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1IBSNBDPMPHZ▯PG▯1BJO Name: Carlotta Giacchero Email: cg1320@ic.ac.uk0#+&$5*7&4▯ • Understand mechanisms of action, targets, and side effects of core drugs • Explain the effects of morphine at a cellular level • Outline the pain pathway and the effects of morphine on it • Apply the WHO Pain Ladder to the prescription of painkillers • Understand different opioids’ interactions with the brain • Explain the metabolism of codeine to morphine • Identify the signs of an opioid overdose and describe its treatment • Differentiate NSAIDs from paracetamol $03&▯%36(4▯▯1BSBDFUBNPM Primary Mechanism of Action Drug Target Main Side Effects Other Info • Still not totally clear • Unclear • Relatively safe drug with few • Analgesic and anti-pyretic • At peripheral sites - inhibit • 5HT3 receptors/Cannabinoid common side effects. • NO anti-inflammatory cyclooxygenase, a reuptake activity peroxidase enzyme involved proteins/Peroxidase OVERDOSE: • In many medications so in conversion of arachidonic • Liver damage, less chance of accidental acid to prostaglandins frequently renal damage. overdose • Ability of paracetamol to • Nausea and vomiting = early • Ingestion of large amounts inhibit peroxidase blocked if features (settle in 24h) of paracetamol remains a excessive levels of peroxide • Onset of right subcostal pain common method of suicide build up (inflammation) after 24h = hepatic necrosis despite legislation • Activation of descending • In 2020, the 14th most serotonergic pathways commonly prescribed drug (?5HT3 receptor activation) in West London • Inhibits reuptake of • Probably most commonly endogenous prescribed over the counter endocannabinoids, ?increase (OTC) medicine in the world. activation of cannabinoid receptors, ?activation of descending pathways.$03&▯%36(4▯▯0QJPJET Primary Mechanism of Drug Target Main Side Effects Other Info Action • Over-arching mechanism • Opioid receptor MILD Prescriptions in the UK have at a cellular level = • nausea & vomiting more than doubled last 20 depressant (increase activity in years • Activation of opioid chemoreceptor trigger In 2020, several ‘weak’ receptors at multiple pain zone) opioids or weak pathway sites = • constipation (opioid opioid/paracetamol decreased receptors in GIT can combinations were among perception/increased reduce gut motility) the most commonly tolerance to pain prescribed drugs in West • Anti-tussive effect - OVERDOSE London (most - Co-codamol) decreased activation of • respiratory depression afferent nerves relaying (direct and indirect cough stimulus from inhibition of respiratory airways to brain control centre)$03&▯%36(4▯▯$P▯"NPYJDMBW Primary Mechanism of Drug Target Main Side Effects Other Info Action • Binds to bacterial • Amoxicillin = penicillin • Well tolerated • Amoxicillin = broad penicillin binding binding proteins • Most common side spectrum (gram + and proteins • Clavulanate = beta effects = nausea and -) semisynthetic • Prevents lactamase diarrhoea antibiotic transpeptidation • Hypersensitivity to (cross-linking for penicillins = relatively bacterial cell wall common, usually synthesis) associated with rash • Clavulanate = beta but can lead to lactamase inhibitor anaphylaxis (bacterial enzyme that • Co-amoxiclav is can degrade beta commonly prescribed lactam antibiotics in hospital conferring resistance)$03&▯%36(4▯▯-BDUVMPTF Primary Mechanism of Drug Target Main Side Effects Other Info Action • Non-absorbable • N/A • Abdominal pain • Begins working within disaccharide • Diarrhoea 8-12 hours, may take • Reaches the large • Flatulence up to 2 days to bowel unchanged • Nausea improve constipation causing water • Often prescribed prior retention via osmosis to commencement of • Metabolised by colonic opioid therapy to bacteria = additional improve symptoms laxative effect associated with constipation8)0▯1BJO▯-BEEFS /4"*%T▯WT▯1BSBDFUBNPM • NSAIDs = anti-pyretic, analgesic, anti-inflammatory • Inhibits COX, stopping arachidonic acid conversion into prostaglandins (sensitise sensory neurons - increase firing rate). • Paracetamol = antipyretic, analgesic - inhibit peroxidase activity, stopping conversion of arachidonic acid to prostaglandin • Inflamed tissue = lots of peroxides released, broken down by peroxidases, cannot be inhibited ANANDAMIDES • Endogenous opioids • Increase = more inhibitory descending pain signals, stopping pain • Anandamide broken down to arachidonic acid • NSAIDs and paracetamol cause build up of arachidonic acid • Prompts slowing down of breakdown = analgesia.PSQIJOF▯&GGFDUT▯BU▯UIF▯$FMMVMBS▯ -FWFM • Binds to opioid receptor (g protein-coupled receptor) • Inhibits adenylate cyclase • less conversion of ATP to cAMP = decreased cellular activity • Reduces Ca2+ influx = reduced exocytosis of NT • Activates/enhances K+ efflux = hyperpolarisation, reducing ability of neuron to fire • Opioids are depressants (decrease function or