Assignment Answers - Pharmacology (14/07/2026)

Question 1: H₁ Antihistamines - Classification, Pharmacological Actions, Therapeutic Uses, and Adverse Effects

Introduction

Classification

First-Generation (Classical / Sedating) H₁ Antihistamines

Second-Generation (Non-Sedating / Atopic) H₁ Antihistamines

Pharmacological Actions

1. Sedation (CNS Depression)

• At very high toxic doses: marked stimulation, agitation, even seizures may precede coma.
• In children: excitation rather than sedation can paradoxically occur.

2. Antinausea and Antiemetic Actions

3. Antiparkinsonism Effects

4. Antimuscarinic (Anticholinergic) Actions

• Reduced secretions (useful in non-allergic rhinorrhea)
• Urinary retention
• Blurred vision
• Dry mouth, constipation, tachycardia

5. α-Adrenoceptor Blocking Actions

6. Serotonin-Blocking Actions

7. Local Anesthetic Action

8. Other Actions (Anti-inflammatory)

Therapeutic Uses

• Allergic rhinitis (hay fever): H₁ antihistamines are second-line after intranasal corticosteroids. Effective for sneezing, itching, rhinorrhea, and ocular symptoms (itchy/watery eyes). Minimally effective for nasal congestion.
• Urticaria and angioedema: Drugs of choice, especially when histamine is the primary mediator.
• Atopic dermatitis: Mainly used for their sedative effect (diphenhydramine), which reduces awareness of itching.
• Contact dermatitis and drug hypersensitivity reactions

• Scopolamine and H₁ antagonists (diphenhydramine, promethazine, meclizine, cyclizine) are the most effective agents.
• Claimed utility in Ménière's syndrome (though efficacy not firmly established).

• Doxylamine + pyridoxine (Diclegis) is FDA-approved for morning sickness.

• Used alongside epinephrine (the primary drug) in anaphylaxis to counter histamine effects.

• First-generation agents (doxylamine, diphenhydramine) are used as OTC sleep aids due to their sedative properties.

• Useful for pruritus of various causes; sedation helps reduce itching awareness.

• Promethazine as preoperative sedation and antiemetic.

Adverse Effects

• Sedation (~50% incidence with first-generation agents; only ~7% with second-generation)
• Dry mouth, urinary retention, blurred vision (anticholinergic)
• Constipation
• Tachycardia
• Impairment of cognition and psychomotor performance
• In children: paradoxical excitation, hyperactivity, insomnia, convulsions

• Postural hypotension (especially phenothiazines)
• Drug allergy (common after topical use)
• GI upset, nausea, epigastric pain

• Resembles atropine toxicity: hyperpyrexia, fixed dilated pupils, flushing, tachycardia, urinary retention, agitation, hallucinations, seizures, coma

• Terfenadine and astemizole (now withdrawn): caused potentially fatal QT prolongation and torsades de pointes, especially when combined with CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin). Mechanism: blockade of HERG (IKr) potassium channels. Both are withdrawn from the US market.

• Additive CNS depression with alcohol, sedatives, anxiolytics
• Additive anticholinergic effects with atropine, TCAs
• Grapefruit juice inhibits CYP3A4 and increases levels of susceptible antihistamines

Question 2: Short Note on Cetirizine

Introduction

Mechanism of Action (MOA)

• It has high selectivity for peripheral H₁ receptors.
• It crosses the blood-brain barrier to a limited extent (less than first-generation agents), accounting for some residual sedation. The FDA labels it as "sedating," though much less so than first-generation drugs.
• Unlike first-generation agents, cetirizine has minimal affinity for muscarinic, α-adrenergic, or dopamine receptors.
• Uniquely among second-generation agents, cetirizine also inhibits mast cell release of histamine and other inflammatory mediators - an action that may involve H₄ receptor activity and is independent of H₁ blockade. This anti-inflammatory property may contribute to its efficacy in pruritic and inflammatory allergic conditions.

