Pharmacodynamics Slides PDF

Pharmacodynamics Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics 1  Learning Outcomes 1. Define the term pharmacodynamics and differentiate it...

Pharmacodynamics Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics 1  Learning Outcomes 1. Define the term pharmacodynamics and differentiate it from pharmacokinetics 2. Describe drug interactions with various types of receptor 3. Give at least one example of a pharmacodynamics action that is not dependent on cell structures 4. Give examples of direct and indirect action of drugs on body systems 5. Define agonist, partial agonist and antagonist in respect to drug action and explain how they may interact at the receptor level 6. Describe dose-response relationship 7. Define and explain the concepts of potency, therapeutic index, therapeutic ratio, efficacy and receptor affinity Sunday, 08 September 2024 2  Learning Objectives 1 - 3 Define the term pharmacodynamics and differentiate it from pharmacokinetics Describe drug interactions with various types of receptor Give at least one example of a pharmacodynamics action that is not dependent on cell structures  Naming medicines Pre-read Pharmacodynamics is what the drug does to the body Pharmacokinetics is what the body does to the drug Sunday, 08 September 2024 4  LOs 1 -3 Core concept: Drug Targets are molecules, the function of which can be modulated by a drug to produce a biological effect. Most drug targets are proteins Core concept: Drug-Target Interaction describes the different ways a drug interacts with a target to produce a biological effect. Sunday, 08 September 2024 5  LOs 1 -3 Core concept: Structure-Activity Relationship describes the relationship between the structural characteristics of a drug and its binding site, and the resultant biological effect. norepinephrine xylazine romifidine detomidine medetomidine Pharmacodynamic interactions can be either structurally dependent (drugs interact with receptor binding sites like a lock and a key), or independent of cell structures e.g. antacid indigestion remedies. Sunday, 08 September 2024 6  Learning Objective 4 Give examples of direct and indirect action of drugs on body systems  Action of drugs Core concept: Mechanism of Drug Action [MoA] refers to the process by which a drug produces a biological effect. MoA of most drugs is via a direct effect on a particular receptor: They either activate the receptor, or they block the receptor e.g. salbutamol e.g. metoprolol activates the β2 adrenoreceptor blocks the β1 adrenoreceptor -> bronchodilation -> decrease cardiac output  Drug and indirect action of drugs Some drugs work via an indirect effect: 1. Direct action on cellular target produces desired response. Drug -> Target -> Desired Effect 2. Indirect action – drug interacts on target that is upstream from the biochemical process that produces the desired response. Drug -> Target -> Intermediate Effect -> Desired Effect Sunday, 08 September 2024 9  Drug and indirect action of drugs 1. Direct action on cellular target produces desired response. e.g. amlodipine blocks L-type calcium channels in vascular smooth muscle and thereby relaxes the muscle 2. Indirect action – drug interacts on target that is upstream from the biochemical process that produces the desired response. e.g. amphetamine inhibits a monoamine transporter mechanism and the metabolism of monoamines. This results in an increase in dopamine (D) and norepinephrine (NE) levels. D and NE in turn are associated with reward pathways in the brain Direct effect Indirect effect Amlodipine blocks Ca2+ Amphetamine acts channels in vascular on targets which lead to smooth muscle and an increase in D and NE. thereby relaxes the D and NE in turn muscle. stimulate reward pathways in the brain Sunday, 08 September 2024 10  Action of drugs Some drugs work via an indirect effect: Opposing physiological effect e.g. glucagon can be used to oppose the effects of insulin Increasing endogenous release e.g. amphetamines increase dopamine levels (neurotransmitter associated with reward) Prevent endogenous release e.g. ACE inhibitors prevent the formation of angiotensin II (thereby reduce aldosterone) Inhibit endogenous re-uptake e.g. some antidepressants (SSIs, TCAs) inhibit the reuptake of certain neurotransmitters Inhibit endogenous metabolism e.g. the MAO inhibitor