Antihistamines: H1 and H2 Blockers

## Histamine Receptors

Histamine is a biogenic amine stored in mast cells, basophils, enterochromaffin-like (ECL) cells, and histaminergic neurons. It acts through four receptor subtypes:

- **H1** -- Smooth muscle contraction, vasodilation, increased vascular permeability, pruritus. Mediates allergic symptoms.
- **H2** -- Gastric acid secretion from parietal cells. Also has cardiac effects (positive chronotropy and inotropy).
- **H3** -- Presynaptic autoreceptor in the CNS, modulates neurotransmitter release. Investigational target for narcolepsy.
- **H4** -- Found on immune cells (eosinophils, mast cells). Investigated for chronic inflammatory conditions.

## First-Generation H1 Antihistamines

Diphenhydramine, chlorpheniramine, hydroxyzine, promethazine, and cyproheptadine cross the blood-brain barrier readily, producing significant CNS effects. They are inverse agonists at H1 receptors (stabilize the inactive receptor conformation rather than simply blocking histamine).

**Clinical uses:** Allergic rhinitis, urticaria, anaphylaxis (adjunct), motion sickness (dimenhydrinate, meclizine), insomnia (diphenhydramine, doxylamine), nausea/vomiting (promethazine), anxiety (hydroxyzine), appetite stimulation (cyproheptadine).

**Side effects:** Sedation (the most significant limitation), anticholinergic effects (dry mouth, urinary retention, constipation, blurred vision, tachycardia), weight gain, QTc prolongation (especially diphenhydramine at high doses). Avoid in elderly patients due to anticholinergic burden and fall risk (Beers Criteria).

## Second-Generation H1 Antihistamines

Cetirizine, loratadine, fexofenadine, desloratadine, levocetirizine, and bilastine were designed to minimize CNS penetration by being substrates of P-glycoprotein efflux pumps at the blood-brain barrier and having reduced lipophilicity.

**Key differences:**
- **Fexofenadine** -- Least sedating, no cardiac effects. Does not cross BBB.
- **Cetirizine** -- Most potent H1 blocker but causes mild sedation in 10-15% of patients at standard doses.
- **Loratadine** -- Prodrug converted to desloratadine. Non-sedating at recommended doses. Available OTC.

Second-generation agents are first-line for allergic rhinitis and chronic urticaria. Guidelines recommend up to 4x standard dosing for refractory chronic urticaria before escalating to omalizumab.

## H2 Receptor Antagonists

Famotidine, ranitidine (withdrawn 2020 due to NDMA contamination), cimetidine, and nizatidine competitively block H2 receptors on gastric parietal cells, reducing basal and meal-stimulated acid secretion by 60-70%.

**Uses:** GERD (mild), peptic ulcer disease (healing and maintenance), stress ulcer prophylaxis, and as adjuncts to H1 antihistamines in acute allergic reactions and anaphylaxis.

**Famotidine** is the preferred H2 blocker -- effective, safe, and free of the drug interactions that limited cimetidine (CYP inhibition affecting warfarin, theophylline, phenytoin) and the antiandrogenic effects (gynecomastia, impotence) cimetidine caused.

PPIs have largely supplanted H2 blockers for acid suppression, but H2 blockers retain utility for on-demand heartburn relief, nighttime acid breakthrough (bedtime H2 blocker added to PPI), and patients preferring intermittent over continuous acid suppression.

## H1 + H2 Combination in Allergic Reactions

In severe urticaria and anaphylaxis management, combining H1 and H2 blockers (e.g., diphenhydramine + famotidine IV) provides more complete histamine blockade than either alone. H2 receptors on vascular smooth muscle contribute to histamine-mediated vasodilation, and blocking them augments the hemodynamic benefit.

## Key Takeaways

- Second-generation H1 antihistamines are first-line for allergic conditions -- effective with minimal sedation.
- Avoid first-generation antihistamines in elderly patients due to anticholinergic and sedation risks.
- Famotidine is the H2 blocker of choice -- cimetidine's drug interactions make it obsolete.
- Combining H1 + H2 blockers in anaphylaxis provides additive benefit beyond H1 blockade alone.