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PH2.6 | PH2.6 | Antihistamines for Allergic Rhinitis — SDL Guide — SDL Guide (Part 2)

Pharmacokinetics, Pharmacodynamics, and Adverse Effects of Antihistamines

Understanding the pharmacokinetic profile of antihistamines explains why dosing schedules differ and why certain patient groups require dose adjustment. All oral H1 antihistamines are well absorbed from the gastrointestinal tract. First-generation agents have relatively short half-lives (4–8 hours for most), requiring dosing three to four times daily, while second-generation agents are formulated as once-daily drugs due to longer half-lives (12–24 hours) and active-metabolite accumulation.

First-generation antihistamines are extensively metabolised by hepatic CYP enzymes and excreted in urine. Their most clinically significant pharmacodynamic consequence beyond H1 blockade is antimuscarinic activity: dry mouth, constipation, urinary retention (caution in benign prostatic hyperplasia), blurred vision, and tachycardia. Sedation can reach a degree equivalent to a hypnotic dose of benzodiazepine — promethazine is used deliberately as a preoperative sedative and antiemetic. CNS depression is additive with alcohol, opioids, and other sedatives — a critical drug interaction. Tolerance to sedation develops over days, but tolerance to antihistaminic effect also develops, limiting long-term utility.

Second-generation antihistamines have wider therapeutic indices. Cetirizine (10 mg once daily) may cause mild sedation in some patients, especially at higher doses; dose reduction is required in renal impairment (excreted unchanged). Loratadine (10 mg once daily) is metabolised by CYP3A4 and CYP2D6 to desloratadine; dose adjustment in severe hepatic impairment. Fexofenadine (120 mg or 180 mg once daily) is a substrate of P-glycoprotein and organic anion transporters — co-administration of grapefruit juice, apple juice, or orange juice significantly reduces its bioavailability by up to 36–73% depending on the specific juice (grapefruit ~36%, apple or orange juice up to 73%) — a clinically relevant interaction to counsel patients about. Terfenadine and astemizole (historical 2nd-gen agents) were withdrawn because of QT prolongation and fatal arrhythmias (torsades de pointes) via CYP3A4-mediated drug interactions — this reinforces why newer agents were developed to avoid cardiac risk.

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The most common ADRs by generation:
- First-gen: sedation, dry mouth, urinary retention, blurred vision, constipation, tachycardia, weight gain (cyproheptadine via antiserotonin effect), extrapyramidal effects (promethazine, high doses)
- Second-gen: generally well tolerated; mild headache, dry mouth at higher doses; cetirizine — occasional drowsiness; fexofenadine — headache, nausea; rare cardiac risk with historical 2nd-gen only

Management of Allergic Rhinitis and Common Cold

The management of allergic rhinitis is stepwise, guided by symptom severity, frequency, and patient-specific factors. The ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines, widely adopted in India, provide a rational framework for prescribing decisions.

Mild intermittent allergic rhinitis: Oral second-generation antihistamines (cetirizine, loratadine, fexofenadine, levocetirizine) are the first-line treatment. They reliably control sneezing, itching, and rhinorrhoea. Topical azelastine nasal spray provides rapid local relief and is an alternative, especially for patients who prefer topical therapy.

Moderate–severe or persistent allergic rhinitis: Intranasal corticosteroids (e.g., fluticasone furoate, mometasone, budesonide) are the most effective single agents, addressing both early and late-phase inflammatory responses. They are recommended as first-line for moderate–severe persistent disease. Oral antihistamines may be added for breakthrough sneezing/itching. The combination of intranasal corticosteroid + antihistamine is superior to either alone for nasal congestion and discharge. Intranasal decongestants (oxymetazoline, xylometazoline) provide rapid decongestion but must not be used for more than 3–5 consecutive days to avoid rhinitis medicamentosa (rebound nasal congestion due to α-adrenergic receptor downregulation). Oral decongestants (pseudoephedrine) can be used short-term but are contraindicated in hypertension, hyperthyroidism, and ischaemic heart disease.

Management of the common cold: The common cold is caused by rhinoviruses and other respiratory viruses. Antihistamines are NOT proven to reduce the duration or severity of cold symptoms in otherwise healthy adults. First-generation antihistamines (chlorpheniramine) remain widely included in combination cold products in India — the rationale being their anticholinergic drying effect on rhinorrhoea — but evidence-based guidelines do not endorse them for cold management. Antibiotics are contraindicated in uncomplicated common cold. Management is supportive: adequate hydration, rest, saline nasal irrigation, and analgesics (paracetamol, ibuprofen) for fever and myalgia. Zinc acetate lozenges started within 24 hours of symptom onset may modestly reduce duration. Vitamin C supplementation in established colds has not shown clinically meaningful benefit.

Special populations:
- Children under 2 years: no antihistamines (first-gen are particularly hazardous; risk of paradoxical excitation and respiratory depression)
- Elderly: avoid first-generation antihistamines (fall risk from sedation + anticholinergic-induced confusion — anticholinergic burden worsens cognitive impairment in those at risk of dementia)
- Pregnancy: chlorpheniramine is traditionally preferred (longest safety record); second-gen agents (loratadine, cetirizine) are considered acceptable in the 2nd and 3rd trimester but avoid in the 1st trimester
- Glaucoma / BPH: avoid all anticholinergic antihistamines (first-generation); use only second-generation