1. Types of antagonists

2. Antagonists, Overview  Definition “An antagonist is a substance that does not provoke a biological response itself, but blocks or reduces agonist-mediated responses”  Antagonists have affinity but no efficacy for their cognate receptors  Binding of antagonist to a receptor will inhibit the function of a partial agonist, an agonist or inverse agonist at that receptor  Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity.  Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex which in turn depends on the nature of antagonist receptor binding.

3. Antagonists, 1-Competitive reversible antagonist  It binds to same site on receptor as agonist  inhibition can be overcome by increasing agonist concentration (i.e., inhibition is reversible)  No significant depression in maximal response (E max ??)  The agonist dose-response curve will be shifted to the right (without a change in the slope of the curve)  Maximal response occurs at a higher agonist concentration than in the absence of the antagonist  It primarily affects agonist potency  Clinically useful  Example: Prazosin at  adrenergic receptors Agonist Antagonist + Agonist EC 50A EC 50B

5. Antagonists, 2- Competitive irreversible antagonist  It binds to same site on receptor as agonist  The antagonist possesses reactive group which forms covalent bond with the receptor  the antagonist dissociates very slowly, or not at all  inhibition cannot be overcome by increasing agonist concentration (i.e., inhibition is irreversible)  Maximal response is depressed (i.e., E max is decreased)  The agonist dose-response curve will be shifted to the right (the slope of the curve will be reduced)  Agonist potency may or may not be affected  The only mechanism the body has for overcoming the block is to synthesize new receptors  Experimental tools for investigating receptor functions  Example: phenoxybenzamine at  adrenergic receptors

6. Competitive reversible antagonist vs Competitive irreversible antagonist Antagonists, contd.

7. Antagonists, 3- Non-competitive antagonist  It does not bind to the same receptor sites as the agonist. It would either:  bind to a distinctly separate binding site from the agonist  decreased affinity of the receptor for the agonist, “allosteric inhibition”,  So, it prevents conformational changes in the receptor required for receptor activation after the agonist binds  “allosteric inhibition”,  or alternatively block at some point the chain of events that leads to the production of a response by the agonist  I nhibition cannot be overcome by increasing agonist concentration (irreversible)  Agonist maximal response will be depressed  Agonist dose-response curve will be shifted to the right (the slope of the curve will be reduced)  Agonist potency may or may not be affected Agonist Antagonist + Agonist  Example: the noncompetitive antagonist action of crystal violet (CrV) on nicotinic acetylcholine receptors is explained by an allosteric mechanism in which the binding of CrV to the extracellular mouth of the resting receptor leads to an inhibition of channel opening

9. Antagonists, contd. 4.Physiologic (functional) antagonist Physiologic antagonism occurs when the actions of two agonists working at two different receptor types have opposing (antagonizing) actions Example 1: Histamine acts at H 1 receptors on bronchial smooth muscle to cause bronchoconstriction, whereas adrenaline is an agonist at the β 2 receptors bronchial smooth muscle, which causes bronchodilation. Example 2: histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump 5.Chemical antagonist Chemical antagonism occurs when two substances combine in solution  the active drug is lost Example : Chelating agents (e.g., dimercaprol) that bind heavy metals, and thus reduce their toxicity 6.Pharmacokinetic antagonist Pharmacokinetic antagonist effectively reduces the concentration of the active drug at its site of action Example: phenobarbital accelerates the rate of metabolic degradation of warfarin

10.  A) Additive: 1+1= 2  B) Synergism: 1+1= 4  C) Potentiation: 1+0= 2

11. Drug-Receptor Bonds 1. Covalent Bond -Very strong -Not reversible under biologic conditions  unusual in therapeutic drugs Example: phenoxybenzamine at  adrenergic receptors The rest of pharmacology is concerned with weak, reversible, electrostatic attractions: 2. Ionic bond -Weak, electrostatic attraction between positive and negative forces -Easily made and destroyed 3. Dipole - dipole interaction -A stronger form of dispersion forces formed by the instantaneous dipole formed as a result of electrons being biased towards a particular atom in a molecule (an electronegative atom). -Example: Hydrogen bonds

12. Drug-Receptor Bonds, contd. 4. Hydrophobic interactions “The tendency of hydrocarbons (or of lipophilic hydrocarbon-like groups in solutes) to form intermolecular aggregates or intramolecular interactions in an aqueous medium” -usually quite weak -important in the interactions of highly lipid- soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “pockets” 5. Dispersion (Van der Waal) forces -Attractive forces that arise between particles as a result of momentary imbalances in the distribution of electrons in the particles. -These imbalances produce fluctuating dipoles that can induce similar dipoles in nearby particles, generating a net attractive force.

13. Drug-Receptor Bonds and Selectivity  Drugs which bind through weak bonds to their receptors are generally more selective than drugs which bind through very strong bonds  This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur  Only a few receptor types are likely to provide such a precise fit for a particular drug structure  To design a highly selective short acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds  Selectivity: Preferential binding to a certain receptor subtype leads to a greater effect at that subtype than others -e.g. salbutamol binds at β 2 receptors (lungs) rather than at β 1 receptors (heart)  Lack of selectivity can lead to unwanted drug effects. -e.g. salbutamol (  2 -selective agonist ) vs isoprenaline (non-specific  -agonist) for patients with asthma. Isoprenaline  more cardiac side effects (e.g., tachycardia)

14.  A measure of drug safety  The ratio of the dose that produce toxicity to the dose that produce effective response  It is obtained from quantal DRC (all-or-none effect ) TD50/ED50  TD50 = The drug dose that produce toxic effect in 50% of population  ED50 = The drug dose that produces a therapeutic or desired response in 50% of population  Examples ◦ Warfarin (narrow index) ◦ Penicillin (wide index) ◦ In general, a larger T.I. indicates a clinically safer drug Standard safety margin (SSM):  SSM= LD1 - 1 x 100  ED99

16.  High therapeutic index ◦ NSAIDs  Aspirin  Paracetamol  Ibuprofen ◦ Most antibiotics ◦ Beta-blockers  Low therapeutic index ◦ Lithium ◦ Neuroleptics  Phenytoin  Phenobarbital ◦ Digoxin ◦ Immunosuppressives Therapeutic Index (T.I.), contd.