antidepressants inhibit metabolism of noradrenaline  Learning Objective 5 Define agonist, partial agonist and antagonist in respect to drug action and explain how they may interact at the receptor level  Drug-Target Interaction Drug-Target Interaction describes the different ways a drug interacts with a target to produce a biological effect. Agonists are endogenous molecules or drugs that interact with a receptor to elicit a biological response. Full agonists - produce the maximum possible effect Partial agonists - produce submaximal effects Antagonists are endogenous molecules or drugs that interact with a receptor and limit or block the effect of agonists Sunday, 08 September 2024 13  Drug-Target Interaction Full agonists - produce the maximum possible effect e.g. methadone Partial agonists - produce submaximal effects e.g. buprenorphine Antagonists - limit or block the effect of agonists e.g. naloxone Sunday, 08 September 2024 14  Case studies Which medicine (methadone, buprenorphine or naloxone) is most suitable for each of these cases? Minnie is undergoing a spay Timmy is being castrated Frodo has been given too much methadone in error Sunday, 08 September 2024 15  Competitive and non-competitive antagonism Competitive antagonist competes with agonist for same receptor binding site. The overall effect depends on the relative concentration of agonist and antagonist If the concentration of agonist (in green) is in excess, the biological effect will be close to maximal. Addition of a competitive antagonist (red) will diminish the effects of the agonist. Agonist (in green) is in excess Antagonist (in red) is in excess Sunday, 08 September 2024 16  Competitive and non-competitive antagonism Non-competitive antagonist either: Binds to a different site on the receptor to the agonist, or Binds to the same site as the agonist so tightly the agonist cannot displace it (irreversible competitive antagonist). Non-competitive …. binds to the antagonist (black) either same site as the binds to a different site or agonist so tightly on the receptor to the the agonist cannot agonist (green) …. displace it Sunday, 08 September 2024 17  What will happen if ….. Bambi is being treated for high blood pressure with low dose metoprolol, a β1 competitive antagonist (slows heart rate). What will happen to Bambi’s heart rate if Simba starts to chase her and she has a massive increase in adrenaline (a β1 agonist)? Agonist (in green) is in excess Antagonist (in red) is in excess Sunday, 08 September 2024 18  What will happen if ….. Winnie the Pooh has had enough of Tigger’s bouncing today and, in order to sedate his annoying friend, he has given Tigger ketamine, a non-competitive antagonist for the NMDA receptor! Tigger hallucinates about his favourite food (extract of malt) and the level of excitatory neurotransmitter glutamate (an agonist for the NMDA receptor) in his brain increases. What will happen to Tigger’s level of sedation? Ketamine, a non- competitive antagonist (black) binds to a different site to glutamate (green) on the NMDA receptor Sunday, 08 September 2024 19 Learning Objective 6 Describe dose-response relationship  Dose response curves Core concept: Dose / Concentration-Response Relationship is the relationship between the dose/concentration of a drug and the magnitude of the response produced. A plot of the log10 dose/concentration on the x-axis and response on the y-axis produces a sigmoid shape known as the log dose/concentration-response curve. Sunday, 08 September 2024 21  Agonists, partial agonists and antagonists Maximum effect Sunday, 08 September 2024 22  Learning Objective 7 Define and explain the concepts of potency, therapeutic index, therapeutic ratio, efficacy and receptor affinity  Drug efficacy and drug potency Core concept: Drug Efficacy is the ability of a drug to elicit a response once bound to a drug target. Different agonists will produce varying levels of response: Full agonist (maximal response), partial agonists (sub-maximal response) efficacy Core concept: Drug Potency refers to the amount of a drug, expressed as the concentration or dose, needed to produce a defined effect. Drug A requires a lower dose to achieve 50% maximal response (EC50) than Drug B. Drug A is said to be more potent than Drug B Thanks Fido, but that’s not what I meant by potent! Sunday, 08 September 2024 24  Affinity and