Diphenhydramine Injection

Diphenhydramine Injection is a sterile, preservative-free parenteral preparation containing 50 mg of diphenhydramine hydrochloride per mL, adjusted to pH 4-6.5 with hydrochloric acid or sodium hydroxide and supplied in single-dose 1 mL vials intended for deep intramuscular or slow intravenous administration.

As a first-generation ethanolamine antihistamine, the formulation is used when oral therapy is impossible or impractical to manage acute IgE-mediated reactions, adjunctive treatment of anaphylaxis (after epinephrine), prophylaxis of blood-product hypersensitivity, motion sickness that precludes enteral dosing, and selected extrapyramidal syndromes.

The drug distributes widely, crosses the blood-brain barrier, and produces rapid onset of action-often within minutes after IV push-because high lipophilicity accelerates central nervous system penetration; the resultant anticholinergic and sedative properties underlie many clinical uses and cautions.

Compounded under section 503B, this outsourced product is dispensed by prescription only; it is not FDA-approved but is prepared to current good manufacturing practice standards, undergoes sterility/endotoxin testing, and must be prescribed and monitored by qualified clinicians.

Diphenhydramine acts as a reversible, competitive antagonist-and more precisely, an inverse agonist-at the histamine H₁ receptor, thereby stabilizing the inactive receptor conformation and preventing histamine-mediated vasodilation, increased capillary permeability, and sensory nerve activation.

Because the molecule readily penetrates the central nervous system, blockade of H₁ receptors in cortical and subcortical arousal pathways diminishes wake-promoting histaminergic signaling, producing dose-dependent somnolence and impairment of attention, memory, and psychomotor speed.

At anticholinergic doses it also antagonizes muscarinic M₁ receptors, potentiating drying of secretions, mydriasis, tachycardia, and decreased gastrointestinal motility; cytochrome P450 isoenzymes (primarily CYP2D6 and 1A2) mediate hepatic N-demethylation, explaining pharmacokinetic variability and drug-drug interaction potential.

Experimental psychometric studies using double-blind crossover designs confirm measurable decrements in sustained attention and reaction time within 0.5-3.5 h after intravenous administration of 50 mg, correlating with cortical H₁ receptor occupancy.

Contemporary reviews emphasize that first-generation agents such as diphenhydramine are inverse agonists rather than simple antagonists and note emerging data on gene-dose effects, transporter interactions, and tolerance development, all of which should temper prolonged off-label use for insomnia.

Parenteral diphenhydramine is contraindicated in premature or full-term neonates because of heightened anticholinergic central toxicity and paradoxical excitation.

The injectable solution must not be used as a local anesthetic or via subcutaneous or intradermal routes owing to reports of local necrosis and limb-threatening extravasation injuries, particularly in fragile pediatric or elderly veins.

Clinicians should avoid administration in patients with known hypersensitivity to ethanolamine antihistamines, narrow-angle glaucoma, symptomatic prostatic hypertrophy, stenosing peptic ulcer, bladder-neck obstruction, or severe chronic obstructive pulmonary disease, as peripheral antimuscarinic effects can precipitate urinary retention, acute angle closure, or bronchial thickening.

Concomitant use with central nervous system depressants-including benzodiazepines, opioids, barbiturates, alcohol, or cannabis-may produce additive sedation, impaired airway reflexes, and respiratory depression; therefore dosing intervals should be staggered or alternative non-sedating antihistamines selected.

Monoamine oxidase inhibitors prolong and intensify diphenhydramine’s anticholinergic actions by decreasing metabolic clearance and augmenting neurotransmitter synaptic levels, so co-administration (or administration within 14 days of MAOI discontinuation) is discouraged.

In vitro and clinical pharmacology data further demonstrate potentiation of xerostomia, hyperthermia, and tachyarrhythmia when combined with other anticholinergic agents such as tricyclic antidepressants or phenothiazines; caution with polypharmacy in geriatric populations is warranted.

Common adverse effects encompass dose-related somnolence, dizziness, disturbed coordination, and mucosal dryness; cardiovascular reactions such as hypotension and palpitations occur less frequently but mandate monitoring when large intravenous boluses (≥ 50 mg) are delivered over < 2 minutes. Large pharmacoepidemiologic reviews and recent randomized trials link first-generation H₁ antihistamines to impaired driving performance, increased fall risk in adults > 65 years, and paradoxical agitation, hallucinations, or seizures in children, underscoring the need for individualized risk-benefit assessment.

Animal reproduction studies at up to five times the human dose revealed no teratogenicity, and epidemiologic surveillance classifies diphenhydramine as pregnancy category B; nevertheless, absence of controlled human trials dictates cautious, short-term use only when expected benefits outweigh fetal risks.

Obstetric pharmacologists emphasize potential neonatal respiratory depression if high maternal doses are administered during labor and recommend avoidance of elective parenteral administration within two weeks of expected delivery unless medically essential.

During lactation, diphenhydramine appears in breast milk at low concentrations, but sedative transfer may blunt infant arousal or theoretically diminish milk production; non-sedating second-generation antihistamines are generally preferred for chronic allergy management in breastfeeding parents.