Toxicology Flashcards
Compare and contrast graded dose-response curves and population dose-response curves and explain the use of population dose-
response curves to evaluate drug safety (Therapeutic Index and Standard Safety Margin).
- Population dose-response curves are generated by arbitrarily defining some specific therapeutic effect (prevention of convulsions, relief of headache, onset of sleep) and then determining the minimum dose to produce this response in each member of the population.
- A single given dose of a drug in an individual test subject will either bring about the desired response or it won’t, i.e., it is all-or-nothing. When these data are plotted as the fraction of population that responds at each dose of drug versus the log of dose administered, a cumulative population dose response curve is obtained.
- Contrast this type of curve with the graded dose-response curves discussed previously where a number of increasing doses of a drug are given to the same subject and the increase in response for each dose is measured (i.e., graded in increments) allowing determination of the maximal effect of the drug (Emax). Quantal dose-response curves are NOT used to determine Emax.
Describe methods of decreasing absorption: Emesis
- Use Ipecac, a local irritant and CNS stim, NOT APOMORPHINE
- Effective orally, give before charcoal
- Don’t use at home
- Contraindications: comatose pt (aspiration), corrosive poison, CNS stimulant like strichnine (seizure), petroleum (pneumonitis), pregnant (weigh risk/benefit)
Describe methods of decreasing absorption: Gastric Lavage
Most rapid and complete method of emptying stomach, but lavage plus emesis removes only about 30% of most oral poisons
• Washing of stomach contents with saline and removal via nasogastric tube
• Best within 60 minutes of poison ingestion, but may be indicated even late because of possibility of delayed absorption
Describe methods of decreasing absorption: Chemical adsorption
Activated Charcoal (more effective than MgO / tannic acid [Res-Q®]).
• Binds drug in gut to limit absorption (but also binds ipecac…)
• Effective without prior gastric emptying and can even reduce elimination half-lives of drugs that have been given IV (back-diffusion of drug from blood with ion-trapping in stomach)
• Generally underutilized or used in insufficient doses, best to give in 10:1 ratio to toxin; serial administration may be helpful (every 4 hrs)
• Difficult to administer and poorly accepted in children, thus home treatment with charcoal is NOT currently recommended by AAP
Describe methods of decreasing absorption: Osmotic Cathartics
Decrease time of toxin in GI tract (via osmotic laxative effect). Indicated if toxin ingestion > 60 min, if toxin is in enteric coated tablets, or if toxin is hydrocarbon.
• Sorbitol 70%: Recommended, given with charcoal to prevent “briquet” formation
• Magnesium citrate or sulfate: Avoid in renal disease or poisonings with nephrotoxic agents
• Sodium sulfate: Avoid use of sodium-containing cathartics in congestive heart failure or hypertension (systemic absorption → fluid overload)
• Polyethylene glycol (Golytely®): Whole bowel irrigation that promotes elimination of entire contents of intestines. For poisoning with sustained-released drugs, metal ions, drug packets.
Describe methods of enhancing elimination: Extracorporeal removal
Potential complications (bleeding, loss of blood elements, fluid / electrolyte disturbances, infection) and expensive
• Hemodialysis / peritoneal dialysis: only good for drug with small Vd, unbound to protein (or it won’t dialyze through filter). Can correct fluid & electrolytes tho :)
• Hemoperfusion: Blood pumped through column of adsorbent material. Good for high MW toxins with poor water solubility, but risk of bleeding (platelet loss) and electrolyte disturbances
Describe methods of enhancing elimination: Enhanced metabolism
- Induction of cytochrome P450 takes too long
- Good for tylenol poisoning tho (enhancement of detoxication metabolic pathways with N-acetylcysteine in acetaminophen toxicity)
- Blocking the enzyme that makes the metabolite works tho (e.g., inhibition of ADH in MeOH or ethylene glycol toxicity)
Describe methods of enhancing elimination: Enhanced renal excretion
• Forced diuresis (push fluids + high efficacy diuretics [furosemide])
Small effect, with danger of fluid overload (worsens pulmonary function), but it does protect the kidney (beneficial effect)
- Block reabsorption from kidney (ion trapping)
- Alkalinize urine with NaHCO3 to trap weak acids [pKa 3.0-7.5] like aspirin or barbiturates
- Acidify urine with NH4Cl or ascorbic acid, trap weak bases [pKa 7.5-10.5] like phencyclidine or amphetamine
- Rarely ever block active reabsorption
Describe methods of enhancing elimination: Chelation of Heavy Metals
- Normally, essential heavy metals like Cu & Fe covalently bond protein nucleophiles
- …but they can covalently bond macromolecules that are essential for normal physiological function causing enzyme inhibition and altering membrane structure (especially in neuronal tissues).
- Treatment: administer chelating agents that complex with free metal ions in body fluids reducing their concentration, and thereby promoting the dissociation of metals from these functional intracellular macromolecules.
NOTE: Must administer proper dose of chelating agents to prevent depletion of body’s essential metals - but they may and thus may also be toxic themselves.
Compare and contrast the concepts of toxicokinetics (seen with toxic amounts of drugs) to “normal” pharmacokinetics (seen with
therapeutic doses and therapeutic plasma levels).
- Absorption (bioavailability [F]): Large amount of ingested drug may slow tablet dissolution, alter GI emptying, or injure GI tract → altered absorption → delayed peak effect
- Volume of Distribution [Vd]: Useful in predicting which drugs will be removed by dialysis / exchange transfusion (best if Vd < 1 L/kg, i.e., low values so most of drug is in plasma)
- Clearance (Metabolism / Excretion): Important to know contribution of each organ (kidney / liver) to elimination of the toxin or drug in planning treatment strategy
- Half-Life (t1/2): 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 (role of hepatic bioactivation to toxic metabolite and
depleted hepatic glutathione in hepatocellular injury) with N-acetylcysteine.
- Normally, ~80% Ac is conjugated with glucuronic acid or sulfate in a phase II reaction
- However, 5-10% proceeds through a phase I CYP450 oxidation (this makes the active metabolite, N-acetyl-p-benzoquinonimine, or NAPQI or Ac*). This metabolite is 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)
Treatment:
• Within 4 hours, administer charcoal & do gastric lavage
• Within 12-36 hours, administer N-acetylcysteine (Mucomyst®)
• 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
• Administer via IV to avoid N/V and interference with charcoal / emetic agent
Describe the basic pharmacodynamic parameters of methanol and ethylene glycol that underlie their toxicities: rapid oral
absorption, metabolism by common hepatic enzyme systems, these metabolic products selectively damage different tissues or
organs, and toxicities of both can be treated through similar interventions (inhibition of toxicating enzymes with fomepizole or
ethanol.
• Methanol and ethylene glycol have minimal toxicity until metabolized to formic acid and oxalic acid via ADH
• Formic acid causes severe acidosis & retinal damage
• Oxalic acid causes acidosis and nephrotoxicity
Treatment:
1. Suppress production of toxic metabolites by inhibiting the rate-limiting enzyme, ADH via
• Infusion of EtOH to maintain a blood level of 0.1 g/ 100 ml (BAC of 0.1%, legally drunk). It’s a competitive inhibitor of ADH and saturates the enzyme, decreasing production of toxins.
• Administer fomepizole (4-methylpyrazole, Antizol®), a specific inhibitor of ADH that does not produce CNS depression. Probably more effective than ethanol , but certainly much more expensive.
2. Hemodialysis to remove methanol or ethylene glycol and their toxic acid metabolites. Early intervention with gastric lavage.
3. Correction of metabolic acidosis with sodium bicarbonate
