Toxicology and Poisoning Flashcards
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: emesis
empties stomach contents rapidly
- Ipecac: emesis after 15-30 minute lag, may repeat once in 20 minutes, local irritation and CNS stimulation of chemoreceptor trigger zone (CTZ), effective orally, must be given BEFORE activated charcoal, Ipecac should no longer be used in HOME treatment
- Apomorphine: dopamine agonist, produces emesis by stimulation of CTZ, rapid action parenterally, respiratory depressant, toxic in children, rarely used today
- Contraindications of emetic agent: comatose pt (lacks gag reflex risk of aspiration), ingestion of corrosive poisons (strong acid/base), ingestion of CNS stimulant (risk of seizures), ingestion of petroleum distillate (risk of pneumonitis, pregnancy category C (weigh the benefit: risk, unknown if drug will cause harm).
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: gastric lavage
most rapid and complete method to empty the stomach, but lavage + emesis only empties 30% of oral poisons. Washing of stomach contents with saline and removal via nasogastric tube, best within 60 minutes of poison ingestion.
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: Chemical adsorption Activated charcoal
binds drug in gut to limit absorption (but also binds Ipecac), effective without prior gastric emptying and can reduce elimination half-lives of drugs that have been given IV (back-diffusion of drug from blood with ion-trapping in stomach), underutilized or used in insufficient doses (best to give 10:1 ratio to toxin), serial admin may be helpful (every 4 hours), difficult to administer and poorly accepted in children, home treatment is NOT recommended.
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: osmotic cathartics
decrease time of toxin in GI tract (osmotic laxative effect), indicated if toxin was ingested ˃60 minutes, if toxin is in enteric coated tablet or if toxin is hydrocarbon.
- Sorbitol 70%: recommended, given with charcoal to prevent “charcoal briquet” formation
- Magnesium citrate or sulfate: avoid in renal disease or poisonings with nephrotoxic agents
- Sodium sulfate: avoid in CHF or HTN (system absorption fluid overload)
- Polyethylene glycol: whole bowel irrigation that promotes elimination of entire contents of intestines, for poisonings with sustained-release drugs, metal ions, drug packets.
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: extracorporeal removal
lots of complications, pt must REALLY need this and treatment must have significantly increased rates of toxin elimination compared to normal hepatic metabolism or renal excretion
- Hemodialysis/peritoneal dialysis: blood pumped through filter, most effective for drugs with small Vd (if large Vd, poorly removed by this method as most of drug is outside plasma), toxin should have low protein binding capacity (if bound to protein, toxin won’t cross dialysis membrane), assists in correcting fluid and electrolyte imbalance
- Hemoperfusion: blood pumped through column of adsorbent material, useful for high MW toxins with poor water solubility, risks: bleeding (removal of platelets) and electrolyte disturbances.
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: enhanced metabolism
induction of cytochrome P450 metabolism is NOT realistic (due to 1-3 day onset of action), enhancement of detox metabolism pathways with N-acetylcysteine in acetaminophen toxicity and thiosulfate in cyanide poisoning, inhibition of metabolism to block formation of toxic metabolites (inhibition of alcohol dehydrogenase in methanol or ethylene glycol toxicity)
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: enhanced renal excretion
: previously popular but unproved value
- Forced diuresis (fluids [normal saline] plus high efficacy diuretics [furosemide]), small effect, with danger of fluid overload, protects kidney (benefit)
- Block reabsorption from kidney: prevention of passive reabsorption via alteration of urinary pH and ion trapping, alkalinize urine with NaHCO3 (trap weak acids pKa=3-7.5 like aspirin and barbiturates), acidify urine with NH4Cl or ascorbic acid (trap weak bases pKa=7.5-10.5 like phencyclidine or amphetamine)
pharmacokinetic interventions that are available for treatment of drug overdoses and poisoning and the limitations and contraindications for each: chelation of heavy metals
combines aspects of enhancing the elimination of the toxin (increases renal excretion) and inactivating the toxin (decreases ability to interact with and damage target tissue)
1. Heavy metal ions: ability of form coordinate covalent bonds with protein side chain nucleophiles, interact with macromolecules that are essential for normal physio function, toxin effects are due to enzyme inhibition and alteration of membrane structure. Treatment: admin of chelating agents that complex with free metal ions in body fluids reducing their concentration and promoting the dissociation of metals from these functional intracellular macromolecules, metal ion-chelator complex is excreted in the kidneys
Toxicokinetics:
the study of the absorption, distribution and elimination of toxic parent compounds and metabolic products that aids in prediction of amount of toxin that reaches site of injury and the resulting damage. A toxic dose of drug may result in alterations of “normal” pharmacokinetics.
Toxicokinetics: Absorption:
large amount of ingested drug may slow tablet dissolution, alter GI emptying, injure GI tract –> altered absorption –> delayed peak effect
Toxicokinetics: Volume of distribution:
useful in predicting which drugs will be removed by dialysis/exchange transfution (low Vd values)
Toxicokinetics: clearance:
important to know contribution of each organ to elimination of the toxin or drug in planning treatment strategy
Toxicokinetics: half-life:
published values are for therapeutic doses, may be prolonged in toxic overdoses due to saturation of the elimination mechanisms
Describe the mechanism of acetaminophen overdose toxicity and its treatment with N-acetylcysteine (role of hepatic bioactivation to toxic metabolite and depleted hepatic glutathione in hepatocellular injury).
- Approximately 70-80% of the parent acetaminophen (Ac) is conjugated with glucuronic acid or sulfate (phase II reaction) - 5-10% proceeds through a phase I cytochrome P450 oxidation (CYP2E1). This metabolite is the chemically reactive N-acetyl-p-benzoquinonimine (NAPQI, designated above as Ac*), a strong electrophile detoxified by phase II GSH-transferase and excreted as a mercapturate.
- The sequence of metabolic events that results in hepatocellular injury involves saturation of the phase II sulfate and glucuronide conjugation pathways by toxic doses. This results in excessive formation of Ac* by the unsaturated phase I P450 pathway, eventual depletion of cellular glutathione, and the binding of NAPQI (Ac*) to critical protein or cellular constituents.
- Predisposing factors for hepatocellular damage are increased CYP2E1 activity and decreased hepatic glutathione content (both occur with excessive alcohol consumption)
Describe the tx of acetaminophen overdose toxicity with N-acetylcysteine (role of hepatic bioactivation to toxic metabolite and depleted hepatic glutathione in hepatocellular injury).
- Early treatment involves activated charcoal and gastric lavage to remove residual drug, best within 4 hours. Vigorous supportive therapy necessary when intoxication is severe.
- N-acetylcysteine (Mucomyst) is recommended within 12-36 hours of ingestion (most effective given within 10 hours)
- This drug is thought to serve as a precursor for glutathione synthesis, providing a source of cysteine (the limiting amino acid precursor). N-acetylcysteine also functions as a nucleophile to capture NAPQI produced from residual acetaminophen
- Administered orally, as a loading dose (140 mg/kg), followed by 70 mg/kg every 4 hours for 17 doses. IV formulation available (Acetadote) with 20 or 48 hour administration protocol.
- Advantages of IV administration include: no nausea and vomiting and no interference with action if emetic agent or charcoal used
