Lecture 8Oct2024 Principles of Pharmacology 2 PDF

Principles of Pharmacology 2 Quantitative pharmacology Studying agonists/antagonists Dr Vassilis Beglopoulos Slides by Dr Chris Smith  How do you study the effects of a drug on receptors? Use an isolated tissue preparation within an organ bath and investigate the effects of th...

Principles of Pharmacology 2 Quantitative pharmacology Studying agonists/antagonists Dr Vassilis Beglopoulos Slides by Dr Chris Smith  How do you study the effects of a drug on receptors? Use an isolated tissue preparation within an organ bath and investigate the effects of the addition of the drug Response Graded Eg response Contraction (mm, %) Change in tension (g) Concentration of agonist  How do you study the effects of a drug on receptors? Use an animal/patient and give them increasing doses of the drug and look at a particular effect Response Graded Eg response Increase in HR Change in BP Change in resp rate dose of agonist Always remember… In vast majority of cases…what is the relationship between dose/concentration and the response? Very low dose  ______________ Low dose  ______________ High dose  ______________ Investigating agonists Important to characterise agonist-induced response at various concentrations – What concentrations would you choose? – If you started at the low concentration, how much would you increase the dose by?  Logarithmic scales 0.001 0.01 0.1 1 10 100 1000 Log10 -3 -2 -1 0 1 2 3 log value can be converted back to linear scale eg log10 10000 = _____ antilog of 4 = 10000 log10 0.003 = ~-2.5 antilog of ~-2.5 = _____ What is the value of the EC50? Tells you the affinity of an agonist for its receptor – If EC50 is low - agonist has high affinity – If EC50 is high - agonist has low affinity 100 % Agonist A Response 50 Agonist B 0 Log10 [agonist] (M) What is the value of the EC50? Tells you the affinity of an agonist for its receptor – If EC50 is low - agonist has high affinity – If EC50 is high - agonist has low affinity o A drug with a high affinity needs to be used at only low concentrations to produce the effect o A drug with a low affinity needs to be used at high concentrations to produce the effect To calculate agonist affinity Determine the EC50 The concentration of agonist which will give a response 50% of the maximum response. How do we do it? Use graph to find EC50 100 % Emax Response 50 0 EC50 00 0 10 Log10 [agonist] This is a log value Take the antilog of this to give the EC50 What is the value of the EC50? Tells you the affinity of an agonist for its receptor Affinity relates to the concentration at which the drug will be active Drug X has an EC50 of 500 nM (5.0 x10-7 M) Drug Y has an EC50 of 50 μM (5.0 x10-5 M) What is the value of the EC50? Which of the two drugs is active at the lowest concentration? If affinity relates to the concentration at which the drug will be active, Which do you think will show the highest affinity? Affinity cf potency? Do we talk of the affinity of a drug when giving it to a person/animal? No o In a person you don’t talk of affinity but potency – If potency is high you need a low dose – If potency is low you need a high dose So potency relates to how big a dose you need to give to gain a particular effect in an intact animal Consider the potency of this drug 100 Morphine % Response 50 0 Log Dose 0 0 00 00 10 33 Drug potency Amount of drug in relation to its effect – drugs may differ in potency, but have similar efficacy Opioid analgesic have different potencies – hydromorphone 1.3mg is equivalent to morphine 10mg – hydromorphine is more potent than morphine – but both drugs can achieve the same max effect Consider the potency of this drug Hydromorphone 100 Potency decreases Morphine L to R % Response 50 Efficacy decreases Top to bottom 0 Log Dose 0 0 00 00 10 33  Originally thought: Drug combines with a Maximum response as receptor to give a drug the curve has leveled off receptor complex 100 % This DR complex gives a Response certain amount of response in the tissue Therefore when all receptors are occupied the 0 maximum response is Log10 [agonist] reached At maximum response, Q Are all drugs acting on the 100% of receptors in same receptors able to complex with drug give the same maximum response? Then we got graph like this…! Morphine 100 Pethidine % Response 50 Codeine 0 Log Dose 00 00 0 0 00 00 10 33 10 But they have each leveled off!33  A re-think was required Led to the idea of different types of agonists Led to the concept of intrinsic activity Some agonists produce a greater response following the occupation of the receptor than others do 1 receptor being occupied Drug Q Drug P results in a response size of: Two types of agonist Full Partial agonist agonist Full response Partial response  Drug efficacy Discovered that 100% receptor occupancy = 100% effect Modified the system such that efficacy is used receptor occupancy is proportional to the effect