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Buprenorphine Codeine Oxycodone Methadone Naloxone Intro Synthetic derivative of the alkaloid thebaine Semisynthetic phenanthrene derivative Synthetic mu opioid antagonist propionnanilide 1st Pure opioid antagonist N-alkyl derivative of oxymorphone Use Rx of moderate to severe pain. More common for outpatient use due to safety profile Naturally occurring phenanthrene derivative. Methyl substitution. Weak affinity andlow potency 50%. Rx of mild to mod pain. Antitussive, antimotility agent and traditionally for head injury patients (no evidence – lack resp and neuro depressive effects) Rx of mild, mod, severe pain, Treat addiction to opioid/weaning programs Neuropathic pain Opioid resistant pain states For the rapid reversal of the effects of opioids. Resp depression. Has been used in animal studies to reverse hypotension 2ndary to hypovolaemic/septic shock. MOA Partial agonist at mu opioid receptors, with high affinity and potency. It has igh affinity but low intrinsic activity at kappa receptors Mu kappa receptors (spinal) Mu NMDA antagonist R- more potent, 10xhigher affinity to opioid receptor. (most of analgesic effect) S – NMDA antagonist. Inhibits reuptake of 5Ht and NAdr Mu kappa and delta R competitive antagonist Pharmace utics CCS. 300mcg/ml and 200/400mcg tablets Low affinity for opioid receptors. (10x less potent) Antitussive effect via specific high affinity codeine receptors 10% of drug metabolised to morphine analgesia and constipating effects 15/30/60mg tablets. Syrup 5mg/ml. CCS fo injection 60mg/ml. and in fixed dose preps with paracetamol, ibuprofen and aspirin. 5mg tablets capsules 5mg/ml solutions SR 10,20,40,80mg tablets And now IV formulation Pure and combined with Tylenol or aspirin Racemic mixture of 2 enantiomers 5, 10 tablets. 40mg dispersible tablets crushed or dissolvable (NG admin) 1,2,10mg/ml solutions 10mg/ml for injection CCS or iv/im 20mcg/ml or 400mcg/ml naloxone HCl 30-60mg 4-6hrly im or o. 70% bio (peak in 1hr) 1mg/kg rectal for paeds. Nt for iv due to hypotension High O bioavailability 75% o bio Hi absorption from GIT (90%) but high 1st pass = 2% 0 bio 1-4mcg/kg incremental doses or 0.4-2.0mg for known overdose. Onset 2min Lasts 20-40mins Infusion 5mcg/kg/hr 46% PB, 2L/kg higly lipd sol/ Pharmacokinetics Absorptio Im/iv 0.3-0.6mg 6-8hrly im n bio 40-90% o bio significant 1st pass effect SL 0.2-0.4 6-8hrly sl bio 44-94% Distributio n Metabolis m 96%PB 3.2L/kg 7%PPB VD 5.4l/kg Liver. Dealkylation then glucuronidation. Excretion Unchanged in faeces and renal.Clearance decreased 30% with GA T1/2 = 5 hrs Methyl group reduces hepatic conjugation. C6G (active). Ndemethylation(norcodeine) and O-demethylation to morphine (via CYP2D6). Genetic polymorphism (10% UK pop and 30% hong kong Chinese poor metabolisers) 10%unchanged renal. 23ml/kg/min t1/2 = 3 hrs 90% PB. high lipid sol. Extensive hepatic conjugation and oxidative degradation to a variety of metabolites main excreted in urine. Active metabolites Glucuronidation to noroxycodone (1% activity) CYP2D6 (interact pot.) to oxymorphone. Liver (and intestinal) CYP3A4 both enantiomer CYP2D6 for R enan. Nil active metabolites Hepatic N3G T1/2 2.5-3hrs T1/2 12-150hrs (35hrs) Excreted almost exclusively in faeces Cl = 25ml/kg/min T1/2 1-1.5 hrs Pharmacodynamics CNS 25x as potent as morphine sedation, analgesia, respiratory depression euphoria, meiosis, NV. Headache, confusion, dizziness CVS Minimal CVS effects Bradycardia (25%) SBP ↓10% RESP GIT GUT SKIN Other Respiratory depression Antitussive Bronchospasm (histamine) ↑PVR Emesis. Delayed gastric emptying Decreased urine output Histamine release Decreases release of luteinising hormone and increases release of prolactin Respiratory depressant effects not completely reversed by naloxone. Doxapram will however. Severe resp dep. with benzos. Complicated pain management intraop. (preadm cease, nonopioid MM mx, regional, or HDU) 10x less potent than morphine few central effects Analgesia Less sedation than morphine CC if overdose or IV. Prolongs QT Torsades (congenital prolonged QT,high doses 60mg, conditions that increase QT –hypoK and hypoMg) Antitussive Some resp depression and ↓response to O2 and CO2 Resp. depression Rapid reversal of opioid effects: Resp depression and sedation Also antagonises analgesia of other opioids Drowsiness at high doses Decreases pain threshold and antagonises placebo effect ↑SNS activity ↑HR, BP pulm edema at high doses a/w arrhythmias (even VF) used in animal sudies to reverse hypotension of septic/hypovol shock Reverses sphincter of Oddi spasm NV with rapid iv admin. Marked decrease in GI motility. NV Low propensity for dependence Withdrawal in opioid addicts Also crosses placenta and may ppte withdrawal in foetus or neonate. Naltrexone Similar drug to naloxone for opioid withdrawal and alcoholism 50mg tablets 100mg dose will block effects of heroin for 48hrs better oral bioavailability T1/2 10hrs