20/02/2020

Pharmacodynamics
BIOL 122 Dr Hemant Mehta
Week 1 Lec C

Drug = any chemical that can alter

biochemical and physiological processes in an
organism

Drugs are used to prevent, to cure and to

diagnose diseases.

Pharmacology is the study of the actions, uses,

mechanisms, and adverse effects of drugs.

Pharmacodynamics

The mechanism by which drugs exert their effects on the body

Includes:
- biochemical mechanisms of action (how drugs act on target
cells to alter cellular function)
- Therapeutic effects

The magnitude of a pharmacological effect depends on the

drug concentration at its molecular target or site of action

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General classification of Drugs effects

Excitation is an increase or enhancement of mental

activity by a drug - eg. stimulation of mental activity by
caffeine.

Inhibition is a decrease of the function produced by a

drug – eg. barbiturates induced sedative-hypnotic effect.

Direct Action refers to the action produced directly by a

drug at the site of contact with drug.

A direct action at one part can at times elicit effects on

remote organs or tissues, which are designated as
indirect action.

For example, noradrenaline constricts the blood vessels

directly, increases blood pressure - it is the direct action.
It reflexively decreases heart rate - that is the indirect
action.

Selectivity: A drug is usually described by its most

prominent effect or by the action thought to be the basis
of that effect.

Cardiac glycosides mainly stimulate myocardium;

diazepam inhibits central nervous system;
streptomycin suppresses tubercle bacilli.

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Therapeutic effect is the effect affecting the physiological

and biochemical functions of the organisms and
pathogenic processes. It is used to prevent and treat
diseases.

After effect: The effect still exists, after withdrawal of

the drug, the drug concentration is below the threshold.
Eg. after taking barbiturate, the person feels hangover
next morning.

Aetiological treatment: drug may eliminate the primary

pathogenic factor and cure disease
eg. antibiotics eliminate pathogenic organisms within
body.

Symptomatic treatment: drug may improve the

symptoms of disease, such as, use aspirin to treat high
fever. In some critical conditions (such as shock,
convulsions, congestive heart failure, high fever, and
severe pain), symptomatic treatment is more urgent than
aetiological treatment.

When a reaction is part of the pharmacological profile

of the drug, it is known as a predictable effect.

Predictable effects take place soon after the drug is

initiated or when a medication dose is increased.

Unpredictable reactions include those that are

immunologically mediated effects, involve genetic
differences in drug metabolism, and whose mechanism of
action is not known.

Unpredictable reactions are more difficult to manage than

predictable reactions.

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Toxic effects mean noxious effects induced by over dosage

of drugs or accumulation of large amount of drugs.

They include acute toxicity which may damage the

functions of circulatory system, respiratory system and
nervous system, and chronic toxicity which may damage
hepatic, renal, bone marrow and endocrine function.

Carcinogenesis, teratogenesis and mutagenesis belong to

chronic toxicity. It is important to avoid the toxic effects;
however, should they occur, they have to be managed rationally
and successfully.

Adverse Drug Reaction

An adverse drug reaction (ADR) is defined as “any

response to a drug which is noxious, unintended and
occurs at doses used for prophylaxis, diagnosis, or
therapy” (WHO, 1970).

Adverse drug reactions (ADRs) are undesirable effects

that occur with the administration of medications at
normal doses.

Adverse Drug Reaction

ADRs have been known to cause significant morbidity &

mortality.

An example of an adverse drug reaction is gastrointestinal

tract (GIT) bleeding with high dose or long term use of
aspirin.

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Side-effect of a drug = An effect other than a primary

one for which a drug is devised; it may be desirable or
undesirable.

ADRs can occur as a part of the normal pharmacological

profile of a particular drug (type A reactions), or they
may be unrelated to the drug (type B reactions).

A commonly used classification system for ADRs

uses five categories, Types A-E:
Type A reactions occur as a normal pharmacological profile
of the drug and are dose related.

Examples include hypotension due to antihypertensives, or

haemorrhage due to anticoagulants.

Such side-effects occur as the drug does not interact only

with its site of intended action, but affects all binding
sites/receptors with which it is compatible.