Similarly to intrinsic activity, efficacy will give an idea on the overall maximum effect of the agonist Drug efficacy The ability of a drug to produce an effect – refers to the maximum therapeutic effect Example Classes of analgesic differ in their efficacy – morphine is a high efficacy analgesic – pethidine is a moderate efficacy analgesic – pethidine can never produce the maximum amount of pain relief achieved by morphine, no matter how great a dose is given Full and partial agonist log conc. effect curves Response Full agonist Partial agonist 0 Log10 [agonist] Can be useful if some of the effects are detrimental How is this difference in overall maximum response indicated? Initial idea was 100% receptor occupancy = 100% effect But with a partial agonist this didn’t seem correct: Led to the concept of intrinsic activity Classification based on efficacy Efficacy relative to endogenous agonist Maximal response to test agonist Intrinsic activity: Maximal response to full agonist How do you calculate intrinsic activity? Full Response Partial H h 0 Log10 [agonist] h = Intrinsic activity Range 0 - 1 H 1= 0=  What is the intrinsic activity of Drug G? Drug F 100 Drug G % Response 50 0 Log Dose a. 100 % c. 1.0 Possible answers b. 70 % d. 0.7 Definitions Affinity Potency Efficacy Intrinsic activity Partial agonist  29 of 27 Three types of antagonist An antagonist prevents the action of the agonist – Eg histamine mediates inflammation erthyma, swelling, tenderness – Goal is to reduce inflammatory response by blocking effects of histamine Cimetidine, cetirizine etc Three approaches possible, either – Chemical – Physiological – Pharmacological  30 of 27 Chemical antagonists A chelator (sequester) of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur)  31 of 27 Physiological antagonists Where the effect of the drug induces an ACh opposing action to salbutamol the action being induced currently Muscarinic It is not acting at the cholinoceptors same receptor type β2 adrenoceptors Often a physiological bronchoconstrictio antagonist is actually n a pharmacological bronchodilation agonist Can’t breathe Can breathe  32 of 27 Pharmacological antagonists The antagonist combines with a receptor, does not produce a response but prevents the action of an agonist Possess ________ but not efficacy Usually the agonist is a physiological substance e.g. a neurotransmitter, or hormone, but it could be another drug  33 of 27 Not quite so simple… There are different types of pharmacological antagonists competitive reversible  34 of 27 Competitive antagonist If you give a high enough concentration of agonist the antagonism can be overcome i.e. there is a competition between the agonist and the antagonist for binding to the receptor  35 of 27 Log conc. curves What happens when you perform a log conc. curve for the effect of an antagonist? Response 0 Log Conc of agonist  36 of 27 Log conc. curves Look at the actions of an antagonist on the response to an agonist control Response 0 Log Conc of agonist  37 of 27 Log conc. curves Look at the actions of an antagonist on the response to an agonist + low dose antagonist control Response 0 Log Conc of agonist  38 of 27 Log conc. curves Look at the actions of an antagonist on the response to an agonist + low dose antagonist control + higher dose Response antagonist Competitive antagonist – parallel rightward shift of the control curve whilst maintaining the 0 maximum. Log Conc of agonist  39 of 27 Not quite so simple… There are different types of pharmacological antagonists competitive reversible irreversible  40 of 27 Irreversible antagonists Binds in an irreversible manner, usually by covalent modification of the receptor Can prevent binding of the agonist Effectively removes those receptors from the population Adding more agonist is useless Only cure: – Make New Receptors by Protein Synthesis.  41 of 27 Irreversible antagonism The effect cannot be overcome by more agonist What happens when you perform a log conc. curve for the effect of an irreversible antagonist? Response 0 Log Conc of agonist  42 of 27 Irreversible antagonism Maximum response is reduced But EC50 remains the same for the unaffected receptors. Binding of the antagonist has not altered the Dose-response curves ability of agonist to bind will have different to “normal” receptors shapes indicating different binding sites  43 of 27 Not quite so simple… There are different types of pharmacological antagonists competitive non-competitive reversible irreversible  44 of 27 Non-competitive antagonists Binds to a site different than the agonist binding site – at an allosteric site Cannot be overcome by adding more agonist May not prevent formation of the ligand- receptor complex, but impairs the conformation change which triggers a response  45 of 27 Non-competitive antagonists allosteric agonist site site agonist Response No Response Non-competitive antagonist No Response