U1L3 mini lect drug examples 2022.pdf

Unit 1 Mini-lecture 2: Examples of drugs and their mechanisms of action Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; University of Galway University ofGalway.ie Opioid drugs • Endogenous liga...

Unit 1 Mini-lecture 2: Examples of drugs and their mechanisms of action Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; University of Galway University ofGalway.ie Opioid drugs • Endogenous ligands: Endorphins and enkephalins • Agonists: Morphine, codeine, bupernorphine, heroin, fentanyl, methadone • Antagonist: Naloxone University ofGalway.ie Endogenous opioids Endorphins Endorphins: a family of endogenous opioid peptides Opioid receptor subtypes: m, d, k & NOP m receptors Opioid agonist drugs Endorphins Opioids (e.g. morphine, heroin, buprenorphine) Analgesia, euphoria Codeine vs morphine • Codeine is a constituent of the opium poppy, along with morphine • Codeine is much less potent than morphine, making it less addictive • However, when given in large enough doses it can produce dependence problems, leading to OTC restrictions From Rang and Dale’s Pharmacology Naloxone Endorphins Opioids (e.g. morphine, heroin) Naloxone, a m receptor antagonist Attenuation of analgesia, euphoria The b receptor Endogenous catecholamine neurotransmitter (noradrenaline) released from nerve terminals b receptors In addition, adrenaline (epinephrine) can activate b receptors following release from the adrenal gland Adrenaline as a drug Adrenaline, a b receptor agonist b receptors Tachycardia, inc. respiration rate Propranolol Propranolol, a nonselective b receptor antagonist b receptors Reduced heart rate and blood pressure NSAIDs Aspirin, ibuprofen Paracetamol: analgesic and antipyretic, but limited anti-inflammatory effects (thus sometimes not classified as an NSAID). University ofGalway.ie Prostaglandin synthesis Membrane phospholipids Arachidonic acid COX Cyclic endoperoxides Thromboxanes COX= cyclooxygenase Platelet aggregation Prostaglandins Pain Aspirin Membrane phospholipids Arachidonic acid X COX Cyclic endoperoxides Aspirin, Ibuprofen:COX inhibitors Thromboxanes COX= cyclooxygenase Inhibits platelet aggregation* Prostaglandins Relieves Pain * At low dose Plasma Cholesterol: a risk factor • Elevated plasma cholesterol is a risk factor for a number of cardiovascular conditions • Reduction of plasma cholesterol is a strategy to reduce risk of such conditions • Pharmacological approaches are taken when others are not sufficient University ofGalway.ie Cholesterol synthesis HMG-CoA reductase HMG-CoA Mevalonic acid Cholesterol Mechanism of Statins HMG-CoA reductase HMG-CoA X Atorvastatin, a HMG-CoA reductase inhibitor Mevalonic acid Cholesterol Lowers plasma cholesterol Dopamine nerve terminal Dopamine Cocaine Dopamine Cocaine, a dopamine reuptake blocker Enhanced dopamine effects Amphetamine Dopamine Enhanced dopamine effects Amphetamine, a dopamine releasing agent and inhibition of dopamine reuptake Locomotor Activity (counts/min) Cocaine and locomotor activity in mice 600 400 200 0 0 50 100 150 200 250 Cocaine Dose (umol/kg) From Katz JL et al. (1999): Behavioral effects of cocaine: interactions with D1 dopaminergic antagonists and agonists in mice and squirrel monkeys. J. Pharmacol. Exp. Ther. 291: 265-279. Methylphenidate (ritalin) Dopamine a dopamine reuptake blocker Enhanced dopamine effects SSRIs (e.g. fluoxetine) Serotonin (5-HT) Fluoxetine Serotonin (5-HT) Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) MDMA Serotonin (5-HT) MDMA, a serotonin releaser and reuptake inhibitor Excessive serotonin effects Benzodiazepines GABA-A receptor Diazepam, a benzodiazepine receptor agonist GABA binds Cl- Channel opens hyperpolarisation Diazepam binds, channel opens more Greater hyperpolarisation Diazepam and air-puff-elicited ultrasonic vocalization in rats From Naito, H (2003): Effect of anxiolytic drugs on air-puff-elicited ultrasonic vocalilzation in adult rats. Exp. Anim. 52: 409-414 % Inhibition 120 100 * 80 60 40 * 20 0 0 0.25 * 0.5 1 Diazepam dose (mg/kg) THC Neurotransmitter CB1 receptors THC, a CB1 receptor agonist THC Neurotransmitter CB1 receptors THC, a CB1 receptor agonist Inhibition of postsynaptic neuronal activity Summary We know how the vast majority of drugs produce their actions, mostly via interactions with protein targets Dose/concentration responses can be constructed using a range of endpoints and subjects University ofGalway.ie