Drug interactions are an important form of Type A reaction.

Type B reactions
Type B reactions are often caused by immunological and
pharmacogenetic mechanisms.
Type B reactions (only occur in some people) include
unwanted effects due to inherited abnormalities
(ie. idiosyncratic reactions), and immunological processes
(ie. drug allergy).
As they are generally unpredictable and not related to drug
dosage, they are difficult to prevent, resulting in high
morbidity and mortality.
An example of a drug having bizarre (type B) effects is
anaphylaxis due to penicillin.

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Anaphylaxis
Angioedema of the face such that the boy is unable to
open his eyes. This reaction was caused by an allergen
exposure.

Source: http//en.wikipedia.org/wiki/Anaphylaxis

Allergy is an adverse reaction that result from previous

sensitisation to a particular chemical or to one that is
structurally similar. Such reactions are mediated by the
immune system.

The terms hypersensitivity and drug allergy are often

used to describe the allergic state.

Type C reactions

Type C reactions are those resulting from long-term

(chronic) drug usage.

Examples include Parkinsonism with phenothiazines, or

colonic dysfunction with laxatives.

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Type D reactions

Type D reactions occur some years after treatment has

finished and may even occur in the offspring of the person
given the therapy.

An example of a drug having delayed effects is secondary

cancer after treatment with a cytotoxic drug.

Type D reactions
Another example is carcinoma of vagina in daughters of
women who took diethylstilbestrol (DES) during pregnancy.
DES is a synthetic oestrogen that was given to some women
during 1940 – 1970 to prevent threatened and recurrent
abortion.
DES caused anatomical abnormalities of uterus, increased
risk of ectopic pregnancy, miscarriage and premature delivery
in the affected daughters.

Fertility rates were also reduced in those daughters, but not

in the sons of women who took DES.

Type E reactions

Type E reactions occur when discontinuation of therapy

is too abrupt.

An example of end-of-use, or withdrawal effects, is

delirium tremens after ceasing heroin intake.

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Drug action on receptors

• Most of the drugs act by interacting with a cellular

component called receptor.

• Receptors are protein molecules present either on cell

surface or within the cell, eg. adrenergic receptors,
cholinergic receptors, insulin receptors, histamine
receptors,…
• Endogenous ligands (eg. neurotransmitters,
hormones), and drugs produce their effects by binding
with their specific receptors.

Agonists and Antagonists

• Drugs that bind to a receptor are termed agonists or

antagonists.

• When a drug is able to bind to and stimulate a

receptor, it is referred to as an agonist.

• An agonist binds to (occupies) and activates the

receptor to produce the same response (measurable
effect) as the endogenous ligand (eg. adrenaline or
dopamine).

Agonists and Antagonists

• An agonist has both an affinity and efficacy, whereas an

antagonist has affinity but not efficacy.

• An antagonist (“blocker”) binds to the receptor and

blocks access of the endogenous ligand, thus
diminishing the normal response.

• Eg. propranolol (β-blocker) can be used in a person

with tachycardia to decrease the heart rate (it blocks
the action of circulating adrenaline and slows HR).

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Ion channels

• Cell membranes are complex structures (consisting of

lipoprotein molecules) that regulate the transport of
ions and metabolites in a highly selective manner
through ion channels.

• Ion channels facilitate maintenance of an

electrochemical gradient between the interior and
exterior of cell.

Ion channel
receptors
Structure:
Protein pores in the
plasma membrane

Drug action on ion channels

• Drugs can target ion channels – eg. amiloride (diuretic)

blocks the entry of Na+ ions into renal tubular cells.

• Verapamil (Ca2+ channel blocker) can be used to relax

muscles - eg. verapamil can be used in the treatment
of cardiac arrhythmias.

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Drug action on carrier molecules

• Normal cell physiology is dependent on the integrity of

the cell membrane.
• Ions and molecules having insufficient lipid solubility are
not able to diffuse across the cell membrane – they (eg.
glucose molecules) must be transported by carriers.
• Carriers are also involved in the uptake of chemicals
acting at nerve terminals, eg. noradrenaline.
• The Tricyclic antidepressants and cocaine are examples
of drugs that inhibit carrier-mediated uptake of
noradrenaline.

