Diphenhydramine

Systematic (IUPAC) name
2-(diphenylmethoxy)-N,N-dimethylethanamine
Clinical data
Trade names	Benadryl, Unisom, Sominex
AHFS/Drugs.com	monograph
MedlinePlus	a682539
Pregnancy cat.	A (AU) B (US)
Legal status	Over-the-counter
Routes	Oral, parenteral (IM), parenteral (IV), topical, suppository
Pharmacokinetic data
Bioavailability	40-60%[1]
Protein binding	98-99%
Metabolism	Various cytochrome P450 liver enzymes: CYP2D6 (80%), 3A4 (10%)[2]
Half-life	5.4 ± 1.8 hours (children)[3] 9.2 ± 2.5 hours (adults)[3] 13.5 ± 4.2 hours (elderly)[3]
Excretion	94% through the urine, 6% through feces [4]
Identifiers
CAS number	58-73-1 Y
ATC code	D04AA32 D04AA33, R06AA02
PubChem	CID 3100
IUPHAR ligand	1224
DrugBank	DB01075
ChemSpider	2989 Y
UNII	8GTS82S83M Y
KEGG	D00669 N
ChEBI	CHEBI:4636 Y
ChEMBL	CHEMBL1620 N
Chemical data
Formula	C17H21NO
Mol. mass	255.355 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C17H21NO/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16/h3-12,17H,13-14H2,1-2H3 Y Key:ZZVUWRFHKOJYTH-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Diphenhydramine hydrochloride ( /ˌdaɪfɛnˈhaɪdrəmiːn/; abbreviated DPH, sometimes DHM) is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason is often used 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 (other trade names in other countries: Dimedrol, Daedalon). It is also available as a generic or store brand medication. It is also found in the name-brand products Nytol, Unisom, Tylenol PM, Excedrin PM, Midol PM and Advil PM, though some Unisom products contain doxylamine instead. It is available as an over-the-counter (OTC) or prescribed HCl injectable. It may also be used for the treatment of extrapyramidal side-effects of many antipsychotics, such as the tremors that haloperidol can cause. In addition, 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 Cincinnati.^[5] In 1946, it became the first prescription antihistamine approved by the U.S. Food and Drug Administration (FDA).^[6]

Uses[link]

Medicinal[link]

Diphenhydramine is a first generation (typical) antihistamine used to treat a number of conditions including: allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms.^[7]

Despite being one of the oldest antihistamines on the market, it is more effective than even some of the latest prescription drugs.^[8] 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.^{[citation needed]}

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, the less sedating drug dimenhydrinate may be preferred for this purpose.

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).

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.^{[citation needed]} As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.

Recreational[link]

Diphenhydramine acts as an analgesia potentiator with morphine in rats.^[9] It is used recreationally as a deliriant, or as a potentiator of alcohol,^{[citation needed]} DXM^{[10][citation needed]} and some opiates.^[11] CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia.^{[citation needed]}

Like its chemical relatives, diphenhydramine has mild to moderate euphoriant actions of its own.

Toxicology also manifests in the autonomic nervous system, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry skin and mucous membranes.^{[citation needed]} Severe restlessness or akathesia can also be a side effect that is made worse by increased levels of diphenhydramine.^[12] Considerable overdosage can lead to cardiac arrest, serious ventricular dysrhythmias, coma, and death.^{[citation needed]}Such a side-effect profile is commonly thought to give ethanolamine-class antihistamines a relatively low abuse liability. The specific antidote for diphenhydramine poisoning (similar to that of Datura or Atropa belladonna poisoning) is physostigmine, usually given intravenously in a hospital.^{[citation needed]}

Diphenhydramine is among the prohibited and controlled substances in the Republic of Zambia.^[13] 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.^[14]

Adverse effects[link]

Like many other first-generation antihistamines, diphenhydramine can cause strong sedation. As such, diphenhydramine has also been used as an anxiolytic because of this side-effect. It is also a 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. Further side-effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), 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.^[15] Some side-effects, such as [Fasciculation|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.^[16]

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.^[17]

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.^[18][19]

Since 2002, the US FDA requires special labeling warning against using multiple products that contain diphenhydramine.^[20] Diphenhydramine has been shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a third day of common dosage.^[21]

Paradoxical reactions to diphenhydramine are documented, in particular, among children, and it may cause excitation instead of sedation^[22]

Diphenhydramine is on the "Beers list" to avoid in the elderly.^[23]

Tolerance and withdrawal[link]

Antihistamines are generally not addicting. Conversely, because of its strong anticholinergic and sedative effect, Diphenhydramine can cause some psychological and physical dependence if a patient has used this medication for quite some time. Symptoms such as rebound insomnia, nausea, vomiting, sweating and frequent urination can occur if the patient discontinues Benadryl, Sominex or other brand names containing Diphenhydramine. Other symptoms such as agitation and anxiety can also transpire.^{[citation needed]}

Chemistry[link]

Diphenhydramine, N,N-dimethyl-(diphenylmethoxy)ethylamine, is synthesized by a simple reaction of benzhydrylbromide and 2-dimethylaminoethanol:^[24][25][26]

Pharmacology[link]

Diphenhydramine is an inverse agonist of the histamine H₁ receptor.^[27] By blocking histamine in the capillaries it can reduce the intensity of allergic symptoms. Diphenhydramine crosses the blood–brain barrier (BBB) and antagonizes the H₁ receptors centrally. Its effects on central H₁ receptors causes drowsiness.^[28]

Like many other first-generation antihistamines, diphenhydramine is also a potent competitive antagonist of muscarinic cholinergic receptors, and, as such, at high doses can cause anticholinergic syndrome.^[29] Diphenhydramine can also act as a antiparkinson agent as a result of the blocking properties to the Muscarinic Acetylcholine Receptors in the brain.

In the 1960s, diphenhydramine was found to inhibit reuptake of the neurotransmitter serotonin.^[30] 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).^[31][32] A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.

Diphenhydramine also acts as a intracellular sodium channel blocker, which is responsible for its actions as a local anesthetic.^[33]

Quantification[link]

Diphenhydramine may be quantitated in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation.^{[citation needed]} Blood or plasma diphenhydramine concentrations are usually in a range of 10-150 μg/L in persons taking the drug orally for its antiemetic, antihistaminic or sedative effects, 0.7-2.7 mg/L (700-2700 μg/L) in those arrested for impaired driving, 1–5 mg/L in survivors of acute overdosage and 5–30 mg/L in victims of fatal overdosage.^{[citation needed]} 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.^[34][35]

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. Rogers SC, Pruitt CW, Crouch DJ, and Caravati EM. "Rapid urine drug screens: diphenhydramine... [Pediatr Emerg Care. 2010] - PubMed - NCBI." National Center for Biotechnology Information. Version 665-6. US National Library of Medicine, 26 Sept. 2010. Web. 2 May 2012. <http://www.ncbi.nlm.nih.gov/pubmed

See also[link]

• Acrivastine
• Anticholinergic
• Cetirizine
• H₁ antagonist
• Diphenhydramine citrate

References[link]

Notes[link]