Pharmacogenomics — MCQs
A patient on warfarin has a high INR. Which drug likely caused this?
Which of the following statements represents the most clinically significant aspect of drug metabolism?
Which drug is contraindicated in G6PD deficiency?
Which of the following cytochromes is involved in monooxygenase mediated detoxification of drugs?
A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?
Which of the following drugs is metabolized by CYP2D6?
Which of the following combinations can result in severe toxicity due to inhibition of cytochrome P450 enzymes?
A 22-year-old man presents with sudden loss of vision in his right eye. Physical examination reveals subluxation of the right crystalline lens. Auscultation of the chest reveals a midsystolic click. Echocardiography shows a floppy mitral valve and a dilated aortic arch. The patient's brother and cousin have similar symptoms. He has been prescribed a beta-blocker. A genetic defect involving which of the following substances is most likely present in this patient?
Which of the following conditions is NOT inherited in an autosomal recessive pattern?
In X-linked recessive (XLR) diseases, a modified inheritance pattern called 'pseudodominance' occurs when?
Pharmacogenomics Indian Medical PG Practice Questions and MCQs
Question 1: A patient on warfarin has a high INR. Which drug likely caused this?
- A. Amiodarone (Correct Answer)
- B. Phenytoin
- C. Carbamazepine
- D. Rifampicin
Explanation: ***Amiodarone*** - Amiodarone is a well-known inhibitor of **CYP2C9**, the primary enzyme responsible for the metabolism of **S-warfarin**, the more potent enantiomer of warfarin. - Inhibition of warfarin metabolism leads to increased warfarin levels, thereby enhancing its anticoagulant effect and causing a **higher INR**. *Phenytoin* - Phenytoin is an **enzyme inducer**, primarily of **CYP2C9** and **CYP3A4**. - Its interaction with warfarin typically leads to **decreased warfarin levels** and a **lower INR**, reducing the anticoagulant effect. *Carbamazepine* - Carbamazepine is a potent **enzyme inducer**, particularly of **CYP3A4** and **CYP2C9**. - Like phenytoin, it generally leads to **increased warfarin metabolism** and a **reduced INR**, thereby decreasing its anticoagulant efficacy. *Rifampicin* - Rifampicin is a strong **inducer of hepatic cytochrome P450 enzymes**, especially **CYP3A4** and **CYP2C9**. - Its co-administration with warfarin significantly **increases warfarin metabolism**, resulting in **lower warfarin concentrations** and a **decreased INR**.
Question 2: Which of the following statements represents the most clinically significant aspect of drug metabolism?
- A. Most common enzyme involved is CYP 3A4/5 (Correct Answer)
- B. Glucuronidation is a phase II reaction
- C. Reduction is a phase I reaction
- D. Cytochrome P450 is involved in phase I reactions
Explanation: ***Most common enzyme involved is Cyp 3A4/5*** - CYP3A4/5 is the **most abundant and clinically significant** cytochrome P450 enzyme, responsible for metabolizing approximately **50% of all clinically used drugs**. - Its widespread involvement means variations in its activity (due to **genetics, drug interactions, or disease**) have a major impact on drug efficacy and toxicity. *Glucuronidation is a phase II reaction* - While correct that glucuronidation is a **Phase II metabolic reaction**, this statement describes a biochemical classification rather than a clinically significant aspect compared to the involvement of CYP3A4/5. - Phase II reactions generally involve **conjugation** to increase water solubility and facilitate excretion, but they do not collectively account for as many drug interactions as CYP3A4/5 alone. *Reduction is a phase I reaction* - This statement is factually correct as **reduction** is indeed a **Phase I metabolic reaction**. - However, it represents a generic classification of a metabolic pathway and doesn't highlight the specific clinical importance or prevalence of a particular enzyme or reaction in drug metabolism. *Cytochrome P450 is involved in phase I reactions* - This is true; the **cytochrome P450 system** is the primary enzyme system for **Phase I metabolism**, which introduces or exposes polar groups to make drugs more reactive. - While fundamentally important, this statement is too broad; it does not specify the most clinically significant *aspect* or *enzyme* within the P450 system compared to directly identifying CYP3A4/5.
Question 3: Which drug is contraindicated in G6PD deficiency?
