Toxicology and Poisoning Flashcards
What are the pharmacokinetic interventions available for overdose treatment/poisoning to prevent absorption?
1) Emesis
2) Gastric lavage
3) Chemical adsorption
4) Osmotic cathartics
Describe emesis. What are examples of emetic agents?
Emesis empties stomach contents rapidly
1) ipecac
2) apomorphine
What are the contraindications of using an emetic agent?
1) Comatose pt (no gag reflex –> risk of aspiration)
2) ingestion of corrosive poisons
3) ingestion of CNS stimulant (risk of seizures)
4) ingestion of petroleum distillate (problem if pregnant)
What is ipecac?
Causes emesis after 15-30 min lag — may repeat once every 20 min
Causes local irritation and CNS stimulation of chemoreceptor trigger zone (CTZ)
Given orally
What is apomorphine?
A dopamine agonist — rapid action given by injection
Causes emesis by stimulation of CTZ
Respiratory depressant, toxic in kids, rarely used today
Describe gastric lavage.
Most rapid and complete method of emptying stomach
Lavage + emesis –> only empties 30% of oral poisons
Wash stomach with saline and removal via nasogastric tube — best w/in 60 min
Describe chemical adsorption.
AKA: activated charcoal
Binds drug in gut to limit absorption (also binds ipecac)
Effective prior to gastric lavage
Can reduce elimination half-lives
Describe osmotic cathartics
Decrease time of toxin in GI tract (osmotic laxative effect)
Needed if toxin ingested >60 mins, enteric coated tablets ingested, or hydrocarbon ingested
What are 4 types of osmotic cathartics?
1) Sorbitol 70%
2) Magnesium citrate/sulfate
3) Sodium sulfate
4) Polyethylene glycol
Describe sorbitol 70%
Recommended osmotic cathartic
Given with charcoal to prevent “charcoal briquet” formation
Describe magnesium citrate/sulfate
A osmotic cathartic
Avoid in renal disease or poisonings with nephrotoxic agents
Describe sodium sulfate
A osmotic cathartic
Avoid in CHF or HTN (system absorption –> fluid overload)
Describe polyethylene glycol
A osmotic cathartic
Whole bowel irrigation that promotes elimination of entire intestine contents
For poisonings with sustained-release drugs, metal ions, drug packets
What are the pharmacokinetic interventions available for overdose treatment/poisoning to enhance elimination?
1) Extracorporeal removal
2) Enhanced metabolism
3) Enhanced renal excretion
4) Chelation of heavy metals
Describe extracorporeal removal. Name 2 types.
Yield lots of complications, only give if the pt really needs this
1) Hemodialysis/ peritoneal dialysis
2) Hemoperfusion
Describe hemodialysis/peritoneal dialysis
Blood pumped through filter — most effective for drugs with small Vd (large Vd —> outside plasma)
Toxin should have low protein binding capacity (won’t cross membrane otherwise)
Corrects electrolyte/fluid imbalance
Describe hemoperfusion
Blood pumped through column of adsorbent material — useful for high MW toxins w/ poor water solubility
Risks: bleeding and electrolyte disturbances
Describe enhanced metabolism
- Enhancement of detox metabolic pathways with N-acetylcysteine (tylenol toxicity)
- Induction of CYP450 not realistic due to delay (1-3 days for onset)
- Inhibition of metabolism to block toxic metabolite formation has been successful (ethanol)
Describe enhanced renal excretion. Name 2 types.
Previously popular but of unproved value
1) Forced diuresis
2) Block reabsorption from kidney
Describe forced diuresis, including its pros and cons.
- A type of enhanced renal excretion
- fluids + high efficacy diuretics
- PROS: protects kidneys
- CONS: small effect with fluid overload danger
Describe process of blocking reabsorption from kidney
- A type of enhanced renal excretion
- prevents passive reabsorption by altering urine pH and ion trapping
- For weak toxic base: acidify urine with NH4Cl/ascorbic acid
- For acidic: alkalinize urine with NaHCO3
Describe the chelation of heavy metals
Combines aspects of enhancing toxin elimination with inactivating the toxin
Describe how heavy metal ions affect the body (poisoning)
Form coordinate covalent bonds with protein side chain nucleophiles — interact with macromolecules essential for normal physiology
Toxin effects due to enzyme inhibition and alteration of membrane structure
Describe the heavy metal treatment process using chelating agents
- Chelating agents form complexes with free metal ions in body fluids
- Reduces concentration, increases dissociation of metals from intracellular macromolecules
- Complex is excreted in kidneys
Describe toxicokinetics
The study of absorption, distribution and elimination of toxic parent compounds and metabolic products
Helps predict toxin amount that reaches injury site and resulting damage
Toxic dose may alter “normal” pharmacokinetics
How does a toxic dose affect absorption (bioavailability, F)?
Large amount of ingested drug may:
1) slow tablet dissolution
2) alter GI emptying
3) injure GI tract
Leads to altered absorption —> delayed peak affect
How does Volume of Distribution (Vd) inform toxicokinetics?
