Drug Toxicity Flashcards Preview

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Flashcards in Drug Toxicity Deck (13):
1

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

2

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

3

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

4

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

5

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

6

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

7

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

8

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)

9

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)

10

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

11

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

12

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

13

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