- A. Primaquine (Correct Answer)
- B. Chloroquine
- C. Quinine
- D. All of the options
Explanation: ***Primaquine*** - **Primaquine** is an antimalarial drug that generates **severe oxidative stress** in red blood cells. - It is **definitively contraindicated** in **G6PD deficiency** as it consistently causes **acute hemolytic anemia**. - Among antimalarials, primaquine poses the **highest risk** and should **never be used** in G6PD-deficient patients. - It is used for radical cure of P. vivax and P. ovale malaria, but alternative regimens must be used in G6PD deficiency. *Chloroquine* - **Chloroquine** can cause hemolysis in **G6PD deficiency**, though the risk is **lower than primaquine**. - It is **not considered fully safe** and should be used with **caution** in G6PD-deficient patients. - At standard doses, the risk is moderate, but hemolysis can occur, especially in certain G6PD variants. - However, it is not absolutely contraindicated and may be used when benefits outweigh risks with close monitoring. *Quinine* - **Quinine** can also cause **hemolysis** in patients with **G6PD deficiency**. - The risk varies with G6PD variant severity and dosage. - In **severe G6PD deficiency**, quinine should be avoided when alternatives are available. - While less consistently problematic than primaquine, it still requires caution and monitoring. *All of the options* - This option is incorrect in the context of this question because **primaquine** is the **most consistently and severely contraindicated** drug. - While chloroquine and quinine can cause hemolysis, they have **variable risk profiles** and may be used cautiously in some situations, unlike primaquine which is **absolutely contraindicated**. - The question asks for "which drug" (singular), indicating primaquine as the primary answer due to its consistent and severe risk.
Question 4: Which of the following cytochromes is involved in monooxygenase mediated detoxification of drugs?
- A. Cytochrome b5
- B. Cytochrome P450 (Correct Answer)
- C. Cytochrome c
- D. NADPH-cytochrome P450 reductase
Explanation: ***Cyt P 450*** - **Cytochrome P450** enzymes are a superfamily of **monooxygenases** that play a critical role in the metabolism and detoxification of a wide variety of endogenous and exogenous substances, including drugs. - They facilitate phase I reactions (e.g., **oxidation**, reduction, hydrolysis), which typically introduce or expose functional groups to make compounds more polar and easier to excrete. *Cytochrome b5* - **Cytochrome b5** is involved in various metabolic reactions, including **fatty acid desaturation** and cholesterol biosynthesis, and can sometimes interact with P450 systems but is not the primary monooxygenase for drug detoxification. - It also participates in the reduction of methemoglobin and can act as an electron donor, but its role in drug detoxification is secondary and accessory to P450. *Cytochrome c* - **Cytochrome c** is a key component of the **electron transport chain** in mitochondria, primarily involved in cellular respiration and ATP production. - It has a crucial role in **apoptosis** when released into the cytosol, but it is not directly involved in drug monooxygenase detoxification. *NADPH-cytochrome P450 reductase* - **NADPH-cytochrome P450 reductase** is an enzyme that transfers electrons from NADPH to **cytochrome P450 enzymes**, enabling their monooxygenase activity. - While essential for P450 function, it is the **reductase** (electron donor) and not the monooxygenase enzyme itself, which is Cytochrome P450.
Question 5: A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?
- A. Isoniazid
- B. Amiodarone
- C. Carbamazepine (Correct Answer)
- D. Cimetidine
Explanation: ***Carbamazepine*** - Carbamazepine **induces cytochrome P450 enzymes**, specifically **CYP3A4** and **CYP2C9**, which are responsible for warfarin metabolism. - This induction leads to a **faster metabolism of warfarin**, thus **decreasing its anticoagulant effect** and thereby reducing the risk of bleeding. *Isoniazid* - Isoniazid is an **inhibitor of cytochrome P450 enzymes**, primarily **CYP2C9**, which metabolizes the more potent S-warfarin isomer. - This inhibition **decreases warfarin metabolism**, leading to **increased anticoagulant effect** and higher risk of bleeding. *Amiodarone* - Amiodarone is a potent **inhibitor of cytochrome P450 enzymes**, significantly **CYP2C9** and **CYP3A4**. - It leads to a **reduced metabolism of warfarin**, causing **elevated INR** and an increased risk of bleeding. *Cimetidine* - Cimetidine is a known **inhibitor of various cytochrome P450 enzymes**, particularly **CYP1A2**, **CYP2C9**, and **CYP3A4**. - Its inhibitory action on warfarin metabolism results in **higher warfarin levels** and an **increased risk of bleeding**.
Question 6: Which of the following drugs is metabolized by CYP2D6?
