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FBS IV, CASE 7, INDIVIDUAL DRUG RESPONSES PHARMACODYNAMICS & AGONIST & ANTAGONIST
WHAT WOULD BE EXPLAINED IN THIS HANDOUT?
I. INTRODUCTION TO PHARMACODYNAMICS Pharmacodynamic definition Important practical consequences of the receptor concepts II. MOLECULAR NATURE OF DRUG RECEPTORS III. AGONIST AND ANTAGONIST Competitive and Irreversible Antagonist Partial Agonist Other Mechanism of Drug Antagonism IV. SIGNALING MECHANISM AND DRUG ACTIONS V. VARIATION IN DRUG RESPONSIVENESS I. INTRODUCTION TO PHARMACODYNAMICS Pharmacodynamic definition Drug actions on target cells and resulting cellular biochemical reaction of in simple terms What the drug does to the body. Important practical consequences of the receptor concepts 1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. 2. Receptors are responsible for selectivity of drug action. 3. Receptors mediate the actions of both pharmacologic agonists and antagonists. II. MOLECULAR NATURE OF DRUG RECEPTORS 1. "Orphan" receptors their ligands are presently unknown. 2. Regulatory proteins such as neurotransmitters, autacoids, hormones. 3. Enzymes may be inhibited or activated by binding a drug 4. Transport proteins Na+/K+ ATPase, for cardioactive digitalis glycosides. 5. Structural proteins tubulin, the receptor for an anti-inflammatory agent. III. AGONIST AND ANTAGONIST Agonist and Antagonist themselves Agonist is a ligand that binds to a receptor and produces a biological effect (direct acting) or a compound that indirectly produces the same effect of a neurotransmitter (indirect acting). Usually mimic neurotransmitter actions. Antagonist is a ligand that binds to a receptor but does not produce a biological effect or a compound that indirectly inhibits the effect of a neurotransmitter. Usually inhibit neurotransmitter actions.
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Classification of Agonist 1. Full Agonist, occupy all the receptors. 2. Partial Agonist, occupy the receptors, but cannot elicit maximal response. 3. Inverse Agonist, opposite the effects of conventional agonist. Classification of Antagonist 1. Competitive Antagonist, interact with the same site of receptors. 2. Noncompetitive Antagonist, interact with different site of receptors. a) Reversible, prevents [antagonist-receptor] b) Irreversible, may form long-lasting bond with receptors Schild equation The concentration (C) of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (the "dose ratio") is related to the dissociation constant (Ki) of the antagonist

For the clinician, this relation has two important therapeutic implications: 1. The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist. 2. Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors.

Other Mechanism of Drug Antagonism 1. Chemical antagonist, by ionic binding that makes the other drug unavailable for interactions. 2. Physiologic antagonism, antagonism between endogenous regulatory pathways mediated by different receptors.

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IV. SIGNALING MECHANISM AND DRUG ACTIONS

1. A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor 2. The signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain 3. The signal binds to the extracellular domain of a transmembrane receptor bound to a protein tyrosine kinase, which it activates 4. The signal binds to and directly regulates the opening of an ion channel 5. The signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. *(A, C, substrates; B, D, products; R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.) V. VARIATION IN DRUG RESPONSIVENESS 1. Hyporeactive or Hyperreactive, the intensity of effect of a given dose of drug is diminished or increased in comparison to the effect seen in most individuals. 2. Tolerance, responsiveness usually decreases as a consequence of continued drug administration. 3. Tachyphylaxis, when responsiveness diminishes rapidly after administration of a drug.

Sources; Basic & Clinical Pharmacology 10th Edition (2007) Jan Bazner-Chandler. Basic Concepts of Pharmacology. http://wings.buffalo.edu/aru/Agonists&Antagonists.html Chandra, Preciella. 2011. PHARMACODYNAMIC : Agonist & Antagonist.

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