firing, including excitatory

neurotransmitters, acetylcholine, norepinephrine, histamine, corticotropin-
releasing factors (CRFs), inhibitory neurotransmitters, GABA and dopamine;
therefore, for normal neuronal activity, there is a need for adequate ions (e.g.,
sodium, potassium, calcium); excitatory and inhibitory neurotransmitters; and
glucose, oxygen, amino acids, and adequate systemic pH.

➢ Epileptics may be genetically predisposed to a lower seizure threshold.

➢ DIENCEPHALIC NERVE GROUP – normally suppresses excessive brain discharge

may be deafferented, hypersensitive, and vulnerable to activation by various
stimuli in epileptics.

➢ During seizure, there is an increased use of energy, oxygen, and consequently, an

increased production of carbon dioxide. Because of the limited capacity to
increase the blood flow to the brain, the blood supply may be oxygen deficient.
The ratio of supply to demand decreases when the seizure episode is
prolonged, leading to increased ischemia and neuronal destruction. Thus, it is
crucial to diagnose seizures and treat them as soon as possible.

• ABNORMAL ELECTRICAL BRAIN ACTIVITY – occurs during a seizure usually

produces characteristic changes on the EEG.
- each part of the cortical area has its own function, and the clinical presentation
of a seizure depends on the site, the degree of irritability of the area, and the
intensity of the impulse.
• Seizure activity may include three major phases:
➢ PRODROME – may precede the seizure by hours or days.
- changes in behavior or mood typically occur during the prodorme.
- this phase may include an aura – a subjective sensation, such as unusual smell or
flashing light.
➢ ICTAL PHASE – the seizure itself. In some cases, a scream or cry heralds its
onset.
➢ POSTICTAL PHASE – takes place immediately after the seizure.
- extensor plantar reflexes may appear.
- the patient typically exhibits lethargy, confusion, and behavioral changes.

CLINICAL EVALUATION
• HISTORY – includes evaluation of the seizure, including interviews of the patient’s
family and eyewitness accounts to establish:
a. The frequency and duration of the episodes
b. Precipitating factors
c. The times at which episodes occur
d. The presence or absence of an aura
e. Ictal activity
f. Postictal state

• PHYSICAL AND NEUROLOGICAL EXAMINATIONS – the tools with which to identify

an underlying etiology to rule out diseases that manifest as seizures

• LABORATORY TESTS – may also identify an underlying etiology

- Liver and kidney function tests, complete blood count, urinalysis, and serum drug
levels (e.g., antidepressants and amphetamines may precipitate seizures) are
necessary.
- Lumbar puncture may be required for evidence of CSF infection for the patient
with a fever who has seizures.

• NEUROLOGICAL IMAGING STUDIES – includes magnetic resonance imaging (MRI)

or computed tomography (CT)- complement electrophysiological studies, can
identify structural brain disorders (anatomical abnormalities).
- MRI – can detect cerebral lesions related to epilepsy and should be used in all
cases, especially in patients with partial seizure, to exclude brain
abnormalities.
- Positron-emission tomography (PET), single-photon-emmission CT (SPECT), and
stable xenon-enhanced x-ray CT – offer functional views of the brain to
detect hypometabolism or relative hypoperfusion. PET and SPECT scans are
not available in all institutions.
- EEG studies – measure the electrical activity of the brain. These studies help to
identify functional cerebral changes underlying structural abnormalities and
are useful with MRI for patients considered for epilepsy surgery.

EEG – useful for classifying the seizure or as an additional diagnostic tool.

- cannot rule seizures in or out, as there are patients with normal interictal
EEGs who have seizure disorders.
- best time to obtain an EEG is during a seizure period. EEG recordings done
while the patient is asleep can often record the abnormal activity; therefore,
EEGs performed during a sleep-induced state under normal conditions or in a
sleep-deprived state can be more sensitive for making a diagnosis.

DISORDERS THAT MIMIC EPILEPSY

Gastroesophageal reflux Movement disorders
Breath-holding spells Shuddering attacks
Migraine Paroxysmal choreoathetosis
Confusional Nonepileptic myoclonus
Basilar Tics and habit spasms
With recurrent abdominal pain and cyclic vomiting Psychological disorders
Sleep disorders (especially parasomnias) Panic disorders
Cardiovascular events Hyperventilation attacks
Pallid infantile syncope Pseudoseizures
Vasovagal attacks Rage attacks
Vasomotor syncope
Cardiac arrythmias
TREATMENT OBJECTIVES
 • To prevent or suppress seizures or reduce their frequency through drug therapy
• To control or eliminate the factors that cause or precipitate seizures
• To prevent serious consequences of seizures, such as anoxia, airway occlusion, or
injury, by protecting the tongue and placing a pillow under the victim’s head
• To encourage a normal lifestyle and prevent the patient from feeling like or being
treated as an invalid
• Short- and long-term side effects
• Drug interactions

THERAPY
• PRINCIPLES OF DRUG THERAPY
A. SEIZURE CONTROL – approximately 50% of epileptics achieve complete
seizure control through drug therapy.
- in another 25%, drugs reduce the frequency of seizures.
- epileptics generally require continuous drug therapy for at least 2 seizure-free
years before the drug discontinuation can be considered.

B.INITIAL TREATMENT
- Before anticonvulsive drug treatment is instituted, treatable underlying causes of
the seizure activity should be excluded.
- A single primary drug that is most appropriate for the seizure type must be
selected. If there is more than one appropriate primary drug, then age, sex, and
compliance of the patient must be considered.
- For patients with newly diagnosed epilepsy, administer low doses for a few days.
Patients may respond to a dosage that is lower that that traditionally prescribed
initially by their physicians, and this may have important implications in terms of
limiting adverse effects. The incidence of adverse effects increases with
increasing drug levels, even when the plasma concentrations are maintained
within the so-called therapeutic or optimal range.
- Approximately one-fourth or one-third of the maintenance dose of a single
medication is used to begin therapy; it is then increased over 3-4 weeks. The
exceptions are phenytoin or penobarbital, which can be started with the loading
or maintenance dose. The dose should be titrated until seizure control or
intolerable side effects occur.
- With the initiation of therapy, blood concentrations of medications should be
measured.
(1) To establish therapeutic ranges and dosage regimens based on symptomatic
toxicity or seizure frequency.
(2) To assess the patient’s compliance with therapy.
(3) To control the correlation among the dose, blood levels, and clinical
therapeutic levels or toxicity.
(a) Phenytoin follows nonlinear kinetics, as drug levels increase
dramatically (more than onefold) with only a small increase in the dose.
However, prior to this twofold increase in drug level with a small
increase in dose, there is a predictable linear increase with dose
increases; for this reason, it is recommended to increase the dose in
small increments to be able to predict when the drug follows nonlinear
kinetic. When this happens, that means the maximum rate of hepatic
enzyme clearance is reached and the body can no longer clear the drug
as it is introduced into the body.
(b) If physical examination reveals a new onset of nystagmus (except with
phenytoin, in which nystagmus develops before clinical intoxication),
ataxia, and unsteady, wide gait, the next dose increase should be
minimal.
(c) There is no justification for increasing drug dosage when a patient’s
seizures are fully controlled, even if the plasma concentration is below
the lower limit of the therapeutic range. If the patient continues to
 have seizures without any evidence of adverse effects at a plasma
concentration near the toxic range, there are two approaches:
(i) Some increase the dosage according to clinical response up to
the highest tolerated limit.
(ii) Some do not increase the dosage because of the likelihood of
producing adverse effects.
(d) Carbamazepine has an autoinduction metabolism property, which
means that if the dose is increased twofold, blood levels increase less
than twofold because of increased metabolism.
(4) To determine the free drug level, which is helpful in patients who are in the
therapeutic range but have side effects or no response. The plasma protein
binding may be altered in these patients by some other disease state or
medication. Because of this alteration, there is more free drug available in
the system than the total level shows, especially with phenytoin, valproic
acid, and carbamazepine.
C. PARADOXICAL INTOXICATION – occurs when a high concentration of a single
drug causes increased frequency of seizures without classical adverse events.
This is common with hydantoins and carbamazepine. The proposed reason is
that their effect on the cerebellum is blocked at high concentrations.
Management usually requires no more than withholding enough doses of the
drug to allow the concentration to drift down.

