Drug Toxicity Flashcards
Define a drug-induced adverse effect.
“an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”
List some of the factors that can influence the development of a drug-induced adverse effect.
Drug Pharmacological properties (PK parameters, TI, affinity for non-target receptors)
Drug dosing
Age and gender (metabolic differences)
Genetics (Genetic susceptibility)
Body weight and Fat distribution (drug distribution and retention)
Smoking/Drinking (drug interactions)
Preexisting conditions/Health Status
-liver/kidney dysfunction
Polypharmacy
-drug-drug interactions
Allergy
-hypersensitivity reactions
Explain how drug toxicity can result from the effects of a drug on its direct molecular target.
Caused by an exaggeration of the desired pharmacological activity
- Changes in exposure or sensitivity to the drug
- Accidental or intentional overdose
- Alteration in drug PK parameters (e.g. impaired kidney/liver or drug interactions)
- Change in drug PD parameters (e.g. increase in receptor number)
- Extended exposure to drug
in intended tissue on intended receptor- there could be high drug concentration, chronic receptor activation/inhibition leading to toxicity
On intended receptor in unintended tissue; (same issues) correct receptor, incorrect tissue; high drug concentration; chronic receptor activation/inhibition
Since caused by the drugs desired mechanism of action- shared by all members of the drug class- A CLASS EFFECT
Explain how drug toxicity can result from “off-target” effects.
- affinity for unintended receptors
- Drug binds to unintended target unrelated to site of action
Very few drugs are so selective that they only interact with one molecular target.
Drug has affinity for unintended receptors and this causes adverse effects by binding and blocking additional receptors
Inappropriate binding of drug to unintended target can activate/inhibit the target
Explain how the metabolism of harmful metabolites can contribute towards drug toxicity.
The metabolism of some drugs can give rise to harmful reactive metabolites that can
cause toxicity by chemically modifying host proteins, DNA and/or lipids.
- metabolism- dependent production can occur in the liver causing hepatoxicity or in extrahepatic tissues
Describe the mechanisms by which an overdose of acetaminophen can cause
hepatotoxicity .
Acetaminophen can cause hepatoxicity at high doses (potentially lethal)
problem w overdose is that Phase II enzymes becomes saturated and another pathway takes over in which N-acetyl benzoquinoneimine (NAPQI) is produced; must be conjugated by Glutathione or hepatotoxicity ensues
w overdose those Phase II enzymes get saturated/depleted… (this overdose and liver failure, death can occur in 2-3 days)
Describe why timely treatment with N-acetyle Cysteine can be effective in the treatment
of acetaminophen poisoning.
Treatment within the first 8-12 h is with N-acetyl Cysteine, which elevates glutathione levels (maintains glutathione reserves in the liver)
Glutathione is crucial to detoxify the highly reactive NAPQI metabolite
Describe how drugs can trigger the immune system to cause adverse effects.
Some drugs (or their metabolites) are chemically very reactive and can covalently modify patient proteins creating a haptenated-protein complex that can stimulate the immune response
Drug-induced immune responses can:
- create drug allergies by making patients hypersensitive to drug re-exposure or to a structurally related drug (e.g. beta lactams)
- promote damaging immune responses causing significant pathology to various tissues most commonly the skin, liver and blood cells
Define idiosyncratic toxicity, the influence
of genetics in developing an iodiosyncratic
drug reaction, and the potential mechanisms involved.
Idiosyncratic drug reactions are those that are unpredictable and appear in a very small number of patients
The risk of developing an idiosyncratic adverse effect is not related to the either the drug’s dose or mechanism of action
There appears to be a strong genetic component for susceptibility to these types of adverse effects
Idiosyncratic adverse effects can be severe and are the most common reason for drug withdrawals
Hypothesis: In individuals that are genetically susceptible (i.e. specific HLA allele
and inactivating polymorphism in a critical drug metabolizing pathway) a highly reactive drug metabolite may not be effectively detoxified and is then able to initiate an acute drug-induced immune response
Define the term teratogen.
A drug that can adversely affect the development of the fetus when given to a pregnant women is known as a teratogen
Describe the classification of
drugs used in pregnancy and identify categories of drugs that can and cannot be used in the treatment of women who are pregnant.
Category A- Adequate and well controlled studies have failed to demonstrate a risk to
the fetus in the 1st trimester and no evidence of risk in later trimesters
Category B- Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no well-controlled studies in pregnant women
Category C- Animal reproduction studies have shown an adverse effect on the fetus, and there are no controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks
Category D- There is positive evidence of human fetal risk, but potential benefits may warrant use in pregnant women despite the risk
Category X- Studies in animals and humans have demonstrated fetal abnormalities, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits
What is the following an example of?
Lidocaine is a local anesthetic; blocks Na+ channels in neurons at site of administration; overdose or inappropriate administration can cause channel blockade in the CNS causing tremors, seizures and even death.
“On target” effects in unintended tissue
Chlorpromazine is an antipsychotic medication works by blocking Dopamine D2 receptors. Side effects include weight gain, sedation, tachycardia, incontinence, sexual dysfunction, and sometimes dry mouth blurred vision and constipation. What kind of adverse effect is this?
off target effects
drug has affinity for unintended receptors
Numerous compounds have been shown to be capable of interacting with the cardiac hERG channels and blocking their activity
- hERG is a subunit of cardiac potassium channels critical for the cardiac action potential
- Inhibition of hERG channels can result in serious toxicity
What is this an example of?
“off target effects”
Drug binds to unintended target unrelated to site of action
Interactions of drugs with the hERG channel promoting the long QT syndrome
Explain how drug enantiomers can cause adverse drug effects?
Drug Enantiomers can also be the cause off target effects
Some drugs are administered as racemic mixtures of different drug enantiomers (racemic drug mixture)
- Enantiomeric structures are mirror images of each other
- Drug receptors are exquisitely sensitive to a drugs 3-D structure and can distinguish between the different enantiomers
- While one enantiomer is pharmacologically active and promotes the desired effect, the other can be completely inactive, but in some cases can bind to an alternative target to cause adverse effects
