Monograph of Diphenhydramine

Introduction

Diphenhydramine is a first‑generation, non‑selective antihistamine that blocks histamine H1 receptors and exhibits significant anticholinergic activity. It is widely used for the treatment of allergic reactions, acute motion sickness, insomnia, and as a component of many combination analgesic preparations. The drug was first synthesized in the early 1940s and entered clinical use in the 1946 United States Food and Drug Administration (FDA) approval for the treatment of allergic rhinitis. Since then, extensive pharmacological and clinical data have accumulated, establishing diphenhydramine as a reference compound for the first‑generation antihistamine class.

Understanding the pharmacological properties of diphenhydramine is essential for pharmacy and medical students, as the drug remains a staple in over‑the‑counter formulations and is frequently encountered in clinical practice. The monograph aims to provide a detailed, evidence‑based overview that integrates basic science with practical therapeutic considerations.

• Identify the pharmacodynamic and pharmacokinetic characteristics of diphenhydramine.
• Explain the clinical indications and contraindications associated with the drug.
• Apply knowledge of drug interactions and patient‑specific factors to optimize therapy.
• Analyze clinical case scenarios to illustrate dose selection and risk mitigation strategies.
• Recognize the relevance of anticholinergic burden in the elderly and other vulnerable populations.

Fundamental Principles

Core Concepts and Definitions

Diphenhydramine is classified as a small‑molecule, lipophilic compound with a molecular formula of C₁₇H₂₁NO. Its therapeutic action is primarily mediated through competitive inhibition of histamine H1 receptors on peripheral and central tissues. The drug also antagonizes muscarinic acetylcholine receptors, leading to anticholinergic side effects such as dry mouth, blurred vision, urinary retention, and sedation.

Key pharmacological terms relevant to diphenhydramine include:

• Potency – the concentration required to produce a given effect.
• Efficacy – the maximal response achievable by the drug.
• Half‑life (t_½) – the time required for plasma concentration to reduce by 50 %.
• Clearance (Cl) – the volume of plasma from which the drug is completely removed per unit of time.
• Volume of distribution (V_d) – a theoretical volume that relates the amount of drug in the body to the concentration in plasma.

Theoretical Foundations

Diphenhydramine’s pharmacodynamics can be described by the receptor occupancy model: the proportion of receptors occupied (RO) is a function of drug concentration (C) and the equilibrium dissociation constant (K_D):

RO = C / (C + K_D).

This relationship explains the dose‑response curve, where increasing concentrations result in higher receptor occupancy until a plateau is reached. The anticholinergic effects arise from similar occupancy of muscarinic receptors, albeit with different K_D values that account for the drug’s broader receptor profile.

Pharmacokinetic modeling often employs a one‑compartment model with first‑order absorption and elimination. The plasma concentration over time (C(t)) follows:

C(t) = (F × Dose × k_a) / (V_d × (k_a – k_el)) × (e^–k_elt – e^–k_at),

where F is the bioavailability, k_a is the absorption rate constant, and k_el is the elimination rate constant. For oral administration, the peak concentration (C_max) and time to peak (t_max) are typically observed within 1–2 h, reflecting moderate absorption kinetics.

Key Terminology

• Bioavailability (F) – the fraction of an administered dose that reaches systemic circulation.
• First‑pass metabolism – hepatic metabolism that reduces bioavailability before the drug reaches systemic circulation.
• Therapeutic index – ratio of toxic dose to therapeutic dose; diphenhydramine has a relatively narrow index in elderly patients.
• Anticholinergic burden – cumulative effect of multiple anticholinergic agents, often quantified using scales such as the Anticholinergic Cognitive Burden (ACB) score.

Detailed Explanation

Pharmacodynamics

Diphenhydramine’s primary therapeutic effect arises from blockade of peripheral H1 receptors, which mitigates histamine‑induced vasodilation, edema, and pruritus. In the central nervous system, H1 antagonism produces sedation, which is exploited for short‑term insomnia. The anticholinergic activity is mediated by blockade of M1–M5 muscarinic receptors, leading to the characteristic side‑effect profile. Pharmacodynamic potency is higher for H1 receptors than for muscarinic receptors, but the latter contribute significantly to adverse events.