selectivity Core concept: Drug Affinity is the binding strength of a drug to a target. Drugs with a high affinity for their receptors are less easily displaced e.g. by a competitive antagonist. Sunday, 08 September 2024 25  Affinity and selectivity Core concept: Drug Selectivity is a drug’s ability to discriminate between drug targets. e.g. propranolol is a non-selective beta-blocker – it acts on β1 receptors in the heart and β2 receptors in the lungs, whereas metoprolol selectively acts on β1 receptors in the heart Sunday, 08 September 2024 26  Adverse Drug Reaction / Adverse Drug Event Core concept: Adverse Drug Reaction or Adverse Drug Event are terms that refer to any harmful or undesirable response to a drug. Adverse drug reactions are traditionally classified as: Type A - linked to the pharmacological effects of a drug thus are predictable/dose-dependent Type B - have no link with the pharmacological mechanism of action and are thus unpredictable/idiosyncratic e.g. methadone is used as an analgesic, but it also causes constipation as it inhibits peristalsis -> increased water absorption e.g. procaine penicillin ADR in horse https://www.facebook.com/Last-Stop-Horse- Rescue-324557567565076/videos/beaus- reaction-to-medication/1149457151741776/ Sunday, 08 September 2024 27  Therapeutic range A drug needs to reach a certain level in the plasma to achieve the necessary concentration at its site of action to be fully effective – the Therapeutic range CP - Plasma Therapeutic Concentration range Time Sunday, 08 September 2024 28  Suboptimal levels Below the therapeutic range, the drug will not achieve the necessary concentration at its site of action and its effect will be suboptimal clinically CP - Plasma Concentration Sub-optimal effect or no effect Time Sunday, 08 September 2024 29  Minimum effective concentration (MEC) Minimum effective concentration (MEC) is the minimum plasma concentration required to produce the therapeutic effect CP - Plasma Concentration Minimum Effective Sub-optimal effect Concentration or no effect (MEC) Time Sunday, 08 September 2024 30  Toxic effects Above a certain concentration, a drug will cause unacceptable toxic effects Toxic effects CP - Plasma Concentration Time Sunday, 08 September 2024 31  Minimum toxic concentration (MTC) Minimum toxic concentration (MTC) is the minimum plasma concentration at which unacceptable toxicity occurs. Toxic effects Minimum Toxic Concentration CP - Plasma Concentration Time Sunday, 08 September 2024 32  Therapeutic Index (TI) Core concept: Therapeutic Index, a measure of drug safety, is the ratio between the dose/concentration of a drug producing toxicity and the dose/concentration that produces a therapeutic effect. Toxic effects CP - Plasma Therapeutic Concentration range Sub-optimal effect or no effect Time Sunday, 08 September 2024 33  Therapeutic Index (TI) The larger the therapeutic index, the more favourable the drug's margin of safety. When administering a drug with a low therapeutic index, greater care needs to be taken to minimise drug toxicity, including monitoring its plasma concentration. e.g. gentamicin and digoxin Toxic effects CP - Plasma Concentration In this example the therapeutic Therapeutic range range is narrow, drug level monitoring will be required Sub-optimal effect or no effect Time Sunday, 08 September 2024 Additional concepts  Drug tolerance Core concept: Drug Tolerance is the diminished response to a drug following repeated or prolonged exposure. Various mechanisms underly this phenomena, including: Change in receptors Translocation of receptors Exhaustion of mediators Enzyme induction leading to increased drug metabolism Physiological adaptation Increased efflux of drug from cells e.g. caffeine tolerance results from an upregulation of adenosine receptors which caffeine blocks – more receptors reduces the effect of caffeine Sunday, 08 September 2024 36  Individual variation Core concept: Individual variation in drug response refers to differences in response between individuals to the same dose of a drug. Individual variation results from many factors, including, but not limited to, differences in individuals’: Body size and composition Diet and gut flora Health status including organ function Liver enzyme profile Drug transporter profile We’re not the same. We are individuals!! Sunday, 08 September 2024 37  