Pharmacodynamics

Bitek Brian
 Pharmacodynamics
• Pharmacodynamics can be defined as the study of the biochemical, cellular, and
physiological effects of drugs and their mechanisms of action.

• OR simply could be put as “what the drug does to the body”.

• A drug receptor refers to a cellular macromolecule or macromolecular complex

with which the drug interacts to elicit a cellular or systemic response.

• Many drug receptors are proteins that normally serve as receptors for
endogenous regulatory ligands and these are termed as physiological receptors.
 Pharmacodynamics
• Drugs commonly alter the rate or magnitude of an intrinsic cellular or
physiological response rather than create new responses.

• Drugs that bind to receptors and mimic the regulatory effects of the endogenous
signaling compounds are termed agonists.

• If the drug binds to the same recognition site as the endogenous agonist, the
drug is said to be a primary agonist.

• Allosteric agonists bind to a different region on the receptor, referred to as an

allosteric site.
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• Molecules that bind to receptors but do not activate generation of a signal are
referred to as antagonists.

• The antagonist may bind at the same site that an endogenous compound binds.

• Antagonism can also occur when the drug/molecule interacts at other sites on
the receptor (allosteric antagonism).

• Consequently, they interfere with the ability of an agonist to activate the

receptor.
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• Antagonism may occur by compounds combining with the agonist (chemical
antagonism)
E.g. protamine, a protein that is positively charged at physiologic pH, can be used
clinically to counteract the effects of heparin, an anticoagulant that is negatively
charged.

• Functional /physiological antagonism by indirectly inhibiting the cellular or

physiological effects of the agonist.
E.g. Glucocorticoids lead to increased blood sugar, an effect that is
physiologically opposed by insulin.

• Agents that are only partially as effective as agonists are termed partial agonists.
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• Receptors are postulated to exist in the inactive, nonfunctional form and in the
activated form.

• In the absence of any agonists, some receptors exist in the activated form and
produce some physiologic effect termed as constitutive activity.

• Many receptors exhibit some constitutive activity in the absence of a regulatory

ligand and drugs that stabilize such receptors in an inactive conformation
reducing constitutive activity are termed inverse agonists.
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• In the presence of a full agonist, partial and inverse agonists will behave as
competitive antagonists.

• Partial agonists are said to have low intrinsic efficacy (activity) because they do
not stabilize drug bound receptors in the activated configuration.

• Affinity of a drug can be defined as the strength of the reversible interaction

between a drug and its receptor.
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PHARMACODYNAMICS DRUG INTERACTIONS
Synergistic interactions
•Synergism-Enhanced effect: 1+1=3 e.g. cotrimoxazole, a combination of
trimethoprim and sulfamethoxazole.

•Estrogen-progestin oral contraceptive combination, nitrate propranolol

combination used for prophylaxis of angina and the antihypertensive combination
of hydrochlorothiazide-enalapril.
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Additive effect
•Here 1+1=2. E.g. analgesic effect of two analgesic drugs, additive central nervous
system depression on concurrent use of two or more drugs.

•Also addition of neuromuscular blocking effect of a competitively blocking skeletal

muscle relaxant and an aminoglycoside antibiotic.

Potentiation
•Denoted as 1+0=2 e.g. levodopa-carbidopa, in which carbidopa facilitates and
helps the action of levodopa but its individual indication is not for Parkinson's.

• Epinephrine potentiates the action of lidocaine to produce vasoconstriction and

increase action of local anesthesia.
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• Sulbactam or clavulanic acid (beta lactamase inhibitors) to prevent destruction of
ampicillin or amoxicillin respectively.

Competitive Antagonism
• Here the two drugs combine and compete for the same receptor site.
• Used in management of overdose or poisoning e.g. use of naloxone in acute
opiate overdose, flumazenil in acute benzodiazepine overdose or atropine in
organophosphate poisoning.

