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Questions and Answers
Genetic variation can influence drug metabolizing enzymes.
Genetic variation can influence drug metabolizing enzymes.
True (A)
All genetic components related to drug response are clinically relevant.
All genetic components related to drug response are clinically relevant.
False (B)
CYP2D6 is involved in the conversion of codeine to morphine.
CYP2D6 is involved in the conversion of codeine to morphine.
True (A)
Ultrafast metabolisers of CYP2D6 may experience increased morphine intoxication.
Ultrafast metabolisers of CYP2D6 may experience increased morphine intoxication.
Tamoxifen is active without conversion in the body.
Tamoxifen is active without conversion in the body.
Environmental factors do not influence drug responses.
Environmental factors do not influence drug responses.
Approximately 10% of individuals are null for the CYP2D6 enzyme.
Approximately 10% of individuals are null for the CYP2D6 enzyme.
Pharmacogenetics can help in selecting the correct drug and dosage for patients.
Pharmacogenetics can help in selecting the correct drug and dosage for patients.
CYP3A4/5 enzymes are involved in the metabolism of more than 50% of drugs in use.
CYP3A4/5 enzymes are involved in the metabolism of more than 50% of drugs in use.
Tamoxifen can be metabolized slowly, intermediately, or rapidly depending on a woman's allele combination.
Tamoxifen can be metabolized slowly, intermediately, or rapidly depending on a woman's allele combination.
Azathioprine is used to promote DNA replication.
Azathioprine is used to promote DNA replication.
Myelosuppression can be a side effect of Mercaptopurine treatment.
Myelosuppression can be a side effect of Mercaptopurine treatment.
The main function of phase I metabolism is to increase water solubility of drugs.
The main function of phase I metabolism is to increase water solubility of drugs.
TPMT deficiency can affect the metabolism of azathioprine.
TPMT deficiency can affect the metabolism of azathioprine.
Competing drugs can interfere with the conversion of tamoxifen.
Competing drugs can interfere with the conversion of tamoxifen.
6-thioguanine is a major active metabolite responsible for the activity of azathioprine.
6-thioguanine is a major active metabolite responsible for the activity of azathioprine.
The TMPT genotype has no effect on enzyme activity.
The TMPT genotype has no effect on enzyme activity.
Dosing by TPMT genotype can significantly reduce toxicity incidence.
Dosing by TPMT genotype can significantly reduce toxicity incidence.
DeltaF508 is the most common mutation of the CFTR gene in Ireland.
DeltaF508 is the most common mutation of the CFTR gene in Ireland.
Warfarin is primarily used for increasing blood clotting.
Warfarin is primarily used for increasing blood clotting.
Kalydeco/ivacaftor is effective for Class III & IV mutations of cystic fibrosis.
Kalydeco/ivacaftor is effective for Class III & IV mutations of cystic fibrosis.
A higher dose of medication increases the risk of bleeding and hemorrhage due to a narrow therapeutic range.
A higher dose of medication increases the risk of bleeding and hemorrhage due to a narrow therapeutic range.
VKORC1 polymorphisms typically require higher dose requirements of warfarin.
VKORC1 polymorphisms typically require higher dose requirements of warfarin.
CYP2C9 polymorphisms can lead to lower active drug concentrations.
CYP2C9 polymorphisms can lead to lower active drug concentrations.
Dosing of anticoagulants like warfarin is monitored through international normalized ratio (INR).
Dosing of anticoagulants like warfarin is monitored through international normalized ratio (INR).
Active vitamin K is essential for the activation of factors III, VII, IX, and X.
Active vitamin K is essential for the activation of factors III, VII, IX, and X.
VKORC1 polymorphisms lead to higher warfarin dose requirements.
VKORC1 polymorphisms lead to higher warfarin dose requirements.
CYP2C9 polymorphisms explain approximately 6% of warfarin dose variability.
CYP2C9 polymorphisms explain approximately 6% of warfarin dose variability.
The incidence of Stevens Johnson Syndrome (SJS) is estimated to be 1-5 cases per million population per year.
The incidence of Stevens Johnson Syndrome (SJS) is estimated to be 1-5 cases per million population per year.
The FDA has recommended genetic testing for warfarin since 1995.