Pharmacokinetics

• Oral bioavailability: ~70%; food does not affect extent of absorption (but may slow it slightly)
• Protein binding: ~93%
• Onset: Rapid; effects begin within 1 hour of oral administration
• Duration: ~24 hours; allows once-daily dosing
• Metabolism: Minimal hepatic metabolism (mainly via CYP3A4, minor)
• Excretion: Primarily renal (~70% unchanged in urine); dose reduction needed in renal impairment
• Half-life: ~8-10 hours

Uses

1. Seasonal and perennial allergic rhinitis - relieving sneezing, rhinorrhea, nasal itching, and ocular symptoms
2. Chronic idiopathic urticaria
3. Allergic conjunctivitis
4. Atopic dermatitis / pruritus (particularly its mast cell inhibitory action is beneficial)
5. Acute urticaria / allergic skin reactions
6. Off-label: Exercise-induced urticaria, cold urticaria

Adverse Effects

• Somnolence/drowsiness (most common; ~10-14%; FDA-labeled as sedating but less than first-generation agents)
• Fatigue
• Dry mouth (mild; less than first-generation agents)
• Headache
• Pharyngitis, dizziness
• Rare: Urinary retention, blurred vision
• In renal impairment or overdose, greater sedation can occur
• Generally safe in pregnancy (Category B); excreted in breast milk - use with caution in nursing mothers

Dosing

• Adults and children ≥12 years: 10 mg once daily
• Children 6-11 years: 5-10 mg once daily
• Children 2-5 years: 2.5-5 mg once daily
• Reduce dose in renal impairment (CrCl <31 mL/min): 5 mg once daily

Question 3: Short Note on Fexofenadine

Introduction

Mechanism of Action (MOA)

• Fexofenadine acts as a selective competitive antagonist/inverse agonist at peripheral H₁ receptors, blocking histamine-induced effects.
• It has high specificity for H₁ receptors and essentially no affinity for cholinergic or α-adrenergic receptors, explaining its clean side-effect profile.
• It does not cross the blood-brain barrier significantly - it is a substrate for the P-glycoprotein (P-gp) efflux transporter at the blood-brain barrier, which actively pumps it out of the CNS. This is the principal reason it is essentially non-sedating.
• It also inhibits mast cell and basophil mediator release (histamine, cytokines), contributing to anti-inflammatory effects.
• Prolonged use does not cause tachyphylaxis (tolerance to effects does not develop).
• Unlike terfenadine, fexofenadine does not block cardiac HERG (IKr) potassium channels, so it does not cause QT prolongation.

Pharmacokinetics

• Bioavailability: 30-41% (reduced by fruit juices - apple, orange, grapefruit - which inhibit OATP transporters and reduce absorption by up to 36%)
• Protein binding: 60-70% (mainly albumin and α₁-acid glycoprotein)
• Metabolism: Negligible (<5% of dose metabolized hepatically); excreted largely unchanged
• Excretion: ~80% in feces (biliary/intestinal P-gp efflux), ~10% in urine; unchanged drug
• Half-life: ~11-15 hours; allows once-daily (180 mg) or twice-daily (60 mg) dosing
• Drug interactions: Antacids (Mg/Al hydroxide) reduce absorption - take 2 hours apart. Fruit juices reduce absorption significantly.

Uses

1. Seasonal allergic rhinitis (hay fever): Sneezing, rhinorrhea, nasal/ocular pruritus, lacrimation
2. Chronic idiopathic urticaria: Relief of itching and hives
3. Perennial allergic rhinitis
4. Available in combination with pseudoephedrine (Allegra-D) for rhinitis with congestion
5. Generally the preferred antihistamine in patients who require complete alertness (drivers, pilots, professionals)

Adverse Effects

• Headache (most common)
• Dizziness
• Nausea, dyspepsia
• Fatigue (uncommon)
• No anticholinergic effects (no dry mouth, urinary retention, blurred vision)
• No significant sedation or cognitive impairment
• No QT prolongation (unlike its parent terfenadine)
• No tachyphylaxis
• Rare: Back pain, sinusitis in clinical trials

