Pharmacology Exam III Study Guide

Adrenergic Agonists are also known as sympathomimetics

Adrenergic Agonists work by:

1. Direct receptor binding (most common*all others are indirect)
2. Promotion of NE release
3. Inhibition of NE Reuptake
4. Inhibition of NE Inactivation

Catecholamines vs. Noncatecholamines (two major classes of adrenergic agonists)

Catecholamines:
Epinephrine
Norepinephrine
Isoproterenol
Dopamine
Dobutamine

Cannot be used orally

Brief duration of action
Can’t cross the Blood Brain Barrier

Note about catecholamines: catecholamine solutions should be discarded as soon as

discoloration develops. Because of the short half-lives of catecholamines, they have to be
infused in a constant IV drip.

Noncatecholamines:
Ephedrine
Phenylephrine
Terbutaline

Not metabolized by COMT, and slowly metabolized by MO’s

Much longer half-lives
Can be given orally
Less polar and can cross the Blood Brain Barrier

Adrenergic Agonists and which receptors they hit

Epinephrine – A1, A2, B1, B2
Norepinephrine – A1, A2, B1
Isoproterenol – B1, B2
Dopamine – A1, B1, dopamine
Dobutamine – B1 only
Ephedrine – A1,A2, B1, B2
Terbutaline – B2
Phenylephrine – A1
 ADRENERGIC AGONIST ACTIVATION

**Alpha-1** Activation/Agonist
Good for:
Hemostasis
Nasal Decongestant
Adjunct to local anesthesia
Elevate blood pressure
Mydriasis

BAD/Can Cause
Hypertension
Necrosis
Bradycardia

**Alpha-2** Activation in CNS

Good for:
Reduction of outflow to the heart and blood vessels and for relief of severe pain
It is important to note that Alpha-2 activation in the PNS has no therapeutic
applications. Only CNS.

**Beta-1** Activation
Good for:
Cardiac Arrest
Heart Failure
Shock
AV Heart Block

BAD/Can Cause
Altered Heart Rate
Angina Pectoris

**Beta-2** Activation
Good for:
Asthma
Delay of preterm labor

BAD/Can Cause
Hyperglycemia
Tremor

**Dopamine**
Good for:
Shock
 ADRENERGIC BLOCKERS/ANTAGONISTS

**Alpha-1 Blockade
Good for:
Hypertension
Reversaly of toxicity of A-1 agonist
BPH
Pheochromocytoma
Raynaud’s Disease

BAD/Can Cause:
Orthostatic Hypotension
Reflex tachycardia
Nasal congestion
Inhibit ejaculation
Sodium retention

**Beta-Blockade/Antagonist
Good for:
Angina pectoris
Hypertension
Cardiac dysrhythmias
Myocardial infarction
Heart failure
Hyperthyroidism
Migraine
Stage fright
Pheocrhomocytoma
Glaucoma

BAD/Can Cause (Beta-1)

Bradycardia
Reduced cardiac output
Precipitate heart failure
AV Heart Block
Rebound Cardiac Excitation

BAD/Can Cause (Beta-2)

Bronchoconstriction
Inhibition of Glycogenolysis
Be Able to recognize if a drug is alpha or beta
Refer to table 18-1 on page 162
If it’s Beta, the drug will end in –LOL If it’s an Alpha drug, it will end in –SIN or –
MINE

*Study table 18-2 page 167 and be able to match drug name with receptors blocked

If an Alpha-1 Agonist becomes extravasated, local seepage of the drug can cause
necrosis. The area should be infiltrated with an Alpha-1 Blocking Agent to minimize
injury.

Reflex tachycardia – occurs by triggering the baroreceptor reflex.

*Epinephrine is the treatment of choice for Anaphylactic Shock, which is characterized

by hypotension, bronchoconstriction, and edema of the glottis.

ISA – ability of certain betal blockers to act as partial agonists (pindolol).

Excitatory/inhibitory transmitters
Dopamine is the inhibitory neurotransmitter in the striatum, and Acetylcholine is the
excitatory neurotransmitter.

How does epinephrine work in local anesthetics? Because it can cause alpha-1
mediated vasoconstriction it can delay absorption of local anesthetics, which will prolong
the anesthesia effects.

Pheochromocytoma – tumor of the adrenal medulla which causes huge releases of

epinephrine.

Concerns with beta blockade in diabetic patients suppression of glycogenolysis,

thereby eliminating an important mechanism for correcting hypoglycemia. Suppresses
tachycardia, which normally serves as an early warning signal that blood glucose levels
are falling too low. Why is propranolol dangerous in diabetic patients? By masking
tachycardia, propranolol can delay awareness of hypoglycemia, therby compromising the
patient’s abilty to correct the problem in a timely fashion.

Which drug is irreversible? Rivastigmine (Irreversible Inhibition used in AD and

Parkinsons.)

