L30 Pharmacogenetics Flashcards
What is the range of variations in drug responses?
- severe adverse effects
- lack to therapeutic activity
what are the factors that can influence the drug response phenotype?
- age
- gender
- disease
- genetic variation!
define pharmacogenomics?
study of the role of inheritance in variation in drug responses
why is pharmacogenomics important to study?
because adverse drug reactions are a major cause of morbidity and mortality
what are the 3 types of genetic variation that can influence pharmacotherapy?
- variation in proteins involved in drug metabolism/transport
- variation in drug targets (pharmacodynamic variation)
- variation in proteins associated with unique (idiosyncratic) adverse drug effects
what does absorption, distribution and elimination (what the body does to the drug) define?
pharmacokinetics
what describes what the drug does to the body?
pharmcodynamics
what is the most common factor responsible for pharmacogenetic variation in drug responses?
genetic variation in enzymes that catalyze drug metabolism
*most enzymes in drug metabolism are POLYMORPHIC!
give 4 examples of the polymorphic drug metabolizing enzymes?
- butyrylcholinesterase (pseudocholinesterase) (BChE)
- N-acetyltransferase 2 (NAT 2)
- cytochrome P450 2D6 (CYP2D6)
- thiopurine S-methyltransferase (TPMT)
what type of drug is succinycholine?
depolarizing neuromuscular blocker
what is the function of succinylcholine?
- what receptor does it bind to?
- what NT does it act like?
- what does it cause to happen on the end plate?
- binds to nicotinic receptors
- acts like ACh
- depolarizes the end plate
what is the major difference between ACh and succinylcholine?
succinylcholine is not metabolized at the synapse effectively like ACh (using AChE)
what type of onset and duration does succinyl choline have?
fast onset
short duration
what breaks down and metabolizes succinylcholine?
plasma butyrylcholinesterase
what happens with genetic variation in butyrylcholinesterase?
- main problem
- result
- cause (what is the defected gene)
- how it is transmitted?
- decreased rate of metabolism of succinyl choline
- prolonged paralysis
- defect in BCHE gene
- autosomal recessive trait
what does N-acetyltransferase 2 (NAT 2) catalyze?
ACETYLATION of isoniazid (for TB) and other drugs
what are the 2 classes of patients tc with isoniazid?
- slow acetylators
- fast acetylators
*The rate is inherited!
will slow acetylators have high or love blood levels of drug?
high because they metabolize the drug SLOWER
will fast acetylators have high or low blood levels of drug?
low because they metabolism the drug FASTER
slow acetylators of isoniazid are ____ for an autosomal recessive allele of the enzyme with lower activity levels
homozygous
what acetylators are more prone to toxicity of drugs that are metabolized by acetylation? Why
slow acetylators are prone to toxicity of drugs because they take a long time to metabolize the drugs so the levels are going to rise int he blood and can create serious adverse effects on the pt.
____ may cause neuropathy and hepatotoxicity
isoniazid
______ and _____ may cause SLE
hydralazine and procainadmide
_____ may cause hypersensitivity reactions, hemolytic anemia, SLE
sulfonamides
what drugs were used when studying the CYP2D6 polymorphism?
antihypertensive - debrisoquine
oxytotic - sparteine
if the ratio of decrisoquine/4-hydroxydebrisoquine metabolic ratio is high, what does that indicate?
poor metabolizer
if the ratio of decrisoquine/4-hydroxydebrisoquine metabolic ratio is low, what does that indicate?
ultrarapid metabolizer
poor metabolizers are _____ for the recessive alleles coding for enzymes with low activity
homozygous
extensive metabolizers (normal) are ______ or _____ for the “wild type” allele
homozygous
heterogygous
some ultra rapid metabolizers can have ______ copies of the CYP2D6 gene
multiple (up to 13)
inter individual differences are important with CYP2D6 because they metabolize many commonly prescribes drugs like…
- beta blockers
- antipsychotic
- opiods
- antidepressants
what drug is ineffective in poor metabolizers and why?
codeine
requires CYP2D6-catalyzed conversion from codeine to morphine
what metabolizers can overdose with standard doses of codeine and suffer from respiratory depression or arrest?
ultrarapid metabolizers
what does TPMT catalyze?
S-methylation of the anticancer thiopurines (6 mercaptopurine and azathioprine)
____ of the anticancer thiopurine inactivates them!
methylation
thiopurines have a ________therapeutic index and some pts may suffer from life-threatening _____
narrow
myelosuppression
about 1/300 individuals are ____ for a polymorphism that leads to LOW TPMT activity
homozygous
the individuals who are homozygous for low TPMT activity have an increased risk for ____ when treated with standard doses of thiopurine drugs , so these pts have to be tx with _____ of the standard dose
myelosuppression
1/10
why does warfarin make dosing problematic?
- therapeutic window
- variability
because it has a narrow therapeutic winnow and
wide inter individual variability
what does under-anticoagulation result in
thrombosis
what does over-anticoagulation result in
bleeding episodes
warfarin
- what type of mixture?
- what are the 2 types?
- are they both metabolized by the same enzyme?`
- racemic
- S-warfarin***** (3-5x more potent) and R warfarin
- stereoismoers are metabolized by DIFFERENT enzymes
which gene is most involved in the metabolism of S-warfarin?
CYP2C9 - VERY polymorphic!
pts who carry the variant alleles require ____ doses of warfarin to achieve an anticoagulant effect and they also have an increased risk for ____ during warfarin therapy
decreased
increased
what is the molecular target for warfarin?
vitamin K epoxide reductase
the gene that encodes the enzyme for vitamin K epoxide reductase complex 1 (VKORC1) how a number of _____
polymorphisms
what do idiosyncratic drug reactions result from? what is a classic example?
interactions between the drug and a unique aspect of the physiology of the individual patient
deficiency of G6PD
what is the normal function of G6PD
protects RBCs from oxidative injury
what does diminished G6PD impair?
- cell can’t form NADPH which is important for the maintenance of the reduced glutathione pool
- this results in a decrease in the cellular detoxification of free radicals and peroxides formed within the cell
what is the most common G6PD polymorphism? how much enzyme function is reduced with this polymorphism?
G6PD A
causes a 90-95% reduction of the enzyme function
what are some other drugs that can cause oxidative stress on RBCs?
- sulfonamides
- antimalarials
- chloramphenicol
what happens if a pt with G6PD deficiency is exposed to
- sulfonamides
- antimalarials
- chloramphenicol
- FLAVA beans
may develop hemolytic anemia
Describe malignant hyperthermia
-potentially fatal genetic disorder of skeletal muscle
how is malignant hyperthermia triggered?
by volatile inhalation anesthetics (halothane) and depolarizing skeletal muscle relaxants (succinylcholine)
how is malignant hyperthermia transmitted?
autosomal dominant - but its rare
what is one of the main causes of death due to anesthesia?
malignant hyperthermia
what are the sx/s of malignant hyperthermia syndrome?
- tachycardia
- hypertension
- severe muscle rigidity
- hyperthermia
- hyperkalemia
- acidosis
what is the cellular mechanism behind malignant hyperthermia?
- altered control of what?
- defected gene?
altered control of Ca2+ release from the SR
defect in the ryanodine receptor gene (RYR1)
what is the most reliable test to establish susceptibility to malignant hyperthermia?
the Caffeine-Halothane muscle contracture test
how was drug genetic variation measured then and now?
then - urinary excretion levels
now - DNA -based tests
—Amplichip CYP450 tests
what can the AmpliChip CYP450 test determine?
CYP2D6 and CYP2C19 genotypes
