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Tuesday, August 19, 2025

Antihistamines


Introduction

Antihistamines are a pharmacological class of agents that antagonize or block the effects of histamine, a biogenic amine involved in a wide range of physiological and pathological processes. Histamine acts on four distinct receptor subtypes—H1, H2, H3, and H4—each mediating different biological functions. Antihistamines are therefore classified based on their receptor selectivity.

Histamine plays crucial roles in allergic responses, gastric acid secretion, neurotransmission, and immune regulation. By selectively targeting histamine receptors, antihistamines are used in the treatment of allergic disorders, anaphylaxis, peptic ulcer disease, gastroesophageal reflux, nausea, motion sickness, insomnia, and certain autoimmune and inflammatory conditions.

Classification of Antihistamines

1. H1-Receptor Antagonists (H1 Blockers)

  • Mechanism of Action: Competitively block H1 receptors, preventing histamine-induced smooth muscle contraction, vascular permeability, and pruritus.

  • Generations:

    • First-generation: Cross the blood–brain barrier (BBB), causing sedation.

    • Second-generation: More selective, less sedating, longer duration of action.

  • Generic Names:

    • First-generation: diphenhydramine, chlorpheniramine, hydroxyzine, promethazine, clemastine, meclizine, brompheniramine.

    • Second-generation: loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, acrivastine.

  • Therapeutic Uses: Allergic rhinitis, urticaria, atopic dermatitis, anaphylaxis (with epinephrine), motion sickness, nausea/vomiting, insomnia (some agents).

  • Adverse Effects: Sedation, dry mouth, blurred vision, urinary retention, constipation (anticholinergic effects).

  • Contraindications: Narrow-angle glaucoma, urinary retention, severe hepatic impairment (some agents).

2. H2-Receptor Antagonists (H2 Blockers)

  • Mechanism of Action: Competitively block H2 receptors in gastric parietal cells, inhibiting basal and stimulated gastric acid secretion.

  • Generic Names: cimetidine, ranitidine (largely withdrawn in many regions), famotidine, nizatidine.

  • Therapeutic Uses: Peptic ulcer disease, gastroesophageal reflux disease (GERD), Zollinger–Ellison syndrome, stress ulcer prophylaxis.

  • Adverse Effects: Headache, dizziness, diarrhea, rare confusion in elderly, gynecomastia and impotence (cimetidine due to antiandrogenic effects).

  • Drug Interactions: Cimetidine inhibits cytochrome P450 enzymes, raising plasma levels of warfarin, theophylline, phenytoin, and others.

  • Contraindications: Hypersensitivity, dose adjustment required in renal impairment.

3. H3-Receptor Antagonists

  • Mechanism of Action: Block presynaptic H3 receptors in the central nervous system, leading to increased release of histamine and other neurotransmitters (acetylcholine, norepinephrine, dopamine).

  • Generic Names: pitolisant, ciproxifan (research), betahistine (mixed H3 antagonist/H1 agonist properties).

  • Therapeutic Uses: Narcolepsy with cataplexy, excessive daytime sleepiness, cognitive disorders (research). Betahistine is used in Ménière’s disease.

  • Adverse Effects: Insomnia, headache, nausea, anxiety.

  • Precautions: Use cautiously in patients with psychiatric disorders or cardiac arrhythmias.

4. H4-Receptor Antagonists

  • Mechanism of Action: Block H4 receptors, which are expressed in bone marrow and leukocytes, modulating immune and inflammatory responses.

  • Generic Names: investigational agents such as toreforant, JNJ 7777120.

  • Therapeutic Uses: Under study for autoimmune disorders, chronic pruritus, asthma, inflammatory bowel disease.

  • Adverse Effects: Limited data; gastrointestinal upset and headache have been observed in trials.

  • Status: Not widely available clinically; still under investigation.

Clinical Uses of Antihistamines

  1. Allergic Conditions

    • Seasonal and perennial allergic rhinitis, conjunctivitis, urticaria, angioedema, atopic dermatitis (H1 blockers).

  2. Anaphylaxis

    • H1 blockers are used adjunctively with epinephrine and corticosteroids.

  3. Gastrointestinal Disorders

    • H2 blockers are used for GERD, peptic ulcers, Zollinger–Ellison syndrome, and prevention of stress-related mucosal bleeding.

  4. Neurological and Vestibular Disorders

    • Meclizine, promethazine, and diphenhydramine are effective for motion sickness and vertigo.

    • H3 antagonists such as pitolisant for narcolepsy.

  5. Dermatological Disorders

    • Chronic spontaneous urticaria, pruritic dermatoses.

  6. Other Uses

    • Hydroxyzine as an anxiolytic.

    • Diphenhydramine and doxylamine as sleep aids.

    • H2 blockers used as part of multimodal therapy in anaphylaxis.

Contraindications

  • Hypersensitivity to the drug or class

  • Narrow-angle glaucoma (for H1 first-generation)

  • Symptomatic prostatic hypertrophy or bladder outlet obstruction (anticholinergic effect risk)

  • Severe hepatic or renal impairment without dose adjustment (H2 blockers)

  • Pregnancy and lactation (some agents contraindicated; others require caution)

Precautions

  • Elderly patients: Risk of cognitive impairment, falls, and delirium with first-generation H1 blockers.

  • CNS depression: Enhanced sedation when combined with alcohol, benzodiazepines, or opioids.

  • Children: First-generation H1 blockers may cause paradoxical excitation.

  • Renal impairment: Adjust doses of H2 blockers and some second-generation antihistamines.

Side Effects

H1 Blockers

  • Sedation (especially diphenhydramine, hydroxyzine, promethazine)

  • Anticholinergic effects: dry mouth, constipation, urinary retention

  • Weight gain (long-term use, e.g., with cetirizine)

  • Rare: arrhythmias, seizures (overdose)

H2 Blockers

  • Headache, dizziness, diarrhea

  • Confusion in elderly (high doses, especially cimetidine)

  • Gynecomastia and impotence (cimetidine)

H3 Blockers

  • Insomnia, anxiety, headache

  • Rare: QT prolongation (pitolisant)

H4 Blockers

  • Limited data, mild GI upset and headache reported in early trials

Drug Interactions

  • H1 Blockers: Potentiation of CNS depressants (alcohol, opioids, sedatives). CYP3A4 interactions (loratadine, fexofenadine).

  • H2 Blockers: Cimetidine inhibits CYP450 isoenzymes, raising drug levels of warfarin, phenytoin, theophylline, diazepam.

  • H3 Blockers: Additive CNS stimulation with psychostimulants.

  • H4 Blockers: Still under investigation.




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