Introduction and Pharmodynamics PDF

Introduction and Pharmodynamics LEARNING OUTCOMES At the end of the lecture you should be able to explain: What is clinical pharmacology? What topics are embraced by clinical pharmacology? Why is clinical pharmacology important...

Introduction and Pharmodynamics LEARNING OUTCOMES At the end of the lecture you should be able to explain: What is clinical pharmacology? What topics are embraced by clinical pharmacology? Why is clinical pharmacology important to your studies? What is the extent of medicines use? What are the challenges for prescribers? How should you organise your learning? Introduction and Pharmodynamics 1  Clinical pharmacology is the study of drug action in man providing the scientific basis for rational, safe and effective prescribing Prescribing is a written order, which included detailed instructions of what medicine should be given to whom, in what formulation and dose, by what route, when, how frequently, and for how long It initiated an experiment in which the prescriber discusses the treatment with the patient and investigates and monitors the effects of the prescribed drug, with the aim of devising a dosage regimen that maximises the beneficial effects and minimises the risk of harms At this review stage prescribers must take into account the ever-present possibility of the occurrence of an adverse drug reaction - it may be necessary to report a reaction to the regulatory authorities so that the risks of adverse reactions for future patient can be estimated more accurately - this process of collecting information on drug safety is known as pharmacovigilance The results of clinical trials have three main consequences: they are used to provide the evidence to the regulator that a medicine is safe and effective when used for its proposed indication - the understanding of its clinical pharmacology, gained from clinical trials is critical in the regulatory process and gaining approval for marketing and thence joining other therapeutic choices available to prescribers. the information from clinical trials becomes widely available, often via formal drug information services, so that it can be Introduction and Pharmodynamics 2  used to aid better decision making by both prescribers and patients. the information is used to guide evidence-based medicine, the process of critically analysing evidence about medicines and applying this to inform a rational decision making process about therapeutics. Pharmodynamics At the end of the lecture you should be able to explain: What is pharmacodynamics? What are the mechanisms of drug action? What are drug receptors? What are non-receptor targets of drug action? What is the relationship between drug dose and response? What are agonists and antagonists? What are efficacy and potency? What is selectivity? What is desensitisation? What is therapeutic index? What is pharmacodyanmics? Study of Biochemical and physiological effects of drugs on the body Mechanism of drug action Relationship between drug dose (or concentration) and drug effect Introduction and Pharmodynamics 3 Introduction and Pharmodynamics 4  Receptor-ligand binding is normally reversible Introduction and Pharmodynamics 5 Introduction and Pharmodynamics 6  Receptor examples Introduction and Pharmodynamics 7  Relationship between drug dose and response Introduction and Pharmodynamics 8  Therapeutic index Introduction and Pharmodynamics 9  What are agonists and antagonists? Introduction and Pharmodynamics 10  Agonists can be defined as ligands that, when bound to a receptor, induce a conformational change that leads to signal transduction and intracellular pharmacological effects Antagonists are ligands that bind effectively to receptors but do not produce the conformational change necessary to initiate an intracellular signal. It should be noted that occupation of the receptors by an antagonist, prevents the binding of any other ligand. Therefore, if the antagonist is introduced into a system in which an agonist is active, it ‘competes’ for receptor occupation and has the potential to 'antagonise' the biological response to the agonist In contrast, non-competitive antagonists inhibit receptor-mediated agonist responses by binding to a different part of the receptor from the agonist or interfere with one of the associated signal transduction pathways. They don't compete with the agonist for receptor occupancy. Simply increasing the concentration of the agonist, even to very high levels, cannot overcome their effects and so the maximum response to the agonist (Emax) is reduced. Most ligands, including drugs, bind to receptors reversibly and eventually dissociate from the target receptor when the ligand concentration is reduced Introduction and Pharmodynamics 11  This means that there can be competitive interaction with other ligands such as antagonists and partial agonists. The addition of a competitive antagonist will lead to a shift in the agonist dose-response curve to the right. In the presence of an antagonist, higher agonist concentrations are now required to achieve a given percentage receptor occupancy (and therefore response). The EDH50 for the agonist dose-response curve is now, in effect higher Introduction and Pharmodynamics 12  What is meant by efficacy and potency of drugs? Introduction and Pharmodynamics 13  What is meant by selectivity? What is desensitisation? Introduction and Pharmodynamics 14  Tolerance is conventionally used to describe a more gradual loss of response to a drug that occurs over days or weeks Tachyphylaxis is used to describe desensitisation that occurs very rapidly, sometimes with the initial dose. Pharmacodynamic causes of desensitisation Reduction in receptor number A process often described as receptor ‘down-regulation’ Changes in receptor structure or function resulting from a chemical modification, such as phosphorylation of receptor proteins Exhaustion of mediators such as signalling molecules like intracellular secondary messengers or exhaustion of stored neurotransmitters Physiological adaptation - where repeated exposure to a drug leads to counteracting physiological responses that diminish its clinical effects Introduction and Pharmodynamics 15 Introduction and Pharmodynamics 16  