Concepts In Pharmacology Lectures 3 PDF

Concepts in pharmacology – lectures 3 CLS4011-U 1 29 October, 2024  How do we tell if a drug works, and if it works well? 2 29 October, 2024  3 key drug properties determine if a drug works, and works safely...

Concepts in pharmacology – lectures 3 CLS4011-U 1 29 October, 2024  How do we tell if a drug works, and if it works well? 2 29 October, 2024  3 key drug properties determine if a drug works, and works safely Selectivity/Specificity Potency Efficacy 3 29 October, 2024  Selectivity/specificity Selectivity - describes the ability of a drug to produce a particular effect and relates to its molecular structure that determines its receptor specificity Receptor specificity - determined by the precise molecular interactions between a drug molecule and a receptor protein (binding, affinity) Some drugs bind only 1 target (e.g., a receptor) whereas other drugs interact with more than 1 target Binding/interacting with more than 1 target is known as promiscuity. Both drugs and receptors can be described as promiscuous if they bind more than 1 target/ligand. Promiscuity can be both a benefit for pharmacology, or a source of off- target/toxic effects 4 29 October, 2024  Drug promiscuity Example 1 – statins - Are HMG-CoA reductase inhibitors which result in reduced cholesterol synthesis in the liver and reduces circulating cholesterol levels - Also reported to modulate nitric oxide synthase gene expression in vascular endothelial cells (promoting vasodilation) and reducing macrophage proliferation (anti-atherosclerosis effects) and reduces inflammatory markers (anti-thrombus formation effects) Example 2 – propranolol - Blocks beta-adrenoceptor beta 1 in the heart which results in reduced heart rate and contractive force – clinical effect - Also blocks beta-adrenoceptor beta 2 which can inhibit bronchial smooth muscle relaxation – can cause bronchospasm in asthmatic and COPD patients – toxic/harmful effect in some patients 5 29 October, 2024  Drug potency Relates to the amount of drug needed to elicit an effect Depends on affinity of the drug for its target - Low affinity means that the drug binds weakly and dissociates readily from the drug. Thus, needs larger amount of drug to get effect - High affinity means drug binds strongly to target. Thus, smaller amount of drug will elicit effect 6 29 October, 2024  Drug potency Dose relates to how much drug is given to an organism For cell-based experiments would plot log drug concentration instead of dose. Potency often expressed as the EC50 of a drug – concentration needed to elicit a 50% of max response 7 29 October, 2024  Drug potency Dose relates to how much drug is given to an Note: Although the sigmoidal curve organism shape is classical for dose-response relationships, For cell-basedit is not experiments the only shape seen - e.g., someconcentration drugs have would plot U- log drug instead of shaped dose-responses dose. Potency often expressed as In addition to the amount of drug added, the EC50 ofthe time a drug – concentration needed to of exposure is very important, especially in cell elicit a 50% of max culture experiments response 8 29 October, 2024  Drug efficacy Ability of a drug to induce a biological or physiological response Drugs can be a full agonist – at specific doses can induce a full biological response Drugs can be partial agonists – drug cannot induce a full biological response regardless of dose Partial agonists can be excellent drugs – reduced chance of overdose Dose of drug needed to have therapeutic effect in 50% of test cells or organisms known as ED 50 9 29 October, 2024  Agonists and antagonists Agonist – Compound which binds a target molecule (e.g., a receptor), and activates that target (i.e., elicits a response from the drug target). Antagonist – Compound which binds to a target molecule (e.g., a receptor) but prevents or does not activate that target (i.e., blocks a response from the drug target) Types of antagonists: - Competitive - Non-competitive - Pharmacokinetic - Physiological 10 29 October, 2024  Competitive antagonism 1.00 maximal effect fractional response 0.75 control + antagonist 0.50 0.25 0.00 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 log [acetylcholine] (M) Effect of the antagonist is “surmountable” i.e., by adding more of an agonist, the effect of the antagonist can be overcome These types of experiments can help pharmacologists understand how a drug works by helping to identify the drug target. 11 29 October, 2024  Non-competitive antagonism 1.00 control fractional response 0.75 + antagonist 0.50 Insurmountable 0.25 (cannot be overcome by high agonist 0.00 -12 -9 -6 -3 concentrations) log [agonist] (M) Effect of the antagonist is not “surmountable” i.e., by adding more of an agonist, the effect of the antagonist cannot be overcome Antagonist binds at allosteric site or irreversibly to active site – cannot be displaced 12 29 October, 2024  Other types of antagonism Pharmacokinetic antagonism Antagonist alters the effect of a compound by altering its ADME – e.g., can increase clearance, alter metabolism, or alters half-life of a drug resulting in a lack of or reduced pharmacological effect e.g., grapefruit juice Physiological antagonism Where two compounds which have opposing effects which cancel each-other out. e.g., Angiotensin II at low concentrations binds to the ATR type 1 receptor, which results in vasoconstriction. At very high concentrations, it can also bind the ATR type 2 receptor which negates the effects of ATR type 1 activation. Angiotensin II has a high affinity for the type 1 receptor, and a low affinity for the type 2 receptor, which is why it only does this at very high concentrations. 13 29 October, 2024  A brief introduction to toxicity Everything is toxic! - Dose is what determines if something acts in a beneficial way, or if it is toxic -e.g., insulin: can be used to control blood glucose levels, at high concentration results in diabetic hypo and can lead to death! - e.g., paracetamol: acts as an effective analgesic, at high concentrations it can kill liver and kidney cells! 14 29 October, 2024  LD50 and TD50 LD50 - The amount of drug needed to kill 50% of test cells or organisms treated with the drug TD50 - The amount of drug needed to cause toxicity in 50% of test cells or organisms treated with the drug - Toxic effect can be dysfunction or cell death 15 29 October, 2024  Therapeutic index Therapeutic index (TI) = LD50 or TD50 / ED50 Gives an indication of how likely a drug is to have side effects or cause toxicity For example – drugs where there is a low TI (the blue and red lines are very close together) require careful dosing as toxicity can occur at therapeutic doses (e.g., Warfarin) For drugs where the therapeutic concentrations are much lower than the toxic ones (i.e., a large TI), you are less likely to have toxicity occur in patients 16 29 October, 2024