Drug Safety, Adverse drug reactions, and Poisoning Flashcards
Compare and contrast graded dose-response curves and population dose-response curves.
Population dose-response curves are used to characterize pharmacologic responses that are all-or-nothing events in a population. Used to determine the percent of population for which a dose is therapeutic and a dose that is legal.
Graded dose response curves show the effects of an increasing number of doses that are given to the same subject. This allows for the determination of the maximal effect of a drug.
Explain the use of population dose-response curves to regulate drug safety.
Dose-response curves provide information to compare the dosage necessary for producing the desired therapeutic effect with the dose that causes an undesirable toxic effect.
The therapeutic index compares midpoint in the population (ED50 and LD50).–> TI= LD50/ED50
Higher the therapeutic index, the safer the drug.
The standard safety margin looks at extremes in the population (ED99 and LD1)
[(LD1/ED99)-1] x 100
Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing.
A: Controlled studies show no risk in 1st trimester, no evidence of risk in later trimesters. Possibility of fetal harm appears remote
B: No evidence of risk in humans
C: Risk cannot be ruled out. Potential benefits may warrant use of the drug in pregnant women despite the potential risks.
D: Positive evidence of human fetal risk, but potential benefits may outweigh the potential risks. If needed in a life-threatening situation or serious disease, drug may be acceptable is safer drugs cannot be used/are ineffective.
X: Contraindicated in pregnancy
Decisions regarding drugs in categories A and X are straightforward, more abiguous in categories B, C and D.
Pharmacokinetic drug-drug/drug-food interactions
Absorption: Decreases in motility slow the passage of the drug to larger absorptive area of the small intestinel decreased absorption rate may lower peak plasma drug levels. Increases in rate of absorption less important.
Physiochemical inactivation via changes in pH or formation of insoluble complexes reduces bioavailability.
Distribution:
Protein binding/displacement interactions: competitive binding may increase amount of free drug
Cellular distribution interactions
Metabolism: Metabolic rate may be increased (inducers) result in reduced/subtherapeutic levels or decreased (inhibitors) resulting in increased/toxic levels. Most interactions occur via effects of CYP450 system.
Excretion: Most excretion interactions occur in the kidneys.
Mechanism includes change in flomerular filtration rate, tubular secretion, and urine pH.
Pharmacodynamic Interactions
Antagonistic effects: occur when 2 drugs with opposite pharmacologic effects given together.
Synergisitic/additive effects: occur when drugs with similar therapeutic effects given together.
Synergistic/additive side effects: Occurs when drugs with similar side effects are given together.
Indirect pharmacodynamic effect: pharmacologic effect of one drug indirectly affects another drug’s action.
Pharmacokinetic interventions for poisoning/overdoses
Emesis: Empties stomach contents rapidly.
-Ipecac (15-30 min lag, effective orally, must be given before charcoal, no longer recommended for home tx)
-Apomorphine: Not recommended any longer, especially in children, respiratory depressant.
General contraindications:
-Patient comatose/stuporous
-Ingestion of corrosive poisons
-Ingestion of CNS stimulant
-Ingestion of petroleum distillate
-Pregnancy category C
Gastric Lavage: Most rapid and complete method of emptying stomach, but lavage+emesis removes only about 30% of most oral poisons
-Best w/in 60 min of poison ingestion
Chemical absorption: Activated charcoal:
- binds drug in gut to limit absorption
- effective without prior gastric emptying, can reduce elimination half lives of drugs
- Best to give in 10:1 ratio to toxin, serial administration may be helpful.
- Difficult to administer and poorly accepted in children, home tx is not recommended.
Osmotic Cathartics: Decrease time of toxin in GI tract
Sorbitol 70% recommended
Magnesium Citrate/sulfate: avoid in renal disease or poisonings with nephrotoxic agents
Sodium sulfate: avoid use of sodium containing cathartic in congestive heart failure or hypertension
Polyethylene glycol (Golytely): Whole bowel irrigation that promotes elimination of entire contents of intestings; used in poisonings of sustained released drugs, metal ions, drug packets.
Toxicokinetics
Toxic dose of a drug may result in alterations of normal pharmacokinetics:
Absorption, Vd, Clearance, and Half life (may be prolonged in toxic overdoses)
Toxicokinetic strategies:
-Prevent/decrease aboprtion of toxin
_inhibition of toxication (prevent convesion to toxic species)
-enhancement of metabolism (detoxication)
-Increased elimation of toxin
Pharmacodynamic strategies–> antidotes
Describe the mechanism of acetaminophen overdose toxicity and its treatment (role of hepatic bioactivation to toxic metabolite and depleted hepatic glutathione in hepatocellular injury).
70-80% of acetaminophen undergoes Phase II metabolism (safe) , while 5-10% of Acetaminophen metabolism proceeds via phase I metabolism to become chemically active metabolite NAPQI. Normally this is detoxified by phase II GSH transferase and excreted.
During toxic doses, phase II metabolism becomes saturated and excessive formations of NAPQI is formed, eventually depletes cellular glutathione, and NAPQI binds to critical cellular/protein components.
Early tx involves activated charcoal and gastric lavage.
N acetylcystein serves as a precursor for glutathion synthesis, and also functions as a nucleophile to capture NAPQI
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.
Both alcohols are well absorbed orally because they’re extensively metabolized to organic acids.
Alcohols themselves have minimal toxicity until metabolized into formic acid/formaldehyde (acidosis, retinal damage) and oxalic acid (acidosis, nephrotoxicity).
Both can be treated by inhibited the rate limiting enzyme alcohol dehydrogenase (via ethanol or fomepizole), hemodialysis, or correction of metabolic acidosis with sodium bicarbonate.
