Histamine & Antihistamines

Histamine is a classic autacoid ("local hormone") synthesised, stored, and released locally to act on H1–H4 receptors. For NEET PG, the high-yield axis is: synthesis from histidine, H1 vs H2 receptor effects, the generational divide between sedating and non-sedating H1 blockers, and the role of H2 blockers in acid-peptic disease.

Histamine: synthesis, storage & metabolism

Histamine is a basic amine formed from the amino acid L-histidine by the enzyme histidine decarboxylase (requires pyridoxal phosphate / vitamin B6 as cofactor). It is widely distributed but concentrated in:

• Mast cells (skin, lung, GI mucosa) and basophils — the main "preformed" pool, stored in granules complexed with heparin and acidic proteins.
• Enterochromaffin-like (ECL) cells of the gastric mucosa — drive acid secretion.
• Histaminergic neurons in the tuberomammillary nucleus of the posterior hypothalamus — regulate wakefulness/arousal (why H1 blockers crossing the blood–brain barrier cause sedation).

Metabolism proceeds by two routes: histamine-N-methyltransferase (converts to N-methylhistamine) and diamine oxidase / histaminase (oxidative deamination). The major urinary metabolite is imidazole acetic acid.

High-yield: Histidine → (histidine decarboxylase, B6 cofactor) → Histamine. Storage is greatest in mast cells and basophils. Histaminergic neurons sit in the tuberomammillary nucleus.

Triggers of histamine release

• Immunological (Type I hypersensitivity): allergen cross-links IgE on mast cells → degranulation. Basis of urticaria, anaphylaxis, allergic rhinitis.
• Chemical/drug-induced (non-immunological): morphine, d-tubocurarine, vancomycin (red-man syndrome), atracurium, polymyxin B, radiocontrast displace histamine directly.
• Physical: trauma, cold, venoms.

Histamine receptors & physiological effects

There are four G-protein-coupled receptors. The first two dominate exam questions.

Receptor	G-protein / 2nd messenger	Key locations	Major effects
H1	Gq → ↑IP3/DAG, ↑Ca²⁺	Smooth muscle, endothelium, CNS, sensory nerves	Bronchoconstriction, ↑vascular permeability (wheal), pruritus & pain, intestinal contraction, wakefulness, vasodilatation (NO)
H2	Gs → ↑cAMP	Gastric parietal cells, heart, uterus, mast cells	Gastric acid secretion, +ve chronotropy/inotropy, vasodilatation
H3	Gi → ↓cAMP	Presynaptic CNS nerve terminals (autoreceptor)	Inhibits histamine and other neurotransmitter release
H4	Gi → ↓cAMP	Bone marrow, eosinophils, mast cells	Chemotaxis, immunomodulation (target in pruritus research)

The "Triple Response of Lewis"

Intradermal histamine produces, in sequence:

1. Red spot (localised vasodilatation, capillaries) — within seconds.
2. Flare (spreading redness via axon reflex, arteriolar dilatation).
3. Wheal (oedema from increased venular permeability).

High-yield: The flare of the triple response is mediated by an axon reflex and is abolished by prior anaesthesia/nerve section. Red spot + wheal are direct H1 effects.

Cardiovascular and other effects

• Vasodilatation (H1 rapid + H2 sustained) → fall in BP; large doses cause flushing, headache, hypotension.
• Heart: H2 → tachycardia and increased force; H1 → slows AV conduction.
• Bronchi: H1 bronchoconstriction (marked in asthmatics).
• Gastric secretion: H2 → potent stimulation of HCl, pepsin and intrinsic factor. Histamine is the final common potentiator of acid secretion (acetylcholine and gastrin also act partly via ECL-cell histamine release).
• Triple gastric stimulants: histamine, gastrin, acetylcholine — all increase parietal-cell acid; blocking H2 dampens responses to all three.

H1 antihistamines (H1 receptor inverse agonists)

H1 blockers are competitive, reversible inverse agonists at the H1 receptor — they stabilise the inactive receptor conformation. They do NOT block histamine release; they antagonise its downstream effects. Conventionally divided into first- and second-generation agents.

First-generation (sedating) H1 antagonists

These are lipophilic, cross the BBB, and have substantial anticholinergic, anti-α-adrenergic, antiserotonergic and local anaesthetic actions.

• Examples: diphenhydramine, dimenhydrinate, promethazine, chlorpheniramine (chlorphenamine), hydroxyzine, cyclizine, cinnarizine, pheniramine.
• Sedation (most marked with diphenhydramine, promethazine; least with chlorpheniramine).
• Antiemetic / anti-motion-sickness: promethazine, dimenhydrinate, cyclizine, cinnarizine.
• Anticholinergic: dry mouth, blurred vision, urinary retention, constipation, tachycardia — caution in BPH, glaucoma.

