IST YEAR 2ND SEMESTER PHARMACOLOGY: UNIT 6

BASIC PRINCIPLES OF PHARMACOKINETICS AND PHARMACODYNAMICS

DEFINITIONS

• Pharmacology - is the science of the interaction of chemical agents (drugs) with living
systems. It encompasses the study of the biochemical and physiologic aspects of drug
effects, including absorption, distribution, metabolism, elimination, toxicity, and specific
mechanisms of drug action.

• Drug - a substance (chemical agent) that affects a biological system in a potentially

useful way. Drugs are used in the prevention, diagnosis, treatment or cure of disease in
man or other animals.

• Poison - Any chemical agent that produces a harmful effect (e.g. arsenic/lead). Note:
drugs in high concentrations become poisons.

• Toxin - a poison of biological origin (e.g. tetrodotoxin)

ABBREVIATIONS

• EC - Effective Concentration (e.g. EC50: the drug concentration producing 50% of a

maximal effect).

• ED - Effective Dose (e.g. ED50: the drug dose producing 50% of a maximal effect; or
alternatively the dose producing the desired effect in 50% of the population. Which
definition is appropriate depends on the context in which the abbreviation is being
applied; i.e. it depends on whether the abbreviation is referring to the results of a
population study, or drug effects on a single animal).
o Example: administering a 1000 mg dose of acetaminophen (ED50) orally will
result in a plasma concentration of 15 ug/ml (EC50), which produces effective
pain relief in 50% of adult patients.

• TD - Toxic Dose (e.g. TD50: the dose producing a toxic effect in 50% of the population).

• LD - Lethal Dose (e.g. LD50: the dose producing a lethal effect in 50% of the
population). LD values almost always refer to animal studies, since lethal doses in
humans are rarely known with any accuracy.
Two Primary Branches of Pharmacology

The two major branches of pharmacology are: pharmacodynamics and pharmacokinetics.

Pharmacokinetics - The study of the absorption, distribution, metabolism and excretion of drugs
from the body. In operational terms “what the body does to drugs”.

To produce its characteristic effects, a drug must be present in an appropriate concentration at its
sites of action. Thus, it is important to know the interrelationship of the absorption, distribution,
binding, biotransformation, and excretion of a drug and its concentration at its locus of action. A
knowledge of the pharmacokinetics of a drug is necessary to answer such therapeutically
important questions as: “By which route should I give this drug?”, “What dose should I give to
produce the desired effect?”, “At what time intervals should the drug be given?”, “What doses
will cause toxicity?”, “Does the patients age, disease state, or concomitant therapy with other
drugs alter the effect of this drug?” A number of phases occur once the drug enters into contact
with the organism, these are described using the acronym LADME:

A) Liberation

The process by which the drug is released from its pharmaceutical form (e.g., capsule, tablet,
suppository, etc.). This must occur before the drug can be absorbed into the body.

Some of the common routes of drug administration are:

1. Oral administration (PO: per os – by mouth) is a route of administration where a substance

is taken through the mouth.

• 80% of medicines used in medical practice are given orally

• route is convenient and economical

• medicine is ingested

o absorbed from the stomach / intestine

o enters hepatic portal circulation: enters liver

o enters general circulation

2. Sublingual (SL)

• medicine is dissolved under the tongue and is absorbed through mucous membranes into
the bloodstream

o route is convenient and economical

o example: sublingual tablets

3. Transdermal (TD)

• medicine contained in a patch is absorbed through the skin

o advantage: medicine dosage is continuous and long-acting

o disadvantage: product is expensive and may cause local irritation due to the
adhesive component

o example: nicotine, oestrogen patches

4. Rectal (PR)

• medicine (in suppository form) is inserted into the rectum where is absorbed through
mucosa into the bloodstream