D. When seizures cannot be controlled, there are TWO OPTIONS:

(2) The initial drug can be substituted with another agent. This is
accomplished by gradually discontinuing the initial drug while
simultaneously increasing the dosage of the second agent. Then the
dosage of the second agent is titrated up to the maintenance level as the
initial agent is gradually discontinued. There are three main advantages of
gradual distribution:
- It allows evaluation of the effects of individual drugs.
- It reduces the risk of toxicity.
- It reduced the risk of adverse drug interactions.
(3) A second drug can be added. Combination therapy is reserved for patients
with severe epilepsy in order to rapidly control the seizures. Rapid control
can be important for psychosocial reasons as well as for the possibility of a
more favorable prognosis.

E. LONG-TERM DRUG TREATMENT

Most physicians review the patient’s condition when the patient has been
seizure free for 2 years. This has important implications in children because
early termination of treatment has better remission rates compared with adults.
It is recommended to gradually decrease the dose, over at least 6 months. The
age of onset of epilepsy, the presence of an underlying neurological condition,
and any abnormal EEGs should be considered.

F. DISEASES AND CONDITIONS THAT ALTER ANTIEPILEPTIC DRUG-PROTEIN

BINDINGS
➢ Liver disease
➢ Hypoalbuminemia
➢ Burns
➢ Pregnancy
➢ High protein-binding drugs or antiepileptic agents.

G. MEDICATIONS. There are drugs that decrease levels of phenytoin,

carbamazepine, Phenobarbital, and primidone by enhancing their metabolism.
These drugs also cause false decreases in thyroid function tests.
➢ Oral contraceptives
 ➢ Oral hypoglycemics
➢ Glucocorticoids
➢ Tricyclic antidepressants
➢ Azathioprine
➢ Cyclosporine
➢ Quinidine
➢ Theophylline
➢ Warfarin
➢ Doxycycline
➢ Levodopa

H. OVERVIEW OF THERAPY IN SEIZURE DISORDER

(1) Monotherapy: Start the drug therapy as a single agent.
(2) Dosage Treatment: Use a low dose for a few days. Patients with newly
diagnosed epilepsy may respond to dosages that are lower than those
prescribed initially by their physicians, and this may have important
implications in terms of adverse effects. The incidence of adverse effects
increases with increasing drug dosage, even when the plasma concentration
is maintained within the so-called therapeutic or optimal range.
(3) Drug monitoring: There is no justification for increasing drug dosage when
a patient is fully controlled, even if the plasma concentration is below the
lower limit of the therapeutic range. If the patient continues to have seizures
without any evidence of adverse effects at a plasma concentration near the
toxic range, there are two approaches:
(a) Some increase the dosage according to clinical response up to the
highest tolerated limit.
(b) Some do not increase the dosage because of the likelihood of
producing adverse events.

I. ADVERSE EFFECTS OF ANTICONVULSIVE DRUGS

➢ ALTERATION IN COGNITION AND MENTATION
SEDATION AND DEPRESSION – the most common symptoms of overdose of
anticonvulsive drugs, but they are difficult to assess.

EXCITATION – can be a paradoxical effect of barbiturates with younger children

and the elderly.
e.g. felbamate can cause restlessness and hyperactivity

➢ DETERIORATION OF MOTOR PERFORMANCE AND PRIMARY COORDINATION –

includes trembling hands, staggering when rounding corners, and
mild limb ataxia. Drugs associated with these effects include
hydantoins, methsuximide, carbamazepine, and primidone. These
effects are less common with barbiturates and lamotrigine and are
rarely seen with gabapentin.

➢ GASTROINTESTINAL SYMPTOM – include nausea and vomiting. Two purposed

mechanisms include:
(1) A local effect on the stomach, as in the case of valproic acid; divalproex
acid, however, has less incidence compared with valproic acid. These
symptoms decrease in incidence if the drug is given with meals.
(2) A brain stem effect, as in the cases of felbamate and carbamazepine.
Nausea and vomiting caused by these drugs are associated with brain-
stem involvement; therefore, drug levels play a role in these symptoms.
Administration in smaller, more frequent doses decreases the incidence
of these symptoms by lowering the transient peak concentration.

➢ APPETITE AND BODY WEIGHT. Few anticonvulsants affect appetite separate

 from nausea and vomiting, including anorexia or increased appetite.
1. Drugs that cause anorexia are flebamate and to a lesser extent,
carbamazepine, ethosuximide, and valproic acid.
2. Drugs that cause increased appetite are valproic acid, and to a lesser
extent, carbamazepine.

➢ HEADACHE AND DIZZINESS

1. Diffuse headaches may be caused by ethosuximide and, to a lesser
extent, by methosuximide and felbamate.
2. A combination of ataxia and loss of eye movement coordination cause
dizziness seen in association with anticonvulsants, which is a part of
motor coordination symptoms.

SPECIFIC ANTISEIZURE AGENTS

USES OF ANTIEPILEPTIC MEDICATIONS BASED ON SEIZURE TYPE

Simple Partial
CHOICE 1: Carbamazepine (alone or combination)
CHOICE 2: Phenytoin
CHOICE 3: Primidone, Lamotrigine
CHOICE 4: Gabapentin, levetiracetam Zonisamide

Complex partial
CHOICE 1: Carbamazepine, Lamotrigine
CHOICE 2: Phenytoin
CHOICE 3: Phenobarbital, Zonisamide
CHOICE 4: Valproic acid, Primidone, Topiramate, Tiagabine

Primary generalized
CHOICE 1:Valproic acid
CHOICE 2: Carbamazepine
CHOICE 3: Phenytoin
CHOICE 4: Phenobarbital

TONIC-CLONIC
CHOICE 1: Lamotrigine
CHOICE 3: Valproic acid
CHOICE 4: Topiramate, Tiagabine

Absence
CHOICE 1: Lamotrigine*, Ethosuximide
CHOICE 2: Zonisamide, Valproic acid

Myoclonic
CHOICE 1: Valproic acid
CHOICE 2: Clonazepam
CHOICE 3: Zonisamide*
CHOICE 4: Felbamate*

Atonic
CHOICE 1: Valproic acid
CHOICE 2: Clonazepam

Status epilepticus
CHOICE 1: Diazepam
CHOICE 2: Phenytoin
CHOICE 3: Phenobarbital

Psychomotor
CHOICE 1: Phenytoin
CHOICE 2: Phenacemide

ANTICONVULSIVE DRUG CLASSIFICATION

BARBITURATES HYDANTOINS SUCCIMIDES

Phenobarbital Phenytoin Ethosuximide
Primidone Mephenytoin Methsuximide
Mephobarbital Ethotoin Phensuximide
Fosphenytoin Zonisamide

OXAZOLIDINEDIONES BENZODIAZEPINE MISCELLANEOUS

Paramethadione Clonazepam Lamotrigine
Trimethadione Diazepam Felbamate
Gabapentin
Carbamazepine
Valproic acid
Phenacemide
Topiramate
Tiagabine
Levetiracetam

CARBAMAZEPINE
MECHANISM OF ACTION – chemically related to tricyclic antidepressants.
- mechanism of action is unknown in the treatment of seizure disorders.
- thought to act by reducing polysynaptic responses and blocking the posttetanic
potentiation.