Second-generation (non-sedating) H1 antagonists

Poorly cross the BBB (less lipophilic, P-glycoprotein substrates) → minimal sedation and negligible anticholinergic effect.

• Examples: cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, bilastine, ebastine, rupatadine, mizolastine.
• Cetirizine is a metabolite of hydroxyzine; fexofenadine is the active metabolite of terfenadine; desloratadine of loratadine; levocetirizine is the active enantiomer of cetirizine.
• Long half-lives → once-daily dosing.

High-yield: Terfenadine and astemizole were WITHDRAWN because they block cardiac IKr (hERG) potassium channels → QT prolongation and torsades de pointes, especially with CYP3A4 inhibitors (ketoconazole, erythromycin) or grapefruit juice. Their safe successors are fexofenadine and desloratadine respectively.

Feature	First-generation	Second-generation
BBB penetration	High → sedating	Low → non-sedating
Anticholinergic effects	Marked	Minimal/absent
Duration	Short (4–6 h)	Long (12–24 h)
Antiemetic/motion-sickness use	Yes (promethazine, cyclizine)	No
QT-prolongation risk	Low	Terfenadine/astemizole (withdrawn)
Examples	Diphenhydramine, chlorpheniramine, promethazine, hydroxyzine	Cetirizine, loratadine, fexofenadine

Mnemonic for sedating first-gen "DPC-H": Diphenhydramine, Promethazine, Chlorpheniramine, Hydroxyzine.

Pharmacokinetics & interactions

• Most are well absorbed orally; first-gen are hepatically metabolised (CYP), second-gen variably (fexofenadine is largely unmetabolised, renally/biliary excreted).
• First-gen potentiate CNS depressants (alcohol, benzodiazepines, opioids).
• Acute overdose of first-gen, paradoxically in children, causes CNS excitation, convulsions, fixed dilated pupils, flushed face, fever — an atropine-like (anticholinergic) toxidrome.

H1 blockers: clinical uses

1. Allergic rhinitis & conjunctivitis (hay fever): second-gen oral agents first line; intranasal azelastine. Most effective for sneezing, rhinorrhoea, itch (less so for nasal blockage — add intranasal steroid).
2. Urticaria & angio-oedema: non-sedating H1 antagonists are first-line; dose can be uptitrated 4-fold in chronic spontaneous urticaria. Add H2 blocker or omalizumab if refractory.
3. Atopic/contact dermatitis pruritus: sedating agents at night (hydroxyzine).
4. Motion sickness & vestibular disorders: hyoscine (scopolamine) is most effective; among antihistamines — promethazine, dimenhydrinate, cyclizine, cinnarizine. Take before travel.
5. Antiemetic: promethazine, doxylamine + pyridoxine for nausea/vomiting of pregnancy (drug of choice).
6. Common cold: first-gen for their drying anticholinergic action (symptomatic only).
7. Premedication & sedation: promethazine (sedative + antiemetic + anticholinergic); also part of "lytic cocktail."
8. Acute allergic reactions/anaphylaxis: adjunct only — chlorpheniramine/diphenhydramine IV. Adrenaline is the drug of choice; antihistamines do NOT replace it.
9. Parkinsonism / drug-induced dystonia: diphenhydramine (anticholinergic).

High-yield: In anaphylaxis, the drug of choice is intramuscular adrenaline (0.5 mg, 1:1000, anterolateral thigh). Antihistamines and steroids are second-line adjuncts and never delay adrenaline.

High-yield: Cyproheptadine (H1 + antiserotonergic) is used for carcinoid-related diarrhoea, cold urticaria, appetite stimulation, and serotonin syndrome.

H2 antihistamines (H2 receptor blockers)

H2 blockers competitively inhibit histamine at gastric parietal-cell H2 receptors → reduce basal and stimulated (food, gastrin, vagal) acid secretion, with greatest effect on nocturnal acid. They reduce both acid volume and pepsin.

• Examples: cimetidine, ranitidine, famotidine, nizatidine, roxatidine.
• Potency: famotidine > ranitidine > cimetidine.

Clinical uses

• Peptic ulcer disease, GERD, Zollinger–Ellison syndrome (high dose), stress-ulcer prophylaxis, dyspepsia. Largely superseded by proton pump inhibitors (more potent, longer-lasting acid suppression).

Cimetidine — the exam favourite for adverse effects

Adverse effect	Mechanism
Gynaecomastia, galactorrhoea, ↓libido, impotence	Anti-androgenic + ↑prolactin
CYP450 inhibition → ↑warfarin, phenytoin, theophylline, diazepam levels	Potent enzyme inhibitor
Confusion (elderly, renal failure)	CNS penetration
↓Creatinine clearance (apparent)	Inhibits tubular creatinine secretion

High-yield: Cimetidine causes gynaecomastia (anti-androgen) and is a potent CYP450 inhibitor. Ranitidine and famotidine do NOT have these effects — preferred when drug interactions matter.

