Pharmacology 2 - Dr Wai Ling Kok (2024-25) PDF

Pharmacology 2 - How do drugs act? Dr Wai Ling Kok Acknowledgement: Dr Zoë Brookes  Learning objectives To introduce some basic principles that underpin drug action To consider the concepts of drug affinity and efficacy To introduce the...

Pharmacology 2 - How do drugs act? Dr Wai Ling Kok Acknowledgement: Dr Zoë Brookes  Learning objectives To introduce some basic principles that underpin drug action To consider the concepts of drug affinity and efficacy To introduce the dose-response curve To show how the dose-response curve may be used to help understand the dynamics of drug agonism and antagonism To relate this discussion to drugs encountered in the dental surgery To provide insight into recent drug developments  Terminology Pharmacokinetics (what the body does to the drug) The way the body deals with the drug over time (Absorption, Distribution, Metabolism, Excretion) Pharmacodynamics (what the drug does to the body) The effects of drugs on the body, biochemical and physiological effects This session will focus on routes of administration and how drugs act on the body (pharmacodynamics), so that you understand how drug effector-receptor activation results in a physiological response General principles Drugs act at a specific molecular site to exert their effects Typically these sites are enzymes, cell surface receptors or cytosolic receptors When binding to its pharmacological target site a drug will have a predictable and repeatable action More than one drug may bind to a particular receptors site. When this happens the pharmacological action of a drug may be modified Drugs acting at different molecular sites may potentiate or inhibit the actions of others Bioavailability Reminder: Biovailability is the proportion of administered drug reaching the systemic circulation As well as factors affecting absorption from the gut, once in the bloodstream, factors affecting the ability of a drug to reach its intracellular or extracellular site of action include: Tissue perfusion (type of tissue) Hydrophilic/hydrophobic nature of the drug Lipid solubility Drug-protein binding within plasma (highly bound drugs, e.g. to albumin are less bioavailable/less active) Blood brain barrier Placental barrier What are the four ways drug can enter the cells? Drugs entering the cell There are four main ways drugs can enter the cell: Diffusion through a lipid membrane Carrier mediated transport Diffusion through aqueous pores (aquaporins) Pinocytosis Target sites for drugs Ion channels Enzymes Receptors Others (transporters, carrier molecules) These may be embedded in the cell membrane and therefore drugs, which are large molecules, do not always have to enter the cell to exert their physiological effects Terminology https://www.pharmacologyeducation.org/resources/glossary/p Drugs can cause a physiological response, reduce it or inhibit it completely depending on the dose given. Thus, drugs are described using the following terms: Receptors Agonists Partial agonist Antagonists Competitive antagonists Non-competitive antagonists Physiological antagonist These will be explained in the context of drug dose-response curves However, first understand the nature of interaction of the drug with the target site Receptor binding May take place at the cell surface May involve receptors coupled to G-protein or second messenger systems e.g. noradrenaline May involve ligand gated ion channels e.g. lidocaine May involve binding to cytosolic receptors e.g. glucocorticoids Receptors, different types: Receptors (intracellular signalling) Agonists bind to receptors to activate intracellular second messenger systems Receptors (intracellular signalling) Agonists often regulate intracellular Ca2+ and cAMP as the link to the physiological effector response, e.g. noradrenaline: Pharmacological terms Agonist A drug that binds to a receptor and initiates a physiological response Affinity of a drug How strongly a drug can bind to its receptors Efficacy of a drug How ‘big’ the response generated after a drug binds to it’s receptors Dose response curves quantify efficacy, as it is assumed the response elicited is proportional to the number of receptor sites occupied A drug with greater ‘potency’ will initiate a larger response with a lower dose Pharmacological terms When considering mechanisms of action the following are sometimes used: ED50 median effective dose, is the dose required to achieve 50% of the desired effect in 50% of the population TD50 median toxic dose, is the dose required to get 50% of the population reporting the specific toxic effect LD50 median lethal dose, is the dose required to achieve 50% mortality from toxicity Dose response curves These involve plotting the dose of a drug (x) against the response (y) A simple example of this could be: giving an increasing doses of blood pressure drug in vivo and recording the blood pressure at each dose Log dose response curves Dose response curves initially follow a hyperbola shape They are converted into a log dose to extend the x axis to make it more easy to calculate EC50 values However, an ‘antilog’ calculation then has to be performed to calculate back and find the actual EC50 From these curves you can also calculate the dose needed to elicit the maximum response (Emax) Decreased responses to agonists When drugs are given repeatedly their effects can decrease, When the decreases in effect occurs quickly (minutes), this is called tachyphylaxis /desensitisation When this occurs more slowly (days weeks) this is called tolerance Drug resistance is something different, e.g. with antimalarial drugs or antibiotics Changes in the receptor itself can cause desensitisation e.g. suxamethonium; and downregulation in the numbers of receptors can cause tolerance e.g. insulin With other drugs e.g. barbiturates relates to increased metabolism Partial agonists This is not desensitisation Partial agonist are drugs that cannot elicit the maximum response as a full agonist would, and the reasons for this are not always known No matter how much drug is given the drug cannot elicit a full response Antagonists Antagonists are drugs that bind to receptors but do not activate them They