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Antihistaminics - Complete 2nd MBBS Pharmacology (KDT-Pattern)

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1. CLASSIFICATION OF ANTIHISTAMINICS

H1 Antihistaminics (H1 Blockers)

H2 Antihistaminics

• Cimetidine, Ranitidine, Famotidine, Nizatidine (see Chapter 62 - peptic ulcer)

H3 Antihistaminics

• Pitolisant (used in narcolepsy)

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2. MECHANISM OF ACTION (MOA)

• They are more effective in preventing than reversing symptoms once established.
• First-generation agents also bind muscarinic-cholinergic, alpha-adrenergic, and serotonin receptors - hence multiple additional effects.
• Second-generation agents are made polar (e.g., by adding carboxyl groups - cetirizine is the carboxylated derivative of hydroxyzine), which prevents BBB penetration and limits CNS effects.
• Some agents (azelastine, ketotifen) also have mast cell-stabilizing effects in addition to H1 blockade.

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3. COMPARISON: CONVENTIONAL vs. SECOND GENERATION ANTIHISTAMINICS

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4. NON-SEDATIVE (SECOND GENERATION) ANTIHISTAMINICS

Enumeration

1. Fexofenadine - truly non-sedating; active metabolite of terfenadine; excreted unchanged in feces
2. Loratadine - truly non-sedating; metabolized by hepatic CYP system
3. Desloratadine - active metabolite of loratadine; truly non-sedating
4. Cetirizine - partially sedating; carboxylated hydroxyzine; excreted unchanged in urine
5. Levocetirizine - active R-enantiomer of cetirizine; partially sedating
6. Azelastine - also topical (nasal spray, ophthalmic); mast cell stabilizer
7. Olopatadine - topical ophthalmic; mast cell stabilizer
8. Acrivastine - short-acting

Advantages over 1st Generation

1. No sedation (or minimal) - do not cross the BBB due to polar/carboxylated structure
2. Longer duration of action (12-24 hours) - once daily dosing improves compliance
3. More selective for peripheral H1 receptors - fewer side effects
4. No anticholinergic effects - no dry mouth, no urinary retention, no blurred vision
5. No paradoxical excitation in children
6. Suitable for daytime use - pilots, drivers, students, skilled workers
7. No tolerance development to antiallergic effect (tachyphylaxis does not develop as readily)

Two Key Indications

1. Allergic rhinitis - drug of choice; controls sneezing, rhinorrhoea, and itching (though not nasal congestion)
2. Chronic urticaria - preferred over first generation for long-term management

Precautions

• Cetirizine/levocetirizine: Dose reduction required in renal impairment (excreted unchanged in urine); may still cause mild sedation
• Loratadine/desloratadine: Dose reduction in hepatic impairment (CYP metabolism)
• Fexofenadine: Avoid taking with grapefruit juice or antacids (reduced absorption)
• Driving/operating machinery: Even "non-sedating" agents can cause mild drowsiness in some individuals - patients should be warned
• Cardiac precaution: Older 2nd-gen agents terfenadine and astemizole (now withdrawn) caused fatal QT prolongation/torsades de pointes with CYP3A4 inhibitors (ketoconazole, erythromycin) - current agents (fexofenadine, loratadine) are safe

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5. H1 ANTIHISTAMINICS - USES (HIGH-YIELD)

1. Allergic conditions - Allergic rhinitis (drug of choice), urticaria, angioedema, allergic conjunctivitis, drug rashes, atopic dermatitis
2. Anaphylaxis - Adjunct only (NOT drug of choice - epinephrine is DOC; antihistamines cannot reverse massive histamine release quickly)
3. Motion sickness and vertigo - Diphenhydramine, dimenhydrinate, meclizine, promethazine (taken BEFORE travel; ineffective once symptoms start); meclizine also useful for vestibular vertigo
4. Nausea and vomiting - Promethazine, diphenhydramine (block central H1 and M1 receptors in vestibular and chemoreceptor pathways)
5. Pruritus - Topical/systemic (chlorpheniramine, hydroxyzine)
6. Pre-medication/sedation - Promethazine, hydroxyzine
7. Insomnia - Diphenhydramine, doxylamine (OTC sleep aids)
8. Appetite stimulation - Cyproheptadine (5-HT antagonist action; used in children with poor appetite)
9. Cough - Promethazine (combination cough syrups)
10. Common cold - Reduce rhinorrhoea, sneezing, itching; no evidence for reducing cold duration
11. Blood transfusion reactions - Premedication with chlorpheniramine
12. Serotonin syndrome - Cyproheptadine (5-HT antagonist)

Note: H1 antihistaminics are NOT indicated in bronchial asthma - histamine is only one of several mediators causing bronchoconstriction; leukotrienes, prostaglandins also contribute. Epinephrine is DOC in systemic anaphylaxis.

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6. ADVERSE EFFECTS

CNS Effects (mainly 1st generation)

• Sedation - most common; chlorpheniramine, diphenhydramine, promethazine, hydroxyzine
• Fatigue, dizziness, lack of coordination, tremors
• Paradoxical CNS stimulation in children - hyperactivity, insomnia, convulsions (diphenhydramine)
• Elderly more sensitive to CNS effects

Anticholinergic Effects (1st generation)

• Dry mouth, dry nasal passages
• Blurred vision (cycloplegia)
• Urinary retention (especially in elderly males with BPH)
• Constipation
• Tachycardia

Cardiovascular

• Terfenadine, astemizole (withdrawn): QT prolongation, torsades de pointes
• Current agents: generally safe

GI Effects

• Nausea, vomiting, epigastric distress, anorexia (or increased appetite - cyproheptadine)

Topical

• Contact dermatitis with topical diphenhydramine

Overdose (especially children)

• Hallucinations, excitement, ataxia, convulsions, deep coma, cardiorespiratory collapse

Drug Interactions

• CNS depressants + alcohol: potentiation of sedation
• MAOIs: exacerbate sedative and anticholinergic effects - AVOID combination
• CYP inhibitors (ketoconazole, erythromycin) + terfenadine/astemizole: QT prolongation (reason for withdrawal)
• Cholinesterase inhibitors (donepezil): anticholinergic H1 blockers may reduce efficacy in Alzheimer's treatment

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7. PRECAUTIONS

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Quick Summary Table for Exam

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