o advantage: used for unconscious or vomiting patients

o disadvantage: medicine may be incompletely or irregularly absorbed

o examples: analgesic and anti-nauseant suppositories

5. Inhalation

• medicine is inhaled as a gas, aerosol or mist

• route is usually intended to allow medicine to act directly on lung tissue

o advantage: inhaled medicine produces a rapid onset of action

o disadvantage: inhaled medicine may irritate lung tissue

o examples: bronchodilator mist

6. Intranasal

• medicine is absorbed through the mucosa membranes in the nose into the bloodstream

o examples: anti-congestion nasal spray

7. Parenteral (intravenous - IV, intramuscular - IM, subcutaneous - SQ)

• advantages:

o produces a faster response than oral or rectal routes

o avoids unpredictable absorption through gastrointestinal system

o useful in unconscious patients

 • disadvantages:

o requires sterile conditions to prevent infections

o more costly than other routes of administration

o pain at the injection site

• Medicine is absorbed (enters the blood stream and becomes bioavailable) differently by
the body depending on how it is administered. Orally administered medicine must be
digested before the active pharmaceutical ingredient (API) enters the bloodstream (is
absorbed); the API of an intravenously administered medicine enters the bloodstream
immediately.

A) Absorption

It refers to how medicines enter the bloodstream. There are several routes of administration:

B) Absorption

The process by which the drug reaches the bloodstream. A drug must be absorbed and achieve
adequate concentration at its site of action in order to produce its biological effects. When a drug
is applied to a body surface (e.g., G.I. tract, skin, lungs, etc.), its rate of absorption will determine
the time for its maximal concentration in plasma and at the receptor to produce its peak effect.
The following factors affect drug absorption:

• Bioavailability describes the rate and concentration at which the drug appears in
circulation. It is expressed as a percentage of the dose that was initially administered.
o Bioavailability is affected by two mechanisms:
▪ First pass effect: Orally administered drugs are absorbed from the GI tract
and reach the liver via the portal circulation, where they undergo some
degree of metabolism before they enter systemic circulation. This
decreases the bioavailability of the drug.
▪ Ability to pass through lipid membranes: dependent on the nature of the
substance (see the table below)
• Bioequivalence: Two pharmaceutical forms of the same drug are said to be bioequivalent
if they exhibit the same bioavailability when administered in equal doses.

C) Distribution

Distribution refers to how medicines are distributed throughout the body and reach their intended
target. The blood, total body water, extracellular, lymphatic and cerebrospinal fluids are involved
in movement of drug through the body. Depending upon its chemical and physical properties, the
drug may be bound to plasma proteins or dissolved in body fat, delaying its progress to its site of
action, metabolism or excretion. The degree of medicine distribution depends on its physical and
chemical properties and its ability to penetrate cell membranes, blood vessels, the blood-brain
barrier, etc.

• Blood-Brain Barrier (BBB)

Only fat-soluble medicines and very small molecules are able to penetrate the tight cell
connections which separate the circulating blood from the brain (the blood-brain barrier, BBB) to
have a pharmacologic effect

• Example: heroin has a greater effect on the brain than morphine because of its
greater fat-solubility

• Plasma Protein Binding

Many medicines bind reversibly with plasma proteins such as albumin, so the protein-medicine
binding profile determines distribution and elimination rate. Only unbound or ‘free’ medicines
may:

• diffuse through capillary walls

• produce a pharmacologic effect

• be metabolised and excreted

• After medicine has been administered, it is distributed throughout the body to reach its
final target.

D) Metabolism (Medicine Biotransformation)

How drugs are handled biochemically by the body and include hydrolysis, conjugation, and
oxidation-reduction. Metabolism is the enzymatic conversion of one chemical compound into
another. Most metabolism of medicine occurs in the liver, although some processes occur in the
gut wall, lungs, and blood plasma. On the whole, as drugs are metabolised their therapeutic
effect changes.

The complex liver enzyme system converts fat-soluble medicines to water-soluble metabolites
which can then be eliminated by the kidneys.

(1) “First-Pass Effect” (Liver)

• Substances (medicines, toxins, foods, etc.) absorbed into the bloodstream from the GI
tract, enter the liver via the hepatic portal vein before entering the general circulation.