ADMINISTRATION AND DOSAGE

Adults and children older than 12 years old
= initial dose of 200 mg twice daily.
= increased to 800-2000 mg daily (usually in two divided doses
Children under age 12
= 10-20 mg/kg daily in two or three divided doses

PRECAUTIONS AND MONITORING EFFECTS

- Used with caution among patients with bone marrow depression. A CBC should
be obtained and platelets measured to determine baseline levels before
therapy, and levels should be monitored during therapy. Aplastic anemia and
agranulocytosis have been reported.
- Tricyclic antidepressants should be avoided if there is a history of
hypersensitivity to tricyclics. MAO inhibitors should be discontinued 2 weeks
before carbamazepine therapy.
- It should be used cautiously in patients with glaucoma because of its mild
anticholinergic effects.
- It is an enzyme inducer; therefore half-life decreases over 3-4 weeks (t1/2 18-54
hours; t1/2 10-25 hours); for maximal enzyme induction, levels should be
rechecked to avoid breakthrough seizures.
- Metabolized in the liver to 10-11 epoxide, which also has anticonvulsant
activity; it may induce its own metabolism.
ADVERSE EFFECTS
 - Physician should be notified if any of the following adverse effects occur:
jaundice, abdominal pain, pale stool, darkened urine, unusual bruising and
bleeding, fever, sore throat, or an ulcer in the mouth.
- The most common side effects are dizziness, drowsiness, unsteadiness,
nausea, and vomiting.

CNS EFFECTS – dizziness, ataxia, and diplopia.

- if diplopia and ataxia are common and occur after a dose, the schedule could
be adjusted to include more frequent administration or a larger proportion of
the dose at night.
- May decrease with chronic administration.

GI EFFECTS – nausea, vomiting and anorexia

METABOLIC EFFECTS – hyponatremia
HEMATOPOIETIC EFFECTS – aplastic anemia is rare.
- thrombocytopenia and anemia respond to a cessation of drug therapy.
- Leukopenia is the most common
DERMATOLOGICAL EFFECTS – pruritic and erythematous rashes, the Stevens-
Johnson syndrome, and lupus erythematosus.

SIGNIFICANT INTERACTIONS
- antiepileptic drugs (phenytoin, primidone, phenobarbital) – decrease the level
of carbamazepine (increase metabolism). VALPROIC ACID increases the level
of carbamezepine (decreases metabolism).
- OTHER MEDICATIONS (erythromycin, isoniazid, cimetidine, propoxyphene,
diltiazem, and verapamil increase the level of carbamazepine (decrease
metabolism).

PHENYTOIN
MECHANISM OF ACTION – inhibits the spread of seizures at the motor cortex and
blocks posttetanic potentiation by influencing synaptic transmission. There is an
alternation of ion fluxes in depolarization, repolarization, and membrane stability
phase and alternating calcium uptake in presynaptic terminals.
- Phenytoin is effective for the treatment of generalized tonic-clonic (grand mal)
seizures and for partial seizures, both simple and complex. It is not effective for
absence seizures.

ADMINISTRATION AND DOSAGE

Adults = 300-700 mg, with adjustments made as needed
(a) Regular daily doses above 500 mg are poorly tolerated
(b) A loading dose of 900 mg to 1.5 g may be given intravenously. The
infusion rate should not exceed 50 mg/min. (Alternatively, an oral
loading dose may be given)
Children = 4-7 mg/kg divided every 12 hours.
= IV loading dose of 15 mg/kg may be given
Phenytoin sodium is available as capsules and parenteral solution.
Phenytoin is available as tablets and oral suspension.

PRECAUTIONS AND MONITORING EFFECTS

- IV phenytoin should not be used in patients with sinus bradycardia, sinoatrial
block, second- and third-degree atrioventricular (AV) block, or Adam-Stokes
syndrome).
- It should be used cautiously among patients with myocardial insufficiency and
hypotension.
- Elimination of phenytoin converts from first-order elimination (proportional to its
concentration) to zero-order elimination (a fixed amount per unit time), usually at
 high therapeutic levels. The daily dose of phenytoin can be increased 100 mg
daily until therapeutic blood levels are attained, after which increases of 30-50 mg
will avoid two- to threefold increase in blood levels.
- It is necessary to measure free drug levels or correct the total level when
aluminum levels are abnormal or the patient has renal failure.

ADVERSE EFFECTS
- The physician should be notified if any of the following adverse effects occur:
swollen or tender gums, skin rash, nausea and vomiting, swollen glands,
bleeding, jaundice, fever, or sore throat (i.e., signs of infection or bleeding).

CNS EFFECTS – ATAXIA, (limiting side effect), dysarthria, and insomnia.

- transient hyperkinesia may follow IV phenytoin infusion. Alcoholic beverages
should be avoided while on this medication.
GI EFFECTS – nausea and vomiting.
- Phenytoin should be taken with food to enhance absorption and decrease GI
upset.

DERMATOLOGICAL EFFECTS – maculopapular rashes sometimes with fever,

Stevens_Johnson syndrome, and lupus erythematosus. Frequent brushing and
appropriate oral care may reduce gingival hyperplasia.

CONNECTIVE TISSUE DISORDERS – coarsening of the facial features.

HEMATOPOIETIC EFFECTS – thrombocytopenia, leukopenia, and granulocytopenia.

MISCELLANEOUS EFFECTS – hyperglycemia and increased body hair.

SIGNIFICANT INTERACTIONS
➢ Antiepileptic drugs (carbamazepine, valproic acid, clonazepam, phenobarbital) –
decrease the level of phenytoin (increase metabolism.
➢ Phenytoin increases the conversion of primidone to Phenobarbital (increases
metabolism).
➢ Other medications such as disulfiram, isoniazid, chloramphenicol, and
propoxyphene increase the level of phenytoin (decrease metabolism). Drugs
whose efficacy is impaired by phenytoin include corticosteroids, digitoxin,
doxycycline, estrogens, furosemide, oral contraceptives, quinidine, rifampin,
theophylline, vitamin D and enteral nutritional therapy. Coumarin and warfarin
anticoagulants increase the serum phenytoin levels and prolong the serum half-
life of phenytoin by inhibiting the metabolism.

FOSPHENYTOIN
MECHANISM OF ACTION – water-soluble prodrug of phenytoin.
- it is converted to phenytoin by the bloodstream phosphatases, with a half-life of
about 8 minutes in both adults and children.
- It is indicated for patients who cannot take oral drugs, and in the acute
treatment for status epilepticus.
- administered via IV or intramuscular (IM) injection.
- characteristics similar to phenytoin.

ADVANTAGES
- an aqueous solution, unlike phenytoin, which is an alkaline solution; therefore,
there is no need to add propylene glycol and ethanol to the solution.
- Causes less soft-tissue injury at the site of injection. When administered by IM
injection, it is completely absorbed and has more predictable serum
concentration than IM-injected phenytoin.

VALPROIC ACID
 MECHANISM OF ACTION – increases levels of GABA
- potentiates a postsynaptic GABA response by inhibiting the enzymatic response
for the catabolism of GABA.
- affects the potassium channel, creating a direct membrane-stabilizing effect.

ADMINISTRATION AND DOSAGE

Adults = administered orally in a usual dose of 1000-3000 mg daily in divided
doses.
Children = administered orally in a dose of 15-60 mg/kg daily, divided into
two or three doses.
- Medications should be taken with food to reduce GI upset.
- Tablets or capsules should be swallowed, not chewed, to avoid irritation of the
mouth and throat.

PRECAUTIONS AND MONITORING EFFECTS

There are some reports of hepatotoxicity and increased liver function tests,
which are mostly reversible. The severity and incidence of hepatotoxicity
increase when the patient is younger than 2 years of age.

