Diphenhydramine

1. Drug Name

• Generic Name: Diphenhydramine

• Brand Names: Benadryl, Sominex, Nytol, and others

2. Drug Classification

• Class: Antihistamine

• Subclass: First-generation H1-receptor antagonist

• Other Classifications: Sedative, Anticholinergic, Anti-emetic

3. Mechanism of Action

• Histamine Blockade: Diphenhydramine works by blocking the histamine H1 receptors in the body, which are involved in allergic responses. Histamine is a key mediator of allergic symptoms such as itching, sneezing, and runny nose. By blocking these receptors, diphenhydramine helps reduce allergic symptoms.

• CNS Depression: As a first-generation antihistamine, diphenhydramine is known to cross the blood-brain barrier, resulting in sedative effects. It inhibits histamine in the brain, which plays a role in wakefulness, leading to drowsiness and sedation.

• Anticholinergic Effects: Diphenhydramine also has anticholinergic properties, blocking acetylcholine receptors and contributing to side effects like dry mouth, blurred vision, and urinary retention. These properties also make it effective as a short-term treatment for motion sickness.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Diphenhydramine has an oral bioavailability of approximately 40-60%. The drug is absorbed well from the gastrointestinal tract.

  • Peak Plasma Concentration: It reaches peak plasma levels within 2 to 4 hours after oral administration.

• Distribution:

  • Volume of Distribution (Vd): The volume of distribution is approximately 3-5 L/kg.

  • Protein Binding: Diphenhydramine is approximately 98% protein-bound to albumin.

• Metabolism:

  • Liver Metabolism: Diphenhydramine is metabolized primarily in the liver by cytochrome P450 enzymes (mainly CYP2D6), resulting in various metabolites.

• Excretion:

  • Half-life (t½): The half-life of diphenhydramine is approximately 4-8 hours, but this may be prolonged in elderly individuals or those with hepatic or renal impairment.

  • Excretion: The drug is excreted in the urine, primarily as metabolites, with a small amount of unchanged drug.

• Special Considerations:

  • Elderly Patients: The elimination half-life of diphenhydramine can be prolonged in elderly patients, increasing the risk of sedation and anticholinergic effects.

  • Hepatic/Renal Impairment: Dose adjustments may be necessary in patients with liver or kidney dysfunction due to reduced metabolism and excretion.

5. Indications

• Primary Indications:

  • Allergic Rhinitis: Diphenhydramine is used to treat symptoms of allergic rhinitis, including sneezing, itching, and watery eyes.

  • Urticaria (Hives): It is used to manage the symptoms of urticaria, reducing itching and rash.

  • Insomnia: Due to its sedative effects, diphenhydramine is often used as a short-term sleep aid for insomnia.

  • Motion Sickness: Diphenhydramine is used to prevent and treat nausea, vomiting, and dizziness associated with motion sickness.

  • Cough: It is used in combination with other agents in cough syrups to relieve symptoms of cold and flu.

• Off-Label Uses:

  • Anxiety: In some cases, diphenhydramine is used off-label to manage mild anxiety due to its sedative properties.

  • Parkinsonism: Due to its anticholinergic effects, diphenhydramine may be used to treat some of the extrapyramidal symptoms of Parkinson's disease or drug-induced parkinsonism.

• Special Populations:

  • Pediatrics: Diphenhydramine is approved for use in children aged 2 years and older for allergy relief and for managing insomnia.

  • Geriatrics: Caution is advised in elderly patients due to increased risk of sedation, confusion, and anticholinergic side effects like urinary retention and dry mouth.

6. Dosage and Administration

• Adult Dosing:

  • Allergic Rhinitis and Urticaria: 25-50 mg orally every 4-6 hours (maximum 300 mg per day).

  • Insomnia: 50 mg taken 30 minutes before bedtime.

  • Motion Sickness: 50 mg 30 minutes before travel, then every 4-6 hours as needed.

• Pediatric Dosing:

  • Allergic Rhinitis and Urticaria:

    • Children aged 2 to 5 years: 6.25 mg every 4-6 hours (maximum 25 mg per day).

    • Children aged 6 to 11 years: 12.5-25 mg every 4-6 hours (maximum 150 mg per day).

    • Children aged 12 years and older: Same as adult dosing.

  • Insomnia: Use caution in children due to potential for overdose and excessive sedation.

• Renal/Hepatic Impairment: Dose reductions may be necessary in patients with hepatic or renal dysfunction due to slowed metabolism and excretion.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity: Known hypersensitivity to diphenhydramine or any of its ingredients.

• Relative Contraindications:

  • Severe Hepatic or Renal Impairment: Caution is advised, and dose adjustments are necessary in patients with significant liver or kidney dysfunction.

