Antihistamines

Definition and Classification

Antihistamines are pharmacological agents that inhibit the effects of histamine, a biologically active compound involved in allergic reactions, gastric acid secretion, inflammation, and neurotransmission

These drugs are broadly classified based on the histamine receptor subtype they target and their generation

Main Classes

H1-receptor antagonists (used for allergy, urticaria, rhinitis, motion sickness)

H2-receptor antagonists (used for acid reflux and peptic ulcer disease)

Other: selective H3 and H4 receptor modulators under investigation

This profile focuses on H1-antihistamines

H1-ANTIHISTAMINES

Generations and Characteristics

First-Generation H1-Antihistamines

Cross the blood-brain barrier

Cause significant sedation and anticholinergic side effects

Shorter half-life; multiple daily doses needed

Examples: diphenhydramine, chlorpheniramine, hydroxyzine, promethazine, clemastine, cyproheptadine, dimenhydrinate

Second-Generation H1-Antihistamines

More selective for peripheral H1 receptors

Less sedating due to limited CNS penetration

Longer half-life; once-daily dosing common

Examples: loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, bilastine, rupatadine

Mechanism of Action

Antihistamines competitively antagonize histamine at the H1 receptor

This prevents histamine-induced symptoms such as vasodilation, increased capillary permeability, smooth muscle contraction, and sensory nerve stimulation

Some may act as inverse agonists, stabilizing the inactive form of the H1 receptor

First-generation drugs also have off-target effects: anticholinergic, antiadrenergic, and serotonergic receptor binding

Indications

Allergic Conditions

Allergic rhinitis (seasonal and perennial)

Urticaria (acute and chronic spontaneous)

Allergic conjunctivitis

Atopic dermatitis (as adjunctive therapy)

Anaphylaxis (as supportive therapy after epinephrine)

Insect bite reactions

Food allergy symptoms (not primary treatment)

Non-Allergic Uses

Motion sickness (diphenhydramine, promethazine, dimenhydrinate)

Nausea and vomiting (promethazine)

Vertigo (meclizine, cinnarizine)

Sleep aid (diphenhydramine, hydroxyzine, doxylamine)

Pruritus of various causes

Migraine prophylaxis (cyproheptadine)

Parkinsonism and extrapyramidal symptoms (diphenhydramine)

Sedation in preoperative care (hydroxyzine)

Dosage and Administration

Varies widely by drug, patient age, and indication

Typically oral tablets, syrups, or capsules

Topical forms available (diphenhydramine cream)

Parenteral forms used in emergency or inpatient care (e.g. promethazine IM/IV)

Example Doses

Diphenhydramine: 25–50 mg every 4–6 hours (max 300 mg/day)

Cetirizine: 10 mg once daily

Loratadine: 10 mg once daily

Fexofenadine: 120–180 mg once daily

Hydroxyzine: 25–50 mg up to 4 times daily

Promethazine: 12.5–25 mg every 4–6 hours

Pediatric Doses

Lower doses based on weight and age

Some second-generation antihistamines (cetirizine, loratadine) are approved for infants ≥6 months

First-generation antihistamines should be avoided in infants and used cautiously in young children

Pharmacokinetics

Absorption: rapid oral absorption

Onset: varies; 15–60 minutes for oral agents

Duration: longer in second-generation drugs (up to 24 hours)

Metabolism: hepatic, primarily via CYP450 enzymes (especially CYP3A4 and CYP2D6)

Excretion: renal and fecal routes

Half-life: short in first-generation agents (4–6 hours), longer in second-generation (12–24 hours)

Contraindications

Known hypersensitivity to the drug or class

Neonates and premature infants (first-generation)

Narrow-angle glaucoma

Severe liver impairment (caution)

Prostatic hypertrophy (first-generation agents)

Breastfeeding (diphenhydramine, promethazine may suppress lactation)

Prolonged QT syndrome (caution with some agents like mizolastine or high-dose cetirizine)

Precautions

Use caution in elderly due to increased anticholinergic burden

Monitor for CNS depression, especially when combined with alcohol or sedatives

Avoid in activities requiring mental alertness (first-generation)

May cause paradoxical excitation in children

Caution in patients with hepatic or renal dysfunction (dose adjustments)

