Genetic Basis of Drug Response — MCQs

10 questions

The cytochrome involved in monooxygenase-mediated detoxification of drugs is:

Pharmacodynamics deals with:-

HLA-B*5701 is an allele associated with hypersensitivity to abacavir. Which of the following is the parent allele of HLA-B*5701?

Mutation in GLUT-2 causes which syndrome?

What is the mechanism of metabolism for alcohol, aspirin, and phenytoin at high doses?

Therapeutic drug monitoring is done for:

A patient given one of the following drug develops low grade fever, muscle and joint ache, chest pain and skin rashes. Lab investigations showed presence of antihistone antibodies. Symptoms however subsided after discontinuation of the drug. Which is the drug that caused the reaction?

Which of the following best describes a Type B adverse drug reaction?

A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?

Q10

A pregnant woman exposed to a teratogenic drug during the first trimester is most likely to result in which of the following defects?

Genetic Basis of Drug Response Indian Medical PG Practice Questions and MCQs

Question 1: The cytochrome involved in monooxygenase-mediated detoxification of drugs is:

A. Cyt P 450 (Correct Answer)
B. Cytochrome b5
C. Cytochrome c
D. Cytochrome oxidase

Explanation: ***Cyt P 450*** - **Cytochrome P450 (CYP450)** enzymes are a superfamily of heme-containing monooxygenases primarily responsible for the **metabolism of xenobiotics**, including the detoxification of drugs. - They catalyze oxidation reactions, introducing a hydroxyl group to substrates, which typically increases their **hydrophilicity** and facilitates excretion. *Cytochrome c* - **Cytochrome c** is a component of the **electron transport chain** in mitochondria, primarily involved in cellular respiration and energy production. - It acts as an **electron carrier** between Complex III and Complex IV, not directly in drug detoxification. *Cytochrome b5* - **Cytochrome b5** participates in various metabolic reactions, including **fatty acid desaturation** and cholesterol biosynthesis, and can sometimes assist CYP450 enzymes. - However, it does not function as a primary monooxygenase for drug detoxification itself. *Cytochrome oxidase* - **Cytochrome oxidase** (Complex IV) is the terminal enzyme in the **electron transport chain**, responsible for the reduction of oxygen to water. - Its main role is in cellular respiration, and it is not directly involved in drug monooxygenation or detoxification.

Question 2: Pharmacodynamics deals with:-

A. Latency of onset
B. Mechanism of action of a drug (Correct Answer)
C. Transport of drug across the biological membranes
D. Mode of excretion of a drug

Explanation: Detailed study of the **Mechanism of action of a drug** [1][2] - **Pharmacodynamics** describes what the **drug does to the body**, including its **molecular targets** and biochemical effects [3]. - This involves the study of the drug's mechanisms to produce its therapeutic or toxic effects [2]. *Latency of onset* - **Latency of onset** refers to the time it takes for a drug to start producing its effects, which is a pharmacokinetic rather than a pharmacodynamic parameter. - It deals with the drug's absorption and distribution rather than its interaction with the body once it reaches its site of action. *Transport of drug across the biological membranes* - The **transport of drugs across biological membranes** is a key aspect of **pharmacokinetics**, specifically absorption and distribution [1]. - This process determines how much drug reaches its target site, not how it interacts with the target. *Mode of excretion of a drug* - The **mode of excretion** of a drug (e.g., renal, hepatic) falls under **pharmacokinetics**, addressing how the body gets rid of the drug. - This process influences the drug's duration of action and elimination half-life, not its mechanism of action.

Question 3: HLA-B5701 is an allele associated with hypersensitivity to abacavir. Which of the following is the parent allele of HLA-B5701?

A. HLA-B*5
B. HLA-B*51
C. HLA-DQ2
D. HLA-B*57 (Correct Answer)

Explanation: ***HLA-B\*57*** - **HLA-B*57** is the parent allele for **HLA-B*5701**, indicating it is the broader serotype under which specific alleles like *5701 are classified [1]. - The notation **HLA-B\*57** signifies a specific **HLA class I** allele group [1]. *HLA-B\*5* - This option is **incomplete** as an HLA allele notation; it lacks the specific group designation often indicated by two or three digits following the asterisk. - While "B5" exists as a serotype, **"HLA-B*5"** itself is not a standard, complete allele designation reflecting a specific gene variant. *HLA-B\*51* - **HLA-B\*51** is a specific **HLA class I** allele, but it is not directly related to or the parent group of **HLA-B\*5701**. - It is known to be associated with Behcet's disease, a different clinical condition not related to abacavir hypersensitivity. *HLA-DQ2* - **HLA-DQ2** is an allele of **HLA class II**, while **HLA-B\*5701** is an **HLA class I** allele. - Though both are HLA alleles, they belong to different classes and are associated with different disease contexts, with **HLA-DQ2 typically linked to celiac disease**.