The FDA has recommended genetic testing for warfarin since 1995.
SJS is a common adverse effect related to carbamazepine.
SJS is a common adverse effect related to carbamazepine.
HLA-B*1502 is highly prevalent in all populations globally.
HLA-B*1502 is highly prevalent in all populations globally.
VKORC1 polymorphisms account for 25% of the variability in warfarin dosing.
VKORC1 polymorphisms account for 25% of the variability in warfarin dosing.
The incidence of carbamazepine-induced SJS is higher in Asia compared to other regions.
The incidence of carbamazepine-induced SJS is higher in Asia compared to other regions.
Environmental factors such as age and diet can influence drug responses.
Environmental factors such as age and diet can influence drug responses.
All individuals have the same metabolic response to a specific dose of a drug.
All individuals have the same metabolic response to a specific dose of a drug.
CYP2D6 is responsible for converting tamoxifen into its active form endoxifen.
CYP2D6 is responsible for converting tamoxifen into its active form endoxifen.
Poor metabolizers of CYP2D6 experience increased therapeutic effects from standard doses of morphine.
Poor metabolizers of CYP2D6 experience increased therapeutic effects from standard doses of morphine.
Pharmacogenomics can be influenced by a single genetic variation.
Pharmacogenomics can be influenced by a single genetic variation.
Ultrafast metabolizers of CYP2D6 may experience increased toxicity from morphine.
Ultrafast metabolizers of CYP2D6 may experience increased toxicity from morphine.
Not all genetic variations will impact drug metabolism in a clinically relevant manner.
Not all genetic variations will impact drug metabolism in a clinically relevant manner.
CYP2D6 has no impact on the metabolization of codeine.
CYP2D6 has no impact on the metabolization of codeine.
Low activity of the TMPT genotype is associated with homozygote (v/v) individuals.
Low activity of the TMPT genotype is associated with homozygote (v/v) individuals.
Warfarin is primarily used for prevention of thrombosis and embolism.
Warfarin is primarily used for prevention of thrombosis and embolism.
Kalydeco/ivacaftor is ineffective for Class III & IV mutations of cystic fibrosis.
Kalydeco/ivacaftor is ineffective for Class III & IV mutations of cystic fibrosis.
HLA-B*1502 is widely prevalent across all populations globally.
HLA-B*1502 is widely prevalent across all populations globally.
The G551D mutation is among the rarest CFTR mutations in Ireland.
The G551D mutation is among the rarest CFTR mutations in Ireland.
CYP3A4/5 enzymes are responsible for the metabolism of more than 75% of drugs in use.
CYP3A4/5 enzymes are responsible for the metabolism of more than 75% of drugs in use.
Azathioprine is a drug that promotes DNA replication.
Azathioprine is a drug that promotes DNA replication.
Mercaptopurine is used primarily to treat kidney infections.
Mercaptopurine is used primarily to treat kidney infections.
The metabolism of azathioprine can be affected by xanthine oxidase.
The metabolism of azathioprine can be affected by xanthine oxidase.
Tamoxifen requires conversion to its active form to exert its therapeutic effect.
Tamoxifen requires conversion to its active form to exert its therapeutic effect.
TPMT deficiency enhances the effects of azathioprine.
TPMT deficiency enhances the effects of azathioprine.
Phase I metabolism primarily introduces functional groups to increase the excretion of drugs.
Phase I metabolism primarily introduces functional groups to increase the excretion of drugs.
6-Thioguanine is a toxic metabolite with no therapeutic use.
6-Thioguanine is a toxic metabolite with no therapeutic use.
CYP2C9 polymorphisms can lead to higher active drug concentrations.
CYP2C9 polymorphisms can lead to higher active drug concentrations.
The international normalized ratio (INR) is used to monitor dosing of anticoagulants like warfarin.
The international normalized ratio (INR) is used to monitor dosing of anticoagulants like warfarin.
VKORC1 polymorphisms typically result in lower responsiveness to warfarin and higher dose requirements.
VKORC1 polymorphisms typically result in lower responsiveness to warfarin and higher dose requirements.
Increasing the dose of a medication with a narrow therapeutic range can increase the risk of thrombosis.
