Diphenhydramine Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:460791686
Image Class:skin-invert-image
Tradename:Benadryl, Unisom, Nytol, others
Dailymedid:Diphenhydramine
Pregnancy Au:A
Dependency Liability:Low[1]
Routes Of Administration:By mouth, intramuscular, intravenous, topical, rectal
Class:First-generation antihistamine, antimuscarinic, hallucinogen (deliriant)
Atc Prefix:D04
Atc Suffix:AA32
Atc Supplemental:,
Legal Au:S4
Legal Au Comment:/S2 (Pharmacy Medicine) / S3 (Pharmacist Only Medicine)
Legal Ca:OTC
Legal Uk:P
Legal Uk Comment:[2]
Legal Us:OTC
Legal Us Comment:/Rx-only[3]
Legal Un:Unscheduled
Bioavailability:40–60%
Protein Bound:98–99%
Metabolism:Liver (CYP2D6, others)[4]
Elimination Half-Life:Range: 2.4–13.5 h
Excretion:Urine

94%[5]
Feces: 6%

Cas Number:58-73-1
Pubchem:3100
Iuphar Ligand:1224
Drugbank:DB01075
Chemspiderid:2989
Unii:8GTS82S83M
Kegg:D00300
Chebi:4636
Chembl:657
Iupac Name:2-(diphenylmethoxy)-N,N-dimethylethanamine
C:17
H:21
N:1
O:1
Smiles:O(CCN(C)C)C(c1ccccc1)c2ccccc2
Stdinchi: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
Stdinchikey:ZZVUWRFHKOJYTH-UHFFFAOYSA-N

Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. It is a first-generation H1-antihistamine and it works by blocking certain effects of histamine, which produces its antihistamine and sedative effects. Diphenhydramine is also a potent anticholinergic.[6] It is mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremors in parkinsonism, and nausea. It is taken by mouth, injected into a vein, injected into a muscle, or applied to the skin. Maximal effect is typically around two hours after a dose, and effects can last for up to seven hours.[7]

Common side effects include sleepiness, poor coordination, and upset stomach.[7] There is no clear risk of harm when used during pregnancy; however, use during breastfeeding is not recommended.[8]

It was developed by George Rieveschl and put into commercial use in 1946.[9] [10] It is available as a generic medication,[7] [7] In 2022, it was the 258th most commonly prescribed medication in the United States, with more than 1million prescriptions.[11] [12]

Its sedative and deliriant effects have led to some cases of recreational use.[13]

Medical uses

Diphenhydramine is a first-generation antihistamine used to treat several conditions including allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms.[14] [15] Diphenhydramine also has local anesthetic properties, and has been used as such in people allergic to common local anesthetics such as lidocaine.[16]

Allergies

Diphenhydramine is effective in the treatment of allergies.[17], it was the most commonly used antihistamine for acute allergic reactions in the emergency department.[18]

By injection, it is often used in addition to epinephrine for anaphylaxis,[19] although its use for this purpose had not been properly studied.[20] Its use is only recommended once acute symptoms have improved.[17]

Topical formulations of diphenhydramine are available, including creams, lotions, gels, sprays, and eye drops. These are used to relieve itching and have the advantage of causing fewer systemic effects (e.g., drowsiness) than oral forms.[21]

Movement disorders

Diphenhydramine is used to treat akathisia and parkinsonism caused by antipsychotics.[22] It is also used to treat acute dystonia including torticollis and oculogyric crisis caused by typical antipsychotics.

Sleep

Because of its sedative properties, diphenhydramine is widely used in nonprescription sleep aids for insomnia. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol) in Tylenol PM and ibuprofen in Advil PM. Diphenhydramine can cause minor psychological dependence.[23] Diphenhydramine has also been used as an anxiolytic.[24]

Diphenhydramine has also been used off-prescription by parents in an attempt to make their children sleep and to sedate them on long-distance flights.[25] This has been met with criticism, both by doctors and by members of the airline industry, because sedating passengers may put them at risk if they cannot react efficiently to emergencies,[26] and because the drug's side effects, especially the chance of a paradoxical reaction, may make some users hyperactive. Addressing such use, the Seattle Children's Hospital argued, in a 2009 article, "Using a medication for your convenience is never an indication for medication in a child."[27]

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of diphenhydramine in the treatment of insomnia, because of poor effectiveness and low quality of evidence.[28] A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found little evidence to inform the use of diphenhydramine for insomnia.[29]

Nausea

Diphenhydramine also has antiemetic properties, which make it useful in treating the nausea that occurs in vertigo and motion sickness. However, when taken above recommended doses, it can cause nausea (especially above 200 mg).[30]

Special populations

Diphenhydramine is secreted in breast milk.[31] It is expected that low doses of diphenhydramine taken occasionally will cause no adverse effects in breastfed infants. Large doses and long-term use may affect the baby or reduce breast milk supply, especially when combined with sympathomimetic drugs, such as pseudoephedrine, or before the establishment of lactation. A single bedtime dose after the last feeding of the day may minimize the harmful effects of the medication on the baby and the milk supply. Still, non-sedating antihistamines are preferred.[32]

Paradoxical reactions to diphenhydramine have been documented, particularly in children, and it may cause excitation instead of sedation.