ADVERSE EFFECTS
- Contact the physician if abdominal pain, nausea, vomiting, or anoxia occurs;
these could be symptoms of pancreatitis.
- CNS EFFECTS – tremor, ataxia, diplopia, lethargy, drowsiness, behavioral
changes, and depression.
- GI EFFECTS – nausea and increased appetite. Enteric-coated divalproex sodium
may reduce these side effects.
- DERMATOLOGICAL EFFECTS – alopecia and petechiae.
- HEMATOPOIETIC EFFECTS – thrombocytopenia, bruising, hematoma, and
bleeding.
- HEPATIC EFFECTS – minor elevations of aspartate aminotransferase (AST),
alanine aminotransferase (ALT), and lactate dehydrogenase (LDH).
- ENDOCRINE EFFECTS – decreased levels of prolactin, resulting in irregular
menses, and secondary amenorrhea.
- PANCREATIC EFFECTS – acute pancreatitis
- METABOLIC EFFECTS – hyperammonemia due to renal origin. Discontinuation
may be considered if lethargy develops.
SIGNIFICANT INTERACTIONS
- PRIMIDONE decreases valproic acid clearance (increases metabolism)
- PHENOBARBITAL and PHENYTOIN – displace protein binding, resulting in an
increased total phenytoin level and an increase or no change of free
phenytoin.
- CLONAZEPAM – increases CNS toxicity in patients on valproic acid.
- ASPIRIN – increases the level of valproic acid.
- WARFARIN – inhibits the secondary phase of platelet aggregation.
- ANTACIDS – increase the level of valproic acid.
- LABORATORY TESTS
- False-positive urine ketone tests may result among patients taking
valproic acid; thus, diabetic patients must use caution when using urine
tests.
- Antiepileptic drugs may alter thyroid function tests.

PHENOBARBITAL
MECHANISM OF ACTION – it increases the seizure threshold by decreasing synaptic
excitation by stimulating postsynaptic GABA-A receptor inhibitor responses as a CNS
depressant.
ADMINISTRATION AND DOSAGE
 Adults = administered orally at 90-300 mg daily (in three divided doses or as a
single dose at bedtime).
Children = 3-6 mg/kg daily in two divided doses. Adjustment is made as needed.
PRECAUTIONS AND MONITORING EFFECTS
- It produces respiratory depression, especially with parenteral administration.
- It should be used with caution in patients with hepatic disease who may need dose
adjustments.
- It has sedative effects in adults and produces hyperactivity in children.
- Abrupt discontinuation produces withdrawal convulsions. If the drug must be
discontinued, another GABA-A agonist should be sunstituted.
ADVERSE EFFECTS
-Physician should be notified if any of the following adverse effects occur: sore
throat, mouth sores, easy bruising or bleeding, and any signs of infection.

CNS EFFECTS – agitation, confusion, lethargy, and drowsiness. Patients should avoid
alcohol and other CNS depressants.

RESPIRATORY EFFECTS – hypoventilation and apnea.

CARDIOVASCUALR EFFECTS – bradycardia and hypotension.

GI EFFECTS – nausea, diarrhea, and constipation. If GI upset is experienced,

Phenobarbital should be taken with food.

HEMATOLOGICAL EFFECTS – megaloblastic anemia after chronic use (a rare sid

effect)

MISCELLANEOUS EFFECTS – osteomalacia and Stevens-Johnson syndrome, both of

which are rare

SIGNIFICANT INTERACTIONS
-Antiepileptic drugs, such as valproic acid and phenytoin, increase the level of
Phenobarbital (decrease metabolism).
- Other drugs such as acetazolamide, chloramphenicol, cimetidine, and furosemide
increase the level of Phenobarbital (decrease metabolism). Rifampin, pyridoxine,
and ethanol decrease the level of Phenobarbital (increase metabolism).

PRIMIDONE
MECHANISM OF ACTION – it is a metabolite of Phenobarbital and
phenylethylmalonamide (PEMA), which has some anticonvulsive effects. It has
drug characteristics similar to Phenobarbital, with some differences in dose and
half-life.
ADMINISTRATION AND DOSAGE
- It has a short half-life of 7 hours, which may require three-times daily dosing.
- It is tolerated better if started at 50 mg at night for 3 days until the target daily
dose is reached.

ETHOSUXIMIDE
MECHANISM OF ACTION – it may inhibit the sodium-potassium adenosine
triphosphatase (Na+-K+ ATPase) system and the reduced form of nicotinamide-
adenine dinucleotide phosphate (NADPH)-linked aldehyde reductase (which is
necessary for the formation of γ-hydroxybutyrate, which is associated with the
induction of absence seizures).
- It reduces or eliminates the EEG abnormality; however, absence seizures are
the only seizures in which the normal EEG has clinical value (i.e., when the EEG
abnormality is corrected, the seizures are also controlled).
- It is relatively benign anticonvulsant with minimum protein binding.
 ADMINISTRATION AND DOSAGE
It is usually given orally in an initial dose of 500 mg daily in adults and older
children and 250 mg daily in children ages 3-6 years. The dose may be raised by
250 mg every week to a maximum of 1.5 g daily in adults.
PRECAUTIONS AND MONITORING EFFECTS
- blood dyscrasias have been reported, making periodic blood counts necessary.
- there have been reports of hepatic and renal toxicity; thus, periodic renal and
liver function monitoring is necessary.
- cases of systemic lupus erythematosus have been reported.
ADVERSE EFFECTS
GI EFFECTS – nausea and vomiting. Small doses may lessen these effects. It
should be taken with food if GI upset occurs.
HEMATOPOEITIC EFFECTS – eosinophilia, granulocytopenia, leukopenia and
lupus.
CNS EFFECTS – drowsiness, blurred vision, fatigue, lethargy, hiccups and
headaches. Alcoholic beverages should be avoided with this medication.
PSYCHIATRIC-PSYCHOLOGICAL EFFECTS – confusion and emotional instability.
DERMATOLOGICAL EFFECTS – pruritus, photosensitivity, urticaria and Stevens-
Johnson syndrome.
GENITOURINARY EFFECTS – frequency of urination, vaginal bleeding, renal
damage, and hematuria.
MISCELLANEOUS EFFECTS – periorbital edema and muscle weakness. Patients
should also be advised of the risks of exposure to sunlight and ultraviolet
light.

CLONAZEPAM
MECHANISM OF ACTION – it is a potent GABA-A agonist, but its efficacy decreases
over several months of treatment.
ADMINISTRATION AND DOSAGE
Adults = oral agent given in an initial dose of 1.5 mg daily divided two or three
times. The dose may be increased to a maximum of 20 mg daily.
Children = 0.01-0.03 mg daily in two or three doses. The dosage may be
increased to a maximum of 0.2 mg/kg daily.
PRECAUTIONS AND MONITORING EFFECTS
- Patients with psychoses, acute narrow-angle glaucoma, and significant liver
disease should use this medicine cautiously.
ADVERSE EFFECTS
CNS EFFECTS – drowsiness, ataxia, and behavior disturbances in children;
these may be corrected by dose reduction.
RESPIRATORY EFFECTS – hypersalivation and bronchial hypersecretion.
MISCELLANEOUS EFFECTS – anemia, leukopenia, thrombocytopenia,
respiratory depression, anorexia, and weight loss.
SIGNIFICANT INTERACTIONS
- Antiepileptic drugs such as phenytoin, increase the level of clonazepam decrease
metabolism

- Other drugs. Clonazepam decreases the efficacy of levodopa and increases the
serum level of digoxin.

