SAR of barbiturates MCQs With Answer

SAR of barbiturates MCQs With Answer — a focused, practical introduction for B.Pharm students. Understanding the structure-activity relationship (SAR) of barbiturates is essential to predict potency, onset, duration, metabolism, and pharmacological profile of sedative‑hypnotics and anticonvulsants. This set explains how C5 substitutions, thiocarbonyl versus carbonyl (oxygen vs sulfur), alkyl versus aryl groups, lipophilicity, pKa, and hepatic metabolism influence blood‑brain barrier penetration, receptor binding at GABA‑A, and clinical effects. Questions emphasize real drug examples (phenobarbital, pentobarbital, thiopental, methohexital), SAR rules, and safety/pharmacokinetic implications, helping B.Pharm students master medicinal chemistry and therapeutics of barbiturates. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. What is the core chemical scaffold of barbiturate drugs?

• Pyrimidine-2,4,6-trione
• Benzodiazepine-1,4-dione
• Imidazole-4,5-dione
• Thiophene-2,5-dione

Correct Answer: Pyrimidine-2,4,6-trione

Q2. Which substitution is essential for classical barbiturate CNS depressant activity?

• 5,5-disubstitution at C5
• N1-methylation
• Oxygen to sulfur at C4
• Halogenation of the pyrimidine ring

Correct Answer: 5,5-disubstitution at C5

Q3. Thiobarbiturates differ from oxybarbiturates by replacement of which atom?

• Oxygen at C2 with sulfur
• Nitrogen at N1 with sulfur
• Carbonyl at C4 with nitrogen
• Hydrogen at C5 with chlorine

Correct Answer: Oxygen at C2 with sulfur

Q4. Increasing lipophilicity of a barbiturate generally leads to which pharmacokinetic change?

• Faster onset and shorter duration due to redistribution
• Slower onset and longer duration due to tissue trapping
• Decreased blood‑brain barrier penetration
• Reduced hepatic metabolism

Correct Answer: Faster onset and shorter duration due to redistribution

Q5. Introduction of a phenyl (aryl) group at C5 typically causes which effect?

• Increased potency and often prolonged duration
• Complete loss of CNS activity
• Marked decrease in protein binding
• Conversion to an anesthetic gas

Correct Answer: Increased potency and often prolonged duration

Q6. Which of the following is an ultra‑short acting barbiturate commonly used for induction of anesthesia?

• Thiopental
• Phenobarbital
• Pentobarbital
• Amobarbital

Correct Answer: Thiopental

Q7. What is the primary pharmacodynamic mechanism of barbiturates at therapeutic concentrations?

• Positive allosteric modulation of GABA-A receptor enhancing chloride influx
• Competitive antagonism at NMDA receptors
• Inhibition of monoamine oxidase
• Activation of opioid receptors

Correct Answer: Positive allosteric modulation of GABA-A receptor enhancing chloride influx

Q8. Where does oxidative metabolism of barbiturates mainly occur?

• On the C5 alkyl side chains
• On the pyrimidine ring carbons C2 and C4
• At the N1 and N3 nitrogens
• By reductive cleavage of the barbiturate ring

Correct Answer: On the C5 alkyl side chains

Q9. Typical pKa range for many barbiturate acids is approximately:

• 7–8
• 3–4
• 9–10
• 11–12

Correct Answer: 7–8

Q10. Which structural change will abolish classical barbiturate CNS depressant activity?

• Absence of C5 substituents (unsubstituted barbituric acid)
• Replacement of oxygen with sulfur at C2
• Addition of a phenyl group at C5
• Introduction of a hydroxyl on a C5 alkyl chain

Correct Answer: Absence of C5 substituents (unsubstituted barbituric acid)

Q11. Compared to oxybarbiturates, thiobarbiturates are generally:

• More lipophilic and faster in onset
• Less lipid soluble and slower in onset
• Less potent at GABA-A receptors
• Excreted unchanged in urine

Correct Answer: More lipophilic and faster in onset

Q12. Which clinical barbiturate is known for long duration and use as an anticonvulsant?