• The “first-pass effect” allows the liver to metabolise or deactivate medicines and
potentially harmful substances before they are distributed throughout the body.
 • Medicines are converted into less active or inactive metabolites by the liver.

The chief functional cells of the liver (known as hepatocytes) contain all the necessary enzymes
for the metabolism of medicines. Enzymes are proteins that control the speed of chemical
reactions in your body. The main enzymes involved in metabolism belong to the cytochrome
P450 group.

Phase 1 metabolism can involve reduction or hydrolysis of the drug, but the most common
biochemical process that occurs is oxidation. Oxidation is the chemical reaction that occurs for
example when apples turn brown when exposed to the oxygen in air.

Oxidation is catalysed by cytochrome P450 enzymes and results in the loss of electrons from the
drug (electrons are negatively charged subatomic particles).

The medicine is now said to be oxidised. After phase 1 reactions, the resulting medicine
metabolite is often still chemically active. A metabolite is any substance produced during
metabolism. They can be polar and non-polar molecules (or species).

Phase 2 metabolism involves conjugation - that is, the attachment of an ionised group to the
medicine. The attachment of an ionised group makes the metabolite more water soluble. This
facilitates excretion and decreases pharmacological activity.

Renal elimination (via the kidneys as urine)

Biliary elimination (via the gut as faeces/stool)

Some drug metabolites can be toxic, such as those produced from paracetamol. These are
detoxified by Phase 2 conjugation joining with glutathione. Glutathione is the body’s most
powerful antioxidant. It is found inside every single cell in your body.

However, in an overdose situation where the dose of paracetamol is high, there is not enough
glutathione to detoxify the metabolites. They accumulate and cause toxicity; this can result in
hepatitis. As a solution, compounds are made to boost the levels of glutathione so that Phase 2
metabolism can take place, thus detoxifying the paracetamol metabolites fully and reducing the
risk of liver injury.

D) Excretion

Excretion refers to how the body gets rid of a medicine or its metabolites. There are three main
routes of elimination: kidneys, liver, and bowel. Most medicines are excreted as active, partially
active, or inactive metabolites by the kidneys.

1) Excretion by kidneys after medicine metabolism:

 • The liver transforms medicines into compounds which are more readily excreted by
kidneys

• Excretion by kidneys directly into the urine

2) Excretion in faeces

• Entero-hepatic recirculation: metabolised medicine is secreted by the liver in bile and

enters small intestine where it is reabsorbed into the bloodstream from small intestine and
returned to the liver or eliminated in faeces

3) Pulmonary excretion:

• This applies primarily to inhaled anesthetic drugs.

Medicine excretion and age considerations:

• infants have underdeveloped abilities to metabolise and excrete medicines which usually
results in greater sensitivity

• elderly have impaired ability to metabolise and excrete medicines resulting in greater
sensitivity

PHARMACODYNAMICS

Pharmacodynamics - The study of the relationship between concentrations of drug and the
biologic effects (physiological or biochemical) with time. In operational terms “what drugs do to
the body”.

For most drugs it is necessary to know the site of action and mechanism of action at the level of
the organ, functional system, or tissue. For example, the effect may be localized to the brain, the
neuromuscular junction, the heart, the kidney, etc. The mechanism of action can typically be
described in biochemical or molecular terms. Most drugs exert effects on several organs or
tissues, and have unwanted (side) effects as well as therapeutic effects. There is a dose-response
relationship for both therapeutic and side effects. The pharmacologic response depends on the
drug binding to its target. The concentration of the drug at the receptor site influences the drug’s
effect. Factors in the patient that affect responses include age, weight, sex, diet, race, disease,
disorder, trauma, and concurrent treatment with other drugs.

Disorders that affect pharmacodynamic responses include genetic mutations, thyrotoxicosis,

malnutrition, myasthenia gravis, Parkinson disease, and some forms of insulin-resistant diabetes
mellitus. These disorders can change receptor binding, alter the level of binding proteins, or
decrease receptor sensitivity.
Aging tends to affect pharmacodynamic responses through alterations in receptor binding or in
postreceptor response sensitivity.

