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Toxic dose Toxic Mechanism Specific drugs Symptoms Ix Treatment Decontamin ation Elimination Antidote Disposition Tolerance OPIOIDS Single tablet death in children Tramadol: >10mg/kg or >1.5g µ1-receptors analgesia (open K channels) µ2-receptors resp depression, physical dependence, miosis, cough supp, euphoria Peripheral µ-receptors constipation K-receptors meosis, sedation (open Ca channels), decr GI motility, dysphoria, hallucinations Sigma-receptors hallucinations, dysphoria Dopamine receptors N+V Histamine release pruritis Morphine: 20% BA, 40% protein bound; 90% hepatic metabolism; 10% excreted urine unchanged Pethidine: stronger kappa; some 5-HT (can cause SS); 50% BA; 60% protein bound; DOA 3hrs; more euphoria and addiction, seizures Fentanyl: rapid onset of action; DOA 30-40mins; serotonin syndrome Remifentanyl: rapid onset; assoc with muscle rigidity; HL 3-10mins; DOA 5-10mins Codeine: 66% BA Methadone: 100% BA; DOA 12hrs; QTc prolongation; symptoms >24hrs Heroin: crosses BBB; very short DOA (peak 3mins; last few hours); can cause NCPO (immediately or delayed 24hrs); symptoms <6hr; 60% OD deaths occur in company of others; 15% deaths are sudden death after injecting; ambulance called in only 10% fatal cases; no intervention prior to death in 80% Oxycodone: less N+V, less sedating; 50-80% BA Dextropropoxyphene: significant Na channel blocking effect ( long QRS, HB, arrhythmia), seizures if >1g, may require larger doses of naloxone, can cause death in <1hr Tramadol: µ-receptor and M1 action; inhibits reuptake of 5-HT and NAD, stimulate 5-HT release; toxic dose > 1.5g (>10mg/kg); 70-90% BA; HL 5-8hrs; peak level 1-3hrs (3-5hrs if CR); delayed onset Sx >6hrs; mild sedation (coma unusual), less resp depression, no significant CV effects (incr HR, incr BP), orthostatic decr BP, seizures (may be delayed; short), agitation, mydriasis, anaphylactoid reactions; interact with SSRI’s and MAOI’s; effects only partially antagonised by naloxone Buprenorphine: partial agonist; used as alternative to methadone; may precipitate withdrawal in OD, which may last a few days CNS depression (K) / RS depression (µ2) / miosis / hypothermia, skin necrosis, compartment syndrome, rhabdo, hypoxic brain inj, aspiration, hypotension, decr bowel motility, NCPO (may be delayed) Miosis absent in: meperidine, morphine, diphenoxylate, propoxyphene Urine: semi-synthetic and synthetic opioids not detected Diazepam sedation in tramadol Charcoal yes, maybe in tramadol Serum alkalinisation: in dextropropoxyphene MDAC: in dextropropoxyphene, SR Naloxone Indication: GCS <12, RR <6, SaO2 <90% MOA: pure competitive antagonist of mu (maximal here), kappa and delta receptors reverses all effects of opiates Onset: 1-2mins DOA: 20-90mins (longer IM); elimination HL 1hr (3hrs in neonates) Dose: 100mcg IV (400mcg IV if severe, 50mcg if opiate dependent) / 400mcg IM bolus / 800mcg SC / 2mg IN (2mg Q3minly to max 10mg if apnoea (may be needed in body packers, fentanyl, SR); 10mcg/kg in children) rpt IV Q30-60 secs until improvement (to max 2mg) infusion at 2/3 initial dose required per hr (dilute 2mg in 100ml N saline) Observe for at least 2hrs after last dose; give IM if self-discharging High doses may be needed in tramadol, codeine, methadone, dextroP CI: opioid dependence, unless RR <8, GCS <12; give the smallest dose possible and don’t aim for full reversal; withdrawal will last <90mins if induced SE: ACPO, withdrawal (stop infusion recommence when asymptomatic at ½ rate) Observe 4hrs for most PO preps; at least 12hrs if CR / child / tramadol Must be at least 1hr post-naloxone, SaO2 >92%, RR >10, HR >50, normal T, GCS 15 After 2-3/52; rate with which develops and extent varies between pt and drug (eg. Methadone tolerance develops slower than morphine); develops better if large doses at short intervals; tolerance disappears after withdrawal syndrome finishes High: analgesic, sedating (few days to stop), resp depressant (few days to stop), antidiuretic, emetic (several months to stop), euphoric, cough suppressing and hypotensive effects Mod: bradycardia; tolerance occurs to mixed agents but to lesser extent as to pure agonists Low: NOT to miotic, convulsant, constipating; tolerance doesn’t develop to antagonist actions of mixed agonists/antagonists Dependence / withdrawal or to pure antagonists Cross tolerance: occurs, esp with μ-agonists; not only to analgesic properties; can be partial/incomplete Symptoms: Characteristic withdrawal syndrome (not life threatening if natural): Within hr, peaks at 36-72hrs: anxiety, yawning, craving, lacrimation, rhinorrhoea, diaphoresis, myalgia In 12hrs, peaks at 72hrs: irritable, tremor, piloerection, mydriasis In 24-36hrs, peaks at 72hrs: insomnia, spasms, AP+N+V+D Also: incontinence, sweating, hyperthermia, hyperventilation Time of onset, intensity and duration depends on drug used and HL; generally 12hrs after last dose peaks at 2-3/7 stop at 5-6/7; may get dehydration, aspiration Morphine/heroin – in 6-10hrs; peak after 36-48hrs; gone by 7-10 days Meperidine – subsides in 24hrs Methadone – in >24hrs peak at 72-96hrs last for >14/7; less intense Antagonist-precipitated withdrawal: by giving antagonist (eg. Naloxone); begin at 3mins peak to 10-20mins subside in 1hr; Natural withdrawal less severe than aritifical (delirium only occurs with naltrexone withdrawal) Mng: supportive; IVF; antiemetics (octreotide is drug of choice), antidiarrhoeal; clonidine / benzos for agitation; administration of opioids may be helpful Admit if: severe withdrawal, significant complications / intercurrent illness / psych prob Opioid replacement: methadone, buprenorphine Detoxification: using naltrexone, buprenorphine, clonidine; rapid tapering of methadone Supportive care Notes from: Dunn, TinTin, ToxBook, Cameron