Question 4: Mutation in GLUT-2 causes which syndrome?

A. Dandy walker syndrome
B. Beckwith-Wiedemann syndrome
C. Menke's disease
D. Fanconi-Bickel syndrome (Correct Answer)

Explanation: ***Fanconi-Bickel syndrome*** - This syndrome is caused by a **mutation in the GLUT-2 gene**, leading to dysfunctional glucose transport in the liver, kidneys, and intestines. - Key features include **hepatorenal glycogen accumulation**, **renal tubulopathy** (Fanconi syndrome), and **impaired glucose and galactose utilization**. *Dandy-Walker syndrome* - This is a **congenital brain malformation** involving the cerebellum and fourth ventricle. - It is often associated with hydrocephalus, but not directly linked to glucose transporter defects. *Beckwith-Wiedemann syndrome* - This is an **overgrowth disorder** characterized by a high risk of childhood cancer and congenital anomalies. - It is primarily caused by genetic abnormalities on **chromosome 11p15.5** and is unrelated to GLUT-2 mutations. *Menke's disease* - This is a rare X-linked recessive disorder of **copper metabolism**, leading to severe neurological degeneration. - It results from mutations in the **ATP7A gene**, which encodes a copper-transporting ATPase.

Question 5: What is the mechanism of metabolism for alcohol, aspirin, and phenytoin at high doses?

A. First pass kinetics
B. First order kinetics
C. Zero order kinetics (Correct Answer)
D. Second order kinetics

Explanation: ***Zero order kinetics*** - This mechanism occurs when the **metabolic enzymes become saturated at high drug concentrations**, leading to a constant amount (not a constant percentage) of drug being eliminated per unit time. - Alcohol, aspirin, and phenytoin are examples of drugs that exhibit **saturable metabolism**, transitioning from first-order to zero-order kinetics at higher doses. *First pass kinetics* - This describes the **metabolism of a drug by the liver or gut wall enzymes before it reaches systemic circulation** after oral administration. - While relevant to the oral bioavailability of these drugs, it does not describe the specific mechanism of elimination at high doses. *First order kinetics* - In this mechanism, a **constant fraction or percentage of the drug is eliminated per unit of time**, meaning the rate of elimination is directly proportional to the drug concentration. - Most drugs follow first-order kinetics at therapeutic doses because metabolizing enzymes are not saturated. *Second order kinetics* - This is a **less common pharmacokinetic model** where the rate of elimination is proportional to the square of the drug concentration or involves two reactants. - It does not typically describe the common elimination patterns of most drugs, including alcohol, aspirin, and phenytoin.

Question 6: Therapeutic drug monitoring is done for:

A. Aspirin
B. Heparin
C. Phenytoin (Correct Answer)
D. Metformin

Explanation: ***Phenytoin*** - **Phenytoin** has a **narrow therapeutic window**, meaning the difference between an effective and a toxic dose is small, necessitating close monitoring. - Its **variable absorption** and **nonlinear pharmacokinetics** (saturable metabolism) make individual dosing adjustments critical to maintain therapeutic levels and avoid toxicity. *Aspirin* - **Aspirin** is generally not monitored via plasma levels for its analgesic or antiplatelet effects, as its therapeutic effects are often observed at doses where plasma monitoring is not practical or necessary. - Its primary therapeutic use as an **antiplatelet agent** is evaluated by clinical outcomes rather than drug concentration. *Heparin* - **Heparin** is monitored using coagulation tests like **aPTT (activated partial thromboplastin time)** or anti-Xa levels to assess its anticoagulant effect, not direct drug concentration. - Therapeutic drug monitoring for heparin focuses on its **pharmacodynamic effects** on the clotting cascade rather than its absolute plasma concentration. *Metformin* - **Metformin** has a relatively **wide therapeutic index** and its efficacy is primarily measured by reductions in blood glucose and HbA1c, not by plasma drug concentrations. - It is excreted largely unchanged by the kidneys, and dose adjustments are typically made based on **renal function** and glycemic control.

