Chapter 12: Pharmacology of Diphenhydramine

1. Introduction/Overview

Diphenhydramine represents a prototypical and historically significant agent within the first-generation H₁ receptor antagonist class of drugs. Initially synthesized in the 1940s, its introduction marked a pivotal advancement in the therapeutic management of allergic conditions. As an ethanolamine derivative, diphenhydramine possesses a molecular structure that confers not only potent antihistaminic activity but also notable antimuscarinic, antiemetic, and sedative properties. This multifaceted pharmacodynamic profile underpins its diverse clinical applications, which extend beyond its primary indication for allergy symptoms to include uses in motion sickness, insomnia, and parkinsonism. The drug’s widespread availability in numerous over-the-counter formulations necessitates a thorough understanding of its pharmacology among healthcare professionals to ensure its safe and effective use, particularly given its significant potential for adverse central nervous system effects and anticholinergic toxicity.

The clinical relevance of diphenhydramine remains substantial despite the development of newer, less sedating antihistamines. Its efficacy in providing rapid relief from urticaria, allergic rhinitis, and conjunctivitis is well-established. Furthermore, its potent sedative effect is frequently utilized for the short-term management of insomnia, and its antiemetic action is valuable in preventing and treating motion sickness. The drug’s anticholinergic properties also find application in mitigating extrapyramidal symptoms induced by antipsychotic medications. However, the utility of diphenhydramine is counterbalanced by a distinct adverse effect profile, prominently featuring drowsiness, cognitive impairment, and peripheral anticholinergic effects. Its pharmacokinetics and pharmacodynamics also create a significant risk for dangerous interactions with other central nervous system depressants and anticholinergic agents. A comprehensive grasp of these aspects is therefore essential for medical and pharmacy students.

Learning Objectives

• Classify diphenhydramine within the broader categories of antihistamines and describe its chemical structure as an ethanolamine derivative.
• Explain the molecular mechanism of action of diphenhydramine as a competitive inverse agonist at the H₁ receptor and detail its additional actions on muscarinic, serotonin, and sodium channels.
• Outline the pharmacokinetic profile of diphenhydramine, including its absorption, distribution, metabolism by hepatic cytochrome P450 enzymes, and elimination.
• List the approved therapeutic indications for diphenhydramine and describe its common off-label clinical applications.
• Identify the common and serious adverse effects associated with diphenhydramine use, including its anticholinergic toxidrome, and specify major contraindications and drug interactions.

2. Classification

Diphenhydramine is systematically classified within multiple pharmacological and chemical hierarchies, reflecting its diverse properties and origins.

Pharmacotherapeutic Classification

Primarily, diphenhydramine is classified as a first-generation (classic) H₁ receptor antagonist. This classification distinguishes it from second-generation agents (e.g., loratadine, cetirizine) by its pronounced ability to cross the blood-brain barrier, resulting in significant central nervous system effects, including sedation. Within the first-generation subclass, it belongs specifically to the ethanolamine group. Other members of this chemical subclass include dimenhydrinate (a salt of diphenhydramine with 8-chlorotheophylline) and doxylamine. The ethanolamines are characterized by a central oxygen atom and a two-carbon chain linking the amine moiety to the diaryl core, a structure associated with potent antihistaminic activity, marked sedative effects, and considerable antimuscarinic activity. Additional therapeutic classifications for diphenhydramine include:

• Antiemetic: Used for prophylaxis and treatment of nausea and vomiting, particularly motion sickness.
• Sedative-Hypnotic: Employed for its drowsiness-inducing effect to manage insomnia.
• Antiparkinsonian Agent: Used adjunctively to manage drug-induced extrapyramidal symptoms due to its central anticholinergic action.
• Antitussive: Found in some cough and cold preparations, though its efficacy as a standalone antitussive is debated.
• Topical Anesthetic: In certain formulations, it exhibits local anesthetic properties by blocking voltage-gated sodium channels.

Chemical Classification

Chemically, diphenhydramine hydrochloride is described as 2-(diphenylmethoxy)-N,N-dimethylethanamine hydrochloride. Its structure consists of a diphenylmethyl ether group connected via an ethoxy linker to a dimethylaminoethyl moiety. This structure is integral to its pharmacodynamics. The diaryl groups facilitate binding to the H₁ receptor, while the basic tertiary amine, which is protonated at physiological pH, interacts with aspartate residues in the receptor’s transmembrane domains. The ether linkage and the two-carbon chain are hallmarks of the ethanolamine class. The molecule is lipophilic, a property conferred by the aromatic rings and the aliphatic chain, which promotes rapid absorption and penetration into the central nervous system.