• Phenobarbital
• Thiopental
• Methohexital
• Secobarbital

Correct Answer: Phenobarbital

Q13. Branching of alkyl substituents at C5 typically results in:

• Increased potency and more rapid onset
• Loss of central activity
• Complete resistance to hepatic metabolism
• Lower lipid solubility

Correct Answer: Increased potency and more rapid onset

Q14. Which metabolic pathway is most responsible for termination of barbiturate action?

• Hepatic oxidative metabolism followed by conjugation
• Renal tubular reabsorption without metabolism
• Direct hydrolysis of the pyrimidine ring
• Extracellular enzymatic cleavage in plasma

Correct Answer: Hepatic oxidative metabolism followed by conjugation

Q15. Which property most directly determines blood‑brain barrier penetration of barbiturates?

• Lipophilicity (oil/water partition coefficient)
• Molecular weight alone
• pKa only
• Degree of aromaticity only

Correct Answer: Lipophilicity (oil/water partition coefficient)

Q16. A secondary alcohol metabolite formed from C5 alkyl oxidation is typically further processed by:

• Conjugation (glucuronidation or sulfation) and renal excretion
• Conversion back to parent drug
• Incorporation into fatty acids
• Direct exhalation via lungs

Correct Answer: Conjugation (glucuronidation or sulfation) and renal excretion

Q17. Which modification at C5 is most associated with hypnotic/anesthetic rather than anticonvulsant selectivity?

• Short, highly lipophilic branched chains (e.g., thiopental)
• Long polar chains increasing water solubility
• Unsubstituted C5
• Glycosylation of side chain

Correct Answer: Short, highly lipophilic branched chains (e.g., thiopental)

Q18. Barbiturates can induce cytochrome P450 enzymes. This primarily affects drugs that are:

• Metabolized by hepatic microsomal enzymes
• Excreted unchanged in bile
• Renally excreted without metabolism
• Administered by inhalation only

Correct Answer: Metabolized by hepatic microsomal enzymes

Q19. Which clinical effect is more pronounced with barbiturates that are highly lipophilic?

• Rapid loss of consciousness (fast induction)
• Prolonged daytime sedation for days
• Complete lack of respiratory depression
• Minimal CNS penetration

Correct Answer: Rapid loss of consciousness (fast induction)

Q20. What is the effect of adding polar functional groups to C5 side chains?

• Decreased lipid solubility and prolonged duration of action
• Increased BBB penetration and ultra‑short action
• Conversion to active inhalational agents
• Immediate urinary excretion as unchanged drug

Correct Answer: Decreased lipid solubility and prolonged duration of action

Q21. Which example is a short‑acting barbiturate used historically for insomnia and sedation?

• Secobarbital
• Phenobarbital
• Thiopental
• Morphine

Correct Answer: Secobarbital

Q22. In SAR terms, which factor most often increases barbiturate potency at GABA-A?

• Bulky and lipophilic substituents at C5
• Removal of both C5 substituents
• Nitration of the pyrimidine ring
• Formation of a quaternary ammonium salt

Correct Answer: Bulky and lipophilic substituents at C5

Q23. Which of these barbiturate structural features tends to increase metabolic stability (longer half‑life)?

• Less lipophilicity and polar substituents at C5
• Highly branched short alkyl chains at C5
• Sulfur substitution at C2
• Presence of a nitro group on the pyrimidine ring

Correct Answer: Less lipophilicity and polar substituents at C5

Q24. Direct activation (opening) of GABA-A channels by barbiturates occurs at:

• High concentrations above therapeutic range
• Only at nanomolar concentrations
• Only when combined with benzodiazepines
• Never; barbiturates only antagonize GABA

Correct Answer: High concentrations above therapeutic range

Q25. Replacement of the C2 carbonyl oxygen with sulfur typically does what to the compound’s pKa?

• Has little predictable effect on pKa but increases lipophilicity
• Drastically raises pKa to >10
• Immediately converts it into a base
• Makes it non-ionizable at physiological pH

Correct Answer: Has little predictable effect on pKa but increases lipophilicity

Q26. Which pharmacokinetic phenomenon explains why a lipophilic barbiturate has a short clinical duration despite potent CNS effect?