• Non competitive antagonism: e.g. diazepam-bicuculline or norepinephrine-

phenoxybenzamine.
• In many cases this type of interaction is irreversible.
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Dose-Response curves
•Responses to a drug usually increase in direct proportion to the dose being
administered until a point is reached where no further increase in response can be
achieved.

•This relation between drug concentration and effect is traditionally depicted by a

curve (hyperbolic).

•This hyperbolic relation resembles the mass action law that describes the
association between two molecules hence the occupancy theory.

•Receptor occupancy theory assumes that a drug’s response emanates from a

receptor being occupied by the drug.
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• Dose response data is often presented as a plot of the drug effect against the
logarithm of the dose or concentration.
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• Transformation of the data is convenient because it expands the scale of the
concentration axis at low concentrations (where the effect is changing rapidly)
and compresses it at high concentrations (where the effect is changing slowly).

• Otherwise this transformation has no biologic or pharmacologic significance.

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• Potency is explained in a way that when two drugs produce the same responses,
the drug that produces a half-maximal effect (EC50) at a lower concentration is
more potent.

• In a dose response curve, the more potent drug’s curve will lie to the left of the
other.

• Efficacy refers to the capacity of a drug to activate a receptor and generate a

cellular response.

• Thus, a drug with high efficacy may be a full agonist, eliciting, at some
concentration, a full response.
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• Partial agonists have a lower efficacy at a receptor as they do not elicit a full
response at any dose.

• A drug that binds to a receptor and exhibits zero efficacy is an antagonist.

Median effective concentration (EC50)

• Graded response curves are those that measure the changes in a single system
continually.

• Graded dose-response curves have certain limitations in their application to

clinical decision making.
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• For example, such curves may be impossible to construct if the pharmacologic
response is an either-or (quantal) event, such as prevention of convulsions,
arrhythmia, or death.

• Some of these difficulties can be avoided by using Quantal dose response curves.

• This is done by determining the dose of drug required to produce a specified

magnitude of effect in a large number of individual patients or experimental
animals and plotting the cumulative frequency distribution of responders versus
the log dose.

• Median effective dose (ED50)

• Median lethal dose (LD50)
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• Quantal dose-effect curves may also be used to generate information regarding
the margin of safety to be expected from a particular drug.

• One measure, which relates the dose of a drug required to produce a desired
effect to that which produces an undesired effect, is the therapeutic index.

• In animal studies, the therapeutic index is usually defined as the ratio of the LD50
to the ED50 for some therapeutically relevant effect.

• The range between the minimum toxic dose and the minimum therapeutic dose
is called the therapeutic window and is of greater practical value in choosing the
dose for a patient.
 Drug interactions
• Often times there are variations in response to drugs from different individuals.

• Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one

that is rare and not readily explainable.

• Idiosyncratic responses are usually caused by genetic differences in metabolism

of the drug or by immunologic mechanisms, including allergic reactions.

• Responsiveness to a drug tends to decrease over time as a consequence of

continued drug administration, producing what is termed as drug tolerance.

• When responsiveness diminishes rapidly after administration of a drug, the

response is referred to as tachyphylaxis.
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Other key terms to note
•Desensitization of receptors occurs when a receptor is bound and there is
diminished or no elicited response. Occurs with continuous use of agonist drugs.

•Sensitization of receptors…………….

•Down regulation of receptors occurs when the number of receptors on the cell
surface are reduced. Occurs with continuous use of agonist drugs.

•Upregulation of receptors………………
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• Orphan receptors

• Spare receptors or receptor reserve

• Ligand
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• A hypersensitivity reaction can be defined as an adverse reaction, mediated by
the immune system, that results from previous sensitization to a particular
chemical or to one that is structurally similar.

• Hypersensitivity reactions can be divided into four general categories based on

the mechanism of immunological involvement based on Gell and Coomb's
classification.

