Diphenhydramine

For the treatment of allergic symptoms or motion sickness, the standard adult dosage typically ranges from 25 mg to 50 mg taken every 4 to 6 hours. The maximum daily dose should generally not exceed 300 mg in a 24-hour period. For use as a nighttime sleep aid, a single dose of 50 mg is commonly taken 30 minutes before bedtime.

Pediatric dosing is strictly based on age and weight. For children aged 6 to 12 years, the typical dose is 12.5 mg to 25 mg every 4 to 6 hours, not to exceed 150 mg daily. For children under 6 years of age, diphenhydramine should only be used under the direct supervision of a pediatrician, as the risk of toxicity is higher in this population.

Renal Impairment

In patients with significant kidney disease, the interval between doses may need to be extended. Since the drug is primarily excreted as metabolites, clinical monitoring for increased sedation is recommended.

Hepatic Impairment

Because diphenhydramine is extensively metabolized by the liver, patients with hepatic dysfunction (liver failure) may experience prolonged drug effects. Lower doses or increased dosing intervals may be necessary.

Elderly Patients

Older adults (65+) are more sensitive to the anticholinergic effects of diphenhydramine. Healthcare providers often recommend lower starting doses to minimize the risk of confusion, dizziness, and falls.

Diphenhydramine can be taken with or without food. Taking it with food or milk may help reduce potential stomach upset. If using the liquid form, always use a calibrated measuring device (not a household spoon) to ensure an accurate dose. For motion sickness, the first dose should be taken 30 to 60 minutes before the activity that causes the condition. Store the medication at room temperature, away from moisture and direct heat.

If you miss a dose, take it as soon as you remember. However, if it is nearly time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not double the dose to catch up, as this increases the risk of adverse effects.

Signs of a diphenhydramine overdose may include extreme drowsiness, dilated pupils, fever, flushing, agitation, hallucinations, and in severe cases, seizures or cardiac arrhythmias. In the event of a suspected overdose, contact your local poison control center or seek emergency medical attention immediately.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance.

The most frequent side effect of diphenhydramine is somnolence (marked drowsiness). Patients often describe a 'foggy' feeling or decreased alertness that can last several hours. Other common effects include xerostomia (dry mouth), dry nose, and dry throat, which result from the drug's anticholinergic activity. These symptoms typically resolve once the medication is discontinued.

• Dizziness: A feeling of lightheadedness or unsteadiness.
• Gastrointestinal Distress: Nausea, vomiting, or constipation.
• Thickened Bronchial Secretions: This can make it more difficult to clear mucus from the chest.
• Coordination Impairment: Reduced fine motor skills and slower reaction times.

• Paradoxical Excitation: Instead of sedation, some patients (particularly children and the elderly) may experience restlessness, insomnia, or tremors.
• Tachycardia: An abnormally rapid heart rate.
• Photosensitivity: Increased sensitivity of the skin to sunlight.

> Warning: Stop taking Diphenhydramine and call your doctor immediately if you experience any of these.

• Urinary Retention: Difficulty or inability to pass urine, which can lead to bladder pain.
• Visual Disturbances: Blurred vision or increased intraocular pressure (pain in the eyes).
• Severe Hypotension: A significant drop in blood pressure leading to fainting.
• Hematologic Changes: Rare cases of hemolytic anemia or low white blood cell counts (agranulocytosis) have been reported in medical literature.
• Anaphylaxis: Signs include swelling of the face, tongue, or throat, difficulty breathing, and severe rash.

Prolonged use of diphenhydramine, especially in higher doses, may lead to the development of tolerance, where the body requires more of the drug to achieve the same effect. There is also emerging clinical evidence suggesting a potential link between the long-term, daily use of anticholinergic drugs and an increased risk of cognitive decline or dementia in older populations.

No FDA black box warnings currently exist for Diphenhydramine. However, the FDA has issued safety communications regarding the 'Benadryl Challenge' on social media, warning that higher than recommended doses can lead to serious heart problems, seizures, coma, or death.

Report any unusual symptoms to your healthcare provider.