- A. Propranolol (Correct Answer)
- B. Warfarin
- C. Statins
- D. Amiodarone
Explanation: ***Correct Answer: Propranolol*** - **Propranolol** is a non-selective beta-blocker that undergoes extensive **first-pass metabolism**, primarily via the **CYP2D6** and CYP1A2 enzymes. - Genetic variations in **CYP2D6** can significantly affect propranolol's metabolism, leading to altered drug levels and therapeutic responses. *Incorrect: Warfarin* - **Warfarin** is predominantly metabolized by **CYP2C9**, with minor contributions from other CYP enzymes. - Genetic polymorphisms in **CYP2C9** are a major factor in determining individual warfarin dose requirements. *Incorrect: Statins* - Most **statins** (e.g., simvastatin, lovastatin, atorvastatin) are primarily metabolized by **CYP3A4**. - **Fluvastatin** is an exception, being mainly metabolized by CYP2C9, while **rosuvastatin** is largely unmetabolized. *Incorrect: Amiodarone* - **Amiodarone** is primarily metabolized by **CYP3A4** and to a lesser extent by CYP2C8. - Due to its **long half-life** and extensive metabolism, amiodarone has numerous drug interactions, often involving CYP3A4 inhibition.
Question 7: Which of the following combinations can result in severe toxicity due to inhibition of cytochrome P450 enzymes?
- A. Amiodarone + Atorvastatin
- B. Carbamazepine + Atorvastatin
- C. Atorvastatin + Itraconazole (Correct Answer)
- D. Phenytoin + Atorvastatin
Explanation: ***Atorvastatin + Itraconazole*** - **Itraconazole** is a potent inhibitor of **CYP3A4**, the primary enzyme responsible for atorvastatin's metabolism. - Co-administration leads to significantly increased **atorvastatin plasma concentrations**, raising the risk of severe side effects like **rhabdomyolysis** and **hepatotoxicity**. *Amiodarone + Atorvastatin* - **Amiodarone** is a moderate **CYP3A4 inhibitor** and can increase atorvastatin levels, but the inhibition is **less potent** than itraconazole. - While this combination does carry a risk and requires dose adjustment, the interaction is **less severe** compared to the potent inhibition seen with itraconazole. - The direct CYP inhibition leading to severe atorvastatin toxicity is less pronounced than with itraconazole. *Carbamazepine + Atorvastatin* - **Carbamazepine** is a potent **CYP3A4 inducer**, meaning it would increase the metabolism of atorvastatin, potentially *decreasing* its efficacy rather than causing toxicity through inhibition. - This interaction would typically lead to subtherapeutic atorvastatin levels, rather than severe toxicity. *Phenytoin + Atorvastatin* - **Phenytoin** is also a potent **CYP3A4 inducer**, similar to carbamazepine. - Concurrent use would likely lead to enhanced metabolism and **reduced efficacy of atorvastatin**, not increased toxicity due to enzyme inhibition.
Question 8: A 22-year-old man presents with sudden loss of vision in his right eye. Physical examination reveals subluxation of the right crystalline lens. Auscultation of the chest reveals a midsystolic click. Echocardiography shows a floppy mitral valve and a dilated aortic arch. The patient's brother and cousin have similar symptoms. He has been prescribed a beta-blocker. A genetic defect involving which of the following substances is most likely present in this patient?
- A. Collagen
- B. Dystrophin
- C. Fibrillin-1 (Correct Answer)
- D. NF1 protein
Explanation: ### **Explanation** The clinical presentation of **ectopia lentis (lens subluxation)**, **mitral valve prolapse (midsystolic click)**, and **aortic root dilation** in a young patient with a positive family history is classic for **Marfan Syndrome** [1], [3]. **1. Why Fibrillin-1 is Correct:** Marfan Syndrome is an **autosomal dominant** connective tissue disorder caused by a mutation in the **FBN1 gene** on chromosome 15 [3]. This gene encodes **Fibrillin-1**, a glycoprotein that serves as a major structural component of extracellular microfibrils [1]. These microfibrils form a scaffold for **elastin** deposition [2]. Defective fibrillin leads to: * **Skeletal:** Arachnodactyly and pectus deformities. * **Ocular:** Upward and outward (superotemporal) subluxation of the lens [1]. * **Cardiovascular:** Cystic medial necrosis of the aorta, leading to aneurysms, dissection, and mitral valve prolapse [3]. Beta-blockers are prescribed to reduce the rate of aortic dilation. **2. Why Other Options are Incorrect:** * **Collagen:** Defects in collagen synthesis (e.g., COL5A1/COL5A2) are seen in **Ehlers-Danlos Syndrome**. While EDS features joint hypermobility and aortic issues, it does not typically present with ectopia lentis [1]. * **Dystrophin:** Mutations in the dystrophin gene lead to **Duchenne or Becker Muscular Dystrophy**, characterized by progressive muscle weakness and pseudohypertrophy. * **NF1 protein (Neurofibromin):** Mutations lead to **Neurofibromatosis Type 1**, characterized by café-au-lait spots, Lisch nodules, and neurofibromas. **3. High-Yield Clinical Pearls for NEET-PG:** * **Lens Subluxation:** Marfan = **Upward** (Superior); Homocystinuria = **Downward** (Inferior). * **Most common cause of death:** Aortic dissection/rupture [3]. * **Steinberg Sign & Walker-Murdoch Sign:** Clinical bedside tests for arachnodactyly. * **Genetics:** FBN1 mutation also leads to increased **TGF-β** signaling, contributing to tissue weakening.