FELBAMATE
MECHANISM OF ACTION – the drug interacts with glycine modulatory site on N-
methyl-D-aspartate (NMDA) receptors. Blockade of NMDA may contribute to
neuroprotective effects of felbamate.
- it is used as a monotherapy or adjunctive therapy or without secondary
generalization in adults and generalized seizures associated with Lennox-Gestaut
syndrome in childen. The United States Food and Drug Administration (FDA)
recommended that use of felbamate be restricted to only those patients who are
 refractory to other medications and in whom the risk-benefit relationship warrants
its use, because of severe hepatoxicity.
ADMINISTRATION AND DOSAGE
- Adults and children older than 14 years of age.
- Monotherapy, initially 1.2 g in three to four doses daily. The dosage may be
increased in 600-mg increments every 2 weeks to 2.4 g daily based on clinical
response and, thereafter, 3.6 g daily if necessary.
- Adjunctive therapy, 1.2 g in three to four divided doses daily, with reduction of
the dosage of other antiepileptic drugs by 20-33%. The dosage of felbamate
maybe increased in increments of 1.2 g at weekly intervals to a maximum of
3.6 g daily.
- Conversion to monotherapy initially 1.2 g daily in three to four doses, with
reduction of the dosage of other antiepileptic drugs by 33% at week 3. The
felbamate dosage may be increased to 3.6 g daily, and other antiepileptic drugs
discontinued or dosage further reduced in stepwise fashion.
- Children 2-14 years of age with Lennox-Gaustat syndrome, as adjunctive
therapy, initially 15 mg/kg daily in three to four doses. The dosage of other
antiepileptic drugs is reduced by 20%. The amount of felbamate may be
increased in increments of 15 mg/kg at weekly intervals to 45 mg/kg daily.
Further reduction in the dosage of other antiepileptic drugs may be necessary.
PRECAUTIONS AND MONITORING EFFECTS
- There are two very serious toxic effects, aplastic anemia and liver failure, which
lead to death for some patients.
- For aplastic anemia, the onset range from 5-30 weeks of initiation of therapy.
Weekly or biweekly CBCs are recommended initially.
- For liver, toxicity time between initiation of treatment and diagnosis of these
cases ranges from 14-257 days. It is recommended that liver function tests be
performed before initiation of therapy to identify patients who have evidence of
preexisting liver damage. Liver function tests should also be performed weekly
or biweekly. The FDA recommends that this drug be used only in patients who
are refractory to other medications and in whom the risk-benefit relationship
warrants its use.
- Photoallergy or phototoxicity may occur; patients should take protective
measures against exposure to ultraviolet light or sunlight.
- Instruct patients to store medication in its own tightly closed container at room
temperature away form excessive heat, direct sunlight and moisture.
ADVERSE EFFECTS
- If bleeding and blushing occurs, contact your physician.
- Potential to cause aplastic anemia (bone marrow).
- Patient should be monitored for these toxicities by CBCs and liver function tests
weekly or biweekly until discontinuation of any sign of these toxicities occurs.
CNS EFFECTS – insomnia, headache, anxiety, hyperactivity, and fatigue.
CARDIOVASCULAR EFFECTS – peripheral edema, vasoldilation, hypotension, and
hypertension.
OCULAR EFFECTS – diplopia and blurred vision.
GI EFFECTS – anorexia, weight decrease and nausea.
HEMATOLOGICAL EFFECTS – lymphadenopathy, leukopenia, and
thrombocytopenia.
METABOLIC/NUTRITION EFFECTS – hypokalemia and hyponatremia.

SIGNIFICANT INTERACTIONS
- Felbamate and phenytoin. Felbamate causes increase in phenytoin plasma
concentration. Phenytoin doubles felbamate clearance, resulting in 45%
decrease in steady-state trough levels.
- Felbamate and carbamazepine. Felbamate causes a decrease in
carbamazepine levels and an increase in carbamazepine metabolites. In
addition, carbamazepine causes a 50% increase in felbamate clearance,
 resulting in a 40% decrease in steady-state through levels.
- Felbamate and valproic acid. Felbamate causes an increase in valproic acid
levels, but valproic acid does not affect felbamate levels.
- ADVERSE EFFECTS: signs and symptoms associated with increased plasma
level and toxicity are anorexia, nausea, vomiting, insomnia and headache.

GABAPENTIN
MECHANISM OF ACTION – an analogue of GABA
-it increases GABA turnover, but it does not bind to GABA or any other
established neurotransmitter receptor.
-its mechanism of action is currently unknown, although it binds to a specific
receptor in the brain and inhibits voltage-dependent sodium currents.
-it has been shown to be effective as an add-on drug in patients with partial
seizure with or without secondary generalization.
ADMINISTRATION AND DOSAGE
- Patients older than 12 years receive 900 mg to 1.8 g daily, administered as
adjunctive therapy in three divided doses. Titrating to an effective dose
normally can be achieved within 3 days by initiating therapy with 300 mg and
then increasing the dose in 300-mg increments over the next 2 days to
establish a dosage of 900 mg daily in three doses. If necessary, the dosage
may be increased to 1.8 g daily. To minimize potential side effects, especially
somnolence, dizziness, or fatigue, the first dose on day 1 may be administered
at bedtime.
- 3-12 years of age = 10-15 mg/kg/day in 3 divided doses to up to 25-50
mg/kg/day.
- The drug is primarily excreted renally; therefore, the dosage should be
adjusted for patients who have compromised renal function.
- The drug does not bind to plasma protein. There are no significant
pharmakokinetic interactions with other commonly used antiepileptic drugs.
- If gabapentin is discontinued or an alternate anticonvulsant medication is
added, it should be done gradually over a minimum of 1 week.
ADVERSE EFFECTS
- Common side effects are somnolence, ataxia, dizziness, fatigue and
nystagmus.
CNS EFFECTS – somnolence, dizziness, ataxia and fatigue.
GI EFFECTS – dyspepsia, dryness of mouth, constipation, and increased
appetite.
OCULAR EFFECTS – diplopia, blurred vision and nystagmus.
SIGNIFICANT INTERACTIONS
- Antacids and gabapentin. Antacids reduce the bioavailability of gabapentin by
20%; gabapentin could be taken 2 hours after antacid use.
- Cimetidine and gabapentin. Cimetidine decreases the renal excretion of
gabapentin by 14% and consequently increases gabapentin plasma levels
(however, this amount is not clinically significant).
- Oral contraceptives and gabapentin. Oral contraceptives increase the level of
norethindrone by 13%; this amount may not be clinically significant.

LAMOTRIGINE
MECHANISM OF ACTION – Its antipeileptic effect is similar to that of phenytoin. Its
effect may be due to inhibition of voltage-dependent sodium currents and
reduction of sustained repetitive neuronal activity.
- it is indicated for the treatment of partial seizures and secondary generalized
tonic-clonic seizures that are not controlled with other drugs.
- it is also used to treat Lennox-Gastaut syndrome.
- it is a broad spectrum, as well tolerated as monotherapy, and probably the least
teratogenic of the first-line agents. It may aggravate severe myoclonic epilepsy.
 ADMINISTRATION AND DOSAGE
- Adults (older than 16 years) = 50 mg/day in two divided doses [patients taking
valproic acid (VPA) should be given 25 mg every other day], up to 100 mg/day
(up to 25 mg daily with VPA treatment)
- 2-12 years of age = 0.6 mg/kg/day in two divided dosed (0.15 mg/kg/day on
VPA treatment), up to 1.2 mg/kg/day (up to 0.3 mg/kg/day with VPA treatment)
- the smallest available chewable dispersible tablet is 5 mg. Them after 2 weeks,
increase by 0.3 mg/kg/day in one to two divided doses, up to 200 mg/day.
- swallow chewable dispersible tablet whole, chewed, or in dispersing water or
diluted fruit juice. If chewed, consume a small amount of water or dilute fruit
juice to aid in swallowing. To disperse, add the chewable dispersible tablet to
a small amount of liquid (1teaspoon or enough to cover the medication).
- Approximately 1 minute later, when the tablet is completely dispersed, swirl the
solution and consume the entire quantity immediately.
- for patients taking valproic acid, the initial dose is 50 mg daily for 2 weeks,
followed by maintenance doses of 100-200 mg daily in two divided doses.
- reduced clearance in the elderly necessitates dosage reduction.
- patients with hepatic impairment may require dosage reduction because of
reduction in metabolism.
PRECAUTION AND MONITORING EFFECTS
- the value of monitoring plasma concentration has not been established.
- caution should be used for patients taking this drug. It may adversely affect the
patient’s metabolism or complicate the elimination of the drug because of renal,
hepatic, or cardiac impairment.
- lamotrigine binds to melanin and can accumulate in melanin-rich tissue over
time. Periodic ophthalmological monitoring is recommended.
- photosensitization (photoallergy and phototoxicity) patients should take
protective measures against exposure to ultraviolet light and sunlight.
- serious rashes requiring hospitalization have been reported. The incidence of
rashes, including Stevens-Johnson syndrome, is approximately 1% in patients less
than 16 years old and 0.3% in adults. Are cases of toxic epidermal necrolysis or
rash-related death have occurred. Most rashes occur within 2-8 weeks of initial
treatment.
ADVERSE EFFECTS
- most common side effects are dizziness, diplopia, ataxia, blurred vision, nausea,
and vomiting.
CNS EFFECTS – headache, dizziness and ataxia
GI EFFECTS – nausea, vomiting, diarrhea and dyspepsia.
OCULAR EFFECTS – diplopia, blurred vision, and vision abnormality.
DERMATOLOGICAL EFFECTS – pruritus and rash may form similar to that found
when using phenytoin and carbamazepine. In many cases, the rash disappears
during continued therapy, but 1-2% of patients with rash represent a more
serious allergic reaction. Occassionally, patients have developed the Stevens-
Johnson syndrome. Concomitant use with valproic acid may increase the
likelihood of serious rash. The occurrences of life-threatening rash that were
reported developed within 2-8 weeks following therapy; other cases of rash
have been reported developing up to 6 months after therapy. The incidence of
rash is higher in children than in adults.
- monotherapy during pregnancy found no teratogenic effect.
SIGNIFICANT NTERACTIONS
- Carbamazepine decreases lamotrigine concentration by 70% and increases
carbamazepine levels.
- Phenobarbital or primidone decreases lamotrigine concentration by 40%.
- Valproic acid decreases the metabolism of lamotrigine and extends its half-life
to 60 hours, which necessitates a dose reduction.