Diphenhydramine is a central nervous system (CNS) depressant. Patients should be aware that its effects are cumulative when combined with other sedating substances. It should be used with extreme caution in patients with conditions that may be exacerbated by anticholinergic activity, such as asthma or cardiovascular disease.

No FDA black box warnings for Diphenhydramine.

• Respiratory Conditions: Use with caution in patients with a history of asthma, emphysema, or chronic bronchitis. The drying effect of the drug can thicken secretions and make breathing more difficult.
• Glaucoma: Diphenhydramine may increase intraocular pressure and should be avoided in patients with narrow-angle glaucoma.
• Prostatic Hypertrophy: Patients with an enlarged prostate may experience worsened urinary retention while taking this medication.
• Cardiovascular Risk: Due to its potential to cause tachycardia (fast heart rate) and hypotension (low blood pressure), it should be used cautiously in those with heart disease.

While routine lab monitoring is not typically required for short-term OTC use, patients on long-term or high-dose prescription diphenhydramine may require periodic assessments of:

• Liver Function Tests (LFTs): To ensure the liver is processing the drug effectively.
• Cognitive Assessment: Especially in elderly patients to monitor for signs of confusion or delirium.

Diphenhydramine significantly impairs the mental and physical abilities required for driving or operating heavy machinery. The impairment can persist even the morning after taking the drug as a sleep aid. Do not engage in hazardous activities until you know how this medication affects you.

Alcohol consumption must be avoided while taking diphenhydramine. Alcohol synergistically increases the sedative effects of the drug, leading to dangerous levels of respiratory depression and impaired motor control.

For short-term use, diphenhydramine can typically be stopped without tapering. However, if used chronically for sleep, sudden discontinuation may result in 'rebound insomnia,' where sleep difficulties temporarily worsen. Discuss a cessation plan with your doctor if you have been using it daily.

> Important: Discuss all your medical conditions with your healthcare provider before starting Diphenhydramine.

• Elarofluzavir: Using diphenhydramine with certain antiviral or specialized medications may lead to decreased efficacy or increased toxicity. Always verify specific contraindications with a pharmacist.
• MAO Inhibitors (MAOIs): Taking diphenhydramine with or within 14 days of an MAOI (e.g., phenelzine, selegiline) can significantly prolong and intensify the anticholinergic and CNS depressive effects of the antihistamine.

• Potassium Chloride (Oral): Anticholinergics like diphenhydramine slow gastrointestinal transit time, which can increase the risk of potassium-induced GI lesions or ulcers.
• CNS Depressants: Combining diphenhydramine with opioids (e.g., oxycodone), benzodiazepines (e.g., alprazolam), or antipsychotics increases the risk of severe sedation and respiratory distress.

• CYP2D6 Substrates: Diphenhydramine is an inhibitor of the CYP2D6 enzyme. It may increase the plasma levels of drugs metabolized by this enzyme, such as metoprolol or certain antidepressants (e.g., venlafaxine).
• Other Anticholinergics: Use with other drugs having anticholinergic properties (like amitriptyline or ipratropium) can lead to 'anticholinergic toxicity,' characterized by hot skin, blurred vision, and delirium.

There are no major contraindications regarding specific foods; however, taking the medication with a high-fat meal may slightly delay the time it takes to reach peak concentration (Tmax), though it does not typically reduce the overall absorption.

• Valerian and Kava: These herbs have sedative properties and may enhance the drowsiness caused by diphenhydramine.
• St. John's Wort: May alter the metabolism of various drugs, though the specific interaction with diphenhydramine is generally considered mild.

Diphenhydramine may interfere with allergy skin tests. Patients should typically stop taking antihistamines at least 4 days before such testing to avoid false-negative results. It may also occasionally cause false-positive results in urine drug screens for methadone or certain tricyclic antidepressants.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking.

• Hypersensitivity: Diphenhydramine must never be used in patients with a known allergy to the drug or any of its excipients.
• Neonates and Premature Infants: The drug is contraindicated in this population due to a high risk of CNS stimulation, seizures, and death.
• Breastfeeding: Because the drug is excreted in breast milk and may inhibit lactation, its use is generally contraindicated or strongly discouraged in nursing mothers.