Mechanisms that involve altered pharmacokinetics: Increased drug metabolism - where repeated exposure to a drug increases the capacity of the liver to metabolise it, … or increasing capacity to actively remove the drug from the cell In addition to the alterations in pharmacodynamic and pharmacokinetic processes already considered, there are some other common reasons why the response to a drug might be seen to diminish over time. These include: changes in physiology (such as increased body weight or the effects of ageing) progression of the underlying disease process interactions with other drugs, and quite commonly reduced adherence to the drug regimen. Key points Drugs exert their effects by binding to and altering the function of specific target molecules (e.g. receptors, enzymes, ion channels or transporters). In doing so, they can mimic the actions of endogenous substances in the body, prevent these actions or otherwise alter the function of biologically active molecules. Ligands, including drugs, often act by binding reversibly to receptors, which are mostly specialised glycoproteins located on the cell membrane. The proportion of receptors occupied, and therefore the biological response they produce, is dose-dependent. There are four main types of receptor: G-protein-coupled receptors, enzyme- linked receptors, ligand-gated ion channels and nuclear receptors. The affinity with which ligands bind varies according to their function: low affinity binding enables rapid fine modulation while high affinity binding enables prolonged responses at low ligand concentration. Cell surface receptors are not the only targets of drug action. Introduction and Pharmodynamics 17  Voltage-gated ion channels open in response to changes in transmembrane voltage (rather than ligand binding) and enable specific ions to cross the otherwise impermeable cell membrane - drugs can inhibit this action by blocking the channel or binding to inhibit its action. Enzymes are proteins that catalyse the formation of important cellular products or degrade other molecules - drugs are able to inhibit this action by acting as a competitive substrate, binding to cause an allosteric change in the protein or interfering with a co-factor. Transporter proteins enable molecules and ions to cross the cell membranes - drugs can inhibit this activity by binding to the transporter or interfering with binding of the substrate. The relationship between drug dose (which is normally directly related to drug concentration around target receptors) and the biological response is called the dose-response curve. The dose-response curve is normally plotted on a logarithmic dose scale where it appears as a sigmoid curve. The maximum response is known as Emax and the dose that produces a 50% maximal response is called the ED50. Competitive antagonists cause the dose-response curve to be displaced to the right. Partial agonists produce a similar dose-response curve to full agonists for that receptor but with a lower Emax. Ligands (including drugs) that activate receptors to cause signal transduction and intracellular events leading to a biological response are known as agonists. Ligands that bind to the same receptors but do not cause biological responses are known as antagonists. Partial agonists have properties that are intermediate between agonists and antagonists. Competitive antagonists compete with agonists for receptor binding sites but the antagonism can always be overcome by very high agonist concentrations. Introduction and Pharmodynamics 18  Non-competitive antagonists inhibit agonist responses by binding to other receptor sites or interfering with signal transduction mechanisms and their effects cannot be overcome by higher agonist concentrations. The dose-response curves for the beneficial and adverse effects of drugs can be compared on the same plot Therapeutic index is the ratio between the dose of a drug that causes adverse effects and the dose that achieves therapeutic benefits and can be calculated by comparing the ED50 from the relevant dose-response curves Drugs with a low therapeutic index require cautious dose titration and their effects need to be carefully monitored, often with the help of blood tests There is considerable inter-individual variation in the dose-response curves for the same drug and so, even with a cautious approach to prescribing, some patients will experience adverse effects The efficacy of a drug is a measure of its capacity to produce a biological effect - the maximum biological effect produced by a drug is known as Emax The term therapeutic efficacy is used to describe the comparison of drugs that produce the same therapeutic effects on a biological system but do so by different pharmacological mechanisms The potency of a drug is an expression of the amount of a drug required to produce biological effects and is normally expressed as the ED50 or the dose required to produce 50% of the maximum effect Selectivity of agonists and antagonists for receptors enables those receptors to be classified and sub-typed Agonist selectivity for two subtypes of a receptor is the ratio of the ED50 from the dose–response curves plotted for responses mediated via the respective subtypes Desensitisation to the effect of a drug is a common phenomenon; when it occurs rapidly it is known as ‘tachyphylaxis’ and when it occurs more slowly it is known as ‘tolerance’. The mechanisms that cause desensitisation can be divided into those that are due to altered responsiveness of tissues at a cellular level (pharmacodynamic Introduction and Pharmodynamics 19  causes) and those that are due to altered handling of the drug by the body or the target tissue (pharmacokinetic causes). Pharmacodynamic desensitisation may result from a reduction in receptor numbers (down-regulation), modification of receptor structure (e.g. phosphorylation of key amino acids), depletion of mediators responsible for the drug effect, or the emergence of counter-regulatory physiological changes. Pharmacokinetic desensitisation results from an increased rate of elimination of the drug, meaning that the same dose progressively produces decreased tissue concentrations (and therefore, pharmacological effect). Introduction and Pharmodynamics 20