• Redistribution from brain to muscle/fat
• Immediate renal excretion of parent drug
• Lack of protein binding
• Rapid biliary secretion as unchanged drug

Correct Answer: Redistribution from brain to muscle/fat

Q27. Phenobarbital’s relatively long duration is mainly due to:

• Lower lipid solubility and slower hepatic metabolism
• Sulfur at C2 increasing redistribution
• High renal clearance as unchanged drug
• Direct agonism at opioid receptors

Correct Answer: Lower lipid solubility and slower hepatic metabolism

Q28. Which structural modification at the pyrimidine core most commonly converts a barbiturate into an inactive compound?

• Removal of the 5,5-disubstituted alkyl/aryl groups
• Substitution of C2 oxygen with sulfur
• Introduction of an additional carbonyl at C3
• Methylation of a C5 alkyl chain

Correct Answer: Removal of the 5,5-disubstituted alkyl/aryl groups

Q29. Which of the following is a major clinical risk associated with barbiturate SAR that increases lipophilicity?

• Higher abuse potential and overdose risk due to rapid CNS entry
• Total absence of respiratory depression
• Inability to cross the placenta
• Resistance to all metabolic enzymes

Correct Answer: Higher abuse potential and overdose risk due to rapid CNS entry

Q30. Which site on the barbiturate structure interacts with the GABA-A receptor binding pocket most critically?

• C5 substituents that interact with a hydrophobic pocket
• N3 hydrogen only
• Pyrimidine ring nitrogen N1 exclusively
• Terminal carboxyl group (absent in barbiturates)

Correct Answer: C5 substituents that interact with a hydrophobic pocket

Q31. A barbiturate designed with increased water solubility at physiological pH would most likely have:

• Polar or ionizable groups on side chains
• Additional aromatic rings on C5
• Replacement of C2 oxygen with sulfur
• Long branched alkyl chains at C5

Correct Answer: Polar or ionizable groups on side chains

Q32. Which barbiturate is least likely to be used as an intravenous anesthetic due to slow onset?

• Phenobarbital
• Thiopental
• Methohexital
• Thiopental

Correct Answer: Phenobarbital

Q33. Which structural feature commonly increases duration of action by reducing metabolic clearance?

• Polar functionality that reduces lipophilicity and increases plasma binding
• Short branched alkyl groups increasing lipophilicity
• Thio substitution at C2 only
• Conversion to a volatile analog

Correct Answer: Polar functionality that reduces lipophilicity and increases plasma binding

Q34. Which of the following statements about barbiturate protein binding and SAR is correct?

• Increased lipophilicity generally increases plasma protein binding
• Less lipophilic compounds always bind more to proteins
• Protein binding is independent of structure
• Only ionizable barbiturates bind to plasma proteins

Correct Answer: Increased lipophilicity generally increases plasma protein binding

Q35. Which clinical property correlates with rapid redistribution of a lipophilic barbiturate?

• Short duration of hypnotic effect after IV bolus
• Persistent sedation for several days after single dose
• Absence of hepatic metabolism
• Primary renal excretion as glucuronide

Correct Answer: Short duration of hypnotic effect after IV bolus

Q36. Which of the following barbiturate examples contains a phenyl group at C5?

• Phenobarbital
• Thiopental (no phenyl)
• Methohexital (no phenyl)
• Pentobarbital (no phenyl)

Correct Answer: Phenobarbital

Q37. How does introduction of unsaturation (double bond) in a C5 substituent generally affect activity?

• Can increase lipophilicity and alter metabolic pathway, changing onset/duration
• Always abolishes activity entirely
• Converts barbiturate into a benzodiazepine
• Makes compound completely water soluble

Correct Answer: Can increase lipophilicity and alter metabolic pathway, changing onset/duration

Q38. Which assay or approach is most relevant when studying SAR effects on receptor binding?

• Radioligand binding and functional GABA-A electrophysiology
• Urine dipstick testing only
• In vitro bacterial growth inhibition
• Plasma glucose measurement

Correct Answer: Radioligand binding and functional GABA-A electrophysiology

Q39. Conjugation reactions following oxidation of barbiturate side chains typically involve which cofactor for glucuronidation?

