Pharmacodynamics Lecture Notes PDF

1 AIMS AND OBJECTIVES 1. The aim of this lecture is to provide you with an understanding of drug-receptor interactions to eventually help you consider therapeutic decisions in clinical practice. 2. To this end the quantitative relationship between drug concentration and response...

1 AIMS AND OBJECTIVES 1. The aim of this lecture is to provide you with an understanding of drug-receptor interactions to eventually help you consider therapeutic decisions in clinical practice. 2. To this end the quantitative relationship between drug concentration and response are presented and the concepts underlying agonist and antagonist drug action described. 3. At the end of this lecture you should know what is meant by the terms: affinity, efficacy, potency, agonist, antagonist and partial agonist. 2 Objective-1: Discuss Drugs and their Targets  Medical pharmacology is the science of the interactions of chemicals (drugs) with the human body.  In many cases, drugs produce their effects by interacting with targets, which are mostly proteins; (with some exceptions e.g. some antimicrobial and antitumour drugs bind DNA ) 3 pharmacodynamics  Drug + target interactions Many drugs targets are receptors Receptor = a protein that contains a site for binding endogenous ligands like steroid receptor If a drug binds to non-endogenous ligand site, that site is called acceptor like enzyme blocker Objective- 2: Explain the relevance of the concentration of drug molecules 7 Drug-receptor interactions:  Most drugs bind reversibly with receptors.  Binding is governed by association and dissociation.  Binding obeys the low of mass action: ie. It is related to the concentrations of reactants and products 8  Objective- 3: Explain Affinity, Efficacy and Potency Drug Concentration and Drug Response Drugresponse is generally proportional to number of receptor sites bound by the drug. Target receptors can exist at different tissues throughout the body. Affinity : describes strength of drug binding with receptor. Efficacy: describes ability of drug-bound receptor to produce a response. 13 Agonists :Some drugs bind to receptors and cause a response - these drugs have both affinity and efficacy. Antagonists: Some drugs bind to receptors but do not cause a response - these drugs have affinity only. They block the effects of agonists ie. prevent receptor activation by agonists. 14 Objective: The concept of the spare receptors Spare receptors are the unoccupied fraction of receptors when the agonist achieves Emax I.e Emax is achieved at subBmax So it is just a reverse concept to the partial agonist when SubEmax achieved at Bmax The clinical and functional importance of spare receptors: 1. It provides hormonal and energy economy like achievement of efficient O2 exchange in resting level of adrenaline stimulation of bronchial beta2R, so provide efficient physiological response 2. It ensures Emax and maintained drug efficacy even in case of pathological receptor down-regulation like post-ischemic HF. So that Emax for dobutamine (beta2R stimulant) may be maintained even in HF. 19 Gyukkkkjhn 20 Concentration/Dose Response Curves  Emax = Maximum Response  EC50 = Effective Concentration giving 50% of the maximal response Potency denotes the amount of drug needed to produce a given effect. In dose-response measurements, the effect usually chosen is 50% of the maximal effect and the concentration or dose causing this effect is called the EC50 The number of receptors also governs potency. 21 22 23 24 Objective-: Explain what is meant by “partial agonist and full agonist”  When comparing the ability of different agonists to evoke responses in a tissue, it is sometimes observed that some drugs cannot produce a maximal effect, even with full receptor occupancy.  These drugs are referred to as partial agonists. 25  The EC50 of a partial agonist is equal to its Kd.  The potency of a drug is dependent on both its affinity and efficacy; therefore partial agonists can be more or less potent than full agonists.  A partial agonist may not always be a partial agonist, depending on the tissue and the biological response. 26 9 27 Objective-: Explain the different types of Antagonists  There are three different types of Antagonists (Block the effects of agonists) 1. Reversible Competitive Antagonism 2. Irreversible Competitive Antagonism 3. Non-Competitive Antagonism 29 31 1. Reversible Competitive Antagonism  The commonest form and most important in therapeutics, relying on a dynamic equilibrium between ligands and receptors  IC50 – Concentration of Antagonist giving 50% inhibition.  Kd – Concentration of Antagonist needed to give 50% occupancy  Reversible competitive antagonists can be overcome by high concentrations of agonists, thus cause a parallel shift to the right of the agonist concentration-response curve. 32 33  2. Irreversible Competitive Antagonism  Occurs when the antagonist dissociates slowly, or not at all.  Irreversible competitive antagonisms cause a parallel shift to the right of the agonist concentration-response curve and at higher concentrations suppress the maximal response as spare receptors are filled by the antagonist, not leaving enough receptors free to illicit a maximal response. 34 35 The characteristics of the agonist and antagonists 1. It is determined only after Bmax (full occupancy of D+R) to decide whether it is full or partial agonist 2. Agonist is a tissue dependent response. Eg some partial agonists in the heart are full agonists in the lung. 3. The inverse agonist has Emax < 0 4. The antagonist has Emax = 0 and Bmax > agonist 5. The partial agonist has Emax < full agonist Emax and Bmax > or = agonist Bmax