Diphenhydramine

Usage

Diphenhydramine is primarily used to treat allergic reactions (including anaphylaxis, angioedema, urticaria, pruritus), cold and flu symptoms (rhinorrhea, sneezing, cough), motion sickness, and insomnia. It can also be utilized for Parkinsonism and dystonic reactions. Its pharmacological classifications include:

• Antihistamine: Specifically, a first-generation H1 receptor antagonist.
• Antimuscarinic: Exhibits anticholinergic properties.
• Antiparkinsonian: Can be used to manage some symptoms of Parkinson’s disease.
• Sedative/Hypnotic: Induces drowsiness and promotes sleep.
• Local Anesthetic: Can provide local pain relief.

Mechanism of Action: Primarily, diphenhydramine competitively antagonizes the H1 histamine receptor. It also possesses antimuscarinic (anticholinergic) activity and acts as a sodium channel blocker, contributing to its diverse effects.

Alternate Names

While “diphenhydramine” is the generic name, it is also known by a variety of brand names such as:

• Benadryl (most common)
• Sominex
• Nytol
• Compoz
• Unisom SleepTabs (combination product)
• And many others

How It Works

Pharmacodynamics: Diphenhydramine’s primary action is as an inverse agonist at the H1 histamine receptor. By blocking histamine’s actions, it reduces allergic symptoms like vasodilation, increased vascular permeability, bronchoconstriction, and itching. The antimuscarinic effects contribute to the drying of secretions, reduced gastrointestinal motility, and potential cognitive effects. Sodium channel blockade results in local anesthetic properties.

Pharmacokinetics:

• Absorption: Diphenhydramine is well-absorbed orally, reaching peak plasma concentrations in 1-4 hours. IM and IV administration have rapid onset of action.
• Metabolism: Extensively metabolized in the liver, primarily via CYP2D6.
• Elimination: Excreted primarily in the urine, with a half-life of 4-8 hours (longer in elderly patients and those with hepatic impairment).

Mode of Action: Diphenhydramine competitively binds to the H1 receptor, preventing histamine from binding and initiating its downstream effects. It similarly competes at muscarinic receptors. It also blocks sodium channels, though this is less prominent at typical doses.

Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: H1 receptor inverse agonist, muscarinic receptor antagonist.

Elimination Pathways: Primarily renal excretion of metabolites; hepatic metabolism by CYP2D6.

Dosage

Standard Dosage

Adults:

• Oral: 25-50 mg every 4-6 hours as needed. Maximum daily dose: 300 mg.
• IM/IV: 10-50 mg every 4-6 hours as needed. Maximum daily dose: 400 mg. Administer IV at a rate not exceeding 25 mg/minute.

Children:

• Oral/IM/IV: Dosages based on weight (1-2 mg/kg/dose) or age:
  • 2-5 years: 6.25 mg every 4-6 hours as needed, max 37.5 mg/day
  • 6-11 years: 12.5-25 mg every 4-6 hours as needed, max 150 mg/day
  • 12+ years: Adult dosing
• Pediatric Safety: Avoid use in neonates and infants under 2 years unless specifically directed by a physician. Use caution in young children due to increased risk of paradoxical excitation and other adverse effects.

Special Cases:

• Elderly Patients: Start with lower doses and titrate carefully due to increased sensitivity and risk of adverse effects (confusion, dry mouth, constipation, etc.).
• Patients with Renal Impairment: Dose adjustments may be necessary based on the degree of impairment.
• Patients with Hepatic Dysfunction: Reduce the dose and monitor closely for adverse events.
• Patients with Comorbid Conditions: Exercise caution in patients with cardiovascular disease, glaucoma, prostatic hypertrophy, etc.

Clinical Use Cases

• Intubation: Not routinely used for intubation.
• Surgical Procedures: Can be used as a local anesthetic (1% solution).
• Mechanical Ventilation: Used off-label for sedation, but not recommended as a first-line agent.
• Intensive Care Unit (ICU) Use: May be used for sedation, but not routinely.
• Emergency Situations (e.g., anaphylaxis): 25-50 mg IV/IM, may repeat as needed. Epinephrine is first-line treatment.

Dosage Adjustments:

Adjustments required for renal/hepatic impairment and for patients with specific comorbidities.