TOPIRAMATE
 MECHANISM OF ACTION – a derivative of fructose.
- it decreases rapid hippocampal neuronal firing, possibly because of sodium-
or calcium-channel inhibition.
- it is also a weak carbonic anhydrase inhibitor and a sodium-channel blocking
agent.
- it potentiates the the activity of GABA. It has been shown to be effective
adjunctive therapy for partial seizure treatment in adults, tonic-clonic seizures,
infantile spasms, and Lennox-Gastaut syndrome.
ADMINISTRATION AND DOSAGE
- 17 years and older = 25-50 mg/day, up to 400 mg/day in two divided doses.
- 2-16 years of age = 1-3 mg/kg/day, up to 5-9 mg/kg/day in two divided
doses.
- Topiramate is 80% bioavailable, and food does not affect its bioavailability.
- Dose adjustment is necessary for patients with renal and hepatic
impairments.
- Enzyme-inducing anticonvulsive drugs can decrease topiramate levels, but it
has significant effect on metabolism of other anticonvulsive drugs.
- initial treatment is 50 mg daily, followed by titration to an effective dosage.
More than 400 mg daily has not been shown to improve response.
PRECAUTION AND MONITORING EFFECTS
- Increased incidence of kidney stones (renal calculus) in older patients who
received this drug. Patients should be advised to increase intake of fluids.
- Paresthesia is a common side effect of anhydrase inhibitors.
ADVERSE EFFECTS
- Physician should be notified if any of the follwoign side effects occur:
▪ Breast pain in females
▪ Nausea and tremor, which are dose-related side effects
▪ Back pain, chest pain, dyspepsia or leg pain.
CNS EFFECTS – psychomotor slowing, difficulty with concentration and
speech, somnolence, fatigue, asthenia, weight loss, cognitive
disturbances and difficulties, tremors, dizziness, ataxia and headache.
GI EFFECTS – nausea, vomiting and gastroenteritis.
GENITOURINARY EFFECTS – renal calculi
CV EFFECTS – chest pain, palpitation and vasodilation
OCULAR EFFECTS – abnormal vision, eye pain and diplopia
HEMATOLOGICAL EFFECTS – anemia, epistaxis, leukopenia and aplastic
anemia.
SIGNIFICANT INTERACTIONS
- Phenytoin and carbamazepine will increase clearnace
- Topiramate increases the clearance of other drugs that are cleared by
cytochrome P450 (CYP450).

TIAGABINE
MECHANISM OF ACTION – designed to act on the inhibitory action of GABA by
blocking its uptake, thereby prolonging its action after synaptic release.
- it is indicated as adjunctive therapy for partial seizures and secondary
generalized tonic-clonic seizures.
ADMINISTRATION AND DOSAGE
- Starting dose of 4 mg daily for 2 weeks may be increased 4-8 mg weekly
thereafter, to a maintenance dose of 32-56 mg daily.
- Maximum recommended dosage for children is 32 mg daily; maximum
recommended dosage for adults is 56 mg daily.
- A high-fat meal decreases the rate of tiagabine absorption but does not
affect the extension of absorption. Tiagabine should be taken with food.
PRECAUTIONS AND MONITORING EFFECTS
- generalized weakness: moderately severe to severe weakness has been
reported. It resolves in all cases after reduction in dose or discontinuation of
 therapy.
- ophthalmic effects, as indicated by animal studies, include the possibility for
residual binding to retina and melanin binding; this finding, however, has not
been confirmed in human studies. Periodic ophthalmological monitoring is
necessary.
DERMATOLOGICAL EFFECTS – possibility of severe rash to Stevens-Johnson
syndrome, as reported in clinical studies.
ADVERSE EFFECTS
CNS EFFECTS – confusion, dizziness and fatigue.
GI EFFECTS – upset stomach, nausea, mouth ulceration and anorexia.
SIGNIFICANT INTERACTIONS
Phenobarbital, phenytoin, and carbamazepine will increase tiagabine clearance

ZONISAMIDE
MECHANISM OF ACTION – not well known.
- it may block the sensitive sodium channels and T-type calcium channels.
- It is an effective agent for refractory partial seizures, generalized seizure
indicated for adjunct therapy for partial seizure for adults, infantile spasm,
mized seizure types of Lennox-Gestaut syndrome, myoclonic, and generalized
tonic-clonic seizures.
ADMINISTRATION AND DOSAGE
- adults and children older than 16 years of age = 100 mg daily; within 2
weeks, increase to 200 mg/daily in 2-week bases, up to 600 mg daily.
- can be taken with or without food.
PRECAUTIONS AND MONITORING
- may increase mean concentration of serum creatinine and BUN; renal function
should be monitored periodically.
- may increase serum alkaline phosphatase
- may produce drowsiness
SIDE EFFECTS
- Contact the physician if sudden pain and abdominal pain occurs or if blood in
urine is detected; these symptoms could indicate a kidney stone. Increase fluid
intake to decrease the risk of stone formation. Also, contact the physician if
fever, sore throat, oral ulcer, or easy bruising is seen; these symptoms could be
due to a hematological complication.
SIGNIFICANT INTERACTIONS
-It induces liver enzymes by increasing metabolism and through clearance of
zonisamide and decreases half-life.
- Food will delay absorption but will not affect the bioavailability of the drug.

LEVETIRACETAM
MECHANISM OF ACTION – a pyrrolidone derivative and is chemically unrelated to
other antiepileptic drugs.
- it displays inhibitory properties in the kindling model in rats.
- it is used as an adjunctive therapy in the treatment of partial seizure in
adult patients.
ADMINISTRATION AND DOSAGE
- staring dose of 1000 mg/day given in two divided doses may be increased
every 2 weeks, to a maximum of 3000 mg/day.
PRECAUTIONS AND MONITORING EFFECTS
- hematological effects are minor, but there is a statistically significant decrease
compared to placebo in total man RBC count, mean hemoglobin, and mean
hematocrit.
- decrease in WBC count and neutrophil count
- also causes drowsiness
SIDE EFFECTS
- MOST COMMON: somnolence, weakness (asthenia), infection and dizziness.
 CNS – somnolence, dizziness, depression, nervousness
CARDIOVASCULAR – palpitation, tachycardia, vascular insufficiency
RESPIRATORY – pharyngitis, rhinitis, increase cough
MISCELLANEOUS – weakness, headache, infection
SIGNIFICANT INTERACTIONS
- it does not influence the plasma concentration of existing antiepileptic drugs,
and other antiepileptic drugs do not influence the pharmacokinetic effects of
levetiracetam.

VAGUS NERVE STIMULATION

- used as an adjunctive therapy for adults and children over 12 years of age whose
partial seizures are refractory to antiepileptic medications.
- a programmable signal generator that is implanted in the patient’s left upper
chest has a bipolar VNS lead that connects the generator to the left vagus nerve
in the neck, a programming wand that uses radio-frequency signals to
communicate noninvasivley with the generator, and the handheld magnets used
by the patient or caregiver to manually turn the stimulator on or off.
- the implantation procedure usually lasts 1 hour under general anesthesia. Once
programmed, the generator will deliver intermittent stimulation at the desired
setting until any additional programming is entered.