Vd can predict which drugs will be removed by dialysis/exchange transfusion
Best if Vd<1L/kg — low values b/c most of drug is in plasma
How does Clearance inform toxicokinetics?
important to know contribution of each organ to eliminating toxin/drug for treatment strategy
How does Half-Life inform toxicokinetics?
Published values are for therapeutic doses
T1/2 may be prolonged in toxic overdoses due to saturation of elimination mechanisms
Describe the general mechanism of toxicity for acetaminophen (Ac)
70-80% of parent Ac —> glucoronic acid/sulfate (Phase II rxn)
5-10% —> CYP450 oxidation (Phase I rxn) — chemically reacts with NAPQI
What is NAPQI?
A strong electrophile detoxified by phase II GSH-transferase and excreted as a mercapturate
Binds with Ac
Describe the results of acetaminophen toxicity on the mechanistic level
- Hepatocellular injury
- Involves saturation of Phase II sulfate and glucuronide conjugation pathways by toxic doses
Leads to:
1) excessive formation of Ac (P450 pathway)
2) depletion of cellular glutathione
3) binding of NAPCI to critical protein/cellular components
What are the 2 predisposing factors for hepatocellular damage due to acetaminophen toxicity?
1) Increased CYP2E1 activity
2) Decreased hepatic glutathione content
Both occur with excessive alcohol consumption
What are the 4 stages of toxicity symptoms with acetaminophen?
1) Initial 24 hours
2) 24-48 hours
3) 72-96 hours
4) 7-8 days
Describe the first stage of Ac toxicity symptoms?
First 24 hours
Symptoms do not reflect potential seriousness
- Nausea
- Vomiting
- Diaphoresis
- Abdominal Pail
Describe the second stage of Ac toxicity symptoms?
24-48 hours
Clinical indications of hepatic damage become apparent
- elevated plasma aminotransferases
- prothrombin time prolonged
Describe the third stage of Ac toxicity symptoms?
72-96 hours
Peak hepatotoxicity
Potential for severe hepatic necrosis predicted by relation…
- Ac plasma levels
- Time post-ingestion (including t1/2)
Describe the fourth stage of Ac toxicity symptoms?
7-8 days
Recovery if timely treatment
If specific treatment not received —> severe liver damage in 10% with 10-20 of them eventually dying of liver failure
Describe the treatment for acetaminophen toxicity
Early treatment: activated charcoal and gastric lavage (w/ vigorous supportive therapy if severe)
12-36 hours post-ingestion: N-acetylcysteine
Describe N-acetylcysteine
Recommended 12-36 hours post-ingestion (most effective in 10)
Function:
- Precursor for glutathione synthesis
- Nucleophile to capture NAPQI produced from residual Ac
How is N-acetylcysteine administered?
Orally or IV
Why is IV admin of N-acetylcysteine better than oral?
- No nausea/vomiting
- No interference with action if emetic agent or charcoal used
When do symptoms present due to methanol/ethylene glycol toxicity?
Delayed by 8-36 reflecting time necessary for metabolism to acid metabolites
Severe metabolic acidosis —> 4-12 hours
Describe methanol poisoning
Results in visual disturbance (snowstorm effect) — formic acid affects optic disc and retina
Death always preceded blindness leading to sudden stopping of breathing
Describe ethylene glycol poisoning
Results in kidney damage — b/c of calcium oxalate crystals deposition —> acute renal failure in most pts
Describe the mechanism of toxicity for methanol/ethylene glycol
Both well-absorbed via oral route —> metabolizes to organic acids (minimal toxicity until then)
1) Methanol –> formic acid
2) ethylene glycol —> oxalic acid
What is the rate-limiting enzyme of the methanol/ethylene glycol mechanism of toxicity? What is its significance?
Alcohol dehydrogenase
Cornerstone of treatment is inhibition of this enzyme!!
What are the 3 treatment options for methanol/ethylene glycol poisoning?
1) Suppression of toxic metabolite production
2) Hemodialysis
3) Correction of metabolic acidosis
Describe suppression of toxic metabolite production as a treatment for methanol/ethylene poisoning
Inhibits the rate-limiting enzyme: alcohol dehydrogenase
What are the two methods of suppression of toxic metabolite production as a treatment for methanol/ethylene poisoning
1) Ethanol infusion
2) Fomepizole administration
Describe ethanol infusion as a treatment for methanol/ethylene poisoning
Maintains a blood alcohol level of 0.1% (legally drunk)
Ethanol functions as competitive inhibitor of alcohol dehydrogenase
Saturates enzyme –> reduces production of formic acid (methanol) and oxalic acid (ethylene glycol)
Describe fomepizole as a treatment for methanol/ethylene poisoning
An inhibitor of alcohol dehydrogenase
Does not produce CNS depression (like ethanol)
More expensive than ethanol
Describe hemodialysis as a treatment for methanol/ethylene poisoning
Removes methanol/ethylene glycol and toxic metabolites
Early intervention with gastric lavage
Describe correction of metabolic acidosis as a treatment for methanol/ethylene poisoning
Uses sodium bicarbonate