Key Points LO - Define the term pharmacodynamics and differentiate it from pharmacokinetics Pharmacokinetics (PK) is the measurement and interpretation of changes in drug concentration in the body over time: PK is what the body does to the drug Pharmacodynamics (PD) explores the relationship between drug concentration at the site of action and the resulting effects: PD is what the drug does to the body Sunday, 08 September 2024 38  Key Points LO - Describe drug interactions with various types of receptor A receptor is a protein molecule whose function is to recognize and respond to endogenous chemical signals The vast majority of drugs act by binding to receptor proteins. Receptors elicit many different types of cellular effects. There are essentially 4 receptor types: ligand-gated ion channels, G protein-coupled receptors, kinase-linked receptors and nuclear receptors Core concept: Drug Targets are molecules (most commonly receptors), the function of which can be modulated by a drug to produce a biological effect. Core concept: Drug-Target Interaction describes the different ways a drug interacts with a target to produce a biological effect. Sunday, 08 September 2024 39  Key Points Core concept: Structure-Activity Relationship describes the relationship between the structural characteristics of a drug and its binding site, and the resultant biological effect. LO - Give at least one example of a pharmacodynamics action that is not dependent on cell structures Pharmacodynamic interactions can be either structurally dependent (drugs interact with specific receptor binding sites like a lock and a key), or structurally non-specific e.g. antacids Sunday, 08 September 2024 40  Key Points LO - Give examples of direct and indirect action of drugs on body systems Core concept: Mechanism of Drug Action [MoA] refers to the process by which a drug produces a biological effect. Most drugs have a direct action that involves interaction with a receptor e.g. amlodipine blocks L-type calcium channels Drug -> Target -> Desired Effect Some drugs have an indirect action e.g. ACE inhibitors prevent the formation of angiotensin II and thereby reduce aldosterone Drug -> Target -> Intermediate Effect -> Desired Effect Sunday, 08 September 2024 41  Key Points LO - Define agonist, partial agonist and antagonist in respect to drug action and explain how they may interact at the receptor level Full agonists produce the maximal possible response, partial agonists produce submaximal responses. Antagonists block or diminish the effects of agonists. They can be competitive (compete for the same binding site as agonist) or non-competitive (act at a different binding site). Sunday, 08 September 2024 42  Key Points LO - Describe dose-response relationship Core concept: Dose / Concentration-Response Relationship is the relationship between the dose/concentration of a drug and the magnitude of the response produced. Drug concentration-response curve - A log drug concentration-effect plot produces a sigmoid curve, mid portion is almost linear Sunday, 08 September 2024 43  Key Points LO - Define and explain the concepts of potency, therapeutic index, therapeutic ratio, efficacy and receptor affinity Core concept: Drug Potency refers to the amount of a drug, expressed as the concentration or dose, needed to produce a defined effect. Core concept: Drug Efficacy is the ability of a drug to elicit a response once bound to a drug target. Core concept: Drug Affinity is the binding strength of a drug to a target. Core concept: Therapeutic Index, a measure of drug safety, is the ratio between the dose/concentration of a drug producing toxicity and the dose/concentration that produces a therapeutic effect. Sunday, 08 September 2024 44  Additional Key Points Core concept: Drug Selectivity is a drug’s ability to discriminate between drug targets. e.g. metoprolol is selective for cardiac β1 adrenoceptors Core concept: Adverse Drug Reaction or Adverse Drug Event are terms that refer to any harmful or undesirable response to a drug. Core concept: Drug Tolerance is the diminished response to a drug following repeated or prolonged exposure. Core concept: Individual variation in drug response refers to differences in response between individuals to the same dose of a drug. Sorry, any excuse to show pictures of Labrador puppies !!!! Sunday, 08 September 2024 45