• UDP‑glucuronic acid (UDPGA)
• NADH
• FAD
• S‑adenosylmethionine (SAM)

Correct Answer: UDP‑glucuronic acid (UDPGA)

Q40. Which structural change would most likely reduce the ability of a barbiturate to cross the placenta?

• Increased polarity and ionizable groups
• Increased lipophilicity
• Addition of a thiocarbonyl at C2
• Conversion to a gas

Correct Answer: Increased polarity and ionizable groups

Q41. Which SAR principle explains why methohexital induces anesthesia faster than phenobarbital?

• Methohexital is more lipophilic and rapidly enters the brain
• Methohexital is less lipophilic and slower to enter brain
• Phenobarbital is a thiobarbiturate while methohexital is not
• Phenobarbital is not metabolized

Correct Answer: Methohexital is more lipophilic and rapidly enters the brain

Q42. Which of the following best describes the relationship between barbiturate molecular size and BBB permeability?

• Smaller, more lipophilic molecules cross the BBB more readily
• Larger molecules always cross the BBB faster
• Molecular size has no effect on BBB permeability
• Only charged large molecules cross easily

Correct Answer: Smaller, more lipophilic molecules cross the BBB more readily

Q43. In drug design, replacing a C5 alkyl hydrogen with a hydroxyl tends to:

• Decrease lipophilicity and may prolong duration by slowing brain entry
• Increase lipophilicity and speed onset
• Convert the drug to a volatile anesthetic
• Make the drug inert to metabolism

Correct Answer: Decrease lipophilicity and may prolong duration by slowing brain entry

Q44. Which barbiturate property most increases the risk of accumulation and prolonged sedation in the elderly?

• High lipid solubility with slow hepatic clearance
• Ultra‑short acting redistribution profile
• Rapid renal excretion of unchanged drug
• Complete lack of plasma protein binding

Correct Answer: High lipid solubility with slow hepatic clearance

Q45. Which substitution pattern is characteristic of many anticonvulsant barbiturates?

• One small alkyl and one aryl substituent at C5 (e.g., 5-ethyl-5-phenyl)
• No substituents at C5
• Only sulfur at N1
• Multiple hydroxyl groups on pyrimidine ring

Correct Answer: One small alkyl and one aryl substituent at C5 (e.g., 5-ethyl-5-phenyl)

Q46. Which structural change is most likely to increase urinary excretion of unchanged barbiturate?

• Adding ionizable polar groups to enhance renal elimination
• Increasing lipophilicity to favor tissue sequestration
• Replacing carbonyls with thiocarbonyls only
• Attaching aromatic rings to increase plasma binding

Correct Answer: Adding ionizable polar groups to enhance renal elimination

Q47. Which clinical property is most directly affected by rapid hepatic metabolism of barbiturate side chains?

• Shorter duration of action
• Higher oral bioavailability
• Increased potency at GABA-A
• Inability to cross BBB

Correct Answer: Shorter duration of action

Q48. Which of the following structural analogs would you predict to have the fastest brain penetration?

• Small, highly lipophilic 5,5-disubstituted thiobarbiturate
• Large, polar 5,5-disubstituted oxybarbiturate
• Unsubstituted barbituric acid
• Barbiturate conjugated to glucuronic acid

Correct Answer: Small, highly lipophilic 5,5-disubstituted thiobarbiturate

Q49. Which clinical interaction is a consequence of barbiturate induction of hepatic enzymes?

• Reduced effectiveness of oral anticoagulants and oral contraceptives
• Increased plasma levels of drugs metabolized by CYP inhibited by barbiturates
• Immediate potentiation of insulin action
• Marked reduction of renal excretion of all drugs

Correct Answer: Reduced effectiveness of oral anticoagulants and oral contraceptives

Q50. In SAR terms, which design strategy would most likely produce a safer, longer‑acting anticonvulsant barbiturate?

• Introduce less lipophilic polar substituents at C5 to slow brain entry and metabolism
• Maximize lipophilicity to ensure ultra‑rapid CNS entry
• Replace the pyrimidine core with a benzene ring
• Remove both C5 substituents to reduce activity

Correct Answer: Introduce less lipophilic polar substituents at C5 to slow brain entry and metabolism

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