Pharmacokinetics in Overdose
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Questions and Answers

What is the dose at which maximal bioavailable absorption of a drug occurs?

  • 30 mg/m2
  • 15 mg/m2 (correct)
  • 25 mg/m2
  • 5 mg/m2

    • What is the primary goal of decontamination in drug overdose?

  • To enhance the elimination of the drug from the body
  • To reduce the absorption of the drug and thus systemic exposure (correct)
  • To increase the half-life of the drug
  • To reduce the bioavailability of the drug

    • What is the time frame within which activated charcoal is generally considered effective for IR preparations?

  • Within 1 hour of ingestion
  • Within 6 hours of ingestion
  • Within 2 hours of ingestion (correct)
  • Within 4 hours of ingestion

    • What is a contraindication for whole bowel irrigation?

    <p>All of the above</p> Signup and view all the answers

    Why is induced emesis never recommended?

    <p>All of the above</p> Signup and view all the answers

    What is the main factor that determines the efficacy of activated charcoal?

    <p>The binding of the drug to activated charcoal</p> Signup and view all the answers

    What is the primary goal of whole bowel irrigation?

    <p>To reduce the GI transit time to reduce absorption</p> Signup and view all the answers

    What is the only form of a drug that can exert a toxic effect?

    <p>Unbound drug</p> Signup and view all the answers

    What is the primary function of elimination in the body?

    <p>To remove a poison or metabolite from the body</p> Signup and view all the answers

    What is the purpose of urinary alkalization?

    <p>To increase the ionization of a weak acid</p> Signup and view all the answers

    What is the primary factor that determines the efficacy of haemodialysis?

    <p>The distribution kinetics of the drug</p> Signup and view all the answers

    What is the mechanism by which urinary alkalization increases the elimination of a weak acid?

    <p>Ion trapping</p> Signup and view all the answers

    What is the common application of haemodialysis in poisoning cases?

    <p>Both of the above</p> Signup and view all the answers

    What is the effect of urinary alkalization on the elimination half-life of a weak acid?

    <p>It decreases the elimination half-life</p> Signup and view all the answers

    What is the primary reason why poisoning can alter gastrointestinal transit and physiology?

    <p>The poison can cause vomiting and diarrhea.</p> Signup and view all the answers

    Why is knowledge of a drug's pharmacokinetics alone not sufficient to predict when peak toxicity will occur?

    <p>Because the clinical effects of the poison can affect gastrointestinal transit time.</p> Signup and view all the answers

    What is the primary reason why modified release preparations can have very delayed absorption in overdose?

    <p>The modified release formulation is already delayed for absorption.</p> Signup and view all the answers

    What is the primary mechanism of paracetamol toxicity?

    <p>Formation of a toxic metabolite.</p> Signup and view all the answers

    Why are large acute overdoses of methotrexate (up to 1g) seem well tolerated?

    <p>Because methotrexate has a nonlinear pharmacokinetics.</p> Signup and view all the answers

    What is the primary reason why absorpion is more rapid for poisons in solution vs solid dosage forms?

    <p>The poison is more readily available for absorption in solution.</p> Signup and view all the answers

    What is the term for a clump of tablets following an overdose, leading to erratic and delayed absorption?

    <p>Pharmacobezoar.</p> Signup and view all the answers

    What is the term for the peak concentration of a drug in the bloodstream?

    <p>Cmax.</p> Signup and view all the answers

    What is the primary target of most specific toxicological treatments?

    <p>Unbound drug</p> Signup and view all the answers

    What is the primary reason for chronic poisoning in the elderly due to digoxin?

    <p>Renal impairment</p> Signup and view all the answers

    What is the primary mechanism of action of digoxin immune fab in treating digoxin overdose?

    <p>It binds to free digoxin and shifts the equilibrium away from receptor binding</p> Signup and view all the answers

    What is the primary exception to the general rule of Phase 1 metabolism being detoxification?

    <p>Pro-drugs</p> Signup and view all the answers

    What is the primary reason for the use of activated charcoal in paracetamol overdose treatment?

    <p>To reduce the need for N-acetylcysteine</p> Signup and view all the answers

    What is the primary feature of 'massive' paracetamol overdose?

    <p>Delayed and erratic absorption</p> Signup and view all the answers

    What is the primary reason for the poorer outcomes in modified release paracetamol overdose despite early treatment?

    <p>Altered PK - delayed peaks, double peaks, mis-match with NAC dose</p> Signup and view all the answers

    What is the primary reason for the banning of modified release paracetamol in Europe?

    <p>Due to altered PK and poorer outcomes</p> Signup and view all the answers

    Study Notes

    Pharmacokinetics in Overdose

    • Most overdoses are oral ingestions, and poisons must be absorbed to cause systemic toxicity.
    • Poisoning can alter GI transit and physiology, leading to saturable processes and non-linear pharmacokinetics.