Type I: Anaphylactic Reactions. Anaphylaxis is mediated by IgE antibodies and

examples include; allergic asthma, anaphylactic shock due to penicillins.

Type II: Cytolytic Reactions. These reactions are mediated by both IgG and IgM
antibodies that activate the complement system e.g. penicillin-induced hemolytic
anemia, quinidine-induced thrombocytopenic purpura.
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Type III: Arthus Reactions. Type III allergic reactions are mediated predominantly
by IgG; the mechanism involves the generation of antigen- antibody complexes.

• These complexes can be deposited anywhere in the body causing destruction e.g.
serum sickness.

Type IV: Delayed Hypersensitivity Reactions. These reactions are mediated by

sensitized T lymphocytes and macrophages.

• The reaction is generated by the production of lymphokines and the subsequent

influx of neutrophils and macrophages.

• E.g. Contact dermatitis caused by poison ivy, Tuberculosis skin test.

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!!!!!Read about Wills and Brown classification of ADRs!!!!!

 Drug targets
• Drug targets refer to those different structures within an organism where a drug
binds/interacts with to bring about a specific pharmacological effect.

• These targets could either be structures within the human body or rather could
be various structures found within microbes.

• Various drug targets are going to mainly include the following;

Receptors
Enzymes
Ion channels
Transporters
Nucleic acids
 Drug targets cont’d
Receptors Agonists Antagonists
Nicotinic Ach receptors Acetylcholine Tubocurarine
Nicotine Α-Bungarotoxin
Beta-adrenoceptor Noradrenaline Propranolol
Histamine (H1-receptor) Histamine Mepyramine
Histamine (H2-receptor) Ranitidine
Opiate (μ-receptor) Morphine Naloxone
5-HT2-receptor 5-Hydroxytryptamine Ketanserin
Dopamine (D2 receptor) Dopamine Chlorpromazine
Bromocriptine
Insulin receptor Insulin
Oestrogen receptor Ethinyllestradiol Tamoxifen
Progesterone receptor Norethisterone Danazol
 Drug targets cont’d
Enzymes Inhibitors False substrates
Acetylcholinesterase Neostigmine
Organophosphates
Choline acetyltransferase Hemicholinium
Cyclooxygenase Aspirin
Xanthine oxidase Allopurinol
Angiotensin Converting Enzyme Captopril
Carbonic anhydrase Acetazolamide
HMG-CoA reductase Simvastatin
Dopa decarboxylase Carbidopa Methyldopa
Monoamine oxidase-A Iproniazid
Monoamine oxidase-B Selegiline
Dihydrofolate reductase Trimethoprim
Methotrexate
DNA polymerase Cytarabine Cytarabine
Enzymes involved in DNA synthesis Azathiaprine
Enzymes of blood clotting cascade Heparin
Thymidine kinase Acyclovir
HIV protease Saquinavir
Reverse transcriptase Didanosine, Zidovudine
 Drug targets cont’d
Ion Channels Blockers Modulators
Voltage-gated sodium channels Local anesthetics Veratridine
Tetrodotoxin
Renal tubule sodium channels Amiloride Aldosterone
Voltage gated calcium channels Divalet cations Dihydropyridines
Beta-adrenoceptor agonists
Voltage gated potassium channels 4-Aminopyridine …….
ATP-sensitive potassium channels ATP Sulfonylureas
GABA-gated chloride channels Picrotoxin Benzodiazepines
Glutamate gated (NMDA) channels Mg2+ Glycine

Carriers/Transporters Inhibitors False substrates

Noradrenaline Uptake 1 Tricyclic antidepressants Amphetamine
Cocaine Methyldopa
Noradrenaline uptake (vesicular) Reserpine
Na+/K+/Cl- co-transporter Loop diuretics
Na+/K+ pump Cardiac glycosides
Proton pump (gastric mucosa) Omeprazole

DNA Drugs that damage DNA directly

Cisplatin, Etoposide, Topotecan, Gemcitabine
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