Indirect acting antiadrenercic agents – do not act on the peripheral receptor, but on the
nerve terminal itself. (reserpine).

Mechanism of Action – clonidine, reserpine

Reserpine causes depletion of NE from postganglionic sympathetic neurons and can
decrease activation of practically all adrenergic receptors. Causes displacement of stored
NE, exposing it to destruction by monoamine oxidase. It supresses NE synthesis by
blocking the uptake of dopamine. Can cause depletion of CNS transmitters which can
lead to depression. Main treatment is Hypertension.

Clonidine causes selective activation of alpha 2 receptors in the CNS specifically areas
associated with autonomic regulation of the cardivascular system. By activating central
alpha 2 receptors, clonidine reduces sympathetic outflow to blood vessels and the heart,
causing bradycardia and decrease in cardiac output, promoting vasodilation, and
decreasing blood pressure. Free of severe side effects. Also used for cancer pain.
Suppresses the firing of sympathetic nerves to the heart.

Methyldopa/Methyldopate – Antihypertensive. Could create a false positive Coomb’s

test.
*Knowing the effects that a drug is capable of producing does not always indicate how
that drug is actually used in a clinical setting because some adrenergic agonists are not
used for all the effects they can produce.

Adaptive changes of CNS

a. increased therapeutic effect
b. decreased side effects
c. tolerance and physical dependence

Tolerance vs. Dependency

Tolerance can be defined as decreased responsiveness to a drug as a result of repeated
drug administration. Patients who are tolerant to a drug requre higher doses to produce
effecte equivalent to those that could be achieved with lower doses before tolerance
developed.

Dependency is an intense subjective need for a particular drug. It is a state in which an

abstinence syndrome will occur if drug use is discontinued. It is the result of
neuroadaptive processes that take place in response to prolonged drug exposure.

Parkinson’s Disease – a neurodegenerative disorder that produces characteristic motor

symptoms: tremor at rest, rigidity, postural instability, and bradykinesia.

Parkinson’s Disease Treatment

Goal is to restore the balance between Acetylcholine (Ach) and Dopamine. To
accomplish this, two types of drugs are used:
1. dopaminergic agents which directly or indirectly cause activation of dopamine
receptors
2. anticholinergic agents which block receptors for Ach.
Deep Brain Stimulation, Pallidotomy, Cell implants.
Levodopa/Carbidopa, COMT inhibitors, MAO-B Inhibitors, Amantadine
See table 21-1 page 184

The enzyme that converts levodopa to dopamine is called decarboxylase

Combining levodopa with a nonselective MAO inhibitor can result in hypertensive
crisis.

*High protein meals can reduce the effects of levodopa

Risk factors for Alzheimers

Age over 65 and heredity (main)
Possibly females have higher risk
Head injury
Low educational level
Production of apoE4
High levels of homocysteine
Low levels of folic acid, and nicotine in cigarette smoke

Refer to table 22-1, 22-2, and 22-3

Pathophysiology of Alzheimer’s:
Early: degeneration of neurons in hippocampus
Late: degeneration of neurons in cerebral cortex

Five important features of Alzheimers:

1. acetylcholine decline
2. beta-amyloid neuritic plaques
3. neurofibrillary tangles
4. apoE4
5. endoplasmic reticulum associated binding protein

Five common drugs for Alzheimers

Cholinesterase inhibitors such as:
Donepezil
Galantamine
Rivastigmine
Tacrine
and
Memantine (blocks neuronal receptors for NMDA, not a cholinesterase inhibitor)

Exacerbators of Alzheimers – Anticholinergic Drugs (Antihistamines), tricyclic

antidepressants, and conventional antipsychotics.

Compare and contrast Donepezil/Tacrine

Tacrine and Donepezil both cause reversible inhibition of AchE.
Tacrine
1. can cause liver injury
2. very short half-life
3. administered orally, food decreases absorption
4. low bioavailability because of first-pass metabolism
Donepezil
1. well absorbed
2. undergoes metabolism in the liver by cytochrome P-450 enzymes
3. prolonged half-life

Discontinuation -When withdrawing from AED’s it is important to taper the medication

over six weeks to several months in order to let the brain adapt.

Rebound hypertension – rebound hypertension is characterised by a large increase in

blood pressure occuring in response to abrupt clonidine withdrawal. Rebound effects
can be avoided by withdrawing clonidine slowly over 2 to 4 days.

BPH- Benign Prostatic Hyperplasia – results from proliferation of cells in the prostate
gland. Symptoms: dysuria, increased frequency of daytime urination, nocturia, urinary
hesitance and intermittence, urinary urgency, a sensation of incomplete voiding, and a
reduction in the siaze and force of the urinary system. Symptoms can be improved
with drugs that block Alpha-1 receptors. Benefits are reduced contraction of smooth
muscle inth bladder neck and prostatic capsule.

Raynaud’s Disease – peripheral vascular disorder characterized by vasospasm in the toes

and figers. Symptoms are local sensations of pain and cold. Alpha blockers supress
symptoms.

