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Pharmacology Principles and painFormat: •MCQ! •Open questions! •Quick recaps! •Audience participation!Content: • Pharmacodynamics • Receptors, ligands and dose-response curves • Selectivity, therapeutic index, toxicity, and withdrawal • Pharmacokinetics • Absorption, distribution, metabolism and elimination • Loading doses and titration • Principles of pain and its management Disclaimer: •You may not have been taught some of these things at this stage! •That is okay! •Most questions can be answered by an educational guess! •We learn more from mistakes than not! •All relevant information can be found in the slide notes! •I take no credit of any photos or diagrams used in this presentationQ1: Who is this? A. Paul Ehrlich B. Robert Boyle C. Rudolf Buchheim D. Louis PasteurQ1: Who is this? A. Paul Ehrlich B. Robert Boyle C. Rudolf Buchheim D. Louis Pasteur 0-100 Pedanius Dioscorides; de Principles of pharmacology: materia medica Historical roots Medieval times Apothecaries, pharmacopeias – not much change th Doctors; clinical observation and •We will focus on mostly Westernish 17 century diagnosing good – therapeutics developments, otherwise this would be and good outcomes limited 1805 Sertürner purifies morphine a longer talk st 1847 Bucheim; 1 institute of pharmacology 1858 Virchow; cell theory •Alternative systems of therapeutics that 1868 First structural chemical fell to obscurity: formula 1878 Pasteur; germ theory • Allopathy (Gregory 1735-1821) 1905 Langley; receptors • Homeopathy (Hahnemann 1755-1843) 1909 Ehrlich; antimicrobial • ‘Alternative / complementary medicine’ chemotherapy 1935 Domagk; sulfonamides WW2 Chain & Florey; penicillin (based on Fleming’s work)Modern pharmacology •Modern science means pharmacology has become quite a big field! •Lots of subdivisions and new ways to make and research compounds! Q2: What type of receptor does salbutamol bind to? A. Mu receptors B. Muscarinic receptors C. Ach receptors D. Adrenoreceptors Q2: What type of receptor does salbutamol bind to? A. Mu receptors B. Muscarinic receptors C. Ach receptors D. Adrenoreceptors Extra points: what does salbutamol do? Pharmacodynamics: How drugs act [on the body] •Ehrlich: ‘corpora non agunt nisi fixata’ •‘magic bullets’ and ‘drug targets’ •Protein targets; • Receptors • Enzymes • Carrier molecules • Ion channels Q3: What adrenoreceptor does salbutamol bind most strongly to? A. B1 receptor B. A2 receptor C. A1 receptor D. B2 receptor Q3: What adrenoreceptor does salbutamol bind most strongly to? A. B1 receptor B. A2 receptor C. A1 receptor D. B2 receptorReceptor classification • Many ways to classify! • Pharmcological response, e.g. H1 and 2 (Black et al 1970) • Molecular cloning • Biochemical pathways • International Union of Basic and Clinical Pharmacology (IUPHAR) Q4: What is something you should think twice about before prescribing to asthmatics? A. Salbutamol B. Bisoprolol C. Theophylline D. Paracetamol Q4: What is something you should think twice about before prescribing to asthmatics? A. Salbutamol B. Bisoprolol C. Theophylline D. ParacetamolDrug-receptor interaction and binding •Agonist/antagonist •Affinity •Efficacy •Specificity •Binding curves Q5: which drug is an irreversible enzyme inhibitor? A. Codeine B. Ibuprofen C. Aspirin D. Lisinopril Q5: which drug is an irreversible enzyme inhibitor? A. Codeine – [prodrug to e.g. morphine] mu receptor agonist B. Ibuprofen – competitive inhibition of COX C. COX-1 and COX-2ersible inhibition of D. Lisinopril – competitive inhibitor of ACEDrug-receptor interaction and binding (2) •Concentration-effect curve •Spare receptors •(Irreversible) Competitive antagonism •Partial agonism •Constitutive