Diphenhydramine Hydrochloride — Veterinary Vademecum Drug Reference

Dosage & Administration Guidelines

Species	Route	Dose	Frequency	Duration & Clinical Notes
Dog	PO	2-4 mg/kg	q8-12h	Duration: As needed for clinical signs Notes: For motion sickness, administer 30-60 minutes before travel.
Dog	IM/IV	1-2 mg/kg	q8-12h	Duration: As needed Notes: IV administration should be slow; may cause hypotension if given rapidly.
Cat	PO	2-4 mg/kg	q8-12h	Duration: As needed Notes: Cats may be more sensitive to anticholinergic effects; use with caution.
Cat	IM/IV	1-2 mg/kg	q8-12h	Duration: As needed Notes: Slow IV administration.
Horse	PO	0.5-1 mg/kg	q8-12h	Duration: As needed Notes: Oral absorption may be erratic; monitor response.
Horse	IV	0.5-1 mg/kg	q8-12h	Duration: As needed Notes: Administer slowly.
Cattle	IM/IV	0.5-1 mg/kg	q8-12h	Duration: As needed Notes: Not commonly used; consider alternatives.
Small Ruminants (sheep/goats)	IM/IV	0.5-1 mg/kg	q8-12h	Duration: As needed Notes: Use with caution; not well studied.
Rabbit	PO	2-5 mg/kg	q8-12h	Duration: As needed Notes: May cause sedation; monitor for GI stasis.
Bird (e.g., psittacines)	PO	2-4 mg/kg	q8-12h	Duration: As needed Notes: Limited data; use with caution.

Clinical Indications & Species Uses

General Indications

Symptomatic relief of allergic reactions
Antiemetic for motion sickness
Mild sedation

Dog (Canine)

Allergic dermatitis (pruritus, urticaria)
Motion sickness (as an antiemetic)
Anaphylaxis (as adjunctive therapy)
Sedation (mild)
Antitussive (non-productive cough)

Cat (Feline)

Allergic dermatitis (pruritus, urticaria)
Motion sickness (as an antiemetic)
Anaphylaxis (adjunctive therapy)
Sedation (mild)

Horse (Equine)

Allergic reactions (urticaria, pruritus)
Anaphylaxis (adjunctive therapy)
Motion sickness (rarely used)

Cattle (Bovine)

Allergic reactions (urticaria, pruritus)
Anaphylaxis (adjunctive therapy)

Small Ruminants (Sheep / Goat)

Allergic reactions (urticaria, pruritus)
Anaphylaxis (adjunctive therapy)

Rabbit & Small Mammals

Allergic reactions (pruritus, urticaria)
Sedation (mild)

Avian & Poultry

Allergic reactions (pruritus)
Sedation (mild)

Exotic & Other Species

Allergic reactions (pruritus) in small mammals (e.g., guinea pigs, ferrets)
Sedation in some exotic species

Pharmacology & Mechanism of Action

Drug Class: Antihistamine (H1 receptor antagonist) | Pharmacological Group: Ethanolamine derivative

Mechanism of Action: Diphenhydramine is a first-generation antihistamine that competitively antagonizes histamine at H1 receptor sites, thereby preventing histamine-mediated effects such as vasodilation, increased vascular permeability, smooth muscle contraction, and pruritus. It also has anticholinergic, antiemetic, sedative, and local anesthetic properties. Its central effects are due to blockade of histaminergic and cholinergic transmission in the brain.

Pharmacodynamics: Diphenhydramine reduces histamine-induced capillary permeability, wheal-and-flare responses, and pruritus. It also causes sedation, reduces motion sickness, and has antitussive effects. In dogs and cats, it is used for allergic dermatitis, urticaria, and motion sickness. Its anticholinergic action may cause dry mouth, urinary retention, and tachycardia. The onset of action after oral administration is typically 15-30 minutes, with peak effects in 1-2 hours.

⚡ Pharmacokinetics Summary

Absorption: Rapidly absorbed from the gastrointestinal tract after oral administration. Bioavailability is approximately 40-70% in dogs due to first-pass metabolism. Peak plasma concentrations occur within 1-2 hours.

Distribution: Widely distributed throughout the body, including the central nervous system. Crosses the blood-brain barrier. Volume of distribution is large (approximately 3-5 L/kg in dogs). Protein binding is approximately 80-85%.

Metabolism: Extensively metabolized in the liver via N-demethylation and deamination, primarily by cytochrome P450 enzymes (CYP2D6 and CYP3A4 in humans; similar pathways in animals).

Excretion: Metabolites are excreted primarily in the urine. A small fraction is excreted unchanged. Biliary excretion also occurs. In dogs, the elimination half-life is approximately 4-8 hours; in cats, it is longer, approximately 8-12 hours.

Half-Life: Dog: 4-8 hours; Cat: 8-12 hours; Horse: 1-2 hours (short).

Bioavailability: Oral: 40-70% in dogs (due to first-pass metabolism).

Protein Binding: Approximately 80-85%.

