Pharmacogenetics Flashcards
NAT Gene effects which drug?
Isoniazid for TB
NAT Gene effects the pharmacology of Isoniazid for tuberculosis
How so?
Rate of acetylation is determined by genetic polymorphisms
What is NAT gene for?
N-Acteyltransferase enzyme
N-Acetyltransferase enzyme is important in which pathway?
Phase II Pathway
What is phase II pathway again?
Drug metabolism - attachment of a sugar/acetyl group to detoxify drug and make easier to excrete
What variation is seen for NAT polymorphisms?
Fast vs Slow acetylators of the drug Isoniazid
Asian - fast metabolizers
White - slower
What is Isoniazid used to treat?
TB
Fast isoniazid are at lower risk for
Toxic effects of liver but lower effectiveness for TB
Low isoniazid are at higher risk for
Toxic effects of liver but higher potency for TB
Isoniazid metabolism is associated with which gene?
NAT
Drugs influenced by CYP3A
Cyclosporine
What is cyclosporine
immunosuppressant
CYP3A and Mechanism of Mutation?
Genetically is less important than other drug metabolism genes because the population distribution is continuous and unimodal
CYP3A Inhibitor
Ketoconazole
Grapefruit juice
CYP3A inducers
Rifampin
So using logic, if CYP3A is a gene that is responsible for drug metabolism, and one of the drugs it targets is cyclosporine,
What should we think about when perscribing cyclosporine to patients on Ketoconazole or Grapefruit juice?
These inhibit CYP3A which metabolizes Cyclosporine (clears) thus, we may have a buildup of immunosuppressant and oversuppress our immune system?
What should we think about when perscribing Rifampin and Cyclosporine simultaneously?
Rifampin is a CYP3A inducer, so we may be excreting cyclospobyrine more rapidly than normal, thus reducing is immunosuppressive activity? may need to perscribe more?
Ketocanazole - a drug to treat fungal infection (topical) - let’s say you want to perscribe it to your patient and your patient is also taking cyclosporine, what would be your concern?
Well, cycosporine is an immunosuppressant that is detoxified/cleared from the body in part by CYP3A - However, ketoconazole is an inhibitor of CY3PA thus, it would seem that if my patient was goint to also start taking ketoconazole, we would need to lower her dose of cyclosporine because she would not be clearing it as fast?
What three specific factors should we be thinking about when we perscribe cyclosporine for immunosuppressant agent?
Ketoconazole
Grapefruit juice and
Rifampin
Ketoconazole inhibits CYP3A
Graprefuit juice inhibitbs CYP3A
and Rifampin induces CYP3A
Your patient loves Grapefruit juice and you perscribe her cyclosporine, what should you consider in terms of dosing?
Maybe a wee bit less because Grapefruit juice is an inhibitor or the enzyme (CYP3A) that clears the cyclosporine from the body?
Your patient is taking Rifampin for a fungal infection… You also want to perscribe Cyclosporine for an immunosuppressant drug… what should you consider?
Rifampin is an inducer of CYP3A - the eznyme that clears cyclosporine - thus you might want to consider a little bit more cyclosporine in this patient
What specific substrates of CYP2D6 should we be aware of?
Tricyclic antidepressants
Codeine
What makes CYP2D6 unique?
It is an activator - unlike most of the enzymes that we are looking at - CYP2D6 is not so much required to clear drugs as it is to activate them?
Let’s say you had a patient that was on a tricyclic antidepressant and you wanted to perscribe them quinidine (antiarrhythmic) what should you take under consideration?
quinidine is an inhibitor of CYP2D6
CYP2D6 is an metabolizer of tricyclic antidepressants
May need to perscribe lower dose Tricyclic antidepressant to account for quinidine inhibition of CYP2D6 clearance
Let’s say you had a patient who was taking fluoxtine (for depression/ocd) and you needed to perscribe them codeine, what should you consider?
Well, Codeine is activated by CYP2D6
CYP2D6 is inhibited by Fluoixitine
Thus, activation of codeine by CYP2D6 may be diminished due to CYP2D6 inhibition, so perscribe a little more codeine?
