L18- Pharmacogenetics Flashcards
what are the factors that can influence drug response (indicate the biggest influencer)
- genetic variation***
- age
- gender
- disease
what are the three types of genetic variation that can influence pharmacotherapy
- variation in proteins involved in drug metabolism/transport (pharmacokinetics)
- variation in drug targets (pharmacodynamics)
- variation in proteins associated with idiosyncratic drug effects
list the common genetic polymorphisms involving drug-metabolizing enzymes (pharmacokinetics)
- NAT2 (N-acetlytransferase)
- BChE (butyrylcholinesterase = pseudocholinesterase)
- CYP2D6
- TPMT (thiopurine S-methyltransferase)
pharmacogenetics is important because…
adverse drug reactions are a major cause of morbidity and mortality
NAT2 catalyzes (1) and is classified as either (2) with high drug levels or (3) with low drug levels
(N-acetyltransferase 2)
1- isoniazid and others
2- slow acetylators (= slow drug metabolism)
3- fast acetylators (= fast drug metabolism)
Slow acetylators of drugs via NAT2 are (1) for a (wild-type/recessive) allele. This will yield (high/low) levels of drugs at normal doses, resulting in (4).
(N-acetyl transferase) 1- homozygous 2- recessive 3- high levels of drug in plasma 4- drug toxicity
For slow acetylators, list the most probable adverse effects for the following drugs:
(1) hydralazine, procainamide
(2) isoniazid
(3) sulfonamides
1- SLE
2- neuropathy, hepatotoxcity
3- hypersensitivty rxns, hemolytic anemia, SLE
isoniazid functions to (1) and is metabolized by (2) enzyme via (3) mechanism
1- antimyobacterial agent
2- NAT2 (N-acetyltransferase)
3- acetylation
Neuromuscular blockers, particularly (1), are used for (2)
1- succinylcholine (depolarizing neuromuscular blocker)
2- cause skeletal muscle paralysis during (or before) surgical procedures
Succinylcholine binds to (1) to mimic (2) function. As a result (3) occurs because of the (4) property of succinylcholine.
1- nAChR
2- acetylcholine (depolarization)
3- flaccid paralysis (local)
4- not metabolized at synapse –> persistent depolarized membrane
Succinylcholine usually takes (1) time to establish effective neuromuscular blockade. (2) degrades it by (3) mechanism, and the blockade lasts about (4) time.
1- w/in 1 min (rapid)
2- butyrylcholesterase (in plasma)
3- hydrolysis (also rapid process)
4- 5-10 mins
A person with decreased metabolism of succinylcholine (and other neuromuscular blockers) is usually the result of defective (1) gene, inherited in (2) fashion. As a result, (3) occurs following succinylcholine administration.
1- BCHE gene
2- autosomal recessive
3- prolonged paralysis
discuss DN and its relationship to butyrylcholinesterase polymorphism
- DN = dibucaine number
- dibucaine inhibits wild-type BChE
- DN > 75 –> homozygous normal enzyme
- DN between 40-70 –> heterozygous atypical enzyme
- DN < 20 –> homozygous atypical enzyme
discuss treatment for an individual with atypical BChE who was given succinylcholine
mechanical ventilation until muscle function returns to normal
CYP2D6 is a member of the phase I metabolism, P450 family and metabolizes the following drugs: (1). Polymorphism of CYP2D6 can be describe as one of the following [include genetic reason why]: (2), (3), (4)
1- antidepressants, antiarrhythmics, analgesics
2- poor metabolizers, homozygous for recessive allele (=> low CYP2D6 activity)
3- extensive metabolizers, hetero-/homo-zygous for wild-type allele
4- ultra metabolizers, multiple copies of CYP2D6 gene (up to 13 copies)
(1) and (2) were drugs (not used pharmaceutically anymore) to test CYP2D6 polymorphism activity
- desbrisoquine, antihypertensive
- sparteine, oxytotic agent
list some commonly prescribed drugs that CYP2D6 metabolizes
- metoprolol, β-blocker
- haloperidol, antipsychotic
- codeine/dextromethorphan, opioids
- fluoxetine/imipramine/desipramine/etc, antidepressants
describe how poor CYP2D6 metabolizers are affected by metoprolol and codeine
Metoprolol: inc adverse effects with normal/low doses, less is metabolized => high levels
Codeine: dec therapeutic effects with normal doses, it is a prodrug that CYP2D6 converts to active morphine
describe how ultra CYP2D6 metabolizers are affected by metoprolol and codeine
Metoprolol: requires higher doses, most is metabolized => low levels
Codeine: overdose to standard dose, most of the prodrug is converted to active morphine by CYP2D6 => respiratory depression or arrest
TPMT catalyses (1) event of (2) type drugs, specifically (3) and (4), as (1) of those drugs will (in-/activate) them. This is important because (2) drugs have (6), and (7) is the key adverse effect if the dosage is mishandled.
