Molecular and Cellular Mechanisms of Drug Action PDF

Molecular Mechanisms of Drug Action 1 PG Lecture Series COCP-KFU  Intending learning outcomes Understand pharmacodynamic concepts Define and describe the importance of molecular drug targets and their actions Demonstrate and interpret consequences of drug intera...

Molecular Mechanisms of Drug Action 1 PG Lecture Series COCP-KFU  Intending learning outcomes Understand pharmacodynamic concepts Define and describe the importance of molecular drug targets and their actions Demonstrate and interpret consequences of drug interaction with their targets. Define and describe receptor affinity and intrinsic activity at molecular level showing understanding as it relates to drug efficacy Pharmacodynamics Concepts Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their mechanisms of action. The effects of most drugs result from their interaction with macromolecular components of the organism. Pharmacodynamics Concept The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular response. Drugs commonly alter the rate or magnitude of an intrinsic cellular response rather than create new responses. Drug receptors are often located on the surface of cells but may also be located in specific intracellular compartments such as the nucleus. Pharmacodynamics Concept Many drugs also interact with acceptors (e.g., serum albumin) within the body. Acceptors are entities that do not directly cause any change in biochemical or physiological response. However, interactions of drugs with acceptors can alter the pharmacokinetics of a drug's actions.  Physiological receptors Many drug receptors are proteins that normally serve as receptors for endogenous regulatory ligands. These drug targets are termed physiological receptors. Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signalling compounds are termed agonists. Physiological receptors If the drug binds to the same recognition site as the endogenous agonist, the drug is said to be a primary agonist. Allosteric (or allotopic) agonists bind to a different region on the receptor referred to as an allosteric or allotopic site.  Physiological receptors Drugs that block or reduce the action of an agonist are termed antagonists. Antagonism generally results from competition with an agonist for the same or overlapping site on the receptor (a syntopic interaction). Antagonism can also occur by interacting with other sites on the receptor (allosteric antagonism). Or by combining with the agonist (chemical antagonism), or by functional antagonism by indirectly inhibiting the cellular or physiological effects of the agonist.  Physiological receptors Agents that are only partly as effective as agonists are termed partial agonists. Many receptors exhibit some constitutive activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed inverse agonists. In the presence of a full agonist, partial and inverse agonists will behave as competitive antagonists. Specificity of Drug Responses The strength of the reversible interaction between a drug and its receptor, as measured by the dissociation constant, is defined as the affinity of one for the other. Both the affinity of a drug for its receptor and its intrinsic activity are determined by its chemical structure. The chemical structure of a drug also contributes to the drug’s specificity.  Specificity of Drug Responses A drug that interacts with a single type of receptor that is expressed on only a limited number of differentiated cells will exhibit high specificity. Conversely, a drug acting on a receptor expressed ubiquitously throughout the body will exhibit widespread effects. Specificity of Drug Responses Many clinically important drugs exhibit a broad (low) specificity because they interact with multiple receptors in different tissues. Such broad specificity might not only enhance the clinical utility of a drug but also contribute to a spectrum of adverse side effects because of off-target interactions.  Specificity of Drug Responses One example of a drug that interacts with multiple receptors is amiodarone, an agent used to treat cardiac arrhythmias. Amiodarone also has a number of serious toxicities, some of which are caused by the drug’s structural similarity to thyroid hormone. Amiodarone toxicities may also be mediated through interactions with receptors that are poorly characterized or unknown.  Specificity of Drug Responses Some drugs are administered as racemic mixtures of stereoisomers. The stereoisomers can exhibit different pharmacodynamic as well as pharmacokinetic properties. For example, the antiarrhythmic drug sotalol is prescribed as a racemic mixture; the D- and L-enantiomers are equipotent as K+ channel blockers, but the L-enantiomer is a much more potent β adrenergic antagonist Specificity of Drug Responses Chronic administration of a drug may cause a downregulation of receptors or desensitization of response that can require dose adjustments to maintain adequate therapy. Chronic administration of nitro-vasodilators to treat angina results in the rapid development of complete tolerance, a process known as tachyphylaxis. Non-receptor interacting Mechanism Some drug effects do not occur by means of macromolecular receptors. For instance, aluminum and magnesium hydroxides [Al(OH)3 and Mg(OH)2] reduce gastric acid chemically, neutralizing H+ with OH+ and raising gastric pH. Mannitol acts osmotically to cause changes in the distribution of water to promote diuresis, catharsis, expansion of circulating volume in the vascular compartment, or reduction of cerebral edema Quantitative Aspects of Drug Interactions With Receptors Receptor occupancy theory assumes that a drug’s response emanates from a receptor occupied by the drug, a concept that has its basis in the law of mass action. The dose-response curve depicts the observed effect of a drug as a function of its concentration in the receptor compartment  Affinity, Efficacy, and Potency In general, the drug-receptor interaction is characterized by (1) binding of drug to receptor and (2) generation of a response in a biological system, where the drug or ligand is denoted as L and the inactive receptor as R. The first reaction, the reversible formation of the ligand-receptor complex LR, is governed by the chemical property of affinity. Potency Potency is defined as when two drugs produce equivalent responses, the drug whose dose-response curve lies to the left of the other (i.e., the concentration producing a half-maximal effect [EC50] is smaller) is said to be the more potent.  