What are the substrates of CYP2D6 that we should know? (2)
Tricyclic antidepressant - metabolism
Codeine - acitvation
What are the inhibitors of CYP2D6 that we should know? (3)
Quinidine
Fluoxetine
Paroxetine (depression/ocd)
CYP2C9 - which drug is associated with this gene?
Warfarin
Warfarin is a substrate of an enzyme encoded by which gene?
CYP2C9 and VKORC1
Mutations in CYP2C9 may effect the metabolism of which drug?
Warfarin
Which drugs are substrates for TMPT gene’s enzyme? (2)
6-mercaptopurine
6-thioguanine
What are 6-mercaptopurine and 6-thioguanine perscribed for?
Immunosuppression
What kind of mutation do we see in TMPT?
Missense mutations destabilize the enzyme
What is the consequence of a missense mutation in the TMPT gene?
Decreased/ absent enzymatic activity?
What happens if you give a child with ALL (leukemia) 6-mercaptopurine or 6-thioguanine for immunosuppression but they have a mutated TMPT?
The mutated TMPT will not clear the 6-mercaptopurine or 6-thioguanine with the efficiency that it should, thus the immunosuppressive effect will overwhelm the child and they may die
Children receiving organ transplants for ALL will likely need to take an immunosuppressive regimen such as 6-mercaptopurine or 6-thioguanine, what should you take under consideration when perscribing these medications?
Whether or not they have a mutation in their TMPT gene that decreases the enzymatic clearance of the immunosuppresants - which would lead to death
What substrates (Drugs) of G6PD should you be aware of? (2)
Sulfonamide
Dapsone
What is unique about G6PD?
It is X-linked
What are sulfonamides?
Antiobiotics
What is dapsone?
Antibiotic but apparently used to treat acne?
Individuals with mutant G6PD - things to consider?
G6PD deficient individuals are susceptible to hemolytic anemia after drug exposures
Which gene (if mutated) may put indivduals who take sulfonamides or dapsone at risk?
G6PD - at risk for hemolytic anemia
Which gene (enzyme) is Warfarin a substrate of?
VKORC1
If you are perscribing Warfarin to a patient and they have a VKORC1 mutation, what should be your concern?
VKORC1 will not be as efficient at reducing vitamin K for recycling - thus may lead to extra bleeding if give Warfarin - because Warfarin is a blood thinner and inhibitor of VKORC1
Warfarin and the US
Warfarin is one of the most commonly perscribed medicines >20 million in US annually
Warfarin mechanism?
VKORC1 gene product (which is responsible for activating vitamin K) - if we block vitamin K activation with Warfarin - plus we already have a mutated VKORC1, we can have severe bleeding and death! - So in individuals with lower activity VKORC1 mutation - give less warfarin!
Pharmacogenetics
the study of differences in drug responses due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
______________ typically involves the study of just a few genes and these genes are selected on a priori knowledge of their role(s) in drug metabolism
Pharmacogenetics
Pharmacogenomics
the genomic approach to pharamcogenetics, concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy
____________ is concerned with identifying sets of alleles at la large number of polymorphic loci in order to distinguish patients who have responded adversely to what was considered a benificial drug
pharmacogenomics
______________ analyzes individual genes and their variants according to what is known about how they influence pharmacokinetic and pharmacodynamic pathways
pharmacogenomics
____________ involves the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites
pharmacokinetics
___________ involves the response resulting from the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways
pharmacodynamics
Investigation of cytochrome p450, glycoronyltransferase, and thiopurine methyltransferase
These are examples of ______________ investigation
pharmacokinetic
Glucose 6 phosphate dehydrogenase, vitamin K epoxide comple - these are examples of_____________ investigation
pharmacodynamic
________________ is concerned with whether or how much drug reaches the target(s)
pharmacokinetics
______________ is concerned with what happens once the drug successfully reaches its target
pharmacodynamics
What investigates drug effect?
pharmacodynamics
What investigates drug removal?
pharmacokinetics
What can pharmacokinetics be broken down into?
Phase I and Phase II
Phase I pharmacokinetics?
Attach a polar group onto the compound to make it more soluble - usually a hydroxylation step
Phase II pharmacokinetics?
Attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
The cytochrome P450 (CYP450) genes encode?
Important enzymes that are very active in the liver and to a lesser extent the epithelium of the small intestine
What do CYP450 enzymes do?