activity of targeted cell).PSQIJOF▯&GGFDUT▯PO▯5IF▯1BJO▯ 1BUIXBZ 1. Transduction of pain stimulus into action potentials 2. Transmission of pain signal from activated nociceptors to spinal cord 3. Perception (reaching brain) after synapse with spinothalamic neurons 4. Modulation of incoming stimulus by brain sending inhibitory signal down to spinal cord • Nociceptors have opioid receptors around them; binding = reduced firing rate = reduced pain sensation • In spinal cord, ability of spinothalamic neuron to be stimulated decreases with opioid binding • The descending pathway is switched off by GABA when there is no pain; Opioids inhibit GABA = activation of descending pathway = disinhibition%JGGFSFOU▯0QJPJET▯BOE▯5IF▯#SBJO • Lipid solubility is the major determinant of passive diffusion into brain tissue. • Then chemical structure of the drug determines ability to bind to opioid receptor. • Morphine not too lipid soluble, can get into brain but slowly • 2 hydroxyl groups = water solubility increased • Codeine only has one hydroxyl group; heroin has no hydroxyl group = most lipid soluble • Phase 1 = active metabolite that can have side chain attached • Phase 2 = side chain attached to make metabolite easier to clear • 6-acetyl-morphine is phase 1 metabolite; morphine-6- glucuronide = water- soluble phase 2 metabolite • To bind receptor, need hydroxyl at position 3 and tertiary nitrogen; codeine and heroin -> metabolite • Heroin most effective due to lipid solubility, converted to morphine in brain • Morphine has active metabolites so its half life does not predict the duration of its effect.PSQIJOF▯UP▯$PEFJOF▯$POWFSTJPO • Divide the total daily dose of morphine by 0.1 to obtain an equivalent dose of codeine. • Total morphine = 2.5 x 4 = 10 mg per day • Morphine to codeine conversion = 10/0.1 = 100 mg codeine per day • Codeine dose (given QDS) = 100/4 = 25mg per dose • Equivalent codeine = 25mg QDS • It is generally recommended that the dose is reduced by 30% to reduce the risk of overdose (25mg x 0.7 = 17.5mg) • Dose reduction may not be necessary in young people with no underlying medical conditions. • Codeine comes in 15mg, 30mg and 60mg doses • Discharge TTA (to take away) = Codeine, 30mg, PO (oral), QDS PRN (as needed)$:1▯"▯ ▯$:1▯"▯▯BOE▯$PEFJOF▯ .FUBCPMJTN • Codeine is primarily a pro-drug for morphine • Can be metabolized to both norcodeine (inactive metabolite) AND morphine (active metabolite) by cytochrome P450 enzymes in liver • CYP3A4 is responsible for ‘fast’ metabolism of codeine to norcodeine • CYP2A6 is responsible for ‘slow’ metabolism of codeine to morphine • 90% of oral codeine is inactivated and 10% activated (weak opioid)0QJPJE▯0WFSEPTF • Low RR, HR and BP • Unresponsive, pale skin, blue lips • Can be caused by renal impairment (can’t clear opioids so overdose) • Constricted pupils- unconscious patients usually have dilated pupils. Diagnostic. • Cardiorespiratory depression- opioid receptors in cardiorespiratory control centre in medulla • Morphine is an opioid receptor agonist. Naloxone is an opioid receptor antagonist. • Agonists possess affinity and efficacy for a receptor; antagonists only possess affinity • Affinity is ability to bind to receptor. Efficacy is ability to produce effect once bound • Similarities: both have hydroxyl group at position 3 and tertiary nitrogen, so both can bind to receptor • Structural differences: short side chain at tertiary nitrogen allows effect; long side chain cannot fit in binding site and blocks receptor • Competitive antagonism: give lots of naloxone to outcompete morphine4#"▯ A patient presents to your GP practice complaining of 10-day joint pain due to her rheumatoid arthritis. She has tried paracetamol and ibuprofen in the past with success, but neither have worked this time around. The pain is getting in the way of her daily activities. What is your next step? A. Advise her to keep taking paracetamol and ibuprofen B. Prescribe co-codamol and paracetamol C. Halt current therapy and prescribe tramadol D. Admit to hospital E. Prescribe co-codamol and tramadol4#"▯"OTXFS▯ A patient presents to your GP practice complaining of 10-day joint pain due to her rheumatoid arthritis. She has tried paracetamol and ibuprofen in the past with success, but neither have worked this time around. The pain is getting in the way of her daily activities. What is your next step? A. Advise her to keep taking paracetamol and ibuprofen B. Prescribe co-codamol and paracetamol C. Halt current therapy and prescribe tramadol D. Admit to hospital E. Prescribe co-codamol and tramadol46.."3:▯ PAIN LADDER: PAINKILLERS: • Proportionate to pain and • Paracetamol is NOT an anti-inflammatory previous interventions MORPHINE: OPIOIDS: • Depressant of cellular activity • Lipid solubility determines • Overdose treated with naloxone speed of effect5)"/,▯:06▯ Please fill in the Feedback form! Name: Carlotta Giacchero Email: cg1320@ic.ac.uk QR code