How drugs Act :General principles Lecture 2

1. Objectives/ Learning outcome: How drugs Act :General principlesLecture 2 • Define various targets of drug actions • Define receptor, types and examples • Describe agonist and antagonist and their characteristics. • Mechanism of antagonism • Desensitization and Tachyphylaxis

2. Targets of drugs action Drugs are effective because they bind to particular targets proteins, a drug will not work unless it is bound.. One of the basic tenets of pharmacology is that drug molecules must exert some chemical influence on one or more constituents of cells in order to produce a pharmacological response. In order words drugs molecules must be bound to particular constituents of cells and tissue in order to produce an effect.

3. Ehrlich summed it up thus; ‘Corpora non agunt nisi fixata’( in this context, ‘A drug will not work unless it is bound’. Therefore understanding the nature of these binding sites, and the mechanisms by which the association of drug molecules with a binding site leads to a physiological response, constitutes the major trust of pharmacological research. Most drugs produce their effects by binding, in the first instance, to protein molecules often called “Targets”.

4. Classification of drug binding sites: There are four major binding sites for drugs which are :- Enzymes, Ion-channels, Carrier molecules and Receptors. Enzymes: Many drugs target enzymes, by competitive inhibition of the enzyme either reversibly e.g. neostigmine on acetylcholinerase or irreversibly e.g. aspirin, acting on cyclooxygenase.

5. Ion-channels: Drugs either open or block ion channels by directly acting on the channels or via receptors or G-proteins that are coupled with the channels. Carrier molecules: Carrier molecules are required for the transport of ions and small organic molecules across cell membranes. e.g. of these carrier proteins are those required for transport of: – glucose and amino acids into cells, ions and organic molecules by renal tubules, calcium and sodium out of cells, and uptake of neurotransmitter precursors (e.g. choline) neurotransmitters (e.g. noradrenaline).

6. Receptors: Receptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body the chemical messengers being the various hormones, transmitters and other mediators. Many therapeutically useful drugs act either as agonist or antagonist on receptors for known endogenous mediators.

7. Types of receptors: Receptors proteins are produced by the cells that express them, these receptor types are: i) channel-linked(ionotropic), ii) G-protein coupled, iii) Kinase-linked, and iv) Nuclear receptors. i) Channel-linked (ionotropic): These are membrane receptors that are coupled directly to an ion-channel, e.g. nicotinic acetylcholine and glutamate receptors. ii) G-protein coupled (metabotropic) :Membrane receptors, coupled to intracellular effectors system via a G-protein e.g. muscarinic acetylcholine and adrenergic receptors.

8. In many cases these intracellular domain are enzymatic in nature (with protein Kinase or guanylate cyclase activity). e.g. insulin and various cytokines and growth factors. iii) Kinase-linked: These are membrane receptors which incorporates an intracellular protein kinase domain in their structure. iv) Nuclear receptors : These are receptors that regulates gene transcription e.g. steroid hormones, thyroid hormones and other agents such as retinoic acid and vitamin D.

9. Agonist and Antagonist Agonist: Agonist is a substance/drug that binds to and activates a receptor, in the process mimicking the effect of a natural neurotransmitter or hormone. .It initiates changes in cell function ,thereby producing effects of various types e.g. Phenylepherine. Types of Agonist: • Full agonist:These are drugs that induces maximum response the cells or tissues can give in high concentration e.g. Acetylcholine.

10. 2) Partial agonist: These are drugs that induces only a submaximal response on the cells or tissues. Features of Agonist: Potency:The amount of drug that is needed to produce a given response. Affinity : The tendency of a drug to bind to receptors. Efficacy :The ability of the drug to produce a desired therapeutic effect.

11. Antagonist: Antagonist is a substance that binds to and block a receptor, thereby preventing a natural neurotransmitter or hormones or drug from exerting its effect. It binds to site but does not cause any action. It has no efficacy because it generates no change in physiological action e.g. Atropine.

12. Type of antagonist: 1) Antagonism by receptor block: Receptor-block antagonism involves two important mechanisms: Reversible and Irreversible competitive antagonism. Competitive Antagonism : These occurs when two drugs compete for the same receptor site. The two drugs compete with each other, because the receptor can bind only one drug molecule at a time.

13. Reversible antagonism: parallel shift of the agonist log concentration-response curve without reduction in maximal response. rate of dissociation of the antagonist molecules is sufficiently high that a new equilibrium is rapidly established on addition of the agonist. Irreversible antagonism: Irreversible or non-equilibrium competitive antagonism occurs when the antagonist dissociates very slowly, or not at all, from the receptors, with the result that no change in the antagonist occupancy takes place when the agonist is applied.

14. Chemical antagonism:These is a situation where two drugs combine in solution, as a result the effect of the active is lost. Examples include the use of chelating agents (e.g. dimercaprol) that bind to heavy metals and thus reduce their toxicity. Pharmacokinetic antagonism: Pharmacokinetic antagonism describes the situation in which the antagonist effectively reduces the concentration of active drug at its site of action.

15. This could be through increase in metabolic degradation of active drug, or reduction of the rate of absorption or renal excretion e.g. Phenobarbitone induces liver enzymes and accelerates the metabolism of warfarin.

16. Non-competitive antagonism:Non-competitive antagonism describes the situation where the antagonist blocks at some point the chain of events that leads to production of response by the agonist. Physiological Antagonism: Physiological antagonism is a term used to describe the interaction of two drugs whose opposing actions in the body tend to cancel each other.

17. Desensitisation and Tachyphylasis: • Desensitisation and tachyphylasis:when a drug given continuously or repeatedly, the effect of the drug gradually diminishes. It occurs in a course of few minutes. • Tolerance:gradual decrease in responsiveness to drug, taking days or weeks to develop • Refractoriness: the loss of therapeutic efficacy. • Drug resistance: loss of effectiveness of antimicrobial drugs or antitumour drugs.

18. Many different mechanism can give rise to this type of phenomenon. They include • Change in receptors • Loss of receptors • Exhaustion of mediators • Increased Metabolic Degradation • Physiological Adaptation

19. End Of Lecture 2 Thank You