Isoniazid – synthesis and mechanism MCQs With Answer

Isoniazid (INH) is a cornerstone antitubercular prodrug used in first-line therapy for tuberculosis. This concise introduction covers INH’s chemical synthesis, activation by mycobacterial catalase-peroxidase (KatG), inhibition of mycolic acid biosynthesis via InhA, and clinically relevant pharmacokinetics and toxicity. Key concepts include acetylation by NAT2 (fast/slow acetylators), mechanisms of resistance, hepatotoxicity, peripheral neuropathy from pyridoxine depletion, and simple synthetic routes from isonicotinic acid derivatives. These focused MCQs are tailored for B.Pharm students to reinforce medicinal chemistry, mechanism of action, metabolic pathways, and safety monitoring. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the primary molecular target of activated isoniazid in Mycobacterium tuberculosis?

• DNA gyrase
• Enoyl-acyl carrier protein reductase (InhA)
• RNA polymerase
• Peptidoglycan transpeptidase

Correct Answer: Enoyl-acyl carrier protein reductase (InhA)

Q2. Which enzyme in Mycobacterium tuberculosis activates isoniazid to its reactive form?

• N-acetyltransferase 2 (NAT2)
• Catalase–peroxidase (KatG)
• Monoamine oxidase
• Cytochrome P450 3A4

Correct Answer: Catalase–peroxidase (KatG)

Q3. The chemical name of isoniazid is:

• Isonicotinic acid hydrazide
• Isonicotinic acid methyl ester
• Isoniazid benzyl ether
• Isonicotinol sulfate

Correct Answer: Isonicotinic acid hydrazide

Q4. A common synthetic route to isoniazid involves reaction of isonicotinoyl chloride with which reagent?

• Hydrazine hydrate
• Sodium borohydride
• Ammonia gas
• Methanol

Correct Answer: Hydrazine hydrate

Q5. Isoniazid is classified pharmacologically as a:

• Fluoroquinolone antibiotic
• Antitubercular, mycolic acid synthesis inhibitor
• Aminoglycoside
• Beta-lactam antibiotic

Correct Answer: Antitubercular, mycolic acid synthesis inhibitor

Q6. Which metabolic pathway primarily determines plasma half-life of isoniazid in humans?

• Glucuronidation by UGT enzymes
• N-acetylation by NAT2
• Sulfation by SULT enzymes
• Hydroxylation by CYP2E1 only

Correct Answer: N-acetylation by NAT2

Q7. Fast and slow acetylator phenotypes affect which clinical parameter of isoniazid?

• Mode of action at bacterial cell wall
• Plasma elimination half-life and toxicity risk
• Ability to penetrate cerebrospinal fluid
• Protein binding percentage

Correct Answer: Plasma elimination half-life and toxicity risk

Q8. The main mechanism by which isoniazid causes peripheral neuropathy is:

• Direct axonal demyelination via free radical attack
• Competitive inhibition of pyridoxine metabolism leading to deficiency
• Immune-mediated demyelination
• Accumulation of vitamin B12

Correct Answer: Competitive inhibition of pyridoxine metabolism leading to deficiency

Q9. Which co-therapy is recommended to prevent INH-induced peripheral neuropathy?

• Folic acid
• Vitamin B6 (pyridoxine)
• Vitamin C
• Iron supplements

Correct Answer: Vitamin B6 (pyridoxine)

Q10. A major adverse effect requiring routine monitoring during isoniazid therapy is:

• Renal failure
• Hepatotoxicity (elevated liver enzymes)
• Cardiomyopathy
• Pancreatitis

Correct Answer: Hepatotoxicity (elevated liver enzymes)

Q11. Which mutation commonly confers high-level resistance to isoniazid in M. tuberculosis?

• Mutations in katG gene (e.g., Ser315Thr)
• Mutations in 23S rRNA
• Mutations in gyrA only
• Mutations in penA gene

Correct Answer: Mutations in katG gene (e.g., Ser315Thr)

Q12. Another resistance mechanism involves mutations in the inhA promoter. What effect does this produce?

• Overexpression of InhA leading to low-level INH resistance
• Complete loss of cell wall synthesis enzymes
• Increased uptake of INH into cells
• Hyperactivation of KatG

Correct Answer: Overexpression of InhA leading to low-level INH resistance

Q13. The reactive species formed after KatG activation of INH primarily interacts with which cellular cofactor to inhibit InhA?

• FAD (flavin adenine dinucleotide)
• NAD+ (nicotinamide adenine dinucleotide)
• CoA (coenzyme A)
• ATP

Correct Answer: NAD+ (nicotinamide adenine dinucleotide)

Q14. Isoniazid’s bactericidal activity is most pronounced against which bacterial population?

• Rapidly dividing extracellular bacteria only
• Intracellular replicating Mycobacterium tuberculosis in active lesions
• Dormant, non-replicating bacilli exclusively
• Gram-negative aerobic bacilli

Correct Answer: Intracellular replicating Mycobacterium tuberculosis in active lesions

Q15. Which laboratory test should be monitored before and during isoniazid therapy to detect hepatotoxicity?

