factors that influence drug response phenotype
age, gender, disease, genetic variation
study of the role of inheritance in variation in drug response
pharmacogenomics
why is pharmacogenomics important
adverse drug reactions are major cause of morbidity and mortality
average interindividual difference in terms of base pairs
3 million bp
used to optimize drug efficacy and reduce adverse effects
knowledge of patient’s DNA sequence
three types of genetic variation that can influence pharmacotherapy
pharmacokinetic variation (variations in proteins involved in drug metabolism or transport)
pharmacodynamic variation (variation in drug target)
variation in proteins associated with idiosyncratic adverse drug effects.
most common factor responsible for pharmacogenetic variation in drug responses
genetic variation in enzymes that catalyze drug metabolism
do major enzymes in drug metabolism show polymorphism
yeah
drugs used during surgery to cause skeletal muscle paralysis
neuromuscular blockers such as succinylcholine
4 main enzymes that exhibit polymorphism
- Butyrylcholinesterase (Pseudocholinesterase) (BChE)
- N-acetyltransferase 2 (NAT2)
- Cytochrome P450 2D6 (CYP2D6)
- Thiopurine S-methyltransferase (TPMT)
why is the duration of succinylcholine (neuromuscular blockade) so short between 5-10 mins
rapid hydrolysis by plasma butyrylcholinesterase
onset of neuromuscular blockade
quickly ~1 min
what happens with patients who have a genetic variation in butyrylcholinesterase
decreased metabolism of succinylcholine leading to prolonged muscular paralysis
inheritance pattern of butyrylcholineterase
autosomal recessive
good at inhibiting normal butyrylcholinesterase (bad at inhibiting its polymorphic variation)
dibucaine
catalyzes the acetylation of isoniazid and other drugs (include sulfonamide, hydralazine, procainamide)
N-acetyltransferase 2 (NAT2)
what are slow and fast acetylators (of NAT2)
slow acetylators - catalyze isoniazid slowly and have high blood drug levels
fast acetylators - catalyze isoniazid rapidly and have low blood drug levels
inheritance pattern of NAT2 polymorphism
autosomal recessve
slow acetylators (of NAT2) are more prone to what
toxic effects of drugs that are metabolized by acetylation
isoniazid can cause what?
neuropathy and hepatotoxicity
Hydralazine and procainamide may cause what
systemic lupus erythematosus
Sulfonamides may cause what
hypersensitivity reactions, hemolytic anemia, and systemic lupus erythematosus
CYP2D6 is a member of what family
CYP450
CYP2D6 metabolizes what types of drugs
antidepressants, antiarrhythmics, and analgesics.
two important drugs used to talk about CYP2D6
antihypertensive debrisoquine and the oxytotic agent sparteine
extensive metabolizes of CYP2D6 have what genotype
heterozygous or homozygous for the wild type allele
main reason people can be ultra rapid metabolizers by CYP2D6
they have multiple copies of the CYP2D6 gene up to 13
why is codeine ineffective in poor metabolizers by CYP2D6
it requires CYP2D6 catalyzed conversion to morphine
when do people suffer adverse effects to metoprolol
if they are poor metabolizers of CYP2D6
way to overcome ultra rapid metabolizers of codeine by CYP2D6 and its disadvantage
you can overcome by giving higher doses but can overdose on codeine (respiratory depression or arrest)
Thiopurine S methyltransferase (TPMT) catalyzes what reaction
S-methylation of the anticancer thiopurines, 6-mercaptopurine and azathioprine
problem with TPMT polymorphism
thiopurines have short therapeutic window so if not quickly methylated, it can be life threatening and lead to myelosuppression
patients with low TPMT levels have to treated with what percentage of standard dose
10%
oral anticoagulant
warfarin
does warfarin have a big therapeutic window
nah
under anti-coagulation and over anti-coagulation can result it
under - thrombosis
over - bleeding episodes
there is an S-warfarin and and R-warfarin meaning that warfarin is?
a racemic mixture
which form of warfarin is more potent
S-warfarin by 3-5 times
which one of the racemic mixture of warfarin metabolizes more warfarin
R-warfarin
patients with CYP2C9 have variant alleles that have lower activity hence requiring ______ dose of warfarin to achieve therapeutic effect and have increased risk for _______ during warfarin therapy
decreased, hemmorhage
multiple gene that affect both pharmacokinetics and pharmacodynamics of a drug
warfarin
molecular target for warfarin
Vitamin K epoxide reductase (inhibits its)
what does Vitamin K epoxide reductase do?
reduces Vitamin K and brings it back to its active form:
Vitamin K epoxide –> reduced Vitamin K
what does reduced Vitamin K do?
provides carboxyl group for clotting factor precursor, glutamic acid, (using gamma glutamyl carboxylase) to become clotting factor, carboxy glutamic acid
gene that encodes vitamin k epoxide reductase
vitamin k epoxide reductase complex 1 (VKORC1) <—has polymorphism
interindividual variability is huge which what drug
warfarin
difference between using R-warfarin and S-warfarin on vitamin K epoxide reductase
S-warfarin - uses CYP2C9 and makes 6-hydroxywarfarin and 7-hydroxywarfarin
R-warfarin - make metabolites using CYP1A1, CYP1A2, CYP3A4
what causes idiosyncratic (pertaining to an individual) drug effects?
interaction between drug and unique aspect of physiology pertaining to the particular individual
example of idiosyncratic drug effect
glucose 6 phosphate dehydrogenase deficiency (G6PD deficiency), malignant hyperthermia
what does G6PD do
prevents red blood cells from oxidative damage
what happens when G6PD deficiency
electrons not provided to NADP+ to form NADPH hence reduction in glutathione pool to reduce peroxide to water
drugs that cause oxidative stress
sulfonamides, antimalarials, chloramphenicol
what happens when exposed to sulfonamides, antimalarials, and chloramphenicol and person has G6PD deficiency
hemolytic anemia (also be caused by fava beans)
inheritance of malignant hyperthermia
autosomal dominant
malignant hyperthermia is the main cause of death due to?
anesthesia
symptoms of malignant hyperthermia
tachycardia, hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, acidosis, death
malignant hyperthermia is caused by a defect in ____________ resulting in ________
ryanodine receptor gene (RYR1), altered control of calcium release from SR
ryanodine receptors are located between what?
SR and DHPR protein (senses voltage in plasma protein)
what happens when abnormal RYR1 receptor
unregulated release of calcium –> acute hyperthermia crisis
used to establish susceptibility to malignant hypethermia
caffeine halothane muscle contracture test
results of increased calcium intracellularly
- the increased Ca2+ concentration causes sustained muscle contraction which generates heat
- accelerated levels of aerobic metabolism produce CO2 and deplete O2 and ATP
- a switch to anaerobic metabolism worsens acidosis with the production of lactate
- energy stores get depleted
- muscle fibers die leading to hyperkalemia and myoglobinuria.
how does the caffeine halothane muscle contracture test work
- piece of muscle taken from thigh and several strips of muscle prepared
- strip placed in a physiological bath and it is attached to an electrical stimulator that produces a twitch every ten seconds then strength of contraction is measured
- halothane is added and normal muscle would not move from its baseline by more than 0.5g
used to figure out genotype for CYP2D6
- from phenotype
- urinary excretion of metabolite of drug
- DNA based tests
- AmpliChip CYP450 Test (uses microarrays - also determines CYP2C19 genotype)