Increasing the dose of a medication with a narrow therapeutic range can increase the risk of thrombosis.
Hypothetically, vitamin K is essential for the activation of factors II, IV, IX, and X in the coagulation cascade.
Hypothetically, vitamin K is essential for the activation of factors II, IV, IX, and X in the coagulation cascade.
VKORC1 polymorphisms account for about 25% of the variability in warfarin dosing.
VKORC1 polymorphisms account for about 25% of the variability in warfarin dosing.
The FDA has recommended genetic testing for warfarin since 2007.
The FDA has recommended genetic testing for warfarin since 2007.
Carbamazepine-induced Stevens Johnson Syndrome (SJS) is more frequent in Europe than in Asia.
Carbamazepine-induced Stevens Johnson Syndrome (SJS) is more frequent in Europe than in Asia.
HLA-B*1502 is prevalent in many regions worldwide, effectively predicting SJS risk.
HLA-B*1502 is prevalent in many regions worldwide, effectively predicting SJS risk.
The incidence of Stevens Johnson Syndrome is estimated at 1-5 cases per million population annually.
The incidence of Stevens Johnson Syndrome is estimated at 1-5 cases per million population annually.
CYP2C9 polymorphisms influence warfarin dosing variability by explaining approximately 25% of dose requirements.
CYP2C9 polymorphisms influence warfarin dosing variability by explaining approximately 25% of dose requirements.
Increased genetic testing for drugs like warfarin could help reduce adverse effects.
Increased genetic testing for drugs like warfarin could help reduce adverse effects.
Sodium channels are targeted by the drug carbamazepine.
Sodium channels are targeted by the drug carbamazepine.
CYP2D6 plays a significant role in the activation of tamoxifen to endoxifen.
CYP2D6 plays a significant role in the activation of tamoxifen to endoxifen.
Genetic variations associated with drug response are only influenced by environmental factors.
Genetic variations associated with drug response are only influenced by environmental factors.
Individuals with null CYP2D6 genes will experience the same therapeutic effect from standard codeine doses as those with fully functional genes.
Individuals with null CYP2D6 genes will experience the same therapeutic effect from standard codeine doses as those with fully functional genes.
Ultrafast metabolizers of CYP2D6 are at risk of experiencing therapeutic failure when using standard doses of morphine.
Ultrafast metabolizers of CYP2D6 are at risk of experiencing therapeutic failure when using standard doses of morphine.
The conversion of codeine to morphine is primarily mediated by CYP2C9.
The conversion of codeine to morphine is primarily mediated by CYP2C9.
Pharmacogenomics can be influenced by multiple genetic variations across various genes.
Pharmacogenomics can be influenced by multiple genetic variations across various genes.
All individuals respond uniformly to the same dosage of a drug due to consistent genetic factors.
All individuals respond uniformly to the same dosage of a drug due to consistent genetic factors.
Tamoxifen has a therapeutic effect without being converted into endoxifen.
Tamoxifen has a therapeutic effect without being converted into endoxifen.
Functional groups such as -COOH are introduced during Phase II metabolism.
Functional groups such as -COOH are introduced during Phase II metabolism.
The main function of Phase II metabolism is to prepare drugs for elimination by increasing their water solubility.
The main function of Phase II metabolism is to prepare drugs for elimination by increasing their water solubility.
Mercaptopurine is used to treat conditions such as leukemia and promotes DNA replication.
Mercaptopurine is used to treat conditions such as leukemia and promotes DNA replication.
Azathioprine is inactive until it is metabolized by thiopurine methyl transferase.
Azathioprine is inactive until it is metabolized by thiopurine methyl transferase.
Homozygote (v/v) individuals exhibit high/fast activity of the TMPT genotype.
Homozygote (v/v) individuals exhibit high/fast activity of the TMPT genotype.
6-MP is a significant oxidized metabolite of azathioprine that has high therapeutic efficacy.
6-MP is a significant oxidized metabolite of azathioprine that has high therapeutic efficacy.
Kalydeco/ivacaftor is shown to be effective for Class I & II mutations of cystic fibrosis.
Kalydeco/ivacaftor is shown to be effective for Class I & II mutations of cystic fibrosis.
