Introduction: H1 antagonists (histamine H1 receptor antagonists) are essential in pharmacology for allergic disorders, classified as first‑generation and second‑generation agents. This topic covers classification, structure–activity relationships (SAR), mechanism of action (including inverse agonism), pharmacokinetics, adverse effects and therapeutic uses such as allergic rhinitis, urticaria, motion sickness and insomnia. Key SAR features — two aromatic rings, a linking spacer and a basic tertiary amine — determine potency, selectivity and CNS penetration. Clinical relevance includes examples (diphenhydramine, chlorpheniramine, loratadine, cetirizine, fexofenadine), metabolism (CYP interactions) and safety (sedation, anticholinergic effects, QT risk). Now let’s test your knowledge with 30 MCQs on this topic.
Q1. Which feature most characterizes first‑generation H1 antagonists compared to second‑generation agents?
- High selectivity for peripheral H1 receptors with minimal CNS effects
- Pronounced sedation and anticholinergic effects
- Long plasma half‑life and once‑daily dosing
- Strong P‑glycoprotein efflux at the blood‑brain barrier
Correct Answer: Pronounced sedation and anticholinergic effects
Q2. Which structural motif is central to the SAR of most H1 antagonists?
- A single aromatic ring with a carboxylate group
- Two aromatic rings separated by a 2–3 atom spacer and a basic tertiary amine
- A steroid nucleus with a basic side chain
- An aliphatic chain with a primary amine
Correct Answer: Two aromatic rings separated by a 2–3 atom spacer and a basic tertiary amine
Q3. Modern H1 antagonists commonly act as which of the following at the H1 receptor?
- Full agonists
- Neutral antagonists
- Partial agonists
- Inverse agonists
Correct Answer: Inverse agonists
Q4. Which of the following is a second‑generation H1 antagonist?
- Diphenhydramine
- Chlorpheniramine
- Loratadine
- Promethazine
Correct Answer: Loratadine
Q5. Terfenadine was withdrawn from the market primarily because it caused:
- Excessive sedation and coma
- Severe anticholinergic dry mouth
- QT prolongation and torsades de pointes due to hERG channel blockade
- Renal failure from crystal nephropathy
Correct Answer: QT prolongation and torsades de pointes due to hERG channel blockade
Q6. Which physicochemical property most increases CNS penetration of H1 antagonists?
- High polarity and presence of a carboxylate group
- Strong P‑glycoprotein substrate activity
- High lipophilicity and low efflux by P‑gp
- High molecular weight and multiple ionizable groups
Correct Answer: High lipophilicity and low efflux by P‑gp
Q7. Antimuscarinic side effects (dry mouth, blurred vision, urinary retention) are most associated with which class?
- Second‑generation non‑sedating H1 antagonists
- First‑generation H1 antagonists
- Monoclonal anti‑IgE antibodies
- Selective H2 receptor antagonists
Correct Answer: First‑generation H1 antagonists
Q8. Which cytochrome P450 isoenzyme commonly metabolizes many H1 antagonists?
- CYP1A2
- CYP3A4
- CYP2E1
- CYP4A11
Correct Answer: CYP3A4
Q9. Why is the basic tertiary amine important in H1 antagonist SAR?
- It confers irreversible binding to the receptor
- It ensures the drug is fully nonionized at physiological pH
- It provides ionic interaction with the receptor and influences pKa near physiological pH
- It causes covalent modification of histamine
Correct Answer: It provides ionic interaction with the receptor and influences pKa near physiological pH
Q10. Which H1 antagonist is most commonly used as an antiemetic and for motion sickness?
- Fexofenadine
- Promethazine
- Loratadine
- Desloratadine
Correct Answer: Promethazine
Q11. Which second‑generation H1 antagonist is considered least sedating in clinical practice?
- Cetirizine
- Chlorpheniramine
- Fexofenadine
- Diphenhydramine
Correct Answer: Fexofenadine
Q12. Which H1 antagonist is commonly used as an OTC sleep aid due to its sedative effects?
- Loratadine
- Fexofenadine
- Diphenhydramine
- Desloratadine
Correct Answer: Diphenhydramine
Q13. Which structural modification reduces CNS penetration and sedative potential of H1 antagonists?
- Addition of a bulky lipophilic alkyl chain
- Conversion to a zwitterionic carboxylate (polar) form
- Removal of the tertiary amine
- Introduction of a small hydrophobic methyl group
Correct Answer: Conversion to a zwitterionic carboxylate (polar) form
Q14. Compared with many first‑generation agents, second‑generation H1 antagonists typically have:
- Shorter duration of action and more frequent dosing
- Greater sedation and stronger anticholinergic effects
- Longer half‑life and once‑daily dosing
- Higher CNS accumulation and abuse potential
Correct Answer: Longer half‑life and once‑daily dosing
Q15. Orthostatic hypotension seen with some H1 antagonists is primarily due to blockade of which receptor?