Metabolize a wide number of drugs
The CYP family is particularly active in ___________ metabolism (90% of commonly used medication)
Phase I
Which enzyme takes part in metabolism over 40% of all drugs used in clinical medicine?
CYP3A4
Why is the CYP complex (cytocrhome P450) important to learning genetics?
There is wide genetic polymorphic variation with phenotypic consequences in the CYP families of genes
Which gene is required for codeine activation to morphine?
CYP2D6
CYP2D6 is involved in __________ metabolism of over 70 drugs
phase I metabolism
Mutations affecting function
Frameshift consequence?
alter reading frame
no activity
Splicing consequence
skip exons and/or alter reading frame
no activity
Missense consequence
alter protein function
usually reduced activity
Based on the combination of alleles (WT / null / hyper / hypo / etc.) there are three major phenotypes typically assigned
normal
poor (includes null)
ultrarapid/ultrafast
Note: in addition to CYP variation in the human species as a whole, what other variation should you consider?
Ethnic population differences
A single glass of grapefruit juice can inhibit ___________ activity for 24-48 hours (largely through intestinal inhibition) Thus, grapefruit juice can affect the side-effect profiles of many of the _______ substrates.
CYP3A
Drinking grapefruit juice while taking felodipine for hypertension can lead to significant __________________ due to potentiation of the felodipine effect since CYP3A activity is _______ and metabolism/elimination of felodipine is ___________
hypotension
reduced
slowed
Concerns for Renal transplant patients who develop fungal infections?
Dosage of the immunosuppressive drug cyclosporine (used in kidney transplants for instance) must be reduced by 75% do avoid toxicity when the antifungla ketoconazole is added to treat a fungal infection
Why must cyclosporine dosage be increased when a patient is using ketoconazole for a fungal infection?
Ketoconazole temporarily inhibits CYP3A metabolism which leads to raised levels of cyclosporine which can be neprotoxic
What should we be concerned about in renal transplant patients on cyclosporine who required rifampin prophylaxis?
The dose of cyclosporine must be increased since rifampin is a CYP3 inducer and leads to more rapid metabolism and elimination of cyclosporine
What would happen if you fail to take into account that a patient is on rifampin while also taking immunosuppressive cyclosporine for renal transplant?
The cyclosporine levels will decrease and organ rejection could become a problem
Pharmacogenetic variable response due to?
Individual genes
Pharmacogenomic variable response due to?
multiple loci across the genome
Pharmacogenetics: The study or clinical testing of ___________ that gives rise to ______________ to drugs
genetic variation
differing response
Codeine metabolism
What happens to codeine in the body
10%
80%
10% is converted to the active form (morphine) by CYP2D6
80% is inactivated by CYP3A4
Remember that once a drug is taken, the drug must (3)
- reach its target
- exert its effect
- do the above before being inactivated/eliminated
Pharmacokinetics (ADME)
Absorption
Distribution
Metabolism
Excretion
What describes teh relaitonship between the concentration of drug at its site of action and the observed biological effects?
Pharmacodynamic
Most major drugs are effective only in _ to _ percent of the population
25 to 60
Where are the CYP450 Gene products active?
Liver and intestinal epithelium
What are the three main CYP450 families?
CYP1
CYP2
CYP3
Which mutations would lead to excess drug effect? (expected)
frameshift
splicing
nonsense
missense (Some)
Which mutations would lead to decreased drug effect? (expected)
increased copy number
missense (Some
Standard AZ (azathrioprine) or 6MP (6-mercaptopurine) doses given to individuals with ALL that are homozygous mutant for TMPT can lead to? Why? What should we do instead?
Fatal myelosuppression
Profound immunosuppression
Give 10% normal dose
The number one perscribed anticoagulant is?
Warfarin
Complications of underdosing warfarin?
Clot
Complication of overdosing warfarin?
Bleed
What is VOKRC1’s involvement in the warfarin pathway?
VKORC1 makes VKER which is required for Vitamin K hydroxylation (recycling) for effective clot cascade
What does Warfarin do to VOKRC1?
Inhbits VKER
What is CYP2C9 role in Warfarin pathway?
Warfarin degradation
Warfarin
- intra-individual
- inter-individual
intra - narrow therapeutic window
inter - wide therapeutic range
