Pharmacodynamics Dose response relation Efficacy Potency Therapeutic index

PHARMACODYNAMICS What do drugs to the body?

To have a good fit to only one type of receptor; • Must be

Receptor: The component of a cell or organism that interacts with a drug and

Lippincott Illustration Reviews Pharmacology, 6 th edition

• Receptors largely determine the quantitative relations between dose or concentration of drug

Agonist: binds to receptor and activates it, it brings directly/indirectly an effect Antagonist: binds

Potency • EC 50 (the dose of the agonist at which %50 of the

Katzung&Trevor Basic and Clinical Pharmacology, 13 th edition

Potency vs efficacy • Potent • Efficacious • Efficacy refers to the effect of

Therapeutic index Therapeutic Index: LD 50/ED 50 Therapeutic Index: TD 50/ED 50 Lippincott Illustration

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Cumulative dose-reponse relation In the absence of spare receptors, EC 50 is equal to

antagonism Competetive • Antagonist competes with the agonistfor the same binding site of the

p. D 2 • Measures the affinity of a noncompetetive as well as irreversible

Noncompetetive antagonism • Irreversible (covalent bounds) • When the dose of antagonist is increased,

p. A 2 • Measure of the affinity of a reversible competetive antagonist for

Quantal dose response curve • Like a drug used to the pain • Either

• ED 50: the dose of the drug required to achieve half of

Receptors • Regulatory proteins • Enzymes (dihydrofolate reductase, receptor for methotrexate) • Transport proteins(

Receptors are responsible for selectivity of drug action

Orphan receptors • Their ligands are presently unknown (Farnesoid X receptor, Liver X receptor…)

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Pharmacodynamics Dose response relation Efficacy Potency Therapeutic index

PHARMACODYNAMICS What do drugs to the body?

To have a good fit to only one type of receptor; • Must be sufficiently unique in shape, charge and other properties • For selective binding, MW should be at least 100

Receptor: The component of a cell or organism that interacts with a drug and iniates the chain of events leading to the drug’s observed effects

Lippincott Illustration Reviews Pharmacology, 6 th edition

• Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacological effects • Receptors are responsible for selectivity of drug action • Receptors mediate the actions of pharmacological agonists and antagonists

Agonist: binds to receptor and activates it, it brings directly/indirectly an effect Antagonist: binds to receptor, competes with and prevents binding by other molecules Partial agonist: bind to the same receptor as full agonists and activates them, but does not evoke as great response (even with high concentrations). May act either as an agonist or antagonist Inverse agonist: binds to receptor and reduces its constitutive activity

Lippincott Illustration Reviews Pharmacology, 6 th edition

Potency • EC 50 (the dose of the agonist at which %50 of the effect is produced in presence of antagonist

Lippincott Illustration Reviews Pharmacology, 6 th edition

Efficacy • Emax

Lippincott Illustration Reviews Pharmacology, 6 th edition

Katzung&Trevor Basic and Clinical Pharmacology, 13 th edition

Lippincott Illustration Reviews Pharmacology, 6 th edition

Potency vs efficacy • Potent • Efficacious • Efficacy refers to the effect of a drug. The more effect the more efficacious the drug • Potency refers to the concentration of a drug needed for the effect. The less the concentration required, the more potent the drug

Therapeutic index Therapeutic Index: LD 50/ED 50 Therapeutic Index: TD 50/ED 50 Lippincott Illustration Reviews Pharmacology, 6 th edition

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Cumulative dose-reponse relation In the absence of spare receptors, EC 50 is equal to disociation constant of agonist-drug complex (Kd)

antagonism Competetive • Antagonist competes with the agonistfor the same binding site of the receptor • binding is reversible • Antagonism can be overcome by increasing concentration of agonist or vice versa • Parallel shift of curve to right with increasing concentration of antagonist but maximum response remains same

Katzung&Trevor Basic and Clinical Pharmacology, 13 th edition

p. D 2 • Measures the affinity of a noncompetetive as well as irreversible competetive antagonist for a spesific receptor • Defined as negative logarithm of the molar concentration of noncompetetive antagonist which will reduce the effect of an agonist to one half (%50) its maximum • p. D 2’=p. Dx+log[(E 1/2)-1] • p. Dx, negative molar concentration of the antagonist • E 1, E 2 max contraction heights in the absence and presence of antagonist

Noncompetetive antagonism • Irreversible (covalent bounds) • When the dose of antagonist is increased, maximal response of antagonist will decrease • In the presence of high doses of antagonist, no effect of agonist could be seen

Lippincott Illustration Reviews Pharmacology, 6 th edition

p. A 2 • Measure of the affinity of a reversible competetive antagonist for a spesific receptor • Defined as the negative log of molar concentration of the antagonist which will reduce the effect of double dose of the agonist drug to that of a single dose • p. A 2=-log KB

Quantal dose response curve • Like a drug used to the pain • Either no effect (zero effect) • Or pain relieved (max effect)

Katzung&Trevor Basic and Clinical Pharmacology, 13 th edition

• ED 50: the dose of the drug required to achieve half of the expected response • TD 50: the dose of the drug required to achieve toxicity in half of the subjects given the drug • LD 50: the dose of the drug required to be lethal to half of the subjects given the drug • t 1/2: half life, the amount of time required to lower the concentration for the drug by half

Signaling mechanisms Drug Action

Receptors • Regulatory proteins • Enzymes (dihydrofolate reductase, receptor for methotrexate) • Transport proteins( Na+-K+-ATPase, a receptor for digitalis glycosides) • Structural proteins (tubulin, a receptor for colchicine)

Receptors are responsible for selectivity of drug action

Orphan receptors • Their ligands are presently unknown (Farnesoid X receptor, Liver X receptor…)

Lippincott Illustration Reviews Pharmacology, 6 th edition