  • Glaucoma: Due to its anticholinergic effects, diphenhydramine should be used cautiously in patients with narrow-angle glaucoma.

8. Warnings and Precautions

• CNS Depression: As a first-generation antihistamine, diphenhydramine may cause sedation and drowsiness, which can impair motor skills and cognitive function. Patients should be warned not to operate heavy machinery or drive until they know how the drug affects them.

• Anticholinergic Effects: Diphenhydramine can cause dry mouth, blurred vision, urinary retention, and constipation due to its anticholinergic properties. These effects are particularly concerning in elderly patients.

• Elderly: Use with caution in elderly patients due to an increased risk of sedation, confusion, dizziness, and falls.

• Pregnancy: Diphenhydramine is classified as a Category B drug during pregnancy, which means it is generally considered safe, but should only be used when necessary and under the supervision of a healthcare provider.

• Lactation: Diphenhydramine is excreted in breast milk, so use with caution in breastfeeding mothers, especially when the infant is very young.

9. Adverse Effects

• Common Adverse Effects:

  • Drowsiness: A well-known side effect, often sought after for use as a sleep aid.

  • Dry Mouth: Due to its anticholinergic properties.

  • Dizziness: Common, particularly in elderly patients.

• Less Common but Clinically Significant:

  • Urinary Retention: Especially in older patients or those with pre-existing prostate issues.

  • Blurred Vision: Due to the anticholinergic effect on the ocular muscles.

• Rare/Serious:

  • Severe Allergic Reactions: Anaphylaxis or angioedema can occur, though they are rare.

  • QT Prolongation: In high doses or in susceptible individuals, diphenhydramine may prolong the QT interval, increasing the risk of arrhythmias.

  • Confusion: Especially in elderly individuals, diphenhydramine can cause confusion or delirium.

10. Drug Interactions

• CNS Depressants: Diphenhydramine enhances the sedative effects of other CNS depressants, including alcohol, benzodiazepines, barbiturates, and opiates.

• Monoamine Oxidase Inhibitors (MAOIs): Combining diphenhydramine with MAOIs can increase the risk of side effects such as hypertension, confusion, and seizures.

• Anticholinergic Drugs: The anticholinergic effects of diphenhydramine may be potentiated when combined with other anticholinergic medications, leading to a higher risk of side effects like dry mouth, constipation, and urinary retention.

11. Clinical Pharmacology

• Pharmacodynamics: Diphenhydramine’s pharmacodynamic action is primarily the result of its H1-receptor antagonism, which helps relieve allergic symptoms. Its sedative effects are due to central histamine blockade in the brain. Additionally, its anticholinergic effects contribute to the dry mouth and urinary retention observed in patients.

• Antiemetic Action: Diphenhydramine’s antiemetic action results from its ability to block histamine and acetylcholine receptors in the vestibular system, which helps control nausea and vomiting.

12. Special Populations

• Pregnancy: Category B (considered safe but should be used when necessary).

• Lactation: Excreted in breast milk, so use with caution.

• Pediatrics: Safe for children aged 2 years and older with adjusted doses.

• Geriatrics: Elderly patients may experience greater sedation and anticholinergic effects.

13. Therapeutic Uses

• Primary: Treatment of allergic reactions, rhinitis, urticaria, insomnia, motion sickness, and cough.

• Combinational Therapy: Often used in combination with other drugs in over-the-counter cough and cold medications.

• Clinical Trials: Various studies support its efficacy in treating allergy symptoms and insomnia, particularly for short-term use.

14. Monitoring and Follow-Up

• Symptom Monitoring: Patients should track symptoms such as drowsiness, dizziness, or dry mouth.

• Renal Function: In patients with renal dysfunction, renal function should be monitored, as the drug is excreted via the kidneys.

15. Overdose Management

• Symptoms of Overdose: Overdose symptoms may include severe drowsiness, dry mouth, urinary retention, blurred vision, confusion, hallucinations, and seizures.

• Management: Overdose treatment is symptomatic. Activated charcoal may be used within an hour of ingestion. Seizures should be treated with anticonvulsants, and agitation with benzodiazepines.

16. Patient Counseling Information

• Administration: Advise patients to take diphenhydramine with food to minimize stomach upset, although it can be taken on an empty stomach for faster absorption.

• Adverse Effects: Patients should be informed about the possibility of drowsiness and to avoid activities that require alertness, such as driving.

• Avoid Alcohol: Advise patients to avoid alcohol and other sedatives while on diphenhydramine, as they may increase drowsiness and increase the risk of side effects.

• Use in Children: Caution should be exercised when giving diphenhydramine to young children, particularly for the treatment of sleep problems.