How are poisoning cases resolved?
95% of outcomes in poisoning cases a determined by supportive care. There are 100's of thousands of toxins/poisons, but only 20-25 actual pharmacodynamic antidotes. A pharmacodynamic antidote is something that works at the point of the poisoning, whereas most other treatments involve more rapid clearing of the poison (metabolism & excretion)
What are the possible methods of action for supportive care?
Keep the toxin from getting into the system and distributing to the target, or do something to increase the elimination from the system.
What is the difference between systemic toxicity and local toxicity?
Systemic toxicity occurs when the drug reaches toxic levels in the Cp or tissues, particularly where it has effect. Local toxicity occurs at the site of absorption (stomach, lungs, etc.) where the drug accumulates before being absorbed.
What parameters of pharmacokinetics may change at toxic levels (toxicokinetics), and which are useful to know to plan treatment?
Absorption (Bioavailability [F]) - Slowed tablet dissolution, altered GI emptying, or injured GI tract -> altered absorption -> delayed peak effect. Half life - Only calculated for therapeutic dose, may be altered due to saturation (zero order) kinetics in overdose. Volume of Distribution (Vd) - predicts which drugs can be removed by dialysis/exchange transfusion; best with low Vd as most drug will be in the plasma. Clearance (metabolism/excretion), know the contribution of each organ (liver/kidney) to elimination or excretion of the drug to plan treatment.
What is the general treatment strategy for poisonings?
Decrease the rate in - decrease absorption, inhibition of toxication (prevent conversion to toxic species) Increase the rate out - enhancement of metabolism, increase elimination.
What is emesis and what is one example of an emetic?
Emesis is the rapid emptying of stomach contents (vomiting). Syrup of Ipecac is an emetic. Produces vomiting after 15-30 minute lag due to local irritation, given orally, must be given before charcoal treatment. No longer recommended for home use.
How much toxin is removed by emesis and lavage combined?
~30%, nearly 3/4 of the toxin is still absorbed. Best if used within 60 minutes, but window may be larger due to delayed toxicokinetic absorption.
What does activated charcoal do?
Binds the toxin in the stomach/gut. It is not technically fecal elimination of the drug (which requires processing in the liver -> bile), but prevention of absorption. Given in 10:1 ratios (char:drug), in combination with osmotic sugar (sorbitol) to improve transit through gut.
What are 6 methodologies for decreasing absorption of a drug?
Emetics, lavage, activated charcoal, magnesium citrate/sulfate, sodium sulfate, polyethylene glycol.
What are two examples of compounds that are not toxic until they are metabolized?
Ethanol and ethylene glycol. Ethanol (CH3OH) -> formic acid -> retinal damage. Ethylene glycol -> oxalic acid -> acute renal failure (precipitates). Both of these are metabolized (oxidation rxn) by alcohol dehydrogenase (phase I).
How can methanol or ethylene glycol poisoning be treated?
Fomepizole can be used to inhibit alcohol dehydrogenase. Ethanol (regular alcohol) can competitively inhibit alcohol dehydrogenase and reduce volume of toxic metabolyte.
How is acetaminophen metabolized?
Normally, 80-90% of acetaminophen is metabolized via phase II conjugation reactions (non-toxic), 10-20% metabolized via Phase I CYP2E1 to hepatotoxic metabolyte. Metabolite is then metabolised (detox pathway) by Phase II conjugation with GSH.
What causes acetaminophen toxicity and how is it treated?
Single doses >10-20mg = saturation of Phase II pathway -> increased formation of Phase I toxic metabolite -> eventual saturation of Phase II detox pathway (Glutathione S Transferase) -> liver damage. Treatment is gastric lavage, suuportive therapy, and administration of precursor of glutathione N-Acetylcysteine which increases glutathione AND directly detoxes hepatotoxic metabolite.
How does alcohol contribute to acetaminophen toxicity?
Long term alcohol abuse can induce CYP2E1, leading to greater levels of the enzyme in the liver, and decreases levels of glutathione in the liver, as well as directly causing liver disease. Processing by CYP2E1 produces the toxic metabolite of acetaminophen, and the detox pathway more easily saturated due to decreased glutathione. Max dose for alcoholics is 2mg/day, or none.
What are the differences between Phase I and Phase II processing that come into play in the acetaminophen processing pathway?
Oxidation vs Conjunction processes; CYP450 vs transferase enzymes; significant induction effects vs little induction effects; minimal saturability vs
What sort of drugs respond well to dialysis?
Dialysis pumps the blood through a filter, thus it is most effective on drugs with small Vd (most will be in plasma, high Vd = most drug not in plasma), and drugs with low protein binding capacity. Dialysis assists in the correction of fluid and electrolyte imbalances.
What two chemicals can be used to increase ion-trapping in the urine?
Urine can be alkalinized by NaHCO3 and acidified by NH4Cl. These do not directly alkalinize/acidify the urine, but alkalinize/acidify the system, and the urine follows suit.
How are chelating agenst used?
Chelating agents complex with free metal ions in the blood, decreasing their Cp concentration and promoting their dissociation from macromolecules. Proper dosing is essential to prevent depletion of body's essential metals.