Drug action on enzymes

• Enzymes (biological catalysts) control biochemical reactions

in cells.
• A drug can inhibit the action of an enzyme to alter the
physiological response.
• Eg. Angiotensin-Converting Enzyme can be inhibited by
Captopril (antihypertensive).
Captopril is used in the treatment of hypertension as it
prevents Angiotensin II production (ie. inhibits
vasoconstriction and keeps blood vessels dilated to ease BP).

Drug action on enzymes

Another example:
Neostigmine reacts with acetylcholinesterase to prevent
the inactivation of ACh at the neuro-muscular junction.

Neostigmine is used in the treatment of Myasthenia

gravis, a disease characterised by muscle weakness
resulting from progressive loss of ACh receptors.

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COMPETITIVE AND NON-COMPETITIVE

INHIBITION

Competitive inhibition
• Endogenous substrate and enzyme inhibitor (drug)
compete for the same binding sites. Generally reversible
by increasing the concentration of the substrate.

Non-Competitive inhibition
• Substrate and enzyme inhibitor (drug) compete for
different binding sites. However, binding of a ligand to
one site prevents binding/activation at the other site.

Competitive inhibitors
Normal enzyme action

+ +
Enzyme + substrate enzyme-substrate enzyme + products
complex

Competitive inhibitor

No product
+
Enzyme + inhibitor

Competitive inhibitor has a chemical structure and molecular

geometry similar to the substrate. The inhibitor is able to
block the active site of the enzyme making it unavailable to the
substrate.

Noncompetitive Inhibitors:

+ + No product

Enzyme + Inhibitor + Substrate Substrate-Inhibitor

Complex

Shape of active site has changed, therefore enzyme cannot enter

Non-competitive inhibitor binds to a site other than the active

site. By doing this, it changes the shape of the active site. The
enzyme shape is changed so that it can no longer function.

Heavy metal ions (Pb2+, Hg2+) act in this way.

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Non-specific action of drugs

Due to their physical and chemical properties

Mannitol
Mannitol is used to force urine production in people with
acute (sudden) kidney failure. Increased urine production
helps prevent the kidneys from shutting down, and also
speeds up elimination of certain toxic substances in the
body.

Non-specific action of drugs

Due to their physical and chemical properties
• Direct chemical interaction
- Antacids (MgO, NaHCO3) neutralise HCl acid
- Na citrate binds Ca2+ ions

• Physical-chemical interaction: Protamine and Zn bind

to insulin to form long-acting preparation (Ultralente)
(Also, Protamine sulphate binds Heparin).

Pharmacological drug interactions

• Pharmacokinetic drug interactions occur during

absorption, distribution, metabolism or excretion

• Pharmacodynamic interactions occur when action of

one drug interferes with that of another drug

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Pharmacokinetic drug interaction

eg. interaction occurring during absorption

Drugs can interact in the GIT resulting in decreased or

increased absorption.
Tetracycline is rendered unabsorbable across the small
intestine in the presence of Ca2+ ions (present in milk &
other dairy products):

Tetracyclines + calcium → decreased absorption of tetracyclines

Drug Interactions

Pharmacodynamic drug interactions occur when action of

one drug interferes with that of another drug (may result in
cancellation of drugs’ effects or enhancement); the effect
of one drug is modified by the prior or concurrent
administration of another drug.

Such interactions may result in an antagonistic, synergistic

or unexpected response.

They can be beneficial or harmful.

Pharmacodynamic drug interaction

Eg. Potentiation occurs when 2 drugs act to produce an

effect that is more than additive.

For instance, the 2 antimicrobial drugs sulphonamides - eg.

sulphamethoxazole & trimethoprim. These drugs act at
different points within the pathway for DNA and RNA
synthesis, thereby inhibiting microbial growth.
The antibacterial (bacteriostatic) activity of the mixture is
more potent than if either drug alone is used.

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