(thiopurine S-methyltransferase) 1- S-methylation 2- anticancer thiopurine 3- 6-mercaptopurine 4- azathiourine 5- inactivate 6- narrow therapeutic windows 7- myelosuppression
TPMT polymorphism is inherited in a (1) fashion, with (inc/dec) activity resulting in a risk for (3) with standard doses of (4) drugs. Therefore (5) fraction of (4) doses may be required. (6) are the possible phenotypes.
1- autosomal recessive 2- decreased activity 3- inc risk of myelosuppression 4- anticancer thiopurine 5- 1/10 of normal dose 6- homozygous WT (high activity), heterozygous (medium activity), homozygous recessive allele (low to no activity)
(1) is a (2) type of receptor often over-expressed in NSCLC. (3) is a common inhibitor of (1)/(2) in patients with NSCLC. Patients can have mutations in the (4) site of (1) and have better response to (3) treatment.
(nonsmall cell lung cancer) 1- EGFR (epidermal growth factor receptor) [inc expression due to gain of function mutation] 2- TK (tyrosine kinase) 3- gefintinib 4- ATP binding site
Warfarin is prescribed for (1) with (2) or (3) as complications depending on over or under dosing which is affected by the following: (4).
1- anticoagulant
2- thrombosis in under-anticogulation (low dose)
3- bleeding in over-anticoagulation (high dose)
4- narrow therapeutic window and wider interindividual variabilty
Warfarin dosing can be affected by variations in genes casing changes in its (pharmacodynamics / pharmacokinetics)
BOTH
Warfarin is a racemic mixture where the (R/S) stereotype is more potent. S-warfarin is metabolized by (2). R-warfarin is metabolized by (3). (4) is the most polymorphic gene among these Warfarin metabolizers.
(metabolism in the liver) 1- S >> R (3-5 times more potent) 2- CYP2C9 (hydroxylated) 3- CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP3A4** (hydroxylated or in one case dehydroxylated) 4- CYP2C9 (S and R forms)
describe the effects of pharmacokinetic variation in humans with Warfarin dosing
- CYP2C9 is the only metabolizer for S enatiomers, the more potent form (R enatiomer is mainly CYP3A4)
- variant alleles from wild-type usually yield lower activity
- therefore higher levels of warfarin persist and lower doses are needed in therapy
- they also have a higher risk of bleeding/hemorrhage with normal dosing
Warfarin targets (1) enzyme in order to affect (2) overall. (1) enzyme has high number of polymorphisms, therefore binding to warfarin can vary leading to (3)
1- VKORC1 (vitamin K epoxide reductase complex 1)
2- dec activation of clotting factors (II/prothrombin, VII, IX, X)
3- warfarin doses with 2-fold differences between individuals
G6PD deficiency is the best example of (1) adverse effects of drugs. G6PD is necessary for the generation of (2) so (3) can continue to function to (4).
1- genetic variation with associated idiosyncratic adverse effects
2- NADPH
3- glutathione peroxidase
4- detoxify free radicals and peroxides (w/in cell)
G6PD deficiency is popular among (1) people due to its (2) property
1- African (10-20%)
2- protection against malaria
people with G6PD are susceptible to (1) due to (2) as a result of ingestion of the following drugs, (3), that cause (2)
(Note- dec is G6PD by 90-95%)
1- hemolytic anemia
2- inc oxidative stress on RBCs
3- sulfonamides, antimalarials, chloramphenicol
