Toxicology and Poisoning Flashcards by Eooooo m

What are the pharmacokinetic interventions available for overdose treatment/poisoning to prevent absorption?

1) Emesis
2) Gastric lavage
3) Chemical adsorption
4) Osmotic cathartics

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Describe emesis. What are examples of emetic agents?

Emesis empties stomach contents rapidly

1) ipecac
2) apomorphine

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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)

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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

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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

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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

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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

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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

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What are 4 types of osmotic cathartics?

1) Sorbitol 70%
2) Magnesium citrate/sulfate
3) Sodium sulfate
4) Polyethylene glycol

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Describe sorbitol 70%

Recommended osmotic cathartic

Given with charcoal to prevent “charcoal briquet” formation

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Describe magnesium citrate/sulfate

A osmotic cathartic

Avoid in renal disease or poisonings with nephrotoxic agents

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Describe sodium sulfate

A osmotic cathartic

Avoid in CHF or HTN (system absorption –> fluid overload)

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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

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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

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Describe extracorporeal removal. Name 2 types.

Yield lots of complications, only give if the pt really needs this

1) Hemodialysis/ peritoneal dialysis
2) Hemoperfusion

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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

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Describe hemoperfusion

Blood pumped through column of adsorbent material — useful for high MW toxins w/ poor water solubility

Risks: bleeding and electrolyte disturbances

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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)

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Describe enhanced renal excretion. Name 2 types.

Previously popular but of unproved value

1) Forced diuresis
2) Block reabsorption from kidney

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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

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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

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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