Toxicokinetic.pdf

Toxicokine)c: pharmacokine)cs in overdose. Learning objec)ve - Understand how overdose can alter pharmacokine5c processes/parameters. - Understand how pharmacokine5c knowledge can be used in overdose management. - Describe the mechanism of paracetamol toxicity and understand how overdose a...

Toxicokine)c: pharmacokine)cs in overdose. Learning objec)ve - Understand how overdose can alter pharmacokine5c processes/parameters. - Understand how pharmacokine5c knowledge can be used in overdose management. - Describe the mechanism of paracetamol toxicity and understand how overdose affects paracetamol metabolism. Absorp)on: general principles - Most overdoses are oral inges5ons. - Poisons must be absorbed to cause systemic toxicity. - Poisoning can alter GI transit & physiology. - Saturable processes à non-linear PK. Absorp)on: gastrointes)nal transit )me - GI kine5cs can be altered by clinical effects of the poison e.g. vomi5ng, diarrhoea, delayed gastrointes5nal transit. - This can cause delayed or prolonged absorp5on; t max may be significantly delayed compared to therapeu5c use. - Knowledge of drug PK alone doesn’t help to know when the pa5ent’s going to get peak toxicity. Peak toxicity correlates with the C max. Absorp)on: influence of formula)on - Substances must be dissolved to be absorbed. - Absorp5on more rapid for poisons in solu5on vs solid dosage forms. - Modified release prepara5ons can have very delayed absorp5on in overdose. à already delayed for absorp5on. Pharmacobezoar (rare) (위석) - Clump of tablets following overdose à erra5c and delayed absorp5on. - Generally, with massive overdose of modified release products: o Hydrophilic matrix systems, polymeric coa5ng swells to form a gel layer on the surface of the tablet. o Difficult to predict and iden5fy. o Endoscopic removal a possibility. Clinical example: methotrexate - Methotrexate is a folic acid antagonist. - Low dose methotrexate used for inflammatory condi5ons. o Dose 7.5 – 25 mg on one day per week. - Accidental daily dosing for as liWle as three days à risk of death from immunosuppression. - Conversely, large acute overdoses (up to 1g) seem well tolerated. - Why is this so? o It’s due to non-linear PK. - Saturable absorp)on: Maximal bioavailable absorp)on occurs at a dose of ∼15 mg/m2, spliTng the dose increases bioavailability. - If you take the drug all at once, the drugs will not be absorbed into the circula)on due to satura)on. - Methotrexate clearance is propor)onal to renal func)on. Clinical applica)ons: decontamina)on - Decontamina)on aims to reduce absorp)on and thus systemic exposure of drug. o Ac)vated charcoal. o Whole bowel irriga)on. o Induced emesis. o Gastric lavage. - Decontamina5on methods have risks. - Need to es5mate extent of reduc5on in systemic exposures – is it worth it? Ac)vated Charcoal (AC) - Generally considered within 2h of IR prepara5on, 4h of SR prepara5on. - Efficacy depends on: o how well the drug or toxin binds to AC. o the normal absorp5on proper5es of the drug or toxin. o any effect of the drug or toxin on gastrointes5nal ac5vity (eg ileus) - Risks: aspira5on – should only be used when airway is protected. Can administer by nasogastric tube. Ac)vated charcoal (AC) - Ka es5mates can be useful when determining whether charcoal will be effec5ve. o Not effec5ve for liquid prepara5ons. - Not indicated if good suppor5ve care would ensure a good outcome. Whole bowel irriga)on (WBI) - WBI is large doses of osmo5cally balanced polyethylene glycol (laxa)ve). - Aims to reduce GI transit 5me to reduce absorp5on. o Treatment endpoint: liquid stool, clear effluent. - Considered for metals (don’t bind AC) or slow-release formula5ons e.g. Fe, K, Li, Dil5azem