3. Mechanism of Action

The therapeutic and adverse effects of diphenhydramine are mediated through interactions with several distinct receptor systems and ion channels. Its primary mechanism is historically described as competitive antagonism at the histamine H₁ receptor, though it is more accurately characterized as a competitive inverse agonist.

Histamine H₁ Receptor Antagonism/Inverse Agonism

Histamine exerts its effects in allergic reactions and inflammation by activating G protein-coupled H₁ receptors. Activation leads to the dissociation of the G_q protein, triggering a phospholipase C-mediated increase in inositol trisphosphate (IP₃) and diacylglycerol (DAG), ultimately causing intracellular calcium mobilization and protein kinase C activation. In blood vessels, this results in vasodilation, increased permeability, and edema. In sensory nerves, it causes itching and pain. In the brain, histamine acting on H₁ receptors promotes wakefulness.

Diphenhydramine binds with high affinity to the orthosteric binding site of the H₁ receptor. Rather than merely blocking the binding of histamine (neutral antagonism), it stabilizes the receptor in an inactive conformation, reducing its basal, constitutive signaling activity. This inverse agonist action effectively reverses the effects of histamine. The clinical consequences of H₁ receptor blockade include:

• Reduction of capillary dilation and permeability, mitigating wheal and flare responses, edema, and nasal congestion.
• Suppression of histamine-induced pruritus.
• Antagonism of histamine’s wake-promoting effects in the tuberomammillary nucleus of the hypothalamus, leading to sedation.

Muscarinic Acetylcholine Receptor Antagonism

Diphenhydramine possesses substantial affinity for muscarinic acetylcholine receptors (mAChRs), particularly the M₁, M₂, and M₃ subtypes. This antimuscarinic activity is a direct consequence of its structural similarity to other anticholinergic agents. The tertiary amine group interacts with the receptor’s binding site typically occupied by the quaternary ammonium group of acetylcholine. This action is responsible for a significant portion of the drug’s adverse effect profile.

• Central Antimuscarinic Effects: Blockade of central M₁ receptors contributes to sedation, cognitive impairment, confusion (especially in the elderly), and the suppression of extrapyramidal symptoms.
• Peripheral Antimuscarinic Effects: Blockade of peripheral receptors leads to dry mouth (xerostomia), blurred vision (due to cycloplegia and mydriasis), constipation, urinary retention, and tachycardia.

Serotonin Receptor Antagonism

Diphenhydramine exhibits moderate antagonistic activity at certain serotonin receptor subtypes, notably 5-HT₂ and 5-HT₃. The 5-HT₃ receptor antagonism in the chemoreceptor trigger zone (CTZ) and the vestibular apparatus is believed to contribute to its antiemetic efficacy against motion sickness and other forms of nausea. The 5-HT₂ receptor blockade may have minor implications for its sedative profile.

Local Anesthetic Activity

Diphenhydramine can function as a sodium channel blocker, inhibiting the influx of sodium ions necessary for the initiation and propagation of action potentials in neuronal membranes. This property is concentration-dependent and underlies its use as a topical anesthetic in some dermatological preparations and its potential to cause local numbness when administered via injection.

Inhibition of Neuronal Reuptake

At higher concentrations, diphenhydramine may weakly inhibit the reuptake of serotonin by presynaptic transporters, a mechanism shared with some tricyclic antidepressants. This action is generally considered clinically insignificant at standard therapeutic doses but may contribute to its toxicity profile in overdose.

4. Pharmacokinetics

The pharmacokinetic profile of diphenhydramine is characterized by rapid and extensive absorption, wide distribution, significant hepatic metabolism, and renal excretion of metabolites. These parameters are subject to considerable interindividual variation.

Absorption

Following oral administration, diphenhydramine is rapidly and extensively absorbed from the gastrointestinal tract. Bioavailability is estimated to be between 40% and 60%, reflecting a significant first-pass hepatic metabolism. Peak plasma concentrations (C_max) are typically achieved within 2 to 3 hours post-administration. Absorption is not significantly affected by food, although a high-fat meal may slightly delay the time to C_max without altering the overall extent of absorption. When administered intramuscularly or intravenously, absorption is complete and rapid, with onset of action occurring within minutes.

Distribution

Diphenhydramine is widely distributed throughout body tissues. Its volume of distribution (V_d) is large, approximately 3 to 4 L/kg, indicating extensive tissue binding. The drug is highly lipophilic and readily crosses the blood-brain barrier, accounting for its pronounced central effects. It also crosses the placental barrier and is distributed into breast milk. Protein binding is moderate, ranging from 78% to 85%, primarily to albumin and α₁-acid glycoprotein.

