Exam3lLec8Pharmacogenetics Flashcards
Pharmacogenetics is what?
is 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:
* CYP3A (60%)
* CYP2D6 (25%)
What is another name for Debrisoquine Hydroxylase?
- P4502D6
- CYP2D6
What are the tests for determining metabolizer phenotype of Debrisoquine Hydroxylase?
- Debrisoquine
- Sparteine
- Dextromethorphan ⭐️
What are the four phenotype cateogories?
- poor metabolizers (PM)
- Intermediatre metabolizes (IM)
- Extensive metabolizers (EM)
- Ultra rapid metabolizers (UM)
extrensive and ultra metabaloers are grouped to be called fast metabolizers
What are genotyping tests for mutant alleles ?
Polymerase chain reaction (PCR)
* Advenaces in the molecular genetics of this polymorphism has lead to the promotion of PCR
amplify cyp2d6
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 function gene?
- CYP2D7 and CYPD8 are pseudogenes
- CYP2D6 is function gene
What is the location of CYP2D6 and it’s inheditance?
located on the long arm of chromsomes 22 and is autosomal (passed down from mom and dad)
What are the major classes of currently used drugs which their metabolism are significantly affected by the CYP2D6 polymorphism? ⭐️
- Antiarrhythmic agents
- B-adrenergic receptor antagonists
- anti-psychotics
- 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 of metabolizersdoes this drug affect and what are their symptoms?
4. What P450 enzyme is defective?
⭐️ ⭐️ ⭐️ ⭐️
- antiarrhythmic agents
- narrow therapeutic window
- High concentration (PM) can lead to ventricular tachycardia or fibrillation
- CYP450 2D6
What happens in PM individuals that take tricyclic antidepressants? SX? ⭐️
- They have a narrow therapeutic window
- Symptoms of the overdose are sedation and tremors for pm
Example is Nortriptyline
doctors think the drug is not working in pm pts and they incr dose causing overdose
The more CYP2D6=
the less time in system or lower T 1/2
the less functional cyp2dr the more time or higher T 1/2
What is the impact of therapy in fast, intermediate, poor metabolizers with ACTIVE DRUG and INACTIVE metabolite? ⭐️
Fas: dont reach the TW
Intermediate: are within the therapeutic window
Poor metabolism: reach toxic concentration
reverese occurs in prodrug
codeine is example of drug which require metabolic activation by what?
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, a prodrug, is used for breast cancer. Tamoxifen is a competitive antagonist of estrogen receptor. There is high risk of relapse in PM since drug was never converted to active
POOR metabolizer=
- codeine ineffective
- Tamoxifen relapse
What is the impact of therapy in fast, intermediate, poor metabolizers with INACTIVE PRODRUG and TOXIC metabolite 🌟
Fast: you reach toxic concentration
Intermediate: within the therapuetic range
Poosr: does not reach the therapeutic window bc its not converted to acrtive drugs
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 anti malarial drug primaquine cause acute hemolysis ⭐️
due to reduction in 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 that mainly occurs in African Americans and a more severe type in Mediterranean population (Mediterranean type).
What drugs are affected by N-acetyltransferases in PM? ⭐️
The metabolism of the
* isoniazid
* procainamide (ant-arrhy)
* hydralazine (for HTN)
* caffeine are affected
In pm: can cause drug induced lupus erythematosus
CHIP
What side is fast acetylaters and slow? ⭐️
Left: fast
Right: slow
What does procainamide and hydralazine in PM individuals cause? ⭐️
Drug-induced Lupus Erythematosus can develop with prolong use of drugs with aromatic amines
Hydralazine was seen in the polymorphism of N-acetyltransferases