receptor activation and inverse agonistsDrug-receptor interaction and binding (3) •Two-state receptor model •Biased agonism •Allosteric modulation Q6: Which of the following drugs have a low therapeutic index? A. Digoxin B. Theophylline C. Insulin D. Warfarin Q6: Which of the following drugs have a low therapeutic index? A. Digoxin B. Theophylline C. Insulin D. WarfarinTherapeutic index and alteration of pharmacodynamics • TI: “room for error” • Most drugs, TI is greater than 100 • Notable exceptions • Monitoring • Tolerance, desensitisation & tachyphylaxis • Tolerance; gradual, e.g. days or weeks & with repeated dosing • Desensitisation; faster than tolerance, but with repeated dosing as well •initial doseis; very fast desensitisation, usually • Withdrawal Q7:Which of the following are parenteral methods of administration? A. Subcutaneous B. Buccal C. Intravenous D. Sublingual E. Intrathecal F. Oral G. Intramuscular Q7:Which of the following are parenteral methods of administration? A. Subcutaneous B. Buccal C. Intravenous D. Sublingual E. Intrathecal F. Oral G. IntramuscularPharmacokinetics: what the body does to the drug •A → D → M → E •Administration/absorpt ion •Volume of distribution [Co = D / Vd] •First pass metabolism •Clearance Q8: Which of the following drugs has the shortest half-life [in a healthy adult]? A. Digoxin B. Morphine C. Methotrexate D. Paracetamol Q8: Which of the following drugs has the shortest half-life [in a healthy adult]? A. Digoxin (36-48 hours) B. Morphine (2-4 hours) C. Methotrexate (3-10 hours) D. Paracetamol (1-4 hours)Dosage and safe prescribing •Half-life varies [metabolism, clearance] •Balance rate of administration and elimination •Loading dose •Maintenance dose •Titration •Modified release formulations Q9: A 29 yo underweight, anxious and insomnic patient is due to start an antidepressant because of severe depression, which medication might be ideal? A. Fluoxetine B. Mirtazapine C. Amitriptyline D. Phenelzine Q9: A 29 yo underweight, anxious and insomnic patient is due to start an antidepressant because of severe depression, which medication might be ideal? A. Fluoxetine B. Mirtazapine C. Amitriptyline D. PhenelzineSide effects and adverse drug reactions •Side effect: nontherapeutic benefit • Bad SE = ADR •Type A (augmented) ADRs: • Predictable. Dose dependent, common, early detection, low mortality, can be managed via dose reduction • Drug factors; dose, administration, elimination, interactions • Pt factors; CYP, slow vs fast acetylators •Type B (bizarre) ADRs: • Not predictable, not clearly dose-dependent, uncommon, found post-licensing, high mortality, discontinueBasic principles of pain and its management • Disabling complication of many disease processes • Subjective experience • Normal conditions; • Impulses in small-diameter primary afferent fibres of peripheral nerves • Activation by various stimuli; mechanical, thermal, chemical • Unmyelinated fibres [C]; polymodal nociceptive endings; dull, diffuse, burning pain • Myelinated [Aδ]; sharp, well-localisedTransmission of pain to higher centres and descending pain control • Midbrain (PAG) and brainstem (RVM) --I dorsal horn • Negative-feedback control against excessive pain signalling • Mood and emotions may also modulate pain via influence on these pathways • Mediated by: • Endogenous opioid peptides • 5-HT • Noradrenaline • AdenosineAnalgesic drugs •Opioids; e.g. morphine, diamorphine, codeine •NSAIDs and paracetamol •Opioid and NSAID combination •Neuropathic pain: • TCAs; amitriptyline • Gabapentin • Carbamazepine (in trigeminal neuralgia)Thank you for coming! Email: s1713373@ed.ac.uk Or accessibilityinmedicine@gmail.com Resources: Rang and Dale’s Pharmacology, 8e (online access via library)