Metabolism

Diphenhydramine undergoes extensive hepatic metabolism, primarily via the cytochrome P450 enzyme system. The major isoforms involved are CYP2D6 and, to a lesser extent, CYP1A2, CYP2C9, and CYP2C19. The primary metabolic pathways include:

• N-Demethylation: Successive demethylation of the dimethylamino group to form mono-desmethyl and didesmethyl metabolites.
• Oxidation: Oxidation of the diphenylmethyl moiety.
• Glucuronidation: Conjugation of the parent drug and its oxidative metabolites with glucuronic acid to form water-soluble excretory products.

The N-demethylated metabolites retain some pharmacological activity, though they are less potent than the parent compound. Genetic polymorphisms in CYP2D6 can lead to variability in metabolic rates, potentially affecting both efficacy and toxicity.

Excretion

Elimination occurs predominantly via the kidneys. Less than 5% of an orally administered dose is excreted unchanged in the urine. The majority is eliminated as inactive metabolites, with diphenhydramine-N-oxide and conjugated products being the main urinary excretory forms. A small fraction may be excreted in the bile and feces. The elimination half-life (t_1/2) in adults with normal hepatic and renal function ranges from approximately 4 to 9 hours, with a mean around 8 hours. This half-life can be prolonged in the elderly, neonates, and individuals with hepatic cirrhosis or severe renal impairment.

Pharmacokinetic Parameters and Dosing Considerations

The standard adult oral dose for allergic conditions is 25 to 50 mg every 4 to 6 hours, not to exceed 300 mg daily. For insomnia, a single 50 mg dose at bedtime is typical. The relationship between dose, plasma concentration, and effect is not perfectly linear due to saturable metabolism at higher doses. The onset of action is rapid (15-30 minutes orally), with a duration of action of 4 to 6 hours, aligning with its relatively short half-life. Dosing intervals must be adjusted in populations with altered pharmacokinetics to avoid accumulation and toxicity.

5. Therapeutic Uses/Clinical Applications

Diphenhydramine is employed for a variety of clinical indications, both approved and off-label, leveraging its antihistaminic, anticholinergic, and sedative properties.

Approved Indications

• Allergic Conditions: This is the primary indication. It is effective in relieving symptoms of seasonal and perennial allergic rhinitis (sneezing, rhinorrhea, pruritus), allergic conjunctivitis (itching, redness), and mild, uncomplicated allergic skin manifestations such as urticaria and angioedema. It is also indicated for anaphylactic reactions as an adjunct to epinephrine and supportive care, though it is not a first-line treatment for hemodynamic instability.
• Motion Sickness: Diphenhydramine is effective for the prophylaxis and treatment of nausea, vomiting, and dizziness associated with motion sickness. For prophylaxis, it is typically administered 30 minutes prior to travel.
• Insomnia: Marketed as a sleep aid, its sedative effect is utilized for the short-term management of occasional sleeplessness. Long-term use is not recommended due to tolerance, diminished efficacy, and risk of adverse effects.
• Parkinsonism and Drug-Induced Extrapyramidal Symptoms (EPS): Its central antimuscarinic action is therapeutic for reducing tremor, rigidity, and akathisia associated with idiopathic Parkinson’s disease and for managing acute dystonic reactions and other EPS caused by typical antipsychotic drugs (e.g., haloperidol).
• Cough Suppression: While included in many over-the-counter cough and cold preparations, its antitussive efficacy as a single agent is considered modest and is often attributed to its sedative effect.
• Topical Use: Creams, gels, and sprays containing diphenhydramine are used to relieve itching and pain associated with minor skin irritations, insect bites, and mild burns, leveraging its H₁ blockade and local anesthetic properties.

Common Off-Label Uses

• Acute Dystonic Reactions: Intravenous or intramuscular diphenhydramine is a standard treatment for acute dystonia induced by dopamine receptor antagonists.
• Adjunct in Opioid-Induced Pruritus: Used to mitigate histamine-mediated pruritus that can occur with opioid administration, particularly morphine.
• Sedation in Clinical Settings: Sometimes used for pre-procedural sedation or to manage agitation, though other agents with more favorable profiles are generally preferred.
• Vertigo: May be used to manage symptoms of vertigo from various etiologies due to its effect on the vestibular system.

6. Adverse Effects

The adverse effect profile of diphenhydramine is extensive and is largely a direct extension of its pharmacodynamic actions, particularly its central nervous system penetration and antimuscarinic activity.

Common Side Effects

These effects are frequent, often dose-related, and typically diminish with continued use, though they can be significant.