May mask early signs of ototoxicity when used with aminoglycosides

Adverse Effects

First-Generation

Drowsiness, sedation

Dizziness, impaired coordination

Dry mouth, blurred vision, urinary retention, constipation

Confusion, hallucinations (elderly, high doses)

Paradoxical excitation in children

QT prolongation (promethazine, diphenhydramine overdose)

Second-Generation

Generally well tolerated

Mild headache

Dry mouth

Fatigue

Drowsiness (cetirizine, levocetirizine may cause mild sedation)

Rare: rash, palpitation, hypersensitivity reactions

Serious Reactions

Anaphylaxis (rare)

Seizures (overdose or pediatric use)

Cardiac arrhythmias (high doses or interactions)

Neuroleptic malignant syndrome (promethazine, rare)

Hepatic dysfunction (with chronic use of some agents)

Drug Interactions

CNS Depressants (alcohol, benzodiazepines, opioids)

Additive sedation, increased risk of respiratory depression

MAO Inhibitors

Potentiate anticholinergic effects of first-generation agents

CYP3A4 Inhibitors (e.g. ketoconazole, erythromycin, ritonavir)

May increase serum levels of loratadine, fexofenadine, and others

Anticholinergic Drugs (tricyclics, antipsychotics, antiparkinsonian drugs)

Additive anticholinergic toxicity including delirium, constipation, urinary retention

QT-Prolonging Agents (macrolides, antifungals, antipsychotics)

May increase risk of torsades de pointes with some antihistamines

Juice Interactions

Grapefruit, apple, or orange juice may reduce bioavailability of fexofenadine

Avoid taking fexofenadine with fruit juice

Pregnancy and Lactation

Pregnancy

Generally considered safe in pregnancy, especially loratadine and cetirizine

Diphenhydramine and chlorpheniramine are used with caution

Promethazine is used for nausea/vomiting in pregnancy under guidance

Lactation

Second-generation agents preferred due to lower sedation and transfer into breast milk

Avoid high-dose or prolonged use of sedating antihistamines

Monitor infant for drowsiness or feeding difficulty

Monitoring Parameters

Symptom relief: sneezing, itching, nasal congestion, hives

Sedation or CNS effects

Urinary retention (in elderly men)

QT interval with high doses or interacting medications

Signs of hypersensitivity reactions

Counseling Points

Do not exceed recommended dose

Second-generation drugs preferred for daytime use

Avoid alcohol and CNS depressants

Take with water, not juice (especially for fexofenadine)

Inform healthcare providers about all medications taken

Topical antihistamines are for short-term use only

Store in original container away from heat and moisture

Comparative Notes

First vs Second Generation

First-generation more effective for sleep aid and acute allergic itch but cause more sedation

Second-generation better for chronic use due to fewer CNS effects and longer duration

Antihistamines vs Corticosteroids for Allergy

Antihistamines work quickly on histamine-related symptoms

Nasal corticosteroids better for long-term control of allergic rhinitis and inflammation

Dual-Action Products

Some newer agents like rupatadine or olopatadine have antihistaminic and mast-cell stabilizing activity

Intranasal azelastine is effective in allergic rhinitis with rapid onset

Examples of Combination Therapies

Antihistamine + decongestant (e.g. loratadine + pseudoephedrine)

Antihistamine + corticosteroid (e.g. fluticasone + azelastine nasal spray)

Clinical Guidance

For acute allergic reactions, first-generation agents may provide faster symptom relief

In chronic urticaria, second-generation antihistamines at higher doses may be required

In seasonal allergic rhinitis, combine with nasal corticosteroids for optimal efficacy

For sleep, avoid routine use of diphenhydramine in the elderly due to anticholinergic burden

Examples of Widely Used Antihistamines

First-Generation

Diphenhydramine

Promethazine

Chlorpheniramine

Hydroxyzine

Cyproheptadine

Doxylamine

Dimenhydrinate

Second-Generation

Loratadine

Desloratadine

Cetirizine

Levocetirizine

Fexofenadine

Bilastine

Rupatadine

Mizolastine

Ebastine

Routes of Administration

Oral tablets, syrups, capsules

Ophthalmic drops

Nasal sprays

Topical creams or gels

Intramuscular or intravenous injection in hospital settings

Regulatory Status

Available as prescription and over-the-counter depending on the country and formulation

Some countries regulate sedating antihistamines due to abuse potential (e.g. diphenhydramine)

Included in the WHO Model List of Essential Medicines under specific indications