Seizures are initiated by synchronous, high-frequency discharge from a group of

hyperexcitable neurons called a focus.

Difference in types of seizures

a. Partial
1. simple partial – no loss of consciousness
2. complex partial – impaired consciousness and lack of response
b. Generalized
1. tonic-clonic – major convulsions with rigidity and muscle jerks
2. absence – brief loss of consciousness
3. atonic – sudden loss of muscle tone
4. myoclonic – sudden, rapid muscle contraction
5. status epilepticus – lasting mor than 30 minutes
6. febrile – early childhood seizures related to high fever; not at risk for
developing seizure disorder later

How do Antiepileptic Drugs Work (AED)?

1. supression of sodium influx
2. supression of calcium influx
3. blockade of receptors for glutamate
4. potentiation of GABA
Essentially, slowing the sodium and calcium influx down, slows everything in the
brain.
Glutamate is the primary excitatory transmitter in the CNS
GABA is the inhibitory neurotransmitter in the CNS

All AED’s may pose a risk of suicidal thoughts and behavior.

Commonly used AED’s

Phenytoin – most widely used; first drug to suppress seizures without depressing entire
CNS; slow infusions to prevent cardiovascular collapse; works by selective inhibition of
sodium channels; adverse effects include gingival hyperplasia, Stevens-Johnson
syndrome (rash); slight increases can cause toxicity.
Carbamazepine – dilutes blood, auto-induction; suppresses ADH
Valproic Acid – severe adverse effect is pancreatitis; inhibits CP450
Phenobarbital - oldest and least expensive;

Auto Induction**Because carbamazepine induces hepatic drug-metabolizing enzymes;

by increasing its own metabolism, carbamazepine causes its own half-life to decline.

Wouldn’t giveValproic acid to? Persons under 2 years of age or those with any pre-
existing liver dysfunction, those taking Coumadin. The reason is because it is an inhibitor
of cytochrome P-450.

MOA of levodopa/carbidopa
Carbidopa is used to enhance the effects of levodopa. Carbidopa has no therapeutic
effects of its own, and therefore is always used in conjunction with levodopa. Carbidopa
inhibits decarboxylation of levodopa in the intestine and peripheral tissues, thereby
making more levodopa avaible to the CNS. Carbidopa does not prevent the conversion
of levodopa to dopamine by decarboxylases in the brain because cabidopa is unable to
cross the blood-brain barrier. By increasing the fraction of levodopa available for actions
in the CNS, carbidopa allows the dosage of levodopa to be reduced by about 75%.
Levodopa is converted to dopamine in the brain. You couldn’t use straight dopamine
becaue it can’t cross the BBB and has a short half-life in the blood. The most troubling
effects of Levodopa are dyskinesias (movement disorders)

Work with Levodopa to treat Parkinson’s Disease

COMT inhibitors –
Entacapone
Tolcapone

MAO-B inhibitors –
Selegiline
Rasagiline

All of the above meds would reduce the wearing off of Levodopa.
*A prodrug is a compound that is pharmacologically inactive as administered and
then undergoes conversion to its active form within the body (levodopa/carbidopa).

AED’s for Seizures and their traditional therapeutic levels

Valproic Acid (Depakote) 50-150 mcg/ml
Phenobarbital 20-40 mcg/ml
Carbamazepine (Tegretol) 4-12 mcg/ml
Phenytoin (Dilantin) 10-20 mcg/ml

All traditional AEDs can harm the developing fetus, especially during the first trimester.
However, the fetus and mother are at greater risk from uncontrolled seizures than from
AEDs. Women with major seizure disorders should continue taking AEDs throughout
pregnancy.

If a woman on AED’s becomes pregnant use

1. lowest effective dose
2. mono-therapy when possible

AEDs can accelerate inactivation of other drugs such as oral contraceptives and warfarin.

COMT –Catechol-o-methyl transferase – enzyme to help break down catecholamines.

Present in the liver and intestinal walls.

Intrinsic Sympathomimetic Activity (Partial Agonist Activity) ISA – refers to the

ability of certain beta blockers to act as partial agonists at beta-adrenergic receptors. So
when bound to a receptor, it produces a limited degree of receptor activation while
preventing strong agonists from binding to that receptor to cause full activation.

First dose effect – the first dose of an alpha blocker can cause fainting from profound
orthostatic hypotension.

Familiarize yourself with table 20-1 on page 180 (CNS Neurotransmitters)

*Because the CNS has a bunch of transmitters, with unclear functions, it is difficult
to know exactly how CNS drugs work.

The Blood Brain Barrier has passage limited to:

1. lipid soluble agents
2. drugs able to cross via active transport

Adaptation of the CNS (Central Nervous System) to prolonged drug exposure:

1. increased therapeutic effects
2. decreased side effects (while therapeutic effects remain undiminished)
3. tolerance and physical dependence