Pharmacodynamics I and II PDF

Pharmacodynamics I and II Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Objectives Define the different types of receptors at which drugs can act. Outline receptor mediated signal transduction mechanisms. Describe the relationship between drug...

Pharmacodynamics I and II Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Objectives Define the different types of receptors at which drugs can act. Outline receptor mediated signal transduction mechanisms. Describe the relationship between drug dose and response using graded and quantal dose response curves. Define potency, efficacy, and affinity, and differentiate these parameters on a dose response curve. Differentiate between full, partial & inverse agonists.  Differentiate between synergism, potentiation & additive effects. Differentiate between a competitive and non-competitive antagonist. Define TD50, LD50 and ED50; differentiate between ED50/EC50 Define the concept of a therapeutic window and calculate therapeutic index of drugs. Define desensitization/tachyphylaxis, tolerance & up/down regulation of receptors.  Receptors Therapeutic and toxic effects of drugs result from their interaction with molecules on/in target cells known as receptors. Association of the drug molecule with these special molecules alters biochemical and/or biophysical activity of a cell and consequently the function of an organ. A receptor is defined as the component of a cell (cellular macromolecule or an assembly of macromolecules) that interacts with a drug or an endogenous molecule to initiate a chain of biochemical events leading to an observed biological effect.  Examples of ligands that interact with receptors Neurotransmitters Ions Hormones Immunoglobulins Lipoproteins Carbohydrates Drugs Affinity KD Defines the concentration of the ligand at which 50 % of the receptors are occupied. The lower the KD the higher the affinity. Intrinsic activity (Efficacy) is a measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity. Receptor mediated signal transduction mechanisms Reception Activation of Effectors Transduction Cellular Response Signal Amplification Termination of Signal Intracellular Messengers Feedback Regulation Signal Integration Pathways  Important Receptor Properties Receptors are normal points of control of physiological processes. Under physiological conditions receptors are regulated by endogenous molecules. Drugs mimic or block endogenous regulator molecules. Drugs cannot give cells new functions- only alter pre-existing processes. Drugs are therapeutically beneficial by helping the body use its pre-existing capabilities to patient’s best advantage. In theory it should be possible to synthesize drugs that can alter the rate of any biological process for which receptors exist.  Drug-Receptor Interaction Agonist (ligand) A drug that produces the maximal response is termed a full agonist and has 100% intrinsic activity. Intrinsic activity is the ability of a drug to elicit a response. Full agonists will produce maximal system (tissue) response.  Drug-Receptor Interaction Partial agonist Binds with full affinity like an agonist but produces only partial effects. Even with full Occupancy. Partial agonist have partial intrinsic activity Antagonist Drugs or other endogenous ligands (hormones or neurotransmitters) with very little or no intrinsic activity. Will bind to the receptor with more or less the same affinity as an agonist. Drugs that block stimulation is considered to be an antagonist. Receptors are Physiological Regulatory Molecules They bind the appropriate endogenous ligand (hormones, growth factors and neurotransmitters) and, in response, propagate a regulatory signal in the target cell. Ligand binding domain Effector domain (Transducers)= second messenger, also known as intracellular signaling pathway  Drug Concentration and Response Clinically a complex relationship. Under controlled situations, responses to low doses of a drug increases in an incremental manner. As doses increase, the response increment diminishes. At some point, increasing the dose will result in no further increase in response Dose-Response Curves Arithmetic scale: Easier to observe the linearity of response at low drug concentrations Hard to visualize the effects of large changes in concentration Hard to compare the effects of drugs Dose-Response Curves Logarithmic scale: Larger dose range can be plotted Linear parts of curves allow easy comparison of drugs. Easier to identify drug concentration for a maximum effect.  Dose-Response Curve Log Too little drug, no effect - a subeffective dose. Threshold effect and threshold dose, i.e. a minimally effective dose The plot shows a graded response – increasing dose increases the intensity of effect from point (#2) up to point (#4). The effect is said to be dose-dependent. Ceiling effect, or maximal effect. A higher dose does not increase effect. Response to a maximally effective dose. (Note: the only way to tell if you have reached maximum response is to increase the dose until you get no further increase in response.) Two-state Receptor Theory It proposes that ligand binding results in a change in receptor state from an inactive to an active state based on the receptor's conformation. A receptor in its active state will ultimately elicit its biological response. It is an alternative model of receptor activation. In this model agonists and inverse agonists are thought to have selective binding affinity for the pre-existing resting and active states or can induce a conformational change to a different receptor state. Regulation of the activity of a receptor with conformation-selective drugs Efficacy and Potency Efficacy is the maximum attainable effect. A comparison of effectiveness between two or more drugs requires a comparison of the maximal effects obtained regardless of the dose required to obtain it. Efficacy is that property intrinsic to a particular drug that determines how “good” an agonist the drug is. Efficacy and Potency Potency is the amount of drug required to produce a given effect. Can be defined in several ways: ED% effect (e.g., ED50). Is the dose required for a certain percentage of patients to respond. (e.g., dose where 50% of patients respond). EC50 is the concentration of drug that produces 50% of the maximal response. Competitive Antagonism A. Competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site on the receptor. Response curves for the agonist are shifted to the right in a concentration-related manner by the antagonist such that the EC50 for the agonist increases. Noncompetitive Antagonism B. If the antagonist binds to the same site as the agonist but does so irreversibly or pseudo-irreversibly (slow dissociation but no covalent bond), it causes a shift of the dose-response curve to the right, with further depression of the maximal response. OVERALL DOSE-EFFECT RELATIONSHIPS: BENEFIT vs. TOXCITY vs. DOSE Toxicity - undesired side effect of drug that can range in severity from minor annoyance to death. For every drug there is a dose-response curve for effectiveness and at least one dose-response curve for toxicity. Therapeutic Index (index of safety) Therapeutic Index (index of safety) Ratio of median lethal dose to median effective dose (definition often used in preclinical screening) a. Median effective dose = dose required to produce specified effect in 50% of cases (ED50) b. Median lethal dose = dose required to produce death in 50% of cases (LD50) c. Example: if LD50 = 150 mg and ED50 = 50 mg, 150 Therapeutic index = ------- = 3 50 Similar definition used clinically but median toxic dose refers to dose required to produce some toxic (undesired) effect. Therapeutic Index (TI) The important factor is to have a clear gap between the maximum dose required to produce the therapeutic effect and the minimum dose which will cause death or undesirable side effects. Drugs with a low therapeutic index may only require a small increase in dose to produce toxic effects. A high therapeutic index is good. Regulation of Receptors Regulation of the synthesis and degradation Covalent modification Association with other regulatory proteins Relocalization within the cell Transducer and effector proteins are regulated similarly Regulation of Receptors Desensitization: Occurs after continued stimulation because of adaptation or down-regulation. Also known as tachyphylaxis occurs very rapidly and is very important in therapeutic situations. Example: Attenuated response to continuous administration of b- agonist for asthma.  Upregulation: Higher number receptors due to either too little agonist amount or prolonged use of antagonists. Downregulation: Less number of receptors due to overstimulation with too much agonist. Drug Interactions Synergism-the effect of two drugs is greater than the sum of their individual effects Additive effects- the effect of two drugs is the sum of the effects of each Potentiation- occurs when one drug that does not elicit a response on its own, enhances the response to another drug.