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Diphenhydramine

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Diphenhydramine
Clinical data
Trade namesBenadryl, Unisom, Sominex, ZzzQuil
AHFS/Drugs.comMonograph
MedlinePlusa682539
Pregnancy
category
  • AU: A
Dependence
liability		Very low
Routes of
administration		Oral, IM, IV, topical and suppository
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40–60%[1]
Protein binding98–99%
MetabolismVarious cytochrome P450 liver enzymes: CYP2D6 (80%), 3A4 (10%)[4]
Elimination half-life7 hours (children)[2]
12 hours (adults)[2]
17 hours (elderly)[2]
Excretion94% through the urine, 6% through feces[3]
Identifiers
  • 2-(diphenylmethoxy)-N,N-dimethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.360 Edit this at Wikidata
Chemical and physical data
FormulaC17H21NO
Molar mass255.355 g/mol g·mol−1
3D model (JSmol)
  • O(CCN(C)C)C(c1ccccc1)c2ccccc2
  • 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 checkY
  • Key:ZZVUWRFHKOJYTH-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Diphenhydramine (/ˌdaɪfɛnˈhaɪdrəmiːn/; 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 nonprescription sleep aid, especially in the form of diphenhydramine citrate. It is produced and marketed under the trade name Benadryl by McNeil Consumer Healthcare in the U.S., Canada, and South Africa (trade names in other countries include Dimedrol, Daedalon, and Nytol). It is also available as a generic or store brand medication.

Diphenhydramine was one of the first antihistamines developed in the late 1940s and is the prototype of the ethanolamine class of first-generation antihistamines, which also includes orphenadrine, phenyltoloxamine, doxylamine, and halogenated diphenhydramine derivatives.[citation needed] It was first synthesized by George Rieveschl and first made publicly available through prescription in 1946.[5]

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.[6][7]

Diphenhydramine has been found to have a higher efficacy in treatment of allergies than some second-generation antihistamines (such as desloratadine)[8] but a similar efficacy with others (such as cetirizine).[9] 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 drug or prescription-only solution for injection. Injectable diphenhydramine can be used for life-threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex, as an adjunct to epinephrine.[10]

As a potent antagonist to acetylcholine in muscarinic receptors, diphenhydramine is used to treat Parkinson's disease-like extrapyramidal symptoms caused by antipsychotics. The muscarinic receptor antagonism leads to correction of levels of dopamine, the neurotransmitter responsible for control of motor function in the brain, similar to the effect of other antimuscarinic agents such as atropine.[11] Diphenhydramine can cause strong sedation and has also been used as an anxiolytic as a result.[12] It has also proven to have mild antiobsessive effects in one study researching obsessive–compulsive disorder (OCD) medication. Originally intended to act as a control medication, it in fact produced a significant decrement in OCD symptoms.[13]

Because of these sedative properties, diphenhydramine is widely used in nonprescription sleep aids for insomnia. The maximum recommended dose is 50 mg (as the hydrochloride salt), as mandated by the U.S. FDA. 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 (of which one variety uses diphenhydramine, while another uses doxylamine), Tylenol Simply Sleep, Nytol, ZzzQuil, and Sominex (the version sold in the US and Canada; that sold in the UK uses promethazine). Tolerance against the sedating effect of diphenhydramine builds very quickly; after three days of use at the common dosage, it is no more effective than a placebo[14] (according to one study done with 15 subjects). Diphenhydramine can cause minor psychological dependence when used improperly.[15]

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, such as meclizine, may be preferred for antiemetic use.

Also, topical formulations of diphenhydramine are available, including creams, lotions, gels, and sprays. These are used to relieve itching, and have the advantage of causing fewer systemic effects (e.g., drowsiness) than oral forms.[16] Diphenhydramine also has local anesthetic properties, and has been used as such in patients allergic to common local anesthetics such as lidocaine.[17]

Various derivatives of diphenhydramine including the muscle relaxant orphenadrine (Norflex) and bromodiphenhydramine (Ambrodyl) are used clinically and in research.

Adverse effects

Diphenhydramine is a potent anticholinergic agent. This activity is responsible for 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, increased body temperature (in general, in the hands and/or feet), temporary erectile dysfunction, and excitability, and although it can be used to treat nausea, higher doses may cause vomiting.[18] 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.