inhibit or reduce the response of an agonist, meaning that at increasing dose of antagonists if you repeat the dose response curve it shifts to the right, as higher doses of agonist are required to elicit the same response Antagonist Antagonists Antagonists may be divided into the following types: Competitive Irreversible Non-competitive Chemical Physiological Competitive antagonist More agonist/drug is required to elicit a response so the curve shifts to the right (increased ED50) The agonist displaces the antagonist from the receptor site and is still able to initiate the full response (Emax) Irreversible antagonist Usually binds to the same site as the agonist No matter how much agonist/drug is given the agonist cannot elicit the max response (Emax reduced), as the antagonist cannot be displaced The response elicited is directly proportional to the number of free receptor sites available Antagonists Non-competitive When the antagonist binds somewhere other than the receptor site, to prevent the agonist response, e.g. Ca2+ blockers Chemical When the antagonist bind to the drug, usually within the bloodstream, to inactivate it, e.g. protamine inhibiting the anticoagulant effect of heparin Physiological When two agonists cancelling out each others physiological effects via different mechanisms, e.g. prostacyclin and TXA2 for platelet aggregation Therapeutic index Dose response (toxicity or lethality as response) curves have to be constructed using (toxicity or lethality as the response) LD50 for example would be the dose that kills 50% of animals in a test group The therapeutic index is margin of safety between the dose of a drug that produces the desired effect and the dose that produces toxicity/side effects  ED50 LD50, plotted to lethality, TD50 and LD50 animal studies only Narrow therapeutic index Some drugs have a ‘narrow therapeutic window’ In such cases, only a small difference between the minimum and maximum effective drug concentrations in the blood Small increases in the dose of drug in the blood could lead to toxic effects or lethal effects There can be overlap between the therapeutic and toxic effects More narrow therapeutic index Wider therapeutic index Therapeutic index Examples of drugs with narrow therapeutic indices: Aspirin Carbamazepine Gentamycin Phenytoin Vancomycin Warfarin Pharmacology - dental relevance Cellular/molecular targets for drugs used in dentistry (found in DPF) - antagonists (blockers) and agonists Adrenaline - agonist Non selective adrenergic receptor agonist Receptors: adrenaline acts on both α and β adrenoreceptor sub- types α1 = causes smooth muscle contraction (constriction large blood vessels) Note α2 inhibits transmitter release β receptors = increases cardiac muscle force and rate of contraction (β1 and β2); causes smooth muscle relaxation (respiratory tract); causes vascular smooth muscle relaxation (dilation small blood vessels, β2 only); gluconeogenesis Salbutamol - agonist Selective β2-adrenegic agonist Causes relaxation of the bronchiolar smooth muscle in asthma or COPD Side effects: tremor, anxiety, dry mouth, palpitations, tachycardia, arrhythmias (i.e. adrenergic side effect) Other examples of agonists and antagonists  The Drug Discovery Process - Complex multi- phase process - 10-15 years on average from starting a discovery project to a drug reaching market Image from: https://www.researchgate.net/figure/Schematic-representation-of-the-drug-discovery-process-The-two-main-phases- discovery_fig2_335215729  The Drug Discovery Process Discovery stage: - Initial validation of a new concept for a drug therapy - Identification of likely molecular compounds with some desired activity (e.g. receptor binding – but could be agonists or antagonists at this stage) - Selection from these ‘hits’ of those that also have desired activity (e.g. receptor agonism) – ‘leads’ - Gradual improvement of these leads through Image from: https://www.researchgate.net/figure/Schematic-representation-of-the-drug-discovery-process-The-two-main-phases- discovery_fig2_335215729 iterative chemistry techniques (but  The Drug Discovery Process Development stage: - Preclinical safety testing – animal models but now also a lot of digital ADME testing prior to this to minimise in vivo testing - Clinical trials - Phase 1 – healthy human subjects. Testing for safety, side effects, ADME characteristics, dose ranges, etc. - Phase 2 – small groups of patients with relevant condition. Testing for safety (2a, more like ‘post- Phase 1’) and effective therapeutic dose ranges (2b, more like ‘pre-phase 3’), etc. Image from: https://www.researchgate.net/figure/Schematic-representation-of-the-drug-discovery-process-The-two-main-phases- discovery_fig2_335215729 - Phase 3 – large group,  The Drug Discovery Process Very high attrition rate, especially during discovery stage Therefore, hugely expensive: “Studies have estimated that the R&D cost for a new drug ranges from $314 million to $4.46 billion, depending on therapeutic area, data and modelling assumptions” (Sertkaya A, Beleche T, Jessup A, Sommers BD. Costs of Drug Development and Research and Development Intensity in the US, 2000-2018. JAMA Netw Open. 2024;7(6):e2415445. doi:10.1001/jamanetworkopen.20 24.15445) Image from: https://research.csiro.au/ai4m/ai-for-drug-discovery-our-focus-on-emerging-infectious-diseases/ A drug on the market continues to be monitored even after it is approved, for any emerging safety issues or required dose changes – these are  Summary You should now be able to describe the basic concepts of agonist and antagonist that underpin drug action You should understand the concepts of drug affinity and efficacy You should be able to understand dose-response curves and how they change in the presence of competitive and irreversible antagonists You should understand the terms ED50, Emax and LD50, also in the context of drugs with a narrow therapeutic window You should be able to understand which drugs are agonists and which are antagonists in relation to drugs encountered in the dental surgery You should understand the basic drug discovery process Reading List Rang and Dale’s Pharmacology, Elsiever M.J. Neal, Medical Pharmacology at a Glance, Wiley Blackwell