Pharmacogenetics Flashcards by c k

NAT Gene effects which drug?

Isoniazid for TB

How well did you know this?

Not at all

Perfectly

NAT Gene effects the pharmacology of Isoniazid for tuberculosis
How so?

Rate of acetylation is determined by genetic polymorphisms

How well did you know this?

Not at all

Perfectly

What is NAT gene for?

N-Acteyltransferase enzyme

How well did you know this?

Not at all

Perfectly

N-Acetyltransferase enzyme is important in which pathway?

Phase II Pathway

How well did you know this?

Not at all

Perfectly

What is phase II pathway again?

Drug metabolism - attachment of a sugar/acetyl group to detoxify drug and make easier to excrete

How well did you know this?

Not at all

Perfectly

What variation is seen for NAT polymorphisms?

Fast vs Slow acetylators of the drug Isoniazid
Asian - fast metabolizers
White - slower

How well did you know this?

Not at all

Perfectly

What is Isoniazid used to treat?

How well did you know this?

Not at all

Perfectly

Fast isoniazid are at lower risk for

Toxic effects of liver but lower effectiveness for TB

How well did you know this?

Not at all

Perfectly

Low isoniazid are at higher risk for

Toxic effects of liver but higher potency for TB

How well did you know this?

Not at all

Perfectly

Isoniazid metabolism is associated with which gene?

NAT

How well did you know this?

Not at all

Perfectly

Drugs influenced by CYP3A

Cyclosporine

How well did you know this?

Not at all

Perfectly

What is cyclosporine

immunosuppressant

How well did you know this?

Not at all

Perfectly

CYP3A and Mechanism of Mutation?

Genetically is less important than other drug metabolism genes because the population distribution is continuous and unimodal

How well did you know this?

Not at all

Perfectly

CYP3A Inhibitor

Ketoconazole

Grapefruit juice

How well did you know this?

Not at all

Perfectly

CYP3A inducers

Rifampin

How well did you know this?

Not at all

Perfectly

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?

How well did you know this?

Not at all

Perfectly

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?

How well did you know this?

Not at all

Perfectly

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?

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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?

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

What specific substrates of CYP2D6 should we be aware of?

Tricyclic antidepressants

Codeine

How well did you know this?

Not at all

Perfectly

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?

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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)

1. reach its target 2. exert its effect 3. 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