Topical diphenhydramine is sometimes used especially for people in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research has not shown that this therapy is more effective than others.[33]

Anxiety

Diphenhydramine (as Benadryl) is not typically used to treat anxiety because its long-term use may cause adverse effects, such as memory loss, especially in the elderly. Benadryl is not approved by the US Food and Drug Administration for treating anxiety. On the other hand, hydroxyzine, a first generation antihistamine that lacks significant anticholinergic effects may be used to treat anxiety, although benzodiazepines and antidepressants are considered more effective by most clinicians.[34] The mild anxiolytic effects of hydroxyzine are mostly due to its weak but significant activity as an antagonist of the 5-HT2A receptor, a common target of most antidepressant drugs.

Adverse effects

The most prominent side effects are dizziness and sleepiness.

Diphenhydramine is a potent anticholinergic agent and potential deliriant in higher doses. 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.[35] Diphenhydramine in overdose may occasionally result in QT prolongation.[36]

Some individuals experience an allergic reaction to diphenhydramine in the form of hives.[37] [38]

Conditions such as restlessness or akathisia can worsen from increased levels of diphenhydramine, especially with recreational dosages.[39] Normal doses of diphenhydramine, like other first generation antihistamines, can also make symptoms of restless legs syndrome worse.[40] As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.

Anticholinergic use later in life is associated with an increased risk for cognitive decline and dementia among older people.[41] Drowsiness, memory loss, confusion, dry mouth or constipation may also occur in elderly people.[42]

Contraindications

Diphenhydramine is contraindicated in premature infants and neonates, as well as people who are breastfeeding. It is a pregnancy Category B drug. Diphenhydramine has additive effects with alcohol and other CNS depressants. Monoamine oxidase inhibitors prolong and intensify the anticholinergic effect of antihistamines.[43]

Overdose

Diphenhydramine is one of the most commonly misused over-the-counter drugs in the United States.[44] Overdose symptoms may include [45]

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. Diagnosis of toxicity is based on history and clinical presentation, and in general precise plasma levels do not appear to provide useful relevant clinical information.[46] 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.[47] No specific antidote for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia.[46] Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in people who are prone to these symptoms.[48]

Interactions

Alcohol may increase the drowsiness caused by diphenhydramine.[49] [50]

Pharmacology

Pharmacodynamics


Diphenhydramine[51]
data-sortable Site !Ki (nM) Species Ref
3800+ Human [52] [53]
960–2400 Human
1100–2200 Human
780 Human
1300 Human
2900 Human
1600 Human
2100 Human
20000 Rat [54]
9.6–16 Human [55]
100000+ Canine [56]
10000+ Human [57] [58]
10000+ Human
80–100 Human [59]
120–490 Human
84–229 Human
53–112 Human
30–260 Human
48000–86000 Rat
27100 Human [60]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Diphenhydramine, while traditionally known as an antagonist, acts primarily as an inverse agonist of the histamine H1 receptor.[61] It is a member of the ethanolamine class of antihistaminergic agents.[62] 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 inversely agonizes the H1 receptors centrally.[61] Its effects on central H1 receptors cause drowsiness.

Diphenhydramine is a potent antimuscarinic (a competitive antagonist of muscarinic acetylcholine receptors) and, as such, at high doses can cause anticholinergic syndrome.[63] 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.[64] Diphenhydramine has also been shown to inhibit the reuptake of serotonin. It has been shown to be a potentiator of analgesia induced by morphine, but not by endogenous opioids, in rats.[65] The drug has also been found to act as an inhibitor of histamine N-methyltransferase (HNMT).[66] [67]

Overview of diphenhydramine targets and effects
Biological target Mode of action Effect
Allergy reduction
Sedation
receptors Anticholinergic
Antiparkinson
Sodium channels Local anesthetic