• SURGERY
If seizures do not respond to therapy, surgery may be performed to remove the
epileptogenic brain region. The most common is cortical excision (lobectomy).

INDICATIONS – for surgery of intractable or disabling seizures recurring for 6-12

months. Should be considered for patients with medically refractory seizures.

STEREOTAXIC SURGERY – the surgeon uses three-dimesional coordinates to

guide a needle through a hole drilled in the skull, then destroys abnormal
pathways via small intracerebral incisions.

OTHER SURGICAL APPROACHES – temporal bone resection, removal of the

temporal lobe tip, and cerebral hemispherectomy.

COMPLICATIONS

• CONVULSIVE STATUS EPILEPTICUS

- characterized by rapid repetition of generalized tonic-clonic seizures with no
recovery of consciousness between seizures.
- this life-threatening condition may persist for hours or even days; if it lasts
longer than 1 hour, severe permanent brain damage may result.
- it could be caused by poor therapeutic compliance, intracranial infection or
neoplasm, alcohol withdrawal, drug overdose, and metabolic imbalance.
MANAGEMENT
- A patent airway must be maintained
- If the cause of the condition is unknown, dextrose 50% in water (25-30 mL) is
given via IV in case hypoglycemia is the cause.
- If the seizures persist, DIAZEPAM (10 mg) is administered via IV at a rate not
exceeding 2 mg/min until the seizures stop or 20 mg has been given.
- PHENYTOIN OR PHOSPHENYTOIN is then administered via IV no faster than 50
mg/min to a maximum dose of 11-18 mg/kg. Blood pressure is monitored to
detect hypotension.
- If these measures do not stop the seizures, one of the following drugs is given.
• DIAZEPAM – given as an IV drip of 50-100 mg diluted in 500 mL dextrose 5%
in water, infused at 40 mL/hr until the seizure stops.
• PHENOBARBITAL – given as an IV infusion of 8-20 mg/kg no faster than 100
 mg/min
- If seizures continue despite these measures, one of the following steps is then
taken.
• PARALDEHYDE – given via IV in a dosage of 0.10-0.15 mL/kg diluted to a 4%
solution in normal saline solution
• LIDOCAINE – given in an IV loading dose of 50-100 mg, followed by an infusion
of 1-2 mg/min
• GENERAL ANESTHESIA – induced with ventilatory assistance and
neuromuscular junction blockade.

• NONCONVULSIVE STATUS EPILEPTICUS

- condition presents as repeated absence seizure or complex partial seizures.
- The patient’s mental state fluctuates; confusion, impaired responses, and
automatisms are prominent.
- Initial management typically involves intravenous diazepam.

SEIZURE DISORDER AND PREGNANCY

- The risk of mother and fetus should be discussed, including the risks of fetal
malformation associated with antiepileptic drugs and other genetic factors.

DRUG THERAPY
➢ If the patient is seizure free for at least 2 years, withdrawal of the drug should
be considered. If antiepileptic drug therapy is necessary, a switch to
monotherapy should be made if possible.
➢ Five antiepileptic medications have been used or studied in pregnant patients:
carbamazepine, Phenobarbital, phenytoin, primidone, and VPA. Monotherapy of
lamotrigine during pregnancy found no teratogenic effect. Congenital
malformations associated with these drugs include craniofacial abnormalities,
cardiac defects, and neuronal tube defects. Most of the studies consider paternal
genetic factors, environmental factors, drug dosing or combination therapy.
➢ Antiepileptic drugs interfere with folate metabolism. Administration of folic acid,
4 mg daily, and multivitamins decreases the risk of malformation, especially of the
neuronal tube.
➢ Vitamin K, 10 mg per day for the last 1 or 2 months of gestation, will help to
prevent neonatal hemorrhage, especially in cases of phenytoin or Phenobarbital
use.
➢ Seizure disorder and oral contraceptives. Gabapentin, lamotrigine,
levetiracetam, and tiagabine do not affect the efficacy of oral contraceptives.
➢ Seizure disorder and the elderly population. New generations of antiepileptic
drugs such as levetiracetam and gabapentin may be more useful due to low levels
of protein binding and safer side effects. Also, new generations have less
potential for drug interactions than agents eliminated from the liver.

MONITORING
➢ Free serum antiepileptic drug levels should be monitored monthly, immediately
before the next dose, and the dose should be adjusted to the lowest dose
providing adequate control.
➢ Serum alphafetoprotein levels should be checked and ultrasonography should be
preformed at 16 weeks of gestation to evaluate for fetal neuronal tube defects.
An alternative to these tests is amniocentesis, especially if the mother is taking
valproate or carbamazepine.
➢ Comprehensive ultrasonography should be performed at 18 and 22 weeks of
gestation for patients taking antiepileptic drugs that cause cardiac anomalies.
• Intrapartum plans should include IV administration of a short-acting
benzodiazepine. If there is concern about fetal or maternal respiratory
depression, administering intravenous phenytoin or intramuscular Phenobarbital
 should be considered. Clotting studies should be performed, and 1 mg vitamin K
should be given to the infant. Nurses and physicians should be alerted for
possible hemorrhage of the infant and apprised that the infant may experience
antiepileptic drug withdrawal.

A chapter examination regarding seizure disorder next meeting.

Assessment
SUBJECT PHARMACOLOGY 1 TOPIC ALCOHOLS
IG NUMBER IG-PHA-325LC WEEK NO 17
TERM FINALS SESSION 30 of 30
DATE PREPARED May 2007 DURATION 1.5 HOURS

SECTION DESCRIPTION
Overview of This lesson is intended to discuss the different pharmacologic properties of ethanol,
Session alongside with the different substances of abuse.

Objectives 1. To discuss the basic pharmacology of ethanol

2. To discuss the clinical pharmacology of ethanol
3. To discuss the pharmacology of other alcohols
4. To discuss the history of opioids
5. To discuss the different substances of abuse

Materials 1. Basic and Clinical Pharmacology, Latest edition

2. Pharmacotherapy: A Pathophysiologic Approach, Latest edition
3. Comprehensive Pharmacy Review, Latest edition

Lesson The Alcohols

Outline • Alcohol, primary in the form of ethyl alcohol has occupied an important place in the
history of humankind for at least 8000 years.
• It was a part of the daily life in Western Europe until 19th century.
• Alcoholism- a complex disorder that appears to have genetic as well as
environmental determinants characterized by a continuing alcohol drinking despite
of adverse medical or social consequences related directly to their alcohol
consumption.

BASIC Pharmacology of Ethanol

Pharmacokinetics
• It is a small water-soluble molecule that is absorbed rapidly from the
gastrointestinal tract.
• Peak blood concentrations occur within 30 minutes of ingestion.
• Women have a higher peak concentration than men since women have lower body
content.
• In the central nervous system, the concentration of ethanol rises quickly since the
brain receives a large proportion of blood flow and ethanol readily crosses biologic
membranes.
• Over 90% of ethanol is oxidized in the liver.
• The excretion of small but consistent concentrations of alcohol by the lungs is
utilized for breath alcohol tests.
• The rate of oxidation follows zero-order kinetics.
• Two major pathways of alcohol metabolism to acetaldehyde have been identified,
acetaldehyde is then metabolized by a 3rd metabolic process

A. Alcohol Dehydrogenase Pathway

- The primary pathway for alcohol metabolism involves alcohol
dehydrogenase (ADH), a cytosolic enzyme that catalyzes the conversion of
alcohol to acetaldehyde.
- This enzyme is located mainly in the liver, but can also be found in the
stomach, and brain.
- A significant amount of gastric ADH occurs in the stomach in men, but a
smaller amount occurs in women, who appear to have lower levels of the
gastric enzyme.
- It requires NAD as a cofactor.
- The excess NADH production production appears to underlie a number of
 metabolic disorders that accompany chronic metabolism.
B. Microsomal Ethanol Oxidizing System
- Mixed function Oxidase System
- Uses NADPH as a cofactor in ethanol metabolism
- Utilized pathway when large amounts of alcohol are consumed due to the
depletion of the enzyme aldohol dehydrogenase.
- Increased activity of this ezyme system is observed in chronic alcoholic
patients
- This system is not the primary pathway for ethanol metabolism
C. Acetaldehyde Metabolism
- Resposible for further conversion of acetaldehyde to carbon dioxide and
water.
- Oxidation of aldehyde is inhibited by disulfiram
- When alcohol is consumed in the presence of disulfiram, acetaldehyde
accumulates and causes an unpleasant reaction of facial flushing, nausea,
vomiting, dizziness and headache.