    Absorption

    • GI kinetics can be altered by clinical effects of the poison, such as vomiting, diarrhea, and delayed gastric transit.
    • This can cause delayed or prolonged absorption, and peak toxicity correlates with Cmax.
    • Substances must be dissolved to be absorbed, and absorption is more rapid for poisons in solution versus solid dosage forms.
    • Modified release preparations can have very delayed absorption in overdose.
    • Pharmacobezoar (a rare condition) can occur, where a clump of tablets forms following overdose, leading to erratic and delayed absorption.

    Clinical Example: Methotrexate

    • Methotrexate is a folic acid antagonist, and low-dose methotrexate is used for inflammatory conditions.
    • Accidental daily dosing for as little as three days can lead to a risk of death from immunosuppression.
    • Conversely, large acute overdoses (up to 1g) seem well-tolerated due to non-linear pharmacokinetics.
    • Saturable absorption occurs, and maximum bioavailable absorption occurs at a dose of approximately 15mg/m2.

    Decontamination

    • Decontamination aims to reduce absorption and systemic exposure of the drug.
    • Methods include activated charcoal, whole bowel irrigation, induced emesis, and gastric lavage.
    • Decontamination methods have risks, and it is essential to estimate the extent of reduction in systemic exposure.

    Activated Charcoal

    • Activated charcoal is generally considered within 2 hours of immediate-release preparations and 4 hours of slow-release preparations.
    • Efficacy depends on the binding of the drug or toxin to activated charcoal, normal absorption properties, and any effects on gastrointestinal activity.
    • Risks include aspiration, and it should only be used when the airway is protected.

    Whole Bowel Irrigation

    • Whole bowel irrigation is a treatment that uses large doses of osmotically balanced polyethylene glycol (laxative).
    • It aims to reduce GI transit time to reduce absorption, and the treatment endpoint is liquid stool or clear effluent.
    • It is considered for metals (that don't bind to activated charcoal) or slow-release formulations.

    Distribution

    • Only unbound drug or poison can exert a toxic effect.
    • Only unbound drug can be targeted by most specific toxicological treatments.
    • Saturable processes can occur, leading to increased concentration and saturation of plasma proteins.

    Clinical Example: Digoxin Immune Fab

    • Digoxin is a cardiac glycoside, and poisoning can be life-threatening.
    • Digoxin immune fab is a specific antibody for treating digoxin overdose.
    • It binds free digoxin, shifting the equilibrium away from receptor binding, reducing toxicity.
    • Digoxin-fab complexes are cleared by the kidney.

    Metabolism

    • Phase 1 generally involves detoxification, but there are important exceptions (pro-drugs/pro-poisons).
    • Capacity-limited metabolism can lead to saturation of metabolic enzymes and non-linear kinetics.

    Clinical Example: Paracetamol

    • Paracetamol overdose can be treated with activated charcoal, which reduces the need for N-acetylcysteine (NAC) and hepatotoxicity.
    • Measure serum paracetamol levels and plot on a nomogram to determine treatment.
    • Treat with NAC if indicated, with a rule of thumb that if treated within 8 hours, a good outcome is expected (with some exceptions).

    “Massive” Paracetamol Overdose

    • Delayed and erratic absorption may occur in massive overdose.
    • To dissolve 50g of paracetamol, at least 2400mL intraluminal fluid is required.
    • Biphasic peaks and delayed elevated paracetamol levels (>24h) are common in large overdose.
    • Outcomes are poorer, even with early treatment.

    Elimination

    • Elimination involves the removal of a poison or metabolite from the body.
    • The biliary and renal systems are primarily responsible for elimination.
    • Renal excretion has saturable processes, and can be enhanced.

    Clinical Applications: Enhanced Elimination

    • To increase clearance, methods include urinary alkalization, hemodialysis, and multiple doses of activated charcoal.
    • Hemodialysis is most effective for salicylates, lithium, toxic alcohols, valproic acid, and meqormin.

    Urinary Alkalization

    • Urinary alkalization is used for weak acids, increasing the pH of the filtrate to >7.5.
    • This increases the proportion of ionized drug, decreasing reabsorption, and is known as 'ion trapping'.
    • The most common application is for aspirin/salicylate poisoning, with a 10-fold increase in the amount excreted in urine and a 3-fold reduction in the apparent elimination half-life.

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    Related Documents

    Toxicokinetics in Overdose PDF

    Description

    This quiz covers the effects of overdose on pharmacokinetic processes, paracetamol toxicity, and absorption principles in poisoning cases. Understand how overdose alters pharmacokinetic parameters and how pharmacokinetic knowledge is used in overdose management.

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