Pharmacokinetics

After oral ingestion, diphenhydramine is absorbed in the small intestine with a bioavailability of approximately 50 % due to first‑pass hepatic metabolism. Peak plasma concentrations are reached within 1–2 h. The drug is highly lipophilic, allowing extensive distribution into adipose tissue and the central nervous system. The mean volume of distribution is around 100 L, reflecting significant tissue uptake.

Metabolism occurs primarily via hepatic cytochrome P450 2D6 (CYP2D6) and 3A4 (CYP3A4), producing desmethyldiphenhydramine, a metabolite with comparable activity. Conjugation with glucuronic acid facilitates renal excretion. The elimination half‑life ranges from 4 to 9 h in healthy adults, but can extend beyond 12 h in elderly or chronically ill patients due to reduced hepatic function.

Clearance (Cl) can be approximated by the equation:

Cl = (Dose × F) ÷ AUC,

where AUC (area under the concentration‑time curve) represents overall exposure. For a typical 50 mg oral dose, the AUC is approximately 400 ng·h/mL, yielding a clearance of ~12 L/h. Renal impairment reduces Cl by 20–30 %, necessitating dose adjustments in patients with creatinine clearance <30 mL/min.

Factors Affecting Diphenhydramine Pharmacokinetics and Dynamics

• Age – elderly patients exhibit decreased hepatic clearance and increased V_d, prolonging t_½ and amplifying CNS side effects.
• Genetic polymorphisms – CYP2D6 poor metabolizers may experience higher plasma concentrations, increasing anticholinergic burden.
• Drug interactions – concurrent use of CYP3A4 inhibitors (e.g., ketoconazole) or CYP2D6 inhibitors (e.g., fluoxetine) can elevate diphenhydramine levels.
• Alcohol and CNS depressants – potentiation of sedation and respiratory depression risk.
• Renal or hepatic impairment – reduced elimination leads to accumulation and prolonged adverse effects.

Mathematical Relationships

The concentration–time profile follows first‑order kinetics, expressed as:

C(t) = C₀ × e^–k_elt,

where C₀ is the initial concentration post‑distribution. The elimination rate constant (k_el) is derived from the half‑life:

k_el = 0.693 ÷ t_½.

For a t_½ of 6 h, k_el equals 0.1155 h^–1. The steady‑state concentration (C_ss) achieved with repeated dosing is:

C_ss = (F × Dose) ÷ ( × τ),

where τ represents dosing interval. Understanding these relationships aids in tailoring dosing schedules for specific patient populations.

Clinical Significance

Relevance to Drug Therapy

Diphenhydramine remains a first‑line agent for mild to moderate allergic reactions, especially in settings where rapid onset is required. Its dual antihistaminic and anticholinergic properties render it suitable for acute motion sickness prophylaxis and as an adjunct in procedural sedation for its amnesic effects. The drug’s sedative properties are harnessed for short‑term insomnia management, though caution is advised due to the risk of next‑day impairment.

Practical Applications

Therapeutic dosing schedules vary by indication:

• Allergic rhinitis or urticaria – 25–50 mg orally every 4–6 h, not exceeding 400 mg/day.
• Motion sickness prophylaxis – 25 mg orally 1 h before travel, repeat every 12 h if needed.
• Insomnia – 25–50 mg at bedtime; limited to short durations (≤3 weeks).
• Adjunct for procedural sedation – 25–50 mg IV, often combined with benzodiazepines.

Contraindications include severe anticholinergic sensitivity, narrow‑angle glaucoma, bladder outlet obstruction, and uncontrolled asthma or COPD due to potential bronchoconstriction. Caution is warranted in patients with hepatic or renal dysfunction, and in the elderly where the anticholinergic burden may precipitate delirium or falls.

