Drug Toxicity Flashcards
Define a drug-induced adverse effect.
- predicts hazard from future administration
- warrants prevention, alteration of regimen, or withdrawal
- can be due to single dose or prolonged administration or drug interactions
List some of the factors that can influence the development of a drug-induced adverse effect.
- drug pharmacological properties
- drug dosing
- age
- gender
- genetics
- body weight and fat distribution
- smoking/drinking
- health status
- polypharmacy
- allergy
Explain how drug toxicity can result from the effects of a drug on its direct molecular target.
ON-TARGET INTENDED - intended tissue AND receptor - due to: ==> increased concentration of drug ==> chronic activation or inhibition of receptor target ==> accidental/intentional overdose ==> alterations in PK or PD ==> changes in sensitivity - exaggeration of therapeutic effect - class A effect: same mechanism, shared by all drugs in that class
ON-TARGET UNINTENDED
- intended receptor but in different tissue
Explain how drug toxicity can result from off-target effects.
INTENDED OFF-TARGET
- unintended receptor, same tissue
- low selectivity
UNINTENDED OFF-TARGET
- unintended receptor, different tissue
- low selectivity
OVERALL
- also possibly caused by enantiomers
=> one is pharmacologically active and causes desired effect
=> other could be inactive/null OR bind to a different target
Explain how the metabolism of harmful metabolites can contribute towards drug toxicity.
- metabolites can be harmful and reactive => chemically modify proteins, DNA, or lipids => toxicity
Describe the mechanisms by which an overdose of acetaminophen can cause hepatotoxicity.
- causes hepatotoxicity at high doses (lethal)
- high concentration causes saturation of phase II enzymes (cannot conjugate it all for excretion => phase I metabolite (NAPQI) builds up
- in chronic alcoholics, CYP2E1 is overactive => increased metabolism of acetaminophen => increased production of NAPQI metabolite
- depleted glutathione + saturated phase II enzymes => build up of highly reactive NAPQI metabolite => toxicity
Describe why timely treatment with N-acetyl-cysteine can be effective in the treatment of acetaminophen poisoning.
N-acetyl-cysteine increases glutathione levels => protein conjugation with NAPQI => takes care of metabolite build up => excretion
Describe how drugs can trigger the immune system to cause adverse effects.
- haptenated protein complexes (brought on by drug metabolites) can activate the immune system
- can make patients hypersensitive
- can promote damaging immune responses (rash, SJS, hemolytic anemia, hepatocellular liver injury)
Define idiosyncratic toxicity. What influence do genetics have on developing this drug reaction? What are the potential mechanisms involved?
- unpredictable, unusual
- not observed in clinical or animal trials
- risk of development not related to dose or mechanism of action
- most common organs affected are liver, blood, and skin
- primarily immune-mediated (liked to HLA/MHC genes)
Define teratogen.
drug that can affect the development of a fetus
- depends on maternal ADME and if teratogen can cross placenta
- effects depend on timing of exposure
==> if between 3-8 weeks, organogenesis, developmental effects
Describe the classification of drugs used in pregnancy. Identify which categories of drugs can and cannot be used in the treatment of women who are pregnant.
CATEGORY A - no evidence of risk
CATEGORY B - no evidence in animal trials; no studies in pregnant women
CATEGORY C - risk shown in animal trials; no studies in humans; benefits outweigh risks => prescribe
CATEGORY D - risk of human fetal risk; benefits outweigh risk => prescribe
CATEGORY E - animal and human fetal abnormalities; risks do not outweigh benefits => do not prescribe
Describe organ-specific toxicity in the liver, kidneys, heart. Describe the mechanisms.
LIVER
- main cause of drug withdrawal
- typically due to overproduction of phase I metabolites by CYPs
RENAL
- major route of elimination
- toxic drugs: ACEI, NSAIDS, aminoglycosides, anti-virals, anti-biotics
HEART
- interactions with hERG channels promoting prolonged QT intervals
MECHANISMS
- altered intraglomerular hemodynamics: changes in GFR and vasoconstriction
- tubular toxicity
- inflammation
- crystal nephropathy
Describe the mechanisms by which drugs can induce an immune response.
TYPE 1 HYPERSENSITIVITY
- mast cell degranulation
TYPE 2 HYPERSENSITIVITY
- complement
TYPE 3 HYPERSENSITIVITY
- tissue damage
TYPE 4 HYPERSENSITIVITY
- autoimmune