• Central Nervous System: Sedation, drowsiness, somnolence, fatigue, dizziness, and impaired coordination are the most common. Paradoxical reactions such as excitation, nervousness, insomnia, and euphoria can occur, especially in children and the elderly.
• Anticholinergic Effects: Dry mouth, blurred vision, constipation, urinary hesitation or retention, and tachycardia.
• Gastrointestinal: Epigastric distress, nausea, vomiting, diarrhea, or constipation.
• Miscellaneous: Thickening of bronchial secretions, which can be problematic in patients with asthma or chronic obstructive pulmonary disease.

Serious/Rare Adverse Reactions

• Cognitive Impairment: Significant impairment in cognitive function, memory, and psychomotor performance can occur, mimicking dementia, particularly in the elderly. This can increase the risk of falls and accidents.
• Cardiovascular Effects: Tachycardia is common. At high doses or in susceptible individuals, hypotension, palpitations, and arrhythmias (including QT interval prolongation) have been reported.
• Anticholinergic Toxidrome: Overdose or accumulation can lead to a classic anticholinergic syndrome: “Hot as a hare, dry as a bone, red as a beet, mad as a hatter, blind as a bat.” This includes hyperthermia, dry skin and mucous membranes, flushing, delirium, hallucinations (often visual), mydriasis with blurred vision, ileus, urinary retention, and seizures. This is a medical emergency.
• Hypersensitivity Reactions: Rare cases of anaphylaxis, photosensitivity, and drug rash with eosinophilia and systemic symptoms (DRESS) have been documented.
• Blood Dyscrasias: Extremely rare reports of hemolytic anemia, thrombocytopenia, and agranulocytosis.

Black Box Warnings

Diphenhydramine does not carry a formal black box warning from the U.S. Food and Drug Administration. However, its use in pediatric populations, particularly in infants and young children, is associated with serious risks. The FDA advises against the use of over-the-counter cough and cold medicines containing antihistamines in children under 2 years of age due to the risk of fatal respiratory depression and overdose. Many manufacturers have voluntarily labeled these products as not for use in children under 4 years. Furthermore, the drug’s sedative effects carry explicit warnings about operating machinery or driving.

7. Drug Interactions

Diphenhydramine participates in numerous pharmacodynamic and pharmacokinetic interactions that can potentiate its effects or the effects of co-administered drugs.

Major Drug-Drug Interactions

• Central Nervous System Depressants: Additive sedation and respiratory depression can occur with alcohol, benzodiazepines, barbiturates, opioid analgesics, sedative-hypnotics, skeletal muscle relaxants, and certain antidepressants (e.g., tricyclics, trazodone). This combination significantly increases the risk of accidents and overdose.
• Other Anticholinergic Agents: Concurrent use with tricyclic antidepressants (e.g., amitriptyline), antipsychotics (e.g., clozapine, olanzapine), antiparkinsonian drugs (e.g., benztropine), and antispasmodics (e.g., dicyclomine) can lead to an additive anticholinergic burden, increasing the risk of toxicity (ileus, urinary retention, hyperthermia, delirium).
• Monoamine Oxidase Inhibitors (MAOIs): MAOIs can potentiate the anticholinergic and sedative effects of diphenhydramine. This combination is generally contraindicated or requires extreme caution.
• Drugs Metabolized by CYP2D6: Diphenhydramine is a moderate inhibitor of CYP2D6. It can increase plasma concentrations of substrates such as codeine (reducing its activation to morphine), metoprolol, flecainide, propafenone, and some antidepressants (e.g., venlafaxine, paroxetine).
• Drugs that Prolong the QT Interval: Concomitant use with other QT-prolonging agents (e.g., class IA and III antiarrhythmics, macrolide antibiotics, certain antipsychotics) may have an additive effect on cardiac repolarization, increasing the risk of torsades de pointes.

Contraindications

• Hypersensitivity: Known hypersensitivity to diphenhydramine, other ethanolamine-derivative antihistamines, or any component of the formulation.
• Neonates and Premature Infants: Contraindicated due to increased risk of seizures and death.
• Concurrent Monoamine Oxidase Inhibitor Therapy: As noted above.
• Narrow-Angle Glaucoma: Anticholinergic effects can increase intraocular pressure.
• Severe Urinary Retention or Pyloroduodenal Obstruction: Anticholinergic effects can exacerbate these conditions.
• Severe Asthma or Lower Respiratory Disease: Its atropine-like effect can thicken secretions and impair clearance.

8. Special Considerations

The use of diphenhydramine requires careful evaluation in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or increased susceptibility to adverse effects.