High-yield (recent regulatory): Ranitidine was withdrawn worldwide after detection of the carcinogenic nitrosamine impurity NDMA. Famotidine is the favoured H2 blocker today.

H2 blockers vs Proton pump inhibitors

Feature	H2 blockers	PPIs
Target	Parietal-cell H2 receptor	H⁺/K⁺-ATPase (final step)
Acid suppression	Moderate; best nocturnal	Profound; best post-prandial
Tolerance	Develops over days	No
Onset	Rapid	Needs activation in acid
Use today	On-demand dyspepsia	First line for PUD/GERD

Approach to the allergic patient (stepwise flow)

Identify allergen/trigger → avoid exposure → second-generation oral H1 antagonist (first line) → add intranasal/topical corticosteroid (for rhinitis) or uptitrate H1 dose ×4 (for chronic urticaria) → add H2 blocker / leukotriene modifier → omalizumab or short systemic steroid for refractory disease.

For acute anaphylaxis: Recognise → IM adrenaline immediately → airway/oxygen + IV fluids → IV antihistamine + hydrocortisone as adjuncts → observe for biphasic reaction.

Complications & cautions

• First-gen sedation/impaired psychomotor skills — avoid in drivers, machine operators, and combine cautiously with alcohol.
• Anticholinergic load — avoid in elderly (falls, confusion), glaucoma, BPH.
• Cardiotoxicity — historic terfenadine/astemizole torsades; cetirizine/levocetirizine considered safest in pregnancy among second-gen (loratadine also acceptable).
• Paradoxical excitation/convulsions in children with first-gen overdose.
• Doxylamine + pyridoxine is the only US-FDA-approved drug for nausea/vomiting of pregnancy — safe.

Key differentials / "do not confuse"

• H1 vs H2 effects: bronchoconstriction, wheal, itch, sedation = H1; gastric acid + cardiac stimulation = H2.
• Sedating vs non-sedating divide is purely BBB penetration, not potency.
• Antihistamine vs mast-cell stabiliser: sodium cromoglicate/nedocromil prevent degranulation (prophylaxis), they are NOT receptor blockers.
• Antihistamine vs adrenaline in anaphylaxis — adrenaline is physiological antagonist and life-saving; antihistamine is adjunct.

Recently asked / exam angle

• "Enzyme converting histidine to histamine" → histidine decarboxylase (B6 cofactor).
• "Histaminergic neurons are located in" → tuberomammillary nucleus of posterior hypothalamus.
• "Antihistamine causing gynaecomastia + enzyme inhibition" → cimetidine.
• "Antihistamine withdrawn due to torsades/QT prolongation" → terfenadine, astemizole.
• "Active metabolite of terfenadine / of hydroxyzine / of loratadine" → fexofenadine / cetirizine / desloratadine.
• "Drug of choice for motion sickness" → hyoscine (scopolamine); among antihistamines → promethazine/cinnarizine.
• "Antihistamine used in serotonin syndrome / carcinoid / appetite stimulation" → cyproheptadine.
• "H2 blocker withdrawn due to NDMA carcinogen" → ranitidine.
• "Drug of choice in anaphylaxis" → adrenaline IM.
• "Final common mediator of gastric acid secretion" → histamine (via H2).
• "Triple response flare is mediated by" → axon reflex.

Rapid revision

1. Histamine = histidine → histidine decarboxylase (B6); metabolite = imidazole acetic acid.
2. Stored mainly in mast cells & basophils; CNS source = tuberomammillary nucleus.
3. H1 = Gq (smooth muscle, itch, sedation); H2 = Gs/cAMP (gastric acid, heart); H3 = presynaptic autoreceptor; H4 = immune cells.
4. Triple response of Lewis: red spot → flare (axon reflex) → wheal.
5. First-gen H1 (diphenhydramine, promethazine, chlorpheniramine, hydroxyzine): sedating + anticholinergic + antiemetic.
6. Second-gen H1 (cetirizine, loratadine, fexofenadine): non-sedating, long-acting, first line for rhinitis & urticaria.
7. Terfenadine & astemizole withdrawn → QT prolongation / torsades (hERG block); replaced by fexofenadine & desloratadine.
8. Cimetidine = gynaecomastia + potent CYP450 inhibitor; famotidine/ranitidine spare these.
9. Ranitidine withdrawn → NDMA carcinogen; famotidine now preferred H2 blocker.
10. H2 blockers act on parietal-cell H2; PPIs (final-step ATPase) are more potent and first line for PUD/GERD.
11. Anaphylaxis: adrenaline IM is DOC; antihistamines/steroids are adjuncts only.
12. Cyproheptadine (H1 + anti-5HT) = carcinoid diarrhoea, cold urticaria, serotonin syndrome, appetite stimulation; doxylamine+pyridoxine = nausea/vomiting of pregnancy.