Efficacy Efficacy reflects the capacity of a drug to activate a receptor and generate a cellular response. Thus, a drug with high efficacy may be a full agonist, eliciting, at some concentration, a full response. A drug with a lower efficacy at the same receptor may not elicit a full response at any dose. A drug with a low intrinsic efficacy will be a partial agonist. A drug that binds to a receptor and exhibits zero efficacy is an antagonist.  Additivity and Synergism Drugs with different mechanisms of action are often used in combination to achieve additive and positive synergistic effects. Such positive interactions of two agents may permit use of reduced concentrations of each drug, thereby reducing concentration-dependent adverse effects. Positive synergism refers to the superadditive effects of drugs used in combination.  Additivity and Synergism Drugs used in combination can also demonstrate negative synergism or sub-additive effects, where the efficacy of the drug combination is less than would be expected if the effects were additive. If A and B are super-additive (positive synergism), the relative concentrations of A and B needed to achieve a given response will fall below the additive dose-response concentration. Conversely, if A and B are subadditive (negative synergism), their relative concentrations will lie above the additive does-response concentration. Variability in Individual and Population Pharmacodynamics Individuals vary in the magnitude of their response to the same concentration of a single drug, and a given individual may not always respond in the same way to the same drug concentration.. Individual Variability Contd Drug responsiveness may change because of disease, age, or previous drug administration. Receptors are dynamic, and their concentrations and functions may be up- or downregulated by endogenous and exogenous factors Population Variability Data on the correlation of drug levels with efficacy and toxicity must be interpreted in the context of the pharmacodynamic variability in the population (e.g., genetics, age, disease, and the presence of coadministered drugs). Population Variability The variability in pharmacodynamic response in the population may be analyzed by constructing a quantal concentration-effect curve. The dose of a drug required to produce a specified effect in 50% of the population is the median effective dose. Population Variability The LD50/ED50 ratio is an indication of the therapeutic index, a term that reflects how selective the drug is in producing its desired effects versus its adverse effects. A similar term, the therapeutic window, is the range of steady-state concentrations of drug that provides therapeutic efficacy with minimal toxicity.  In clinical studies, the concentration of a drug required to produce toxic effects can be compared with the concentration required for therapeutic effects in the population to evaluate the clinical therapeutic index. The concentration or dose of drug required to produce a therapeutic effect in most of the population usually will overlap the concentration required to produce toxicity in some of the population, even though the drug’s therapeutic index in an individual patient may be large.  Thus, a population therapeutic window expresses a range of concentrations at which the likelihood of efficacy is high and the probability of adverse effects is low. These however does not guarantee efficacy or safety. Therefore, use of the population therapeutic window to optimize the dosage of a drug should be complemented by monitoring appropriate clinical and surrogate markers for drug effect(s) in a given patient. Factors Modifying Drug Action Numerous factors contribute to the wide patient-to-patient variability in the dose required for optimal therapy observed with many drugs  Route of Administration Route of administration governs the speed and intensity of drug response Parenteral administration is often resorted to for more rapid, more pronounced and more predictable drug action A drug may have entirely different uses through different routes E.G. magnesium sulfate given orally causes purgation, applied on sprained joints—decreases swelling, while intravenously it produces CNS depression and hypotension.  Direct Administration In some cases, it is possible to apply the drug directly on some tissue in order to obtain local action The skin, the mucous membranes of the mouth, eyes, nose, pharynx, rectum, vagina, urinary bladder are available for direct application The aerosol spray is a novel method of direct application; such as nebula of solution containing the drug is forced, under moderate pressure, down the respiratory tract, and in that way the drug acts directly on small bronchi  Sex Maintenance treatment of heart failure with digoxin is reported to be associated with higher mortality among women than among men Several antihypertensives (clonidine, methyldopa, βblockers, diuretics) interfere with sexual function in males but not in females Gynaecomastia and loss of libido is a side effect (of ketoconazole, metoclopramide, chlorpromazine, digitalis) that can occur only in men So is androgens and estrogens to women and men  Environmental Factors And Time Of Administration Several environmental factors affect drug responses Exposure to insecticides, carcinogens, tobacco smoke and consumption of charcoal broiled meat are well known to induce drug metabolism Type of diet and temporal relation between drug ingestion and meals can alter drug absorption,  Tolerance It refers to the requirement of higher dose of a drug to produce a given response Loss of therapeutic efficacy Natural & Acquired Cross tolerance- alcohols and barbiturates Pharmacokinetic/drug disposition tolerance Pharmacodynamic/cellular tolerance Tachyphylaxis is rapid development of tolerance when doses of a drug repeated in quick succession Questions to Ponder 1. How are therapeutic and toxic effects of drugs related? 2. What factors influence the ability of a drug to stimulate or depress the activity of cells or organs? 3. How are these factors related to the therapeutic use of drugs?