histamine and antihistaminics

Compare and Contrast: Conventional vs. Second-Generation Antihistaminics

Chemistry, BBB crossing, receptor selectivity, CNS effects, antichoinergic side effects, duration of action, anti allergic mechanisms

Chemistry Conventional (First Generation)

Highly lipid-soluble

Chemistry Second-Generation Antihistaminics

High water solubility / ionized state

BBB Crossing Conventional (First Generation)

Readily crosses the blood-brain barrier

BBB Crossing Second-Generation Antihistaminics

Minimal to no crossing (poor penetration)

Receptor Selectivity Conventional (First Generation)

Non-selective; blocks H1, muscarinic, alpha-adrenergic, and 5-HT receptors

Receptor Selectivity Second-Generation Antihistaminics

Highly selective for peripheral $H_1$ receptors

Conventional (First Generation) CNS Effects

Marked sedation, drowsiness, psychomotor impairment

Second-Generation Antihistaminics CNS Effects

Non-sedating or minimal sedation

Anticholinergic Side Effects Second-Generation Antihistaminics

Absent or negligible

Anticholinergic Side Effects Conventional (First Generation)

Common (dry mouth, blurred vision, urinary retention)Common (dry mouth, blurred vision, urinary retention)

Duration of Action Conventional (First Generation)

Short-acting (4–6 hours)

Duration of Action Second-Generation Antihistaminics

Long-acting (12–24 hours)Long-acting (12–24 hours)

Anti-allergic mechanisms Second-Generation Antihistaminics

Also inhibits late-phase allergic reaction (mast cell stabilization, ↓ leukotrienes)

Anti-allergic mechanisms Conventional (First Generation)

Only blocks H1 receptor mediated actions

Non-Sedative Antihistaminics Enumeration (Examples)

• Fexofenadine (Active metabolite of terfenadine)

• Loratadine

• Desloratadine

• Cetirizine (Mildly sedating at higher doses)

• Levocetirizine

• Mizolastine

• Ebastine

• Rupatadine (Also possesses PAF antagonist activity)

Non-Sedative Antihistaminics

Advantages over Conventional Antihistaminics

• No Psychomotor Impairment: Does not interfere with driving, operating machinery, or academic performance due to minimal CNS penetration.

• Devoid of Anticholinergic Side Effects: No distressing dry mouth, urinary hesitancy, or blurred vision.

• Longer Duration of Action: Most are given once daily, which significantly improves patient compliance.

• Additional Anti-allergic Properties: Inhibits release of inflammatory mediators (PAF, LT-C4) from mast cells/basophils at therapeutic concentrations.

• No Minimal Cumulative Sedation: Safe for long-term maintenance therapy.

Two Principal Indications Non-Sedative Antihistaminics

Allergic Rhinitis

Chronic Urticaria

Allergic Rhinitis Non-Sedative Antihistaminics

Effective for both perennial and seasonal allergic rhinitis; reduces rhinorrhea, sneezing, and ocular itching.

Chronic Urticaria Non-Sedative Antihistaminics

Provides symptomatic relief from itching, wheals, and erythema without causing daytime drowsiness.

Classification of H1 Antihistaminics

Conventional (First-Generation) Antihistaminics

Second-Generation (Non-Sedative) Antihistaminics

Conventional (First-Generation) Antihistaminics

Highly Sedating

Moderately Sedating

Mildly Sedating

Conventional (First-Generation) Antihistaminics Highly Sedating

Promethazine, Diphenhydramine, Hydroxyzine

Conventional (First-Generation) Antihistaminics Moderately Sedating

Pheniramine, Cyproheptadine, Meclizine

Conventional (First-Generation) Antihistaminics Mildly Sedating

Chlorpheniramine, Dexchlorpheniramine, Triprolidine.

Second-Generation (Non-Sedative)

Fexofenadine, Loratadine, Desloratadine, Cetirizine, Levocetirizine, Azelastine, Rupatadine, Mizolastine

Clinical Uses of H1 Antihistaminics

1. Allergic Disorders (Primary Indication)

2. Motion Sickness and Vertigo

3. Pre-Anesthetic Medication

4. Antitussive / Common Cold Formulations

5. Appetite Stimulation

Adverse Effects of H1 Antihistaminics

CNS effects

Anticholinergic effects

GI Distress

CVS toxicity

Allergic Disorders (Primary Indication)

• Conditions: Allergic rhinitis, seasonal hay fever, urticaria, dermographism, insect bites, and drug rashes.

• Clinical Value: Highly effective against sneezing, rhinorrhea, and intense itching.

• Selection: Second-generation agents (e.g., Cetirizine, Fexofenadine) are preferred due to a lack of sedation.

• Note: Ineffective in bronchial asthma because mediators like leukotrienes (LTB4, LTC4, LTD4) and PAF play a dominant role, not histamine.

Motion Sickness and Vertigo

• Drugs: Promethazine, Diphenhydramine, Meclizine.

• Mechanism: Blockade of central H1 and muscarinic receptors in the vestibular apparatus and vomiting center.

• Administration: Must be taken prophylactically 30 minutes before starting the journey.

Pre-Anesthetic Medication

• Drug: Promethazine (given i.m.).

• Clinical Value: Exploits its triple action: sedative (calms the patient), antiemetic (prevents post-operative vomiting), and anticholinergic (reduces salivary and respiratory secretions).

Antitussive / Common Cold Formulations

• Drugs: Chlorpheniramine, Diphenhydramine.

• Mechanism: First-generation agents are added to cough syrups. Their anticholinergic property dries up a running nose (reduces rhinorrhea), and their sedative action suppresses the central cough reflex.

Appetite Stimulation

• Drug: Cyproheptadine.

• Mechanism: Promotes weight gain by blocking 5-HT2A receptors in the satiety center of the hypothalamus.

Central Nervous System (CNS) Effects

• Sedation and Drowsiness: Most common side effect of first-generation agents due to high lipid solubility and blood-brain barrier (BBB) penetration.

• Psychomotor Impairment: Delayed reaction time, motor incoordination, and impaired concentration.

  • Exam Warning: Patients must be advised not to drive or operate heavy machinery while on conventional antihistaminics.

• Paradoxical Excitation: Restlessness, tremors, and insomnia can occur in children, especially during an overdose.

Anticholinergic (Atropine-like) Side Effects

Seen prominently with first-generation drugs due to competitive blockade of muscarinic receptors:

• Dryness of mouth, throat, and nasal passages.

• Blurring of vision (loss of accommodation due to mydriasis).

• Urinary retention (highly dangerous and contraindicated in elderly males with Benign Prostatic Hyperplasia).

• Constipation.

Gastrointestinal (GI) Distress

Nausea, vomiting, epigastric pain, and altered bowel habits. (Can be minimized if the drug is taken with meals).

Cardiovascular System (CVS) Toxicity

• Cardiac Arrhythmias (Torsades de pointes): Older second-generation agents (Terfenadine, Astemizole) blocked myocardial delayed rectifier K+ channels, leading to QT prolongation.

• This occurred severely when combined with CYP3A4 inhibitors (e.g., Erythromycin, Ketoconazole) that halted their metabolism.

  • Note: Terfenadine and Astemizole are now banned. Modern options like Fexofenadine and Loratadine are structurally safe.

Antihistaminics are primarily classified into two main generations based on their ability to cross the blood-brain barrier (BBB) and cause central adverse effects.

First-Generation (Conventional / Sedative Agents)

Second-Generation (Non-Sedative Agents)

Four Clinical Uses (Indications)

Allergic disorders

Motion sickness and vertigo

Pre anesthetic medication

Antitussive and common cold formulations