• Serum creatinine
• Serum alanine aminotransferase (ALT) and AST
• Complete blood count only
• Serum amylase

Correct Answer: Serum alanine aminotransferase (ALT) and AST

Q16. Isoniazid is primarily eliminated by which route in humans?

• Fecal excretion unchanged
• Renal excretion after metabolism
• Exhalation as CO2
• Biliary excretion of unchanged drug

Correct Answer: Renal excretion after metabolism

Q17. How does slow acetylator phenotype affect isoniazid dosing or toxicity?

• Requires higher dose to be effective
• Increases risk of INH toxicity, may need dose adjustment
• No clinical effect on dose or toxicity
• Leads to reduced bioavailability

Correct Answer: Increases risk of INH toxicity, may need dose adjustment

Q18. Which of the following drugs increases risk of hepatotoxicity when co-administered with isoniazid?

• Rifampicin
• Paracetamol (acetaminophen)
• Both rifampicin and paracetamol
• Amoxicillin

Correct Answer: Both rifampicin and paracetamol

Q19. In medicinal chemistry terms, INH is best described as a:

• Hydrazide derivative of a heteroaromatic carboxylic acid
• Peptide mimetic
• Nucleoside analog
• Sulfonamide derivative

Correct Answer: Hydrazide derivative of a heteroaromatic carboxylic acid

Q20. Which structural feature of isoniazid is critical for its conversion to an acyl radical and subsequent activity?

• Aromatic chlorine atom
• Hydrazide (-CONHNH2) functional group
• Tertiary amine group
• Long alkyl chain

Correct Answer: Hydrazide (-CONHNH2) functional group

Q21. Which assay or test can detect INH resistance related to katG mutations?

• Phenotypic culture-based drug susceptibility testing and molecular PCR for katG
• MIC testing for beta-lactams only
• ELISA for INH antibodies
• Gram staining of sputum

Correct Answer: Phenotypic culture-based drug susceptibility testing and molecular PCR for katG

Q22. Isoniazid therapy is contraindicated or used cautiously in patients with:

• Active hepatic disease or significant baseline transaminase elevation
• Controlled hypertension only
• Mild seasonal allergies
• Hypothyroidism controlled with levothyroxine

Correct Answer: Active hepatic disease or significant baseline transaminase elevation

Q23. Which pharmacokinetic property explains why INH is given once daily for most adult regimens?

• Very high protein binding requiring continuous infusion
• Sufficient plasma half-life and intracellular activity allowing once-daily dosing
• Extremely rapid renal excretion requiring multiple doses per day
• Ineffective oral bioavailability

Correct Answer: Sufficient plasma half-life and intracellular activity allowing once-daily dosing

Q24. In the lab synthesis context, protecting groups are generally unnecessary for formation of isoniazid because:

• The hydrazine reacts selectively with acyl chloride to form hydrazide
• The molecule is highly unstable and cannot be synthesized
• Strong oxidizers are required to form the hydrazide
• It must be synthesized via peptide coupling

Correct Answer: The hydrazine reacts selectively with acyl chloride to form hydrazide

Q25. Which organelle or cellular compartment in M. tuberculosis is most affected by inhibition of mycolic acid synthesis?

• Mitochondria
• Cell membrane and cell wall mycolyl-arabinogalactan layer
• Nucleus
• Ribosomes

Correct Answer: Cell membrane and cell wall mycolyl-arabinogalactan layer

Q26. Which clinical manifestation indicates severe isoniazid-induced neurotoxicity if untreated?

• Peripheral neuropathy progressing to seizures due to pyridoxine deficiency
• Hypertension crises
• Interstitial lung disease only
• Sudden visual loss

Correct Answer: Peripheral neuropathy progressing to seizures due to pyridoxine deficiency

Q27. Co-administration of isoniazid with which drug requires caution because of CYP enzyme inhibition leading to increased levels?

• Phenytoin (antiepileptic)
• Metformin
• Insulin
• Levofloxacin

Correct Answer: Phenytoin (antiepileptic)

Q28. In designing MCQs for synthesis knowledge, which step is essential to highlight about INH manufacture?

• Formation of isonicotinoyl chloride followed by hydrazinolysis to give isoniazid
• Direct hydrogenation of isonicotinic acid without activation
• Photochemical dimerization of isonicotinic acid
• Fermentation-based biological synthesis only

Correct Answer: Formation of isonicotinoyl chloride followed by hydrazinolysis to give isoniazid

Q29. Which population is at higher risk of INH-induced hepatotoxicity?

• Young healthy adults with no liver disease
• Older adults, alcoholics, and those with preexisting liver disease
• Patients with controlled diabetes only
• Pregnant women in first trimester exclusively

Correct Answer: Older adults, alcoholics, and those with preexisting liver disease

Q30. From a drug design perspective, why is INH considered a prodrug?

• It is active in its administered form and does not require activation
• It requires conversion by mycobacterial KatG into reactive species that inhibit InhA
• It is inactive until metabolized by human liver enzymes into a toxic metabolite
• It spontaneously degrades to active fragments in solution

Correct Answer: It requires conversion by mycobacterial KatG into reactive species that inhibit InhA

G S Sachin

I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.

Mail- Sachin@pharmacyfreak.com