• Stenosing Peptic Ulcer: The anticholinergic effects can reduce GI motility, potentially worsening an existing obstruction.
• Pyloroduodenal Obstruction: Similar to ulcers, the reduced motility can lead to complications in patients with gastric outlet obstructions.
• Bladder Neck Obstruction: Can lead to acute urinary retention.

Patients who are allergic to other ethanolamine-derivative antihistamines (such as clemastine or dimenhydrinate) may also experience allergic reactions to diphenhydramine. If you have had a reaction to an antihistamine in the past, inform your healthcare provider before use.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing Diphenhydramine.

Diphenhydramine is historically classified as FDA Pregnancy Category B. This means animal reproduction studies have failed to demonstrate a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women. While it is often used for short-term relief of severe nausea or allergies during pregnancy, it should only be used if clearly needed and under medical supervision, particularly during the third trimester, as it may cause uterine contractions.

Diphenhydramine is excreted in breast milk. Exposure to the infant can cause unusual excitement or irritability. Additionally, because antihistamines can decrease serum prolactin levels, they may interfere with the mother's milk supply. Healthcare providers generally recommend alternative treatments for breastfeeding women.

Diphenhydramine is approved for use in children 6 years and older. In younger children, it can cause paradoxical excitation (hyperactivity) rather than sedation. There have been reports of fatalities in infants and toddlers due to overdosage in multi-symptom cold products. Never use diphenhydramine to make a child sleepy.

According to the American Geriatrics Society (2023) Beers Criteria, diphenhydramine is considered a 'potentially inappropriate medication' for the elderly. Older adults have a higher risk of dizziness, sedation, and hypotension, which significantly increases the risk of falls and hip fractures. It may also worsen pre-existing cognitive impairment or dementia.

In patients with severe renal impairment (CrCl < 10 mL/min), the dosing interval should be increased (e.g., every 12 to 18 hours) to prevent the accumulation of metabolites, although the parent drug itself is mostly metabolized by the liver.

Patients with cirrhosis or other forms of liver disease may have a reduced ability to clear the drug from their system. This can lead to a longer half-life and increased risk of side effects. Dose reductions are often required for these patients.

> Important: Special populations require individualized medical assessment.

Diphenhydramine is a competitive antagonist of the Histamine-1 (H1) receptor. Histamine normally binds to H1 receptors to trigger inflammatory and allergic responses. By occupying these receptor sites, diphenhydramine prevents histamine from binding, thereby inhibiting the allergic cascade. Additionally, it acts as a muscarinic antagonist, blocking acetylcholine's action at parasympathetic nerve endings, which results in its 'drying' (anticholinergic) effects. Its sedative properties stem from its ability to cross the blood-brain barrier and block H1 receptors in the tuberomammillary nucleus of the hypothalamus, which is involved in maintaining wakefulness.

The onset of action for oral diphenhydramine is typically 15 to 30 minutes, with the maximum therapeutic effect occurring between 1 and 3 hours. The duration of action generally lasts between 4 and 8 hours. While it is effective for acute symptom relief, chronic use can lead to pharmacological tolerance, particularly regarding its sedative effects.

| Parameter | Value |

|---|---|

| Bioavailability | 40% - 60% |

| Protein Binding | 78% - 99% |

| Half-life | 2.4 - 9.3 hours |

| Tmax | 1 - 4 hours |

| Metabolism | Hepatic (Primary: CYP2D6) |

| Excretion | Renal (94%) |

• Molecular Formula: C17H21NO·HCl (for the Hydrochloride salt)
• Molecular Weight: 291.82 g/mol
• Solubility: Freely soluble in water and alcohol.
• Description: A white, odorless crystalline powder with a bitter, numbing taste.

Diphenhydramine is a first-generation antihistamine within the ethanolamine class. Related medications in this class include clemastine and dimenhydrinate. Unlike second-generation antihistamines (e.g., fexofenadine), it is characterized by high lipid solubility and significant CNS penetration.