Question 7: A patient given one of the following drug develops low grade fever, muscle and joint ache, chest pain and skin rashes. Lab investigations showed presence of antihistone antibodies. Symptoms however subsided after discontinuation of the drug. Which is the drug that caused the reaction?

A. Paracetamol
B. Furosemide
C. Rifampicin
D. Hydralazine (Correct Answer)

Explanation: ***Hydralazine*** - This drug is a well-known cause of **drug-induced lupus erythematosus (DILE)**, which presents with symptoms like fever, myalgia, arthralgia, pleuritic chest pain, and skin rashes. - The presence of **antihistone antibodies** is a hallmark laboratory finding in DILE, and symptoms typically resolve upon discontinuation of the causative drug. *Paracetamol* - Paracetamol (acetaminophen) is an **analgesic** and **antipyretic** and is generally well-tolerated. - It does not typically cause a lupus-like syndrome or induce the formation of antihistone antibodies. *Furosemide* - Furosemide is a **loop diuretic** primarily used for treating edema and hypertension. - While it can cause side effects like electrolyte imbalances, it is not associated with drug-induced lupus or antihistone antibodies. *Rifampicin* - Rifampicin is an **antibiotic** used to treat tuberculosis and other bacterial infections. - Its side effects can include hepatotoxicity, gastrointestinal disturbances, and reddish discoloration of body fluids, but not typically a lupus-like syndrome with antihistone antibodies.

Question 8: Which of the following best describes a Type B adverse drug reaction?

A. Augmented effect of drug
B. Effect seen on chronic use of drug
C. Delayed effect of drug
D. Unpredictable bizarre reaction (Correct Answer)

Explanation: ***Unpredictable bizarre reaction*** - Type B reactions are **unpredictable**, **bizarre**, and not directly related to the drug's known pharmacological actions. - They often involve **immunological reactions** or genetic predispositions, such as allergies or idiosyncratic responses. *Augmented effect of drug* - This describes a **Type A** adverse drug reaction, which is predictable and results from an **exaggerated pharmacological effect** of the drug. - It is typically dose-dependent and can be managed by adjusting the dosage. *Effect seen on chronic use of drug* - This description can apply to several types of adverse reactions, but it commonly relates to **Type C (chronic) reactions**, where effects occur only after prolonged exposure. - These reactions might be due to **cumulative toxicity** or adaptive changes in the body. *Delayed effect of drug* - This aligns with **Type D (delayed) adverse drug reactions**, which manifest long after the drug exposure has ended or after a period of latency. - Examples include **carcinogenesis** or teratogenesis, occurring months or years later.

Question 9: 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 10: A pregnant woman exposed to a teratogenic drug during the first trimester is most likely to result in which of the following defects?

A. Neural tube defects (Correct Answer)
B. Hypospadias
C. Cleft palate
D. Polydactyly

Explanation: ***Neural tube defects*** - The **neural tube** forms during the **third to fourth week of gestation**, representing the **earliest critical period** of organogenesis in the first trimester. Exposure to teratogens during this period can disrupt its closure. - Examples include **spina bifida** and **anencephaly**, which are severe structural malformations. - Because this is the **earliest organogenesis event**, it is the **most vulnerable** to teratogenic exposure in the first trimester, making neural tube defects the **most likely** outcome when timing is unspecified. - Classic teratogens include **valproic acid**, **carbamazepine**, and **folic acid deficiency**. *Cleft palate* - The palate develops between the **6th and 12th weeks of gestation**, which is also within the first trimester. - This is a **common teratogenic defect** associated with medications like **phenytoin**, **corticosteroids**, and **retinoids**. - However, palate formation occurs **later than neural tube closure**, making it a secondary consideration when the question asks for the "most likely" first-trimester defect. *Hypospadias* - This condition involves incomplete fusion of the **urethral folds**, which occurs during the **9th to 12th weeks of gestation** (late first to early second trimester). - While teratogens can contribute, the critical period extends beyond the first trimester, and it is **less commonly** associated with classic first-trimester teratogen exposure compared to neural tube defects. *Polydactyly* - Characterized by **extra fingers or toes**, this condition most commonly results from **genetic mutations** rather than direct teratogenic exposure. - Limb development occurs during the **fifth to ninth weeks of gestation**; while teratogens can affect limb development (e.g., thalidomide causing limb reduction), polydactyly itself is **rarely** directly linked to teratogen exposure.

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