CYP3A4/5 enzymes contribute to the metabolism of less than 75% of drugs in clinical use.
CYP3A4/5 enzymes contribute to the metabolism of less than 75% of drugs in clinical use.
TPMT deficiency leads to a reduction in the metabolism of azathioprine, potentially increasing toxicity.
TPMT deficiency leads to a reduction in the metabolism of azathioprine, potentially increasing toxicity.
Warfarin is utilized in the treatment of various types of infections.
Warfarin is utilized in the treatment of various types of infections.
The incidence of cystic fibrosis is solely due to the presence of the DeltaF508 mutation.
The incidence of cystic fibrosis is solely due to the presence of the DeltaF508 mutation.
Competing drugs enhance the conversion of tamoxifen into its active metabolites.
Competing drugs enhance the conversion of tamoxifen into its active metabolites.
FDA has recommended genetic testing for Mercaptopurine since 2001.
FDA has recommended genetic testing for Mercaptopurine since 2001.
VKORC1 polymorphisms generally lead to higher dose requirements of warfarin and increased sensitivity to the drug.
VKORC1 polymorphisms generally lead to higher dose requirements of warfarin and increased sensitivity to the drug.
CYP2C9 polymorphisms are associated with a loss-of-function that can cause higher active drug concentrations.
CYP2C9 polymorphisms are associated with a loss-of-function that can cause higher active drug concentrations.
Vitamin K epoxide reductase has no role in the activation of coagulation factors.
Vitamin K epoxide reductase has no role in the activation of coagulation factors.
The international normalized ratio (INR) is used to monitor the dosing of warfarin based on prothrombin levels.
The international normalized ratio (INR) is used to monitor the dosing of warfarin based on prothrombin levels.
Active vitamin K is crucial for activating factors II, VII, VIII, and IX in the coagulation cascade.
Active vitamin K is crucial for activating factors II, VII, VIII, and IX in the coagulation cascade.
Individuals of Asian descent have a reduced risk of Stevens Johnson Syndrome (SJS) when using carbamazepine.
Individuals of Asian descent have a reduced risk of Stevens Johnson Syndrome (SJS) when using carbamazepine.
The VKORC1 polymorphism explains approximately 10% of the dose variability required for warfarin.
The VKORC1 polymorphism explains approximately 10% of the dose variability required for warfarin.
The FDA has recommended genetic testing for warfarin since 2007.
The FDA has recommended genetic testing for warfarin since 2007.
CYP2C9 polymorphisms explain up to 25% of the variations in warfarin dosing requirements.
CYP2C9 polymorphisms explain up to 25% of the variations in warfarin dosing requirements.
Carbamazepine is linked to a significant risk of Stevens Johnson Syndrome only in African populations.
Carbamazepine is linked to a significant risk of Stevens Johnson Syndrome only in African populations.
The global frequency of HLA-B*1502 is the same across all regions of the world.
The global frequency of HLA-B*1502 is the same across all regions of the world.
Stevens Johnson Syndrome occurs in 1-5 cases per million population each year regardless of drug use.
Stevens Johnson Syndrome occurs in 1-5 cases per million population each year regardless of drug use.
VKORC1 genotype can influence the dosage requirements for long-term warfarin treatment.
VKORC1 genotype can influence the dosage requirements for long-term warfarin treatment.
Study Notes
Pharmacogenetics
- The study of how genetic variations influence drug response, affecting both pharmacokinetics (drug metabolism) and pharmacodynamics (drug action).
- It aims to personalize drug therapy by predicting individual responses based on genetic profiles.
Genetic Variation in Drug Metabolism (Pharmacokinetics)
- CYP2D6: Involved in metabolizing codeine to morphine.
- Poor metabolizers experience reduced morphine production, leading to minimal therapeutic effect.
- Ultrafast metabolizers have increased morphine levels, potentially causing intoxication.
- CYP2D6: Also involved in the conversion of tamoxifen (breast cancer drug) to its active form, endoxifen.
- Different CYP2D6 alleles determine the speed of tamoxifen metabolism, influencing treatment effectiveness.