Available Formulations & Strengths

Oral Tablet 25 mg, 50 mg (PO)

Oral Capsule 25 mg, 50 mg (PO)

Oral Liquid (Elixir/Syrup) 12.5 mg/5 mL (PO)

Injectable Solution 50 mg/mL (IM/IV)

Topical Cream (for humans; not commonly used in veterinary medicine) 1-2% (Topical)

Contraindications & Clinical Warnings

Contraindications:

Hypersensitivity to diphenhydramine or other antihistamines
Concurrent use with monoamine oxidase inhibitors (MAOIs)
Severe hepatic disease (use with caution)
Glaucoma (narrow-angle)
Prostatic hypertrophy (may cause urinary retention)
Gastrointestinal obstruction or stenosis
Pregnancy (use only if clearly needed; safety not established)
Lactation (may be excreted in milk; use with caution)

Warnings & Clinical Precautions:

Use with caution in animals with cardiovascular disease, hypertension, or hyperthyroidism.
May cause sedation; avoid concurrent use with other CNS depressants.
Anticholinergic effects may exacerbate dry eye (keratoconjunctivitis sicca) in dogs.
In cats, may cause hyperexcitability or agitation at higher doses.
Use with caution in animals with seizure disorders (may lower seizure threshold).
In food animals, observe withdrawal times; extra-label use requires veterinary oversight.
Do not use in animals with known hypersensitivity to antihistamines.
Use with caution in neonates and geriatric animals.

Adverse Effects & Reactions

Common:

Sedation
Lethargy
Dry mouth
Urinary retention
Gastrointestinal upset (vomiting, diarrhea)
Decreased appetite

Serious / Severe:

Hypotension (especially with rapid IV administration)
Tachycardia
Arrhythmias
Seizures (at high doses or in susceptible animals)
Respiratory depression (at high doses)
Paradoxical excitation (especially in cats)

Rare:

Blood dyscrasias (e.g., agranulocytosis)
Hepatotoxicity
Allergic reactions (including anaphylaxis)
Photosensitivity

Key Drug Interactions

Interacting Drug / Class	Clinical Effect & Mechanism	Severity
CNS depressants (barbiturates, benzodiazepines, opioids)	Additive sedation and respiratory depression.	High
Anticholinergic drugs (atropine, tricyclic antidepressants)	Additive anticholinergic effects (dry mouth, urinary retention, tachycardia).	Moderate
Monoamine oxidase inhibitors (MAOIs)	Increased risk of hypotension and CNS depression; contraindicated.	High
Epinephrine	May potentiate cardiovascular effects (tachycardia, hypertension).	Moderate
Heparin	May reduce anticoagulant effect.	Mild
Metoclopramide	Antagonism of gastrointestinal prokinetic effects.	Mild

Overdose & Toxicity Management

Signs of Toxicity:

Severe sedation
CNS depression or paradoxical excitation
Seizures
Respiratory depression
Hypotension
Tachycardia
Hyperthermia (especially in cats)
Coma

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion and animal is conscious (do not induce if CNS depression is present). Administer activated charcoal to reduce absorption. Provide IV fluids for hypotension. Monitor cardiac and respiratory function. Use benzodiazepines (e.g., diazepam) for seizures. In severe cases, consider physostigmine (anticholinesterase) for central anticholinergic syndrome, but use with caution. Supportive care may include oxygen therapy and mechanical ventilation if needed.

Food Animal Withdrawal Times

🥩 Meat: 3 days🥛 Milk: 3 days

Withdrawal times are not officially established for diphenhydramine in food animals. The values provided are conservative estimates based on pharmacokinetic data and common practice. Always consult regulatory guidelines and a veterinarian for specific withdrawal periods.

Storage, Handling & Regulatory Information

Storage Temperature: Store at room temperature (20-25°C / 68-77°F).

Handling & Special Conditions: Protect from moisture. Keep container tightly closed. Do not freeze oral liquid formulations.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Approved for human use; not specifically approved for veterinary use, but commonly used in veterinary medicine under extra-label provisions.

Extra-Label (Off-Label) Use: In the US, diphenhydramine is not FDA-approved for veterinary use in food animals. Extra-label use in food animals requires a valid veterinary-client-patient relationship and must comply with AMDUCA regulations. Withdrawal times must be established by the veterinarian.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Diphenhydramine is a first-generation antihistamine widely used in veterinary practice for symptomatic relief of allergic reactions, motion sickness, and as a mild sedative. It is generally well-tolerated, but sedation and anticholinergic effects are common. In dogs and cats, it is often used for pruritus associated with atopic dermatitis, but its efficacy is variable; other antipruritic agents (e.g., corticosteroids, oclacitinib) may be more effective. For motion sickness, it is best administered 30-60 minutes before travel. In horses, oral absorption is erratic, so parenteral administration may be preferred for acute allergic reactions. In food animals, extra-label use requires careful attention to withdrawal times. Always consider potential drug interactions and underlying health conditions before prescribing. For severe allergic reactions or anaphylaxis, epinephrine and corticosteroids are primary treatments; diphenhydramine is adjunctive.

References & Literature

📚 Plumb's Veterinary Drug Handbook
📚 Papich Veterinary Pharmacology and Therapeutics
📚 Compendium of Veterinary Products (CVP)