Pregnancy and Lactation

Pregnancy (Category B per former FDA classification): Animal reproduction studies have not demonstrated a risk to the fetus, but adequate and well-controlled studies in pregnant women are lacking. Diphenhydramine crosses the placenta. It should be used during pregnancy only if clearly needed, particularly in the third trimester due to potential anticholinergic effects in the neonate (e.g., seizures) and possible association with retrolental fibroplasia when used close to delivery.

Lactation: Diphenhydramine is excreted in human milk. Due to its potential to cause sedation, irritability, or feeding difficulties in the nursing infant and its potential to suppress lactation via anticholinergic reduction of prolactin, use is not recommended. If use is necessary, the infant should be monitored for sedation and other anticholinergic symptoms.

Pediatric Considerations

Children may exhibit paradoxical excitation (restlessness, insomnia, euphoria) rather than sedation. They are also more susceptible to anticholinergic toxicity, including hallucinations and seizures. As previously noted, the use of cough and cold products containing diphenhydramine is strongly discouraged in children under 4-6 years due to risks of overdose, respiratory depression, and death. Dosing for allergic conditions in children over 2 years is typically weight-based (5 mg/kg/day divided into 4 doses, not to exceed 300 mg/day). Extreme caution is warranted.

Geriatric Considerations

Older adults are exquisitely sensitive to the central and peripheral anticholinergic effects of diphenhydramine. Age-related reductions in hepatic metabolism and renal clearance can lead to increased plasma levels and prolonged half-life. The drug is strongly associated with an increased risk of:

• Confusion, delirium, and cognitive impairment.
• Dizziness, postural hypotension, and falls with resultant fractures.
• Urinary retention and constipation.
• Dry mouth leading to dental caries and difficulty swallowing.

Diphenhydramine is frequently cited on lists of medications to avoid in the elderly (e.g., the Beers Criteria). Safer alternatives (e.g., second-generation antihistamines for allergies, non-pharmacological measures or safer hypnotics for insomnia) should be prioritized.

Renal and Hepatic Impairment

Renal Impairment: Since metabolites are renally excreted, significant impairment (creatinine clearance < 30 mL/min) can lead to metabolite accumulation. While the clinical significance is unclear, dose reduction or increased dosing interval is recommended. The drug should be used with caution.

Hepatic Impairment: Patients with cirrhosis or severe hepatic disease have reduced metabolic capacity, leading to decreased clearance and a prolonged half-life of diphenhydramine. This increases the risk of sedation and other adverse effects. A dose reduction of up to 50% may be necessary, and patients should be closely monitored.

9. Summary/Key Points

Diphenhydramine is a first-generation ethanolamine-derivative H₁ receptor antagonist with a broad spectrum of pharmacological actions and clinical applications.

Bullet Point Summary

• Diphenhydramine is a competitive inverse agonist at the histamine H₁ receptor and possesses significant antimuscarinic, antiemetic (via 5-HT₃ blockade), and local anesthetic properties.
• It is rapidly absorbed after oral administration, undergoes extensive hepatic metabolism primarily via CYP2D6, and has an elimination half-life of approximately 4 to 9 hours.
• Primary therapeutic uses include the management of allergic conditions, motion sickness, short-term insomnia, and drug-induced extrapyramidal symptoms.
• The most common adverse effects are dose-related sedation and anticholinergic effects (dry mouth, blurred vision, constipation).
• Serious risks include cognitive impairment (especially in the elderly), anticholinergic toxidrome in overdose, and additive CNS depression with other sedatives.
• Major drug interactions occur with other CNS depressants, anticholinergic agents, MAOIs, and CYP2D6 substrates.
• Use is contraindicated in neonates, with MAOIs, and in conditions like narrow-angle glaucoma. It requires extreme caution or avoidance in the elderly, young children, and patients with significant hepatic or renal impairment.

Clinical Pearls

• Diphenhydramine’s sedative effect often limits its utility for daytime allergy symptoms; second-generation antihistamines are preferred for this purpose.
• It is an effective treatment for acute dystonic reactions; administer 25-50 mg intramuscularly or intravenously.
• Educate patients about the profound impairment of driving and operating machinery, which can persist into the next day (“hangover” sedation).
• In the elderly, even occasional use for sleep can precipitate confusion or delirium; it should be avoided as a first-line hypnotic.
• Always inquire about over-the-counter sleep aids and “PM” formulations of analgesics, as these commonly contain diphenhydramine, leading to unintentional duplication and overdose.
• For allergic conditions, the benefit of rapid onset must be weighed against the burden of sedation; dosing at bedtime may mitigate daytime drowsiness.

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