- H2 histamine receptors
- Alpha‑adrenergic receptors
- Beta‑adrenergic receptors
- Muscarinic M2 receptors
Correct Answer: Alpha‑adrenergic receptors
Q16. Diphenhydramine is classified chemically as which class of H1 antagonists?
- Ethanolamines
- Piperazines
- Sulfonylureas
Correct Answer: Ethanolamines
Q17. Sedation produced by H1 antagonists results from blockade of which receptor population?
- Peripheral H1 receptors only
- Central H2 receptors
- Central H1 receptors in the brain
- Peripheral H2 receptors in vascular smooth muscle
Correct Answer: Central H1 receptors in the brain
Q18. What distinguishes an inverse agonist from a neutral antagonist at the H1 receptor?
- Inverse agonists increase basal receptor activity
- Inverse agonists stabilize the inactive receptor conformation and reduce constitutive activity
- Neutral antagonists permanently inactivate the receptor by covalent binding
- Neutral antagonists cause receptor internalization
Correct Answer: Inverse agonists stabilize the inactive receptor conformation and reduce constitutive activity
Q19. Which H1 antagonist is commonly recommended as first‑line for chronic spontaneous urticaria due to good efficacy and safety?
- Chlorpheniramine
- Cetirizine
- Promethazine
- Hydroxyzine
Correct Answer: Cetirizine
Q20. Which H1 antagonist is noted for pronounced anticholinergic activity and is often avoided in the elderly?
- Fexofenadine
- Desloratadine
- Diphenhydramine
- Loratadine
Correct Answer: Diphenhydramine
Q21. Which antihistamine was associated with fatal drug interactions when coadministered with erythromycin or ketoconazole?
- Fexofenadine
- Terfenadine
- Cetirizine
- Loratadine
Correct Answer: Terfenadine
Q22. Piperazine derivatives of H1 antagonists are characterized by:
- A steroid backbone with a tertiary alcohol
- A cyclic ring containing two nitrogen atoms
- A monosubstituted benzene with a carboxylate
- A sulfonamide linked to an aromatic amine
Correct Answer: A cyclic ring containing two nitrogen atoms
Q23. Desloratadine is best described as:
- An inactive prodrug of loratadine
- The active metabolite of loratadine with potent H1 activity
- A first‑generation sedating antihistamine
- An H2 receptor antagonist
Correct Answer: The active metabolite of loratadine with potent H1 activity
Q24. Coadministration of terfenadine with strong CYP3A4 inhibitors led to:
- Reduced antihistamine efficacy without safety concerns
- Increased formation of nonactive metabolites
- Inhibition of terfenadine metabolism causing cardiotoxicity
- Enhanced renal clearance of terfenadine
Correct Answer: Inhibition of terfenadine metabolism causing cardiotoxicity
Q25. In acute anaphylaxis, H1 antagonists are used as:
- Primary therapy to replace epinephrine
- An adjunctive therapy along with epinephrine and corticosteroids
- The only necessary therapy for airway compromise
- A contraindicated treatment
Correct Answer: An adjunctive therapy along with epinephrine and corticosteroids
Q26. A pharmacodynamic test demonstrating H1 antagonist activity is:
- Increase in histamine‑induced wheal and flare
- Suppression of histamine‑induced wheal and flare in skin tests
- Elevation of gastric acid secretion
- Prolongation of prothrombin time
Correct Answer: Suppression of histamine‑induced wheal and flare in skin tests
Q27. Which SAR modification generally increases H1 receptor affinity?
- Removing aromatic rings and replacing with aliphatic chains
- Introducing a basic tertiary amine and appropriate aromatic substituents
- Converting the tertiary amine to a quaternary ammonium permanently charged
- Adding a highly polar sulfate group to increase membrane impermeability
Correct Answer: Introducing a basic tertiary amine and appropriate aromatic substituents
Q28. Reduced sedation of fexofenadine compared with older antihistamines is largely due to:
- Greater intrinsic agonist activity at CNS H1 receptors
- Inability to bind peripheral H1 receptors
- P‑glycoprotein‑mediated efflux and polar groups limiting BBB entry
- High lipophilicity and CNS accumulation
Correct Answer: P‑glycoprotein‑mediated efflux and polar groups limiting BBB entry
Q29. Which H1 antagonist is often preferred for motion sickness prophylaxis with minimal daytime sedation?
- Meclizine
- Chlorpheniramine
- Diphenhydramine
- Promethazine
Correct Answer: Meclizine
Q30. The primary pharmacological distinction of many second‑generation H1 antagonists versus first‑generation drugs is:
- Stronger antagonism of muscarinic receptors
- Increased CNS penetration and sedation
- Reduced CNS penetration and minimal anticholinergic effects
- Irreversible covalent binding to H1 receptors
Correct Answer: Reduced CNS penetration and minimal anticholinergic effects
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