Pharmacodynamic drug–drug interactions result in competition for receptor binding sites or alter
postreceptor response.

Basic Principles of Pharmacodynamics

How do Drugs Exert their Effects?

The definition of a drug as any chemical that perturbs a biological system suggests that they can
produce their effects by multiple mechanisms. Examples of multiple mechanisms for drug action
include: chemical interactions with other molecules due to a drugs acidic or basic properties (e.g.
antacids, or Protamine sulfate - a heparin antagonist), their ability to act as a membrane
surfactant (amphotericin B), or their ability to denature proteins (astringents). However, most
drugs exert their therapeutic effects by binding to specific receptor sites. Receptors have two
important properties - they bind drugs (ligands) with relatively high affinity, and after they bind
a drug, they transduce a signal to produce a biological effect. This later property distinguishes
receptors from inert binding sites, such as Albumin or α1-acid glycoprotein, which are blood
proteins that avidly bind many drugs, but do not transduce a signal. Many drug receptors can
transduce biological signals at very low concentrations (i.e. they are highly efficient). For
example, calculations from studies of atropine binding to the intestinal ileum suggest that only
0.02% of the cell surface is composed of acetylcholine receptors.

Receptor Subtypes

Drug receptors can be classified into several major subtypes including:

• Enzymes (e.g. allopurinol inhibition of xanthine oxidase).

• Ion channels (e.g. d-tubocurarine blockade of the nicotinic receptor/channel; verapamil
blockade of Ca channels).
• Membrane receptors (e.g. atropine blockade of muscarinic receptors, epinephrine
stimulation of α- or β- adrenergic receptors). Stimulation of membrane receptors typically
results in the altered activity of membrane-associated enzymes or channels via activation
of specific G-proteins located on the intracellular membrane surface. Exceptions to this
rule are receptors with tyrosine kinase activity. Intracellular receptors (e.g. estrogen
interaction with nuclear receptors).

The Chemical Basis for Drug-Receptor Interactions

Drugs can interact with receptors through a variety of chemical interactions including:

• Electrostatic interactions (hydrogen bonds, Van der Waals forces) - the most common
mechanism.
• Hydrophobic interactions (important for lipid soluble drugs).
 • Covalent bonds (e.g. phenoxybenzamine binding to α-adrenergic receptors) - least
common
• Stereospecific interactions (>50% of drugs exist as stereoisomers and interact
stereospecifically with receptors. e.g. S (-) Carvedilol binds to both α-adrenceptors and β-
adrenergic receptors, whereas R(+) Carvedilol binds selectively to α-adrenergic
receptors).

The Dose Response Relationship

The fraction of receptors occupied by a drug is a function of the drug concentration. As the drug
concentration is increased, a progressively higher fraction of available receptors will become
occupied by drug until all available receptors become bound. An illustration of the relationship
between drug concentration and receptor occupancy by drug

Drugs are commonly divided into two basic categories: agonists and antagonists. Agonists are
drugs that bind and activate receptors. Antagonists are drugs that bind to receptors without
activating them, and consequently prevent the binding of other agonists. If you conceptualize
drug-receptor interactions as a “lock and key” model, agonists are keys that fit into a lock
(receptor) and open (activate) them, whereas antagonists fit into the lock and jam the mechanism.

Agonists

• Potency: the amount of drug required to produce an effect of given intensity. Differences
in drug potency are evaluated by comparing EC50 (or ED50) values.
• Efficacy: the ability of a drug to produce a maximum response. Differences in drug
efficacy are evaluated by comparing differences in maximal response at high drug doses
or concentrations.
• Partial agonists: agonists that produce less than a full response when they fully occupy
their receptors. In contrast, full agonists produce a full or maximal response.