Pharmacokinetics

Oral bioavailability of diphenhydramine is in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.[68] Diphenhydramine, available in various salt forms,[69] such as citrate,[70] [71] hydrochloride,[72] and salicylate,[73] exhibits distinct molecular weights and pharmacokinetic properties. Specifically, diphenhydramine hydrochloride and diphenhydramine citrate possess molecular weights of [74] and,[75] respectively. These variations in molecular weight influence the dissolution rates and absorption characteristics of each salt form.[76]

The primary route of metabolism is two successive demethylations of the tertiary amine. The resulting primary amine is further oxidized to the carboxylic acid.[68] Diphenhydramine is metabolized by the cytochrome P450 enzymes CYP2D6, CYP1A2, CYP2C9, and CYP2C19.[77]

The elimination half-life of diphenhydramine has not been fully elucidated, but appears to range between 2.4 and 9.3 hours in healthy adults.[78] A 1985 review of antihistamine pharmacokinetics found that the elimination half-life of diphenhydramine ranged between 3.4 and 9.3 hours across five studies, with a median elimination half-life of 4.3 hours.[68] A subsequent 1990 study found that the elimination half-life of diphenhydramine was 5.4 hours in children, 9.2 hours in young adults, and 13.5 hours in the elderly.[79] A 1998 study found a half-life of 4.1 ± 0.3 hours in young men, 7.4 ± 3.0 hours in elderly men, 4.4 ± 0.3 hours in young women, and 4.9 ± 0.6 hours in elderly women.[80] In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9 hours.[81]

Chemistry

Detection in body fluids

Diphenhydramine can be quantified in blood, plasma, or serum.[82] 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.[82] Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for people having ingested diphenhydramine.[83] Quantification can be used to monitor therapy, confirm a diagnosis of poisoning in people who are hospitalized, provide evidence in an impaired driving arrest, or assist in a death investigation.[82]

History

In 1943, diphenhydramine was discovered by chemist George Rieveschl and one of his students, Fred Huber, while they were conducting research into muscle relaxants at the University of Cincinnati.[84] Huber first synthesized diphenhydramine. Rieveschl then worked with Parke-Davis to test the compound, and the company licensed the patent from him.[85] In 1946, it became the first prescription antihistamine approved by the US FDA.[86]

In the 1960s, diphenhydramine was found to weakly 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).[87] [88] A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.[89]

In 1975, diphenhydramine was still available only by prescription in the US and required medical supervision.[90]

Society and culture

Marketing

Diphenhydramine is sold under the brand name Benadryl by McNeil Consumer Healthcare in the US, UK, Canada, and South Africa.[91] Trade names in other countries include Dimedrol, Daedalon, Nytol, and Vivinox. It is also available as a generic medication.

Procter & Gamble markets an over-the-counter formulation of diphenhydramine as a sleep aid under the brand ZzzQuil.[92]

Prestige Brands markets an over-the-counter formulation of diphenhydramine as a sleep aid in the US under the name Sominex.[93]

Cultural impact

Diphenhydramine is deemed to have limited abuse potential in the United States owing to its potentially serious side-effect profile and limited euphoric effects and is not a controlled substance. Since 2002, the US FDA has required special labeling warning against the use of multiple products that contain diphenhydramine.[94] 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.[95] [96]

Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia,[97] 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.[98]

Recreational use

Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases of abuse and addiction have been documented.[99] Because the drug is cheap and sold over the counter in most countries, adolescents without access to more sought-after illicit drugs are particularly at risk.[100] People with mental health problems—especially those with schizophrenia—are also prone to abuse the drug, which is self-administered in large doses to treat extrapyramidal symptoms caused by the use of antipsychotics.[101]

Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug.[101] [102] Research has shown that antimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties".[103] A study conducted on adult males with a history of sedative abuse found that subjects who were administered a high dose (400 mg) of diphenhydramine reported a desire to take the drug again, despite also reporting negative effects, such as difficulty concentrating, confusion, tremors, and blurred vision.[104]

In 2020, an Internet challenge emerged on the social media platform TikTok involving deliberately overdosing on diphenhydramine; dubbed the Benadryl challenge, the challenge encourages participants to consume dangerous amounts of Benadryl to film the resultant psychoactive effects and has been implicated in several hospitalisations[105] and at least two deaths.[106] [107] [108]

Further reading

Notes and References

  1. Book: Hubbard JR, Martin PR . Substance Abuse in the Mentally and Physically Disabled . 2001 . CRC Press . 978-0-8247-4497-7 . 26 .
  2. Web site: Benylin Chesty Coughs (Original) - Summary of Product Characteristics (SmPC) . (emc) . 24 February 2022 . 29 