Antihistamines - Complete Pharmacology

1. Definition

2. Classification

By Receptor Type

H1 Antagonists by Generation

• Loratadine, desloratadine
• Cetirizine, levocetirizine
• Fexofenadine
• Azelastine (also available as nasal spray/eye drops)
• Bilastine, rupatadine

3. Pharmacodynamics (Mechanism of Action)

Chemistry and Receptor Binding

Effects on Physiological Systems

• H1 blockers inhibit histamine-induced bronchoconstriction and constriction of GI/uterine smooth muscle
• They block the rapid vasodilator effects mediated by H1 receptors on endothelial cells (via NO release)
• They also inhibit venous constriction in certain vascular beds

• H1 blockers strongly suppress histamine-induced edema, wheal formation, and increased capillary permeability

• Reduce the flare (axon reflex) and pruritus caused by histamine
• Cutaneous pruritus (itching) is the response most readily suppressed

• H1 receptors mediate wakefulness; blockade produces sedation, drowsiness
• At higher doses: ataxia, blurred vision, tinnitus, restlessness, paradoxical CNS excitation (especially in children)
• Antiemetic effect (especially promethazine, dimenhydrinate) via central vestibular/CTZ blockade

• Bind muscarinic receptors - causing dry mouth, urinary retention, constipation, blurred vision, tachycardia

• Some (especially terfenadine and astemizole - now withdrawn) can block cardiac hERG K⁺ channels → QT prolongation → risk of torsades de pointes

• Uniquely has potent antihistamine AND serotonin 5-HT2 receptor antagonist properties, used as an appetite stimulant

4. Pharmacokinetics

First Generation H1 Antagonists

Second Generation H1 Antagonists

H2 Antagonists (Cimetidine, Famotidine, Ranitidine)

• Oral bioavailability 40-90%; cimetidine is a potent CYP450 inhibitor (important drug interaction)
• Primarily renally excreted; dose adjustment needed in renal impairment
• Duration of action 6-12 hours (famotidine longest)

5. Indications (Clinical Uses)

H1 Antagonists

• Allergic rhinitis (seasonal and perennial) - first-line: 2nd generation preferred
• Urticaria (hives) and angioedema - acute and chronic
• Atopic dermatitis / eczema - adjunct for pruritus
• Allergic conjunctivitis - topical azelastine/olopatadine
• Anaphylaxis - adjunct to epinephrine (not first-line alone)
• Drug/food hypersensitivity reactions

• Motion sickness - dimenhydrinate, meclizine, cyclizine
• Nausea and vomiting (antiemetic) - promethazine
• Vertigo - meclizine
• Insomnia (OTC sleep aids) - diphenhydramine, doxylamine
• Preanesthetic medication / sedation - promethazine, hydroxyzine

• Appetite stimulation - cyproheptadine
• Pruritus in cholestasis or uremia
• Common cold (decongestant combinations)
• Transfusion reactions (prophylaxis)
• Prevention of contrast media reactions
• Urticaria pigmentosa (mastocytosis) - H1 + H2 combination

H2 Antagonists

• Peptic ulcer disease (duodenal and gastric)
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome
• Stress ulcer prophylaxis in ICU
• In combination with H1 blockers for refractory urticaria and anaphylaxis

6. Contraindications

Absolute/Relative Contraindications

7. Adverse Effects

First-Generation H1 Antihistamines

• Sedation, drowsiness (most common) - impairs driving, operating machinery
• Dizziness, ataxia, incoordination
• Blurred vision, tinnitus
• Paradoxical excitation in children (restlessness, insomnia, tremors, convulsions)
• Confusion and delirium in elderly (particularly high anticholinergic burden)

• Dry mouth, throat, nasal passages
• Constipation
• Urinary retention
• Blurred vision (cycloplegia/mydriasis)
• Tachycardia
• Decreased GI motility

• QT prolongation (most notably with terfenadine and astemizole - both withdrawn from markets)
• Hypotension (especially IV promethazine)

• Nausea, vomiting, anorexia, epigastric distress
• Diarrhea or constipation

• Photosensitivity (especially phenothiazines like promethazine)
• Paradoxical hypersensitivity reactions
• Hemolytic anemia, agranulocytosis (rare)
• Teratogenicity concern in first trimester (category B generally, but caution advised)

Second-Generation H1 Antihistamines

• Mild headache, fatigue (cetirizine has slightly more sedation than others)
• Dry mouth (mild)
• Rare: QT prolongation (noted with high doses of some agents)
• Weight gain with long-term use (minor)

H2 Antagonists

• Cimetidine: multiple CYP450 drug interactions, gynecomastia, impotence, confusion in elderly (crosses BBB)
• Ranitidine: withdrawn in many countries due to NDMA impurity concerns
• Famotidine: generally well-tolerated; headache, dizziness, constipation
• Thrombocytopenia (rare, class effect)
• Elevated liver enzymes (rare)

8. Side Effects (Summary by System)

Key Clinical Pearls

1. 1st gen vs 2nd gen: First-generation agents sedate because they are lipophilic and penetrate the CNS; second-generation agents (fexofenadine, loratadine, desloratadine) are peripheral-selective and essentially non-sedating.
2. Inverse agonism: Antihistamines are inverse agonists, not neutral antagonists - they actively reduce receptor activity below baseline.
3. Tachyphylaxis: Tolerance to the antiallergic effects can develop with continued use, particularly notable with first-generation agents.
4. Elderly caution: First-generation antihistamines are on the Beers Criteria as potentially inappropriate medications in older adults due to anticholinergic CNS toxicity risk.
5. Allergy skin testing: Oral H1 antihistamines must be stopped 2-7 days before skin prick testing to avoid false-negative results.
6. Cyproheptadine is unique - it acts as both an H1 blocker and a 5-HT2 antagonist, making it useful for conditions like serotonin syndrome, carcinoid-related flushing, and appetite stimulation.

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 43 (Histamine, Bradykinin, and Their Antagonists)
• Tietz Textbook of Laboratory Medicine, 7th Edition - Antihistamines section
• Kaplan and Sadock's Synopsis of Psychiatry - Histamine Antagonists section