Two fundamental properties of agonists are affinity and efficacy. Affinity can be defined as the
tenacity with which a drug binds to its receptor. In statistical terms, it can be defined as the
probability that a drug molecule will bind to an available receptor at any given instant in time.
Efficacy is an inherent property of an agonist that determines its ability to produce its biological
effect. By definition, it is a property of the drug, not the receptor or tissue. Affinity gets the drug
bound to the receptor, and efficacy determines what happens once the drug is bound.

Different drugs that bind to the same receptor and produce the same type of response will
typically differ from each other in terms of their affinity (potency) and/or efficacy. The term
potency is used as a comparative term for distinguishing which agonist has a higher affinity for a
given receptor. The drug which can produce an effect at lower drug concentrations is “more
potent”.
Antagonists

Competitive vs. Noncompetitive Antagonists

Antagonists are drugs that bind to receptors (have affinity), but do not produce a substantial
degree of receptor stimulation (they have very low efficacy). Antagonists are typically classified
as competitive or noncompetitive. Competitive antagonists bind reversibly to the same receptor
site as the agonist. Because they bind reversibly and compete for the same binding site, their
inhibitory effects can be “surmounted” by addition of a higher concentration of agonist. This
effect produces a rightward parallel shift of the dose-response for the agonist (towards higher
concentrations). In the presence of a competitive antagonist, agonists can still produce the same
(e.g. 100%) maximal effect as in the absence of an antagonist, the only difference being that
higher agonist concentrations are needed to produce the same level of effect. The vast majority
of clinically used drugs that act as receptor antagonists are competitive antagonists.
Noncompetitive antagonists either bind irreversibly (e.g. by covalent bonds) to the same site as
the agonist, or bind to a different site which reduces the binding of the agonist by an allosteric
mechanism. The primary effect of a noncompetitive antagonist is a reduction in the maximal
effect produced by the agonist. In contrast to a competitive antagonist, the effect of a
noncompetitive antagonist cannot be reversed by simply increasing the concentration of the
agonist, since the law of mass action does not apply.

Other Mechanisms of Drug Antagonism

There are other types of “antagonism” involving drug effects:

• Physiological antagonism involves drug activation of two different compensatory

biological mechanisms that exist to maintain homeostasis by different mechanisms. For
example, the effect of norepinephrine to increase blood pressure (via stimulation of α-
adrenergic receptors) can be antagonized by administration of acetylcholine, which
causes vasodilation by stimulating muscarinic receptors, resulting in the release of
nitric oxide from the vascular (arteriolar) endothelium. Acetylcholine and norepinephrine
exert their effects through different receptors and signal transduction pathways, which
when activated produced opposing effects (e.g. vasodilation vs vasoconstriction). They
therefore “physiologically” antagonize each other’s effects without interacting with the
same receptors.
• Chemical antagonism occurs when a drug reduces the concentration of an agonist by
forming a chemical complex (e.g. chelating agents). Example: protamine sulfate is a
positively charged substance that when given i.v. will bind to heparin, a strongly
negatively charged anticoagulant drug. As a result, protamine sulfate administration is a
type of “antidote” for heparin overdose, because once heparin binds to protamine sulfate,
it cannot exert its anticoagulant effects.
• Pharmacokinetic antagonism occurs when one drug accelerates the metabolism or
elimination of another (e.g. phenobarbital-induced enzyme induction increases the
metabolism of the anticoagulant coumadin).
Drugs often work on multiple receptors

Drugs often work on more than one receptor, and as a result produce more than one kind of
biological response. One good example is norepinephrine (NE), the sympathetic neurotransmitter
which can relax bronchial smooth muscle, but constrict arterial smooth muscle. This results
from NE binding to different adrenergic receptor subtypes (α and β). Bronchial smooth muscle is
rich in β adrenergic receptors, whereas arterial smooth muscle is rich in α adrenergic receptors.
When stimulated, the α receptor subtype transduces a different type of biological signal
compared to β adrenergic receptors. Each receptor subtype selectively interacts with different G
proteins & thus activate different intracellular messenger pathways, resulting in different
biological responses.