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Diphenhydramine: Map


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Indicated for:

Other uses:


  • Use in neonates and premature infants
  • Use in nursing mothers
  • Use as a local anesthetic
  • Use in people with hypersensitivity to diphenhydramine hydrochloride and other antihistamines of similar chemical structure
Non-medical use/abuse:

  • Used as a deliriant/hallucinogen
Side effects:

Atypical sensations:

  • Feelings of heaviness, hearing disturbance


  • Hypertension in sensitive individuals

Ear, nose, and throat:

  • Dryness of the nose and throat, heartburn


  • Increased or decreased appetite


  • Dryness of the eyes, redness of the eyes, yellowing of the eyes


  • Constipation, nausea


  • Hepatotoxicity in extremely large dosages



  • restlessness, extrapyramidal side-effects, restless-leg syndrome, confusion, clouded thinking, drowsiness, hallucinations, delirium, euphoria, short-term memory loss


  • Agitation, anxiety, emotional lability, depression, excitability (especially in children), paranoia


  • Decreased respiration


Urogenital and reproductive:

  • Urinary retention, sexual dysfunction, vaginal dryness, decreased libido


  • ?

Diphenhydramine hydrochloride ( ) is a chemical mainly used as an antihistamine, antiemetic, sedative, and hypnotic. It is produced and marketed under the trade name Benadryl by McNeil-PPC (a division of Johnson & Johnsonmarker) in the U.S. and Canada, and Dimedrol in other countries. It is also found in the name-brand products Nytol, Unisom, and Advil PM though some Unisom products contain doxylamine instead. It is available as an over-the-counter (OTC) or prescribed HCI injectable. It may also be used for the treatment of extrapyramidal side effects of typical antipsychotics, such as the tremors that haloperidol can cause. Additionally, injectable diphenhydramine can be used for life threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex rather than risking the side effects of epinephrine. It is a member of the ethanolamine class of antihistaminergic agents.

Diphenhydramine was one of the first known antihistamines, invented in 1943 by Dr. George Rieveschl, a former professor at the University of Cincinnatimarker. In 1946, it became the first prescription antihistamine approved by the U.S. Food and Drug Administration (FDA).

The brand Benadryl is currently trademarked in the United States by Johnson & Johnson; however, many drug store chains and retail outlets sell less-costly generic versions.

Pharmacological action

Diphenhydramine works by blocking the effect of histamine at H1 receptor sites. This results in effects such as the increase of vascular smooth muscle contraction, thus reducing the redness, hyperthermia and edema that occurs during an inflammatory reaction. In addition, by blocking the H1 receptor on peripheral nociceptors, diphenhydramine decreases their sensitization and consequently reduces itching that is associated with an allergic reaction. This is why diphenhydramine is a popular choice for treatment of the symptoms of allergic rhinitis, hives, motion sickness, and insect bites and stings.

In the 1960s it was found that diphenhydramine inhibits reuptake of the neurotransmitter serotonin. This discovery led to a search for viable antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). A similar search had previously led to the synthesis of the first SSRI zimelidine from brompheniramine, also an antihistamine.

Common use and dosage

As an antihistamine, the recommended dose for adults is 25–50 mg diphenhydramine every 4–6 hours, not to exceed 50-100 mg every 4–6 hours.

Diphenhydramine is a first-generation antihistamine drug. Despite being one of the oldest antihistamines on the market it is more effective than even some of the latest prescription drugs. Consequently, it is frequently used when an allergic reaction requires fast, effective reversal of the often dangerous effects of a massive histamine release.

Diphenhydramine has sedative properties and is widely used in nonprescription sleep aids with a maximum recommended dose of 50 mg (as the hydrochloride salt) being mandated by the U.S. FDA. In the United Kingdom, Australia, New Zealand, South Africa, and other countries, a 50-100 mg recommended dose is permitted.

The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol). An example of the latter is Tylenol PM. Examples of products having diphenhydramine as the only active ingredient include Unisom gelcaps (the tablet form contains doxylamine, a different active ingredient), Tylenol Simply Sleep, Nytol, and Sominex (the version sold in the US — that sold in the UK uses promethazine). Both types are also sold as generic or store brands.

There are also topical formulations of diphenhydramine available, including creams, lotions, gels, and sprays. They are used to relieve itching, and have the advantage of causing much less systemic effect (i.e. drowsiness) than oral forms.

Side effects

Like many other first-generation antihistamines, diphenhydramine is a potent anticholinergic agent. This leads to profound drowsiness as a very common side-effect. Diphenhydramine has also been used as an anxiolytic because of these sedating side effects. However, other side effects include possibilities of motor impairment (ataxia), dry mouth and throat, flushed skin, rapid or irregular heartbeat (tachycardia), blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), pupil dilation (mydriasis), urinary retention, constipation, difficulty concentrating, short-term memory loss, visual disturbances, hallucinations, irregular breathing, dizziness, irritability, itchy skin, confusion, decreased body temperature (generally in the hands and/or feet), erectile dysfunction, excitability, and delirium. Some side effects such as twitching may be delayed until the drowsiness begins to cease and the person is in more of an awakening mode. Diphenhydramine also has local anesthetic properties, and has been used for patients allergic to common local anesthetics like lidocaine.

The most common cardiac dysrhythmias associated with diphenhydramine overdose are sinus bradycardia, elongated S-T segment interval, and premature ventricular contraction.

Diphenhydramine is similar in its effects to dimenhydrinate, its 8-chlorotheophylline salt, although the latter is approximately 60% the potency in terms of required dosage and is slightly less sedating.

Some patients have an allergic reaction to diphenhydramine in the form of hives.

Since 2002, the US FDA requires special labeling warning against using multiple products that contain diphenhydramine.Diphenhydramine has been shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a third day of common dosage.

Paradoxical reactions to diphenhydramine are documented, particularly amongst children, and it may cause excitation instead of sedation.

Because of potential for more severe side effects, diphenhydramine is on the beers list to avoid in the elderly. (See NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly,

Benadryl Itch Stopping Gel is dangerous when swallowed.

Recreational use

Diphenhydramine is used both clinically and/or recreationally in conjunction with opioids to relieve itching and act as an analgesia potentiator.

It is used recreationally as a hallucinogen, deliriant, depressant, or as a potentiator of alcohol and some opiates.

Diphenhydramine is a moderate CYP2D6 inhibitor, and as a result can cause increases in blood levels of drugs that are CYP2D6 substrates. Diphenhydramine can also have an additive effect with other CNS depressants. Due to its interaction with a broad array of medications, combining diphenhydramine with other medications without medical supervision could have unanticipated and potentially hazardous results.

Many users report a side effect profile consistent with atropine intoxication. This is due to antagonism of muscarinic acetylcholine receptors in both the central and autonomic nervous system which inhibits various signal transduction pathways.

In the CNS, diphenhydramine readily crosses the blood-brain barrier, exerting effects within the visual and auditory cortex.Other CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia.

Toxicology also manifests in the autonomic nervous system, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry skin and mucous membranes.

Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death.

Such a side-effect profile is thought to give ethanolamine-class antihistamines a relatively low abuse liability.

The specific antidote for diphenhydramine poisoning is physostigmine, usually given by IV in hospital.

Diphenhydramine is among the prohibited and controlled substances in the Republic of Zambiamarker . Travelers are advised not to bring this drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing Diphenhydramine .

See also




  • J.A. Lieberman, History of the use of antidepressants in primary care. Primary Care Companion, J. Clinical Psychiatry, 2003; 5 (supplement 7).

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