Genetic Variation in Drug Targets (Pharmacodynamics)
- TMPT: An enzyme responsible for metabolizing azathioprine and mercaptopurine (immunosuppressants used in organ transplant and autoimmune diseases).
- TPMT deficiency: Leads to accumulation of toxic metabolites, causing myelosuppression (decreased white blood cell count, leading to infection).
- Genetic testing for TPMT: Enables dose adjustment based on individual TPMT genotype, significantly reducing toxicity risk.
Genetic Variation in "Off-Target" Genes
- HLA-B*1502: Genetic variant associated with increased risk of Stevens-Johnson Syndrome (SJS), a serious drug reaction, in response to carbamazepine, an anti-epileptic drug.
- HLA-B*1502 testing: Recommended for individuals of Asian descent before carbamazepine therapy to reduce SJS risk.
- Further research is needed to identify additional genetic factors contributing to SJS due to its occurrence despite the absence of HLA-B*1502 in certain populations.
Warfarin: A Case of Polygenic Pharmacogenomics
- VKORC1: A gene involved in vitamin K metabolism, influencing warfarin sensitivity.
- CYP2C9: An enzyme responsible for warfarin metabolism.
- Variations in both VKORC1 and CYP2C9 contribute to a wide range of warfarin dose requirements.
- Genetic testing for VKORC1 and CYP2C9: Enables personalized warfarin dose optimization, reducing bleeding or clotting risks.
- Warfarin is a blood thinner, and dose adjustment is crucial due to its narrow therapeutic range.
- Pharmacogenomics: Combined understanding of genetic and environmental factors affecting drug response.
- Example: Warfarin dosage influenced by:
- VKORC1 and CYP2C9 genotype
- Diet
- Underlying health conditions
- Drug interactions
- Example: Warfarin dosage influenced by:
Pharmacogenetics: Introduction
- The study of pharmacogenetics aims to understand how genetic variations influence drug responses in patients.
- This knowledge can help select the most appropriate drug and dose for safer and more effective treatments.
Factors Influencing Drug Response
- Environmental factors (nurture) play a significant role in drug response, including age, diet, underlying disease, organ function, and drug interactions.
- Genetic factors (nature) are also crucial. DNA sequences determine individual responses to drugs.
Drug Metabolism
- Drug metabolizing enzymes (DMEs), primarily cytochrome P450 (CYP) enzymes, play a crucial role in drug metabolism.
- Phase I metabolism introduces functional groups (e.g., -OH, -NH2, -COOH) into the drug molecule.
- Phase II metabolism (conjugation) attaches hydrophilic groups, increasing water solubility and ease of excretion.
CYP2D6: A Key Enzyme
- CYP2D6 is involved in the metabolism of various drugs, including codeine, tamoxifen, and several other drugs.
- Poor metabolizers of CYP2D6 have reduced therapeutic effects from standard doses.
- Ultrafast metabolizers can experience drug intoxication due to increased metabolism.
Thiopene Methyltransferase (TPMT) and Azathioprine Metabolism
- TPMT is involved in metabolizing azathioprine, a drug used for autoimmune diseases and organ transplants.
- TPMT deficiency can lead to the accumulation of active metabolites, causing toxicity.
- Genetic testing for TPMT genotype can help personalize azathioprine dosing, minimizing toxicity.
Warfarin Dosing and Genetics
- Warfarin is an anticoagulant with a narrow therapeutic index, making accurate dosing critical.
- VKORC1 gene polymorphisms influence warfarin sensitivity, with individuals carrying specific variants requiring lower doses.
- CYP2C9 gene polymorphisms also affect warfarin metabolism, with some variants leading to higher active drug concentrations.
- Genetic testing for VKORC1 and CYP2C9 genotype can help personalize warfarin dosing.
Cystic Fibrosis and CFTR Gene Mutations
- Cystic fibrosis (CF) is caused by mutations in the CFTR gene, which encodes a chloride channel protein.
- DeltaF508 is the most common CFTR mutation, while G551D is another significant mutation.
- Kalydeco/ivacaftor, a drug that targets CFTR, is effective in treating individuals with specific CFTR mutations (Class III & IV).
Stevens Johnson Syndrome (SJS) and HLA-B*1502
- SJS is a severe adverse drug reaction involving skin detachment.