Pharmacodynamics of Alcohol Consumption

A. Central Nervous System
- causes marked sedation and relief of anxiety, and at higher concentrations,
slurred speech, ataxia, impaired judgment, and disinhibited behavior
(intoxication/drunkenness)
- CNS depression. AT high concentrations, it induces coma, respiratory
depression and death.
- Acute ethanol exposure enhances the action of GABA at GABAa receptors,
which is consistent with the ability of GABA-mimetics to intensify many of
the acute effects of alcohol and of GABA A antagonists to attenuate some
actions of ethanol.
- Blackouts- periods of memory loss that occur with high levels of alcohol
may result from inhibition of NMDA receptor activation.
B. Heart
- Myocardial contractility depression
C. Smooth Muscle
- Vasodilation and direct smooth muscle relaxation caused by acetaldehyde
- Hyperthermia
- Uterine relaxation
- It was used intravenously for the suppression of premature labor.

Consequences of Chronic Alcohol Consumption

- It increases oxidative stress coupled with depletion of glutathione, damage to
mitochondria, growth factor dysregulation,and potentiation of cytokine-induced
injury.
- Deaths linked to alcohol consumption are caused by liver disease, cancer,
accidents and suicide.

A. Liver and Gastrointestinal Tract

- liver disease is the most common medical complication
- Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis
- Chronic alcoholics are prone to develop gastritis and have increased susceptibility
to blood and plasma protein loss during drinking, and may lead to anemia and
malnutrition.
B. Nervous System
- The consumption of alcohol inhigh doses over a long period of time results in
tolerance and in physical and pgysiologic dependence.
- Tolerance to the intoxicating effects of alcohol is a complex process.
- Chronic alcohol drinkers when forced to reduce alcohol consumption, experience a
withdrawal syndrome, which indicates the existence of physical dependence.
 - Alcohol withdrawal symptom- characterized by hyperexcitability in mild cases, and
seizures, toxic psychosis and delirium tremens
- Wernicke’s encephalopathy and Korsakoff’s psychosis
- Characterized by paralysis of eye muscles, ataxia and a confused state, that can
progress to coma and death
- Can be reversed by administering thiamine in large doses
C. Cardiovascular system
- Dilated cardiomyopathy with ventricular hypertrophy and fibrosis
- Atrial and ventricular arrhythmia- binge drinking
- Has the ability to raise serum HDL that has protective properties against
atherosclerosis.
D. Blood
- Anemia due to folic acid deficiency
- IDA may result from GI bleeding
- Hemolytic anemia
E. Endocrine System and Electrolyte balance
- Gynecomastia
- Testicular atrophy
- Ascites, edema and effusions
- Decreased protein synthesis and portal hypertension
- Hypo/hyperkalemia resulting to vomiting and diarrhea
- Hypoglycemia
- Impaired hepatic gluconeogenesis
- Lipolysis
- Increased cortisol and growth hormone.
F. Fetal Alcohol Syndrome
- Teratogenic
- Characterized by: intrauterine growth retardation, microcephaly, poor
coordination, underdevelopment of midfacial region, and
minor joint abnormalities
G. Immune System
- suppression of alveolar macrophages
- reduced number and function of T cells
- increased risk of pneumonia
H. Increased Risk of Cancer
- Inreased risk for oral, laryngeal, pharyngeal, esophageal and liver CA.

CLINICAL PHARMACOLOGY OF ETHANOL

Management of Acute Alcohol Intoxication

- the primary goals of therapy include treatment of acute alcohol intoxication, and
prevent severe respiratory depression and aspiration of vomitus.
- Metabolic alterations may require treatment of hypoglycemia and ketosis by
administration of glucose.
- Thiamine is given to protect against Wernicke-korsakoff syndrome
- Potassium salts should be administered if persistent vomiting occurs.
- Low phosphate stores may contribute to poor wound healing, neurologic deficits,
and an increased risk of infection.

Management of Alcohol Withdrawal Syndrome

- Characterized by motor agitation, anxiety, insomnia and reduction of seizure
threshold.
- The major objective of the therapy is to prevent seizures, delirium and arrhythmia
- To basic principles of therapy: Substitute a long-acting sedative-hypnotic drug for
alcohol and then gradually tapering reducing the dose of long-acting drug. (ie
chlordiazepoxide, clorazepate and diazepam)
Pharmacotherapy of Alcoholism
- Disulfiram- aldehyde dehydrogenase inhibitor
- Naltrexone- an inhibitor of oipiod receptors

DRUGS OF ABUSE

Dependence- often associated with drug abuse.

Psychologic dependence- manifested by drug-seeking behavior in which the individual

uses the drug repetitively for personal satisfaction. (eg cigarette smoking)

Physiologic dependence- is present when withdrawal of the drug produces symptoms

and signs that are frequently the opposite of those sought by the user.

Addiction- usually taken to mean a state of physiologic and psychologic dependence.

Tolerance- a decreased response to the effects of the drug. It may either be:
a. Metabolic- increased disposition of drug after chronic use
b. Behavioral – ability to compensate for drug affects
c. Functional- compensatory changes in receptors, effector
enzymes,or membrane actions

Opioids
- The nepenthe (free from sorrow) in odyssey- contains opium
Clinical aspects
- symptoms of opioid withrawal: lacrimation, rhinorrhea, yawning, and sweating.
- Followed by restless sleep, weakness, chills, gooseflesh, nausea, vomiting, muscle
aches and involuntary movements

Barbiturates and other sedative-hypnotics

• Ethanol- the sedative-hypnotic with the longest history of both use and abuse.
• Barbiturates- introduced in 1903
• Meprobamate- 1954, a nonbarbiturate sedative-hypnotic that lacks the
disadvantage of older agents
• BZD- 1960, now the drugs of choice for sedation-hypnosis.

Mickey Finn
• Chloral hydrate

Flunitrazepam
• Roofies

Rapid-onset BZD
• Associated with date rape

STIMULANTS
• Caffeine- Most widely used social drug worldwide
• Nicotine- one of the most widely used licit drugs
• Cocaine- used for at least 1200 years by natives of South American Andes. Koller
is credited with first using the drug as topical anesthetic for eye surgery
• Mathampethamine- Methedrine, “speed”
• MDMA- “ecstacy”, methylenedioxymethampethamine
• Cathinone- a plant from Catha edulis, possess amphetamine-like effects.
• Speedball- cocaine and heroin

HALLUCINOGENS
 • LSD- lysergic acid diethylamide, most common hallucinogen
• Atropa belladonna and Datura stramonium- deliriants
• Mescaline, psylocibin
• Phencyclidine- PCP, angel dust

Marijuana
• Cannabis
• Have three major cannabinol compounds: cannabidiol, tetrahydrocannabinol and
cannabinol.

Inhalants
• Nitrous oxide- “head-shops”
• Ether and chloroform- nephrotoxic, hepatotoxic, and peripheral nerve damage
• Organic nitrites- sexual enhancer
• Amyl nitrite- poppers
• Isobutyl nitrite- locker room, rush

Steroids
• Heavy users may develop edema and jaundice
• Clinical findings may include hypertrophied muscles, acne, oily skin, hirsutism in
females, gynecomastia in males and needle puncture.

Final examination
Assessment