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Diphenhydramine (abbreviated DPH, sometimes DHM) is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties that is mainly used to treat allergies. It is also used in the management of drug-induced parkinsonism and other extrapyramidal symptoms. The drug has a strong hypnotic effect and is FDA-approved as a non-prescription sleep aid, especially in the form of diphenhydramine citrate. It is produced and marketed under the trade name Benadryl by McNeil-PPC (a division of Johnson & Johnson) in the U.S., Canada and South Africa (trade names in other countries include Dimedrol and Daedalon). It is also available as a generic or store brand medication.

Medical uses
Diphenhydramine is a first generation antihistamine used to treat a number of conditions including allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms.

Diphenhydramine is significantly more potent in treatment of allergies than newer generation of antihistamines. Consequently, it is frequently used when an allergic reaction requires fast, effective reversal of a massive histamine release. Diphenhydramine is available as an over-the-counter (OTC) or prescribed HCl injectable. In addition, injectable diphenhydramine can be used for life-threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex, as an adjunct to epinephrine.

It is a potent antagonist to acetylcholine affecting muscarinic receptors and as a result is used to treat parkinson's disease like extrapyramidal symptoms caused by typical antipsychotics. The muscarinic receptor antagonism leads to correction of dopamine, the neurotransmitter responsible for control of motor function in the brain, similar to other antimuscarinic agents such as atropine. Diphenhydramine can cause strong sedation and has also been used as an anxiolytic as a result.



Diphenhydramine sedative properties make it widely used in nonprescription sleep aids for insomnia. The maximum recommended dose of 50 mg (as the hydrochloride salt) being mandated by the U.S. FDA. Diphenhydramine has been shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a third day of common dosage. 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, Tylenol Simply Sleep, Nytol, ZzzQuil, and Sominex (the version sold in the US and Canada; that sold in the UK uses promethazine).

Diphenhydramine also has antiemetic properties which make it useful in treating the nausea that occurs in motion sickness. As it causes marked sedation in many individuals, newer generation antihistamines including Loratadine, Cetirizine, and Dimenhydrinate may be preferred for this purpose.

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. Diphenhydramine also has local anesthetic properties, and has been used for patients allergic to common local anesthetics like lidocaine.

Adverse effects
Diphenhydramine has potent anticholinergic agent, leading to the side-effects of dry mouth and throat, increased heart rate, pupil dilation, urinary retention, constipation, and, at high doses, hallucinations or delirium. Other side-effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia),sedation, difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing, dizziness, irritability, itchy skin, confusion, decreased body temperature (in general, in the hands and/or feet), erectile dysfunction, excitability, and, although it can be used to treat nausea, higher doses may cause vomiting. 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. Acute poisoning can be fatal leading to cardiovascular collapse and death in 2-18 hours and is treated general using a symptomatic and supportive approach. Diagnosis of toxicity is based on history and presentation of the patient and specific levels are generally not useful. There are several levels of evidence strongly indicating diphenhydramine (similar to chlorpheniramine) can block the delayed rectifier potassium channel and consequently prolong the QT-interval, leading to cardiac arrhythmias, such as torsade de pointes. There is no specific antidote for diphenhydramine toxicity, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia.

Some patients have an allergic reaction to diphenhydramine in the form of hives. Paradoxically restlessness or akathesia can also be a side effect that is made worse by increased levels of diphenhydramine. As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.

Special populations
Diphenhydramine is not recommended for patients older than 65 or children under the age of six, unless a physician is consulted. These populations should be treated with second-generation antihistamines such as loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and azelastine. Due to its strong anticholinergic effects, diphenhydramine is on the "Beers list" of drugs to avoid in the elderly.

Diphenhydramine is Category B in the FDA Classification of Drug Safety During Pregnancy. Diphenhydramine is also excreted in breast milk. Paradoxical reactions to diphenhydramine have been documented, particularly among children, and it may cause excitation instead of sedation.

Measurement in body fluids
Diphenhydramine can be quantitated in blood, plasma, or serum. Gas chromatography with mass spectrometry (GC-MS) can be used with electron ionization on full scan mode as a screening test. GC-MS or GC-NDP can be used for quantification. Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for patients who have ingested diphenhydramine. Quantitation can be used monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a death investigation.

Mechanism of action
Diphenhydramine is an inverse agonist of the histamine H1 receptor. It is a member of the ethanolamine class of antihistaminergic agents. By blocking the effects of histamine on the capillaries, it can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier (BBB) and antagonizes the H1 receptors centrally. Its effects on central H1 receptors cause drowsiness.

Like many other first-generation antihistamines, diphenhydramine is also a potent antimuscarinic (a competitive antagonist of muscarinic acetylcholine receptors), and, as such, at high doses can cause anticholinergic syndrome. The utility of diphenhydramine as an antiparkinson agent is the result of its blocking properties on the muscarinic acetylcholine receptors in the brain.

Diphenhydramine also acts as an intracellular sodium channel blocker, which is responsible for its actions as a local anesthetic. Diphenhydramine has also been shown to inhibit the reuptake of serotonin. Finally, diphenhydramine has been shown to be a potentiator of analgesia induced by morphine in rats.

Pharmacokinetics
Oral bioavailability of diphenhydramine is in the range of 40–60% and peak plasma concentration occurs approximately 2–3 hours after administration. The primary route of metabolism is two successive demethylations of the tertiary amine. The resulting primary amine is further oxidized to the carboxylic acid. The half-life is as short as 8 hours in children to 17 hours in the elderly.

History


Diphenhydramine was discovered in 1943 by Dr. George Rieveschl, a former professor at the University of Cincinnati. In 1946, it became the first prescription antihistamine approved by the U.S. Food and Drug Administration (FDA). Diphenhydramine, N,N-dimethyl-(diphenylmethoxy)ethylamine, was synthesized by a simple reaction of benzhydryl bromide and 2-dimethylaminoethanol.



In the 1960s, diphenhydramine was found to inhibit 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.

Society and culture
Diphenhydramine is sometimes abused as a deliriant, or as a potentiator of alcohol, opiates and other depressants. Diphenhydramine is deemed to have limited abuse potential in the United States due its potentially serious side effect profile and limited euphoric effects, and is not a controlled substance. Since 2002, the U.S. FDA has required special labeling warning against use of multiple products that contain diphenhydramine. In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events.

Diphenhydramine is among the prohibited and controlled substances in the Republic of Zambia. 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.