Side Effects

Common Side Effects:

Drowsiness, dry mouth, blurred vision, constipation, urinary retention, dizziness.

Rare but Serious Side Effects:

Confusion, hallucinations, seizures, palpitations, arrhythmias, extrapyramidal symptoms, anaphylaxis.

Long-Term Effects:

Cognitive impairment, tolerance to sedative effects, anticholinergic toxicity.

Adverse Drug Reactions (ADR):

Severe allergic reaction, agranulocytosis, Stevens-Johnson syndrome.

Contraindications

Hypersensitivity to diphenhydramine, narrow-angle glaucoma, urinary retention, severe asthma, MAOI use, newborns and premature infants. Use caution in elderly, patients with cardiovascular disease, and those with hepatic or renal impairment.

Drug Interactions

Alcohol, other CNS depressants (benzodiazepines, opioids), anticholinergics (tricyclic antidepressants, atropine), MAOIs. May inhibit the metabolism of other drugs metabolized by CYP2D6.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: B. Use only if clearly needed and with caution.
• Breastfeeding: Diphenhydramine enters breast milk and may cause drowsiness or irritability in infants. Avoid use or consider safer alternatives if possible.

Drug Profile Summary

• Mechanism of Action: H1 receptor antagonist, antimuscarinic, sodium channel blocker.
• Side Effects: Drowsiness, dry mouth, blurred vision, constipation, dizziness; rarely, seizures, arrhythmias, extrapyramidal reactions.
• Contraindications: Hypersensitivity, narrow-angle glaucoma, urinary retention, severe asthma, MAOI use, newborns.
• Drug Interactions: Alcohol, CNS depressants, anticholinergics, MAOIs.
• Pregnancy & Breastfeeding: Category B; use with caution during pregnancy; avoid during breastfeeding if possible.
• Dosage: Adults: 25-50 mg PO/IM/IV q4-6h (max 300 mg/day PO, 400 mg/day IM/IV). Pediatric: 1-2 mg/kg/dose.
• Monitoring Parameters: Respiratory rate, heart rate, blood pressure, mental status.

Popular Combinations

Often combined with analgesics (acetaminophen, ibuprofen) in cold and flu medications. Use with caution due to additive effects.

Precautions

Standard precautions related to allergies, metabolic disorders, organ dysfunction. Avoid alcohol and other CNS depressants. May impair driving ability. Caution in the elderly and in patients with pre-existing conditions.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Diphenhydramine?

A: Adults: 25-50 mg PO/IM/IV every 4-6 hours, not exceeding 300 mg/day PO or 400 mg/day IM/IV. Children: 1-2 mg/kg/dose every 4-6 hours, with age-specific maximums.

Q2: Can Diphenhydramine be used in children under 2?

A: It is generally not recommended unless specifically directed by a physician. Infants and young children are more susceptible to paradoxical excitation and other side effects.

Q3: What are the primary side effects of Diphenhydramine?

A: Drowsiness, dry mouth, blurred vision, constipation, and urinary retention are common.

Q4: What are the serious side effects to be aware of with Diphenhydramine?

A: Confusion, hallucinations, seizures, cardiac arrhythmias, and extrapyramidal symptoms can occur, although rarely.

Q5: Can Diphenhydramine be used during pregnancy or breastfeeding?

A: It’s a pregnancy category B drug; use cautiously during pregnancy. Avoid during breastfeeding if possible due to potential effects on the infant.

Q6: What are the drug interactions to consider with Diphenhydramine?

A: Alcohol, other CNS depressants, anticholinergic medications, and MAOIs can interact significantly.

Q7: How does Diphenhydramine work as a local anesthetic?

A: It acts as a sodium channel blocker, inhibiting nerve conduction and reducing pain signals.

Q8: Can diphenhydramine be administered intravenously?

A: Yes, but it should be infused slowly (no faster than 25 mg/minute) to minimize the risk of adverse cardiovascular effects.

Q9: Can I use Diphenhydramine long-term for insomnia?

A: It is not ideal for long-term insomnia management due to tolerance development, potential for anticholinergic toxicity, and cognitive impairment.

Q10: What should I do in case of Diphenhydramine overdose?

A: Seek immediate medical attention. Supportive care and symptomatic treatment are the mainstays of managing overdose.