SR, “body packers”. - Risk: aspira5on. Contraindicated if compromised airway, unstable, seizures, bowel obstruc5on/ileus. - Poorly tolerated. Induced emesis. - Never recommended. - Risks of aspira5on – if sedated and begins to vomit. - Interferes with more effec5ve decontamina5on. - Home remedies à drinking salt water à can be more toxic than overdose. Distribu)on - Only unbound drug/posi5on can exert toxic effect. - Only the unbound drug can be targeted by most specific toxicological treatments. (e.g. dialysis, an5dotes). - Where is the “toxic compartment”? o E.g. cardiovascular toxins vs CNS depressants. - Saturable processes: increased concentra5on à satura5on of plasma proteins. o Increased ra5o of free: bound poison. o à Increased Vd. Example: Digoxin immune fab. - Digoxin is a cardiac glycoside. - Poisoning (chronic or acute) can be life-threa)ng. - Chronic poisoning usually happens with elderly à due to renal impairment. - Digoxin immune fab is a specific an5body for trea5ng digoxin overdose. - Immunoglobulin binds free digoxin. o à shijs equilibrium away from receptor binding, reducing toxicity. o à big increase in total digoxin in plasma but free digoxin is undetectable. - Digoxin-fab complexes cleared by the kidney. Metabolism - Phase 1 generally detoxifica5on - Important excep)ons- pro-drugs/pro-poisons o Codeine o Paracetamol (dose dependent) o Toxic alcohols (methanol, ethylene glycol) – enzyme inhibi5on has a role. - Capacity limited metabolism – satura5on of metabolic enzymes à non – linear kine5cs. Clinical example: Paracetamol. Treatment of paracetamol overdose. - Ac5vated charcoal – shown to reduce need for N-acetylcysteine (NAC), reduce hepatotoxicity with large OD. - Measure serum paracetamol level and plot on nomogram. - Treat with NAC if indicated – rule of thumb: if treated within 8h expect good outcome (some excep5ons) “Massive” Paracetamol Overdose - Delayed and erra5c absorp5on may be seen in massive overdose. - To dissolve 50g of paracetamol requires at least 2400mL intraluminal fluid. - Biphasic peaks and delayed elevated paracetamol levels (>24h) common in large overdose. - Outcomes are poorer, even with early treatment. Modified release paracetamol - Difficul5es in management – poorer outcomes despite charcoal and early NAC. - Likely due to altered PK – delayed peaks, double peaks, mis-match with NAC dose. - Banned in Europe. - TGA: S2 à S3 in 2020 Elimina)on - Removal of a poison/metabolite from the body. - Biliary and renal system (mostly). - Renal excre5on has saturable processes e.g. ac5ve secre5on. o Can be saturable at high doses à prolong half-life à non-linear kine5cs. - Can be enhanced. Clinical applica)ons: enhanced elimina)on - To increase clearance o Urinary alkalinisa5on. o Haemodialysis. o Mul5ple doses ac5vated charcoal. Haemodialysis - Efficacy depends on: o Distribu5on kine5cs (small Vd à more removed). o Protein binding (unbound drug gets filtered). o Molecular size (MW < 500) o Water solubility o Concentra5on gradient across membrane. o Flow rate (different types of dialysis). o Ra5o of CL by machine vs endogenous CL. - Most used for salicylates, lithium, toxic alcohols, valproic acid, meqormin. Urinary alkalisa)on - For weak acids, increasing the pH of the filtrate from the usual urine pH of 5–6 to >7.5 will greatly increase the propor5on of drug that is ionised. - As only the nonionised form is significantly reabsorbed, this decreases reabsorp5on and is known as ‘ion trapping’. - Most common applica5on is aspirin/salicylate poisoning. o à 10-fold increase in the amount excreted in urine and a 3- fold reduc5on in the apparent elimina5on half-life. o IV sodium bicarbonate. Urinary alkalinisa)on for salicylate poisoning