L10 Drug Toxicity Flashcards
What are the 9 major factors affecting drug toxicity?
- Drug pharmacological properties (PK, therapeutic index, affinity for non-target receptors)
- Drug dosing
- Age/gender (metabolic differences)
- Genetics
- Body weight/fat distribution (drug distribution/retention)
- Smoking/drinking (drug interactions)
- Pre-existing conditions/health status (liver/kidney dysfunction)
- Polypharmacy
- Allergy (hypersensitivity reactions)
What are the 5 major mechanisms of drug toxicity?
- On target effects
- Off target effects
- Harmful metabolites
- Allergic responses
- Idiosyncratic responses
What are the two general types of on-target adverse effects?
- Intended tissue, intended receptor
2. Unintended tissue, intended receptor
What are the two general types of off-target adverse effects?
- Intended tissue, unintended receptor
2. Unintended tissue, unintended receptor
This type of effect is caused by an exaggeration of the desired pharmacological activity.
On target effects in the same tissue
What are some causes of on target effects in the same tissue?
- Changes in exposure/sensitivity to the drug
- Overdose
- Alteration in PK parameters
- Change in PD parameters
- Extended exposure to the drug
This type of effect is caused by pharmacological activity at the same receptor in different tissue.
On target effects in unintended tissue
How do off-target effects occur?
Drug has affinity for unintended receptors or bind to unintended target unrelated to the site of action
All new drugs are now tested to ensure that they do not bind to hERG channels; when this happens, what are the effects?
Inhibition of hERG channels leads to long QT syndrome, arrythmia, and sudden cardiac death
Drug ___, which are mirror images of each other, can also be the cause of off-target effects.
Enantiomers
The metabolism of some drugs can give rise to harmful ___ that can cause toxicity by chemically modifying proteins, DNA, and/or lipids.
Metabolites
Describe the mechanisms by which an overdose of acetaminophen can cause
hepatotoxicity.
Normally, 95% of acetaminophen is metabolized to its conjugates and excreted. 5% is metabolized to the highly-reactive NAPQ. Glutathione detoxifies this and it is excreted.
When ahigh dose of acetaminophen is given, the phase II enzymes are saturated, and more drug is converted to NAPQ. When glutathione is depleted, hepatotoxicity occurs.
How can an acetaminophen OD be treated?
N-acetyl Cysteine given in the first 8-12 hours; this elevates glutathione levels
What are the three major sites of organ-specific drug toxicity?
Liver, kidney, heart
How do immune-mediated drug reactions occur?
Some drugs or their metabolites are chemically reactive; they covalently modify patient proteins, creating a haptenated-protein complex that can stimulate the immune response.
True or false - the risk of developing an idiosyncratic adverse effect is not related to the drug’s dose or mechanism of action.
True
There appears to be a strong ___ component for susceptibility to idiosyncratic adverse effects.
Genetic
What are the most common reason for drug withdrawals?
Idiosyncratic adverse effects
What are the most frequent organs affected by idiosyncratic toxicity?
Liver, skin, blood cells
Many idiosyncratic adverse effects have been linked to ___ genes.
MHC/HLA
What is a teratogen?
A drug that can adversely affect the development of the fetus when given to a pregnany woman; typically does not effect the mother
Fetal exposure to a teratogen is determined by what two factors?
- Maternal ADME
2. Ability of drug to cross the plasma
Describe the two major developmental timing effects of teratogen exposure.
- Exposure prior to 3rd week of gestation frequently results in fetal death
- Exposure between the 3rd and 8th week of gestation during organogenesis can have profound developmental effects
Describe the 5 categories of drugs used in pregnancy.
Category A: adequate/well-controlled studies fail to demonstrate risk to fetus in 1st trimester, no evidence of risk in later trimesters
Category B: animal studies have failed to demonstrate a risk; no well-controlled studies in pregnant women
Category C: animal studies show an adverse effect, no controlled studies in humans, potential benefits may outweigh risks
Category D: positive evidence of human fetal risk, but potential benefits may outweigh risks
Category X: studies in animals and humans have demonstrated fetal abnormalities, risk outweighs benefit