Question 9: Which of the following conditions is NOT inherited in an autosomal recessive pattern?
- A. Sickle cell anemia
- B. Phenylketonuria
- C. Marfan's syndrome (Correct Answer)
- D. Wilson's disease
Explanation: **Explanation:** The correct answer is **Marfan’s syndrome** because it follows an **Autosomal Dominant (AD)** inheritance pattern. It is caused by a mutation in the **FBN1 gene** on chromosome 15, which encodes **Fibrillin-1**, a critical glycoprotein for the structural integrity of the extracellular matrix. Since it is dominant, a single mutated allele from one parent is sufficient to cause the disease. **Analysis of Options:** * **Sickle cell anemia (A):** This is a classic **Autosomal Recessive (AR)** disorder caused by a point mutation in the HBB gene (Glu6Val). Clinical manifestation occurs only in the homozygous state (HbSS). * **Phenylketonuria (B):** An **AR** metabolic disorder involving a deficiency of the enzyme phenylalanine hydroxylase. It requires two defective alleles for the phenotype to appear. * **Wilson’s disease (D):** An **AR** disorder of copper metabolism caused by mutations in the **ATP7B gene** on chromosome 13. **NEET-PG High-Yield Pearls:** 1. **Marfan’s Syndrome:** Look for "Tall stature, Ectopia lentis (upward dislocation), and Aortic root dilatation." It exhibits **pleiotropy** (one gene affecting multiple systems). 2. **Mnemonic for AR diseases:** "Many Metabolic" diseases are AR (e.g., Glycogen storage diseases, Galactosemia, Cystic Fibrosis, and most enzyme deficiencies). 3. **Mnemonic for AD diseases:** "Structural" proteins are often AD (e.g., Marfan’s, Achondroplasia, Hereditary Spherocytosis, Osteogenesis Imperfecta) [1]. 4. **Exceptions:** Most enzyme deficiencies are AR, but **Hunter Syndrome** and **G6PD deficiency** are X-linked Recessive.
Question 10: In X-linked recessive (XLR) diseases, a modified inheritance pattern called 'pseudodominance' occurs when?
- A. One parent is an affected homozygote and the other is an unaffected homozygote.
- B. One parent is an unaffected heterozygote and the other is an affected homozygote. (Correct Answer)
- C. One parent is normal and the other is an unaffected heterozygote.
- D. Both parents are unaffected.
Explanation: **Explanation:** **Pseudodominance** refers to a situation where a recessive trait appears to follow a dominant inheritance pattern, appearing in every generation. In X-linked recessive (XLR) disorders, this occurs when an **affected male (XᵃY)** mates with a **carrier female (XᴬXᵃ)**. 1. **Why Option B is Correct:** In this scenario, the offspring have a 50% chance of being affected (XᵃXᵃ females or XᵃY males). Because the disease appears in both the parent and the offspring generations, it mimics an Autosomal Dominant or X-linked Dominant pattern. This is "pseudo" (false) dominance because the underlying genotype remains recessive. This is commonly seen in consanguineous populations or for high-frequency recessive alleles (e.g., Color Blindness). 2. **Why Other Options are Incorrect:** * **Option A:** If an affected male (XᵃY) mates with a normal homozygote female (XᴬXᴬ), all daughters are carriers and all sons are normal. No offspring are affected, so it does not mimic dominance. * **Option C:** This is the standard XLR carrier state. Only 50% of sons are affected; the trait typically skips generations. * **Option D:** If both parents are unaffected (and not carriers), no offspring will be affected. **High-Yield NEET-PG Pearls:** * **Lyonization (Skewed):** Another cause of affected females in XLR traits is "Inactivated X-chromosome" theory, where the normal X is silenced, allowing the mutant X to express. * **Turner Syndrome (45, XO):** Females with Turner syndrome can manifest XLR diseases (like Hemophilia) because they only have one X chromosome, similar to males. * **Common XLR Examples:** Hemophilia A/B, Duchenne Muscular Dystrophy, G6PD deficiency, and Color Blindness.
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