- HLA-B*1502, a genetic marker, is strongly associated with carbamazepine-induced SJS, particularly in individuals of Asian descent.
- Pre-treatment genetic testing for HLA-B*1502 can help prevent SJS in susceptible individuals.
Pharmacogenomics: Polygenic Effects
- Pharmacogenomics recognizes that the interplay of various genetic factors influences drug responses.
- Genetic testing for multiple genes can improve drug selection and dosing, further enhancing personalized medicine.
Pharmacogenetics
- Individuals respond differently to a specific dose of a drug due to genetic and environmental factors
- Pharmacogenetics aims to use genetics to predict individual responses and optimize drug selection and dosage for safer and more effective treatment
Factors Influencing Drug Response
- Environmental Factors: Age, Diet, Organ Function, Underlying Disease, Concomitant Therapy, Drug Interactions
- Genetic Factors: DNA codes for specific drug traits, not all genetic components are clinically relevant
Drug Metabolism
- Drug Metabolism Enzymes (DMEs): These enzymes are responsible for converting drugs into active or inactive metabolites
- Phase I Metabolism: Introduces functional groups into drug molecules - prepares drugs for Phase II metabolism
- Phase II Metabolism: Conjugates drug molecules with hydrophilic groups, increasing water solubility for easier excretion
- CYP3A4/5 and UGT: Metabolize over 75% of drugs in clinical use
Example 1: Mercaptopurine & Azathioprine
- Inhibit purine synthesis, inhibiting DNA replication
- Used to treat: Leukemia, Inflammatory Bowel Disease, Organ Transplants, Rheumatoid Arthritis
- Causes myelosuppression: Reduces White Blood Cells (WBC) causing infections, reduces Red Blood Cells (RBC) causing anemia
- Thiopurine Methyltransferase (TPMT): Deficiency in this enzyme can lead to toxic buildup of mercaptopurine metabolites, causing severe side effects
- Genetic testing for TPMT genotype is recommended to adjust dosage and minimize toxicity
Example 2: Tamoxifen
- Tamoxifen is an inactive prodrug converted to active endoxifen by CYP2D6
- Variations in CYP2D6 alleles can influence metabolism speed: slow, intermediate, or rapid
- Some drugs compete for the CYP2D6 enzyme, interfering with tamoxifen conversion
Drug Targets
- Drug Targets: The proteins or molecules that drugs interact with to exert their effects
- Examples: Ion channels, carrier molecules, enzymes, receptors
- Pharmacodynamics: Study of how drugs interact with their targets and produce their effects
Example 3: Cystic Fibrosis
- Caused by mutations in the CFTR gene, leading to various defects in chloride transport
- DeltaF508 is the most common CFTR mutation, G551D is the second most common
- Kalydeco/Ivacaftor: Drug effective for treating Class III and IV CFTR mutations
Example 4: Warfarin
- An anticoagulant used to prevent thrombosis and embolism
- Has a narrow therapeutic range: High dose risks bleeding, low dose risks thrombosis
- VKORC1 Polymorphisms: Influences warfarin responsiveness, with some individuals requiring lower doses
- CYP2C9 Polymorphisms: Influences warfarin metabolism, with some individuals requiring higher doses
- Genetic testing for VKORC1 and CYP2C9 is recommended to optimize warfarin dosage
- FDA recommends genetic testing for warfarin since 2007
Example 5: Stevens Johnson Syndrome (SJS)
- Severe adverse reaction involving skin separation
- Often caused by adverse drug effects
- HLA-B*1502: A specific HLA allele strongly linked to Carbamazepine-induced SJS, primarily in Asian populations
- FDA recommends HLA-B*1502 testing for individuals of Asian descent before Carbamazepine exposure
Conclusion
- Pharmacogenetics plays a crucial role in optimizing drug therapy by considering individual genetic differences
- Genetic testing can help identify patients at risk of adverse drug reactions and guide personalized drug selection and dosing strategies
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Description
This quiz explores pharmacogenetics, focusing on how genetic variations influence drug metabolism and action. Learn about key enzymes like CYP2D6 and TMPT, and their roles in personalizing drug therapy. Test your understanding of these concepts and their clinical implications.