Torsades de pointes can occur as a side effect of diphenhydramine

Acute poisoning can be fatal, leading to cardiovascular collapse and death in 2–18 hours, and in general is treated using a symptomatic and supportive approach.[19] Diagnosis of toxicity is based on history and clinical presentation, and in general specific levels are not useful.[20] Several levels of evidence strongly indicate diphenhydramine (similar to chlorpheniramine) can block the delayed rectifier potassium channel and, as a consequence, prolong the QT interval, leading to cardiac arrhythmias such as torsades de pointes.[21] No specific antidote for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia.[20] Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in patients who are prone to these symptoms.[22]

Some patients have an allergic reaction to diphenhydramine in the form of hives.[23][24] However, restlessness or akathisia can also be a side effect made worse by increased levels of diphenhydramine, especially with recreational dosages.[25] 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 60 or children under the age of six, unless a physician is consulted.[26] These populations should be treated with second-generation antihistamines such as loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and azelastine.[19] Due to its strong anticholinergic effects, diphenhydramine is on the "Beers list" of drugs to avoid in the elderly.[27]

Diphenhydramine is category B in the FDA Classification of Drug Safety During Pregnancy.[28] It is also excreted in breast milk.[29] Paradoxical reactions to diphenhydramine have been documented, in particular among children, and it may cause excitation instead of sedation.[25]

Topical diphenhydramine is sometimes used especially on patients in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.[30]

Measurement in body fluids

Diphenhydramine can be quantified in blood, plasma, or serum.[31] 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.[31] Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for patients having ingested diphenhydramine.[32] Quantification can be used to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a death investigation.[31]

Mechanism of action

Overview of diphenhydramine targets and effects
Biological target Mode of action Effect
H1 receptor
(Peripheral)		 Inverse agonist Allergy relief
H1 receptor
(Central)		 Antagonist Sedation
mAChR Receptors Competitive antagonist Anticholinergic
Antiparkinson
Na channel Blocker Local anesthetic
SERT Inhibitor Mood alteration

Diphenhydramine is an inverse agonist of the histamine H1 receptor.[33] It is a member of the ethanolamine class of antihistaminergic agents.[19] By reversing the effects of histamine on the capillaries, it can reduce the intensity of allergic symptoms. It also crosses the blood–brain barrier and antagonizes the H1 receptors centrally. Its effects on central H1 receptors cause drowsiness.[34]

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.[35] 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.[36] Diphenhydramine has also been shown to inhibit the reuptake of serotonin.[37] It has been shown to be a potentiator of analgesia induced by morphine, but not by endogenous opioids, in rats.[38]

Pharmacokinetics

Oral bioavailability of diphenhydramine is in the range of 40–60% and peak plasma concentration occurs about 2–3 hours after administration.[1] The primary route of metabolism is two successive demethylations of the tertiary amine. The resulting primary amine is further oxidized to the carboxylic acid.[1] The half-life is as short as 8 hours in children to 17 hours in the elderly.[2]

History

Diphenhydramine was discovered in 1943 by George Rieveschl, a former professor at the University of Cincinnati.[39][40] In 1946, it became the first prescription antihistamine approved by the U.S. FDA.[41]

In the 1960s, diphenhydramine was found to inhibit reuptake of the neurotransmitter serotonin.[37] 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).[37][42] A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.[43]

Society and culture

Diphenhydramine is sometimes used recreationally as a deliriant, or as a potentiator of alcohol,[44][45] opiates,[46] DXM and other depressants. Diphenhydramine is deemed to have limited abuse potential in the United States due to 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.[47] 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.[48][49]

Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia,[50] and travelers are advised not to bring the 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.[51]

Recreational use

Diphenhydramine is sometimes used as a recreational drug, often by those without access to illegal drugs.[52] It is used for its sedative properties and (at higher doses) delirium-induced hallucinations. In many people, it can produce a distinctive weak to moderate euphoria due to a rise in the dopamine:acetylcholine ratio in the CNS. A fourth use, perhaps the most common, and one which is used clinically, is to intensify the effects of opioids and to make supplies last longer by lowering opioid requirements for a given targeted objective. Recreational use of diphenhydramine may cause:

  • Dysphoria
  • Hallucinations (auditory, visual, etc.)
  • Heart palpitations
  • Extreme drowsiness
  • Severe dizziness
  • Abnormal speech (inaudibility, forced speech, etc.)
  • Flushed skin
  • Severe mouth and throat dryness
  • Tremors
  • Seizures
  • Inability to urinate
  • Vomiting
  • Motor disturbances
  • Anxiety/nervousness
  • Disorientation
  • Abdominal pain
  • Delirium
  • Coma
  • Death[53]

See also

References

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Further reading


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