Special Considerations

• Safe in renal impairment (dose as 60 mg once daily if eGFR <80 mL/min)
• Grapefruit, apple, and orange juice decrease its bioavailability - patients should take it with water
• Drug interaction: Ketoconazole and erythromycin can increase fexofenadine plasma levels by inhibiting P-gp and OATP1A2 transporters (but no cardiac toxicity since fexofenadine itself has no cardiac channel activity)

Question 4: Pharmacological Management of Vertigo

Definition

Classification of Causes (Clinically Relevant)

1. Peripheral/Otological: BPPV, Ménière's disease, vestibular neuritis, labyrinthitis
2. Central: Cerebellar/brainstem pathology (stroke, tumor, MS)
3. Systemic: Cardiovascular, metabolic
4. Psychogenic: Anxiety, panic disorder

Goals of Pharmacological Treatment

• Vestibular suppression: Reduce acute vertigo symptoms and associated nausea/vomiting
• Disease-specific treatment: Target the underlying cause (e.g., diuretics in Ménière's disease)
• Promote vestibular compensation (avoid prolonged use of suppressants as they inhibit CNS compensation)

Drug Classes Used in Vertigo

1. Antihistamines (H₁ Antagonists) - First-Line for Most Peripheral Vertigo

2. Benzodiazepines - Effective Vestibular Suppressants

3. Anticholinergics

• Scopolamine (hyoscine): Transdermal patch (1.5 mg over 72 h) or oral. Most effective for motion sickness; also used in vestibular disorders. Adverse effects: dry mouth, blurred vision, urinary retention, sedation, confusion in elderly.
• Note: Scopolamine + ephedrine (or amphetamine) is more effective than either alone for motion sickness.

4. Phenothiazines (Dopamine Antagonists)

5. Calcium Channel Blockers

• Flunarizine (cinnarizine derivative): Used in vestibular migraine and Ménière's disease. Not approved in USA/Japan. Adverse effects: weight gain, somnolence, depression, parkinsonism.
• Cinnarizine: Combined H₁ blocker and calcium channel blocker; used for motion sickness and vertigo in Europe.

6. Diuretics (Ménière's Disease-Specific)

• Hydrochlorothiazide + triamterene or acetazolamide
• Furosemide (in acute severe attacks)
• Salt restriction + diuretics form the cornerstone of medical management of Ménière's disease to prevent recurrent attacks.

7. Corticosteroids

• Used in vestibular neuritis to speed recovery and reduce the severity of acute attacks
• Intratympanic dexamethasone or methylprednisolone in Ménière's disease
• Systemic steroids (prednisolone) in acute vestibular neuritis

8. Antiemetics

• Ondansetron (5-HT₃ antagonist): Useful for nausea/vomiting associated with vertigo
• Metoclopramide: Dopamine antagonist; helpful for accompanying nausea

Disease-Specific Pharmacological Regimens

Important Clinical Notes

• Vestibular suppressants should only be used short-term (acute attacks) as they blunt the CNS compensation process that is essential for long-term recovery.
• Vestibular rehabilitation physical therapy is a key non-pharmacological adjunct and should be used alongside pharmacotherapy.
• Paradoxical situations arise in Ménière's disease where patients may take both antihistamines (cinnarizine) and betahistine simultaneously; the rationale is that the centrally acting antihistamine suppresses symptoms while betahistine acts peripherally/via H₃ receptors.

Sources

• Katzung's Basic and Clinical Pharmacology, 16th Edition (Katzung, Trevor, Vanderah) - Chapters 16 & 31
• Cummings Otolaryngology Head and Neck Surgery - Chapter on Antihistamines in Allergic Rhinitis
• Textbook of Family Medicine, 9th Edition - Chapter 18: Vertigo
• StatPearls - Fexofenadine (NCBI)
• StatPearls - Cetirizine (NCBI)
• Pharmacological treatment of vertigo - PubMed review (PMID: 12521357)
• Management of peripheral vertigo with antihistamines - PMC