Lecture 8: Pharmacogenetics Flashcards
What is pharmacogenetics?
A field concerned with unusual (idiosyncratic) drug responses that have a hereditary basis.
A pharmacogenetically related response is different from an _ or _ phenomenon (an adverse reaction to a drug resulting from previous sensitization to the same drug or a closely related one)
Overdose or allergic
Many drugs are metabolized by what?
Cytochrome P50 Enzyme
What are tests for determining metabolizer phenotype?
- Desbrisoquine
- Sparteine
- Dextromethorphan
What are the four phenotype categories?
- Poor metabolizers (PM)
- Intermediate metabolizers (IM)
- Extensive metabolizers (EM)
- Ultra-rapid metabolizers (UM)
What are genotyping tests for mutant alleles ?
Polymerase chain reaction (PCR)
The CYP2D gene clusters on a given allelic DNA fragment may contain between _ copies of functional genes
zero to thirteen copies
Which CYP enzymes are pseudogenes and functional gene?
- CYP2D7 and CYPD8 are pseudogenes
- CYP2D6 is a functional gene
What is located on the long arm of chromosome 22?
CYP2D6 and is autosomal
What are major classes of currently used drugs which their metabolism are significantly affected by the CYP2D6 polymorphism? ⭐️
Antiarrhythmic agents, B-adrenergic receptor antagonists, anti-psychotics, and tricyclic antidepressent
What happens with patients that take B blockers?
is estimated that 15 to 20 percent of patients who undertake therapy with the b-blockers are forced to discontinue their use due to adverse reactions.
Flecanide and propafenone:
1. What type of class?
2. Big or narrow therapeutic window
3. What group does this drug affect with symptoms?
⭐️ ⭐️ ⭐️ ⭐️
- antiarrhythmic agents
- narrow therapeutic window
- High concentration (PM) can lead to ventricular tachycardia or fibrillation.
What happens in PM individuals that take tricyclic antidepressants? ⭐️
Symptoms of the overdose are sedation and tremors
What is the impact of therapy in fast, intermediate, poor metabolizers with ACTIVE DRUG and INACTIVE metabolite? ⭐️
Codeine is an example of a drug that requires what gene for metabolic activation?
CYP2D6-> prodrug
Codeine is nearly ineffective as an _ in 5 to 10 percent of population (_).
Codeine is nearly ineffective as an analgesic in 5 to 10 percent of population (PM).
What is a prodrug that is used for breast cancer? How does it work? How does this drug affect group PM? ⭐️
- Tamoxifen
- It is a competitive antagonist of estrogen receptor
- There is a high risk of relapse in PM
What is the impact of therapy in fast, intermediate, poor metabolizers with INACTIVE PRODRUG and TOXIC metabolite 🌟
What is caused by glucose-6-phosphate dehydrogenase deficiency ⭐️
Increased Susceptibility to Drug-Induced Hemolysis
What drug causes acute hemolysis in approximately 10% of African Americans? ⭐️
anti-malarial drug = primaquine
Why does the anti-malarial drug primaquine cause acute hemolysis? ⭐️
Due to the reduction in the concentration of reduced glutathione (GSH) because there is a Glucose-6-Phosphate Dehydrogenase Deficiency (no NADPH)
There are approximately 300 G6PD variants. What are the two main variants?
- A-type → mainly occurs in African Americans
- More severe type → Mediterranean population (Mediterranean type).
What drugs (4) are affected by N-acetyltransferases? ⭐️
The metabolism of these drugs is affected:
- isoniazid
- procainamide
- hydralazine
- caffeine
What side is fast acetylaters and slow? ⭐️
Left: fast
Right slow
What does rocainamide and hydralazine in PM individuals cause? ⭐️
Drug-induced Lupus Erythematosus can develop with prolong use of drugs with aromatic amines