Clinical Examples

A 70‑year‑old man with chronic obstructive pulmonary disease (COPD) presents with an acute urticarial flare. Initiation of diphenhydramine at 25 mg orally may exacerbate bronchoconstriction; alternative antihistamines with minimal anticholinergic activity (e.g., cetirizine) should be preferred. In contrast, a 25‑year‑old healthy adult with seasonal allergic rhinitis may tolerate standard dosing of 25 mg every 6 h without significant adverse effects.

Clinical Applications/Examples

Case Scenario 1: Elderly Patient with Insomnia

A 68‑year‑old woman reports difficulty initiating sleep for the past month. Her medication list includes amlodipine 10 mg daily and simvastatin 20 mg nightly. She has mild cognitive impairment and a history of falls. Diphenhydramine 25 mg at bedtime is considered; however, the anticholinergic burden may worsen cognition and increase fall risk. A safer alternative would be a non‑sedating antihistamine such as hydroxyzine 25 mg at bedtime, combined with sleep hygiene counseling.

Case Scenario 2: Child with Motion Sickness

A 9‑year‑old boy traveling by car for a family vacation experiences anticipatory nausea. Diphenhydramine 1 mg/kg orally, with a maximum of 50 mg, is appropriate. The child should be instructed to take the dose 1 h before departure. If nausea persists, a second dose may be administered 6–8 h later, ensuring that the total daily dose does not exceed 50 mg.

Case Scenario 3: Adult with Acute Urticaria and Drug Interaction

A 45‑year‑old man presents with widespread urticaria after a bee sting. He is on fluoxetine for depression. Fluoxetine is a potent CYP2D6 inhibitor; concurrent diphenhydramine use could lead to increased plasma concentrations. In this setting, the use of a second‑generation antihistamine such as loratadine, which has minimal CYP interaction, is advisable.

Problem‑Solving Approaches

1. Identify potential drug interactions – Review medications metabolized by CYP2D6/CYP3A4 and adjust dose accordingly.
2. Assess anticholinergic burden – Utilize scoring systems; consider alternative agents if burden exceeds threshold.
3. Tailor dosing in renal/hepatic impairment – Reduce dose or extend dosing interval; monitor for signs of accumulation.
4. Monitor for CNS effects – Evaluate sedation levels, especially in patients with sleep disorders or when combining with CNS depressants.
5. Educate patients – Advise on alcohol avoidance, driving restrictions, and proper dosing intervals.

Summary/Key Points

• Diphenhydramine is a first‑generation antihistamine with significant anticholinergic activity.
• Pharmacodynamic action involves competitive H1 receptor blockade and muscarinic receptor antagonism, leading to both therapeutic effects and adverse events.
• Pharmacokinetic parameters: oral bioavailability ≈ 50 %; t_½ 4–9 h; V_d ≈ 100 L; major metabolites via CYP2D6 and CYP3A4.
• Key equations: C(t) = C₀ × e^–k_elt, Cl = (Dose × F) ÷ AUC, C_ss = (F × Dose) ÷ (Cl × τ).
• Clinical uses: allergic reactions, motion sickness, short‑term insomnia, procedural sedation adjunct.
• Contraindications: severe anticholinergic sensitivity, narrow‑angle glaucoma, bladder outlet obstruction, uncontrolled asthma/COPD.
• Risk factors: elderly, hepatic/renal impairment, CYP2D6 poor metabolizers, concurrent CNS depressants.
• Practical pearls: limit daily dose to ≤ 400 mg; avoid use in patients with high anticholinergic burden; prefer second‑generation antihistamines in patients with risk of cognitive impairment or falls.

Through integration of pharmacological principles with clinical decision‑making, students can achieve a comprehensive understanding of diphenhydramine’s role in modern therapeutics. This knowledge supports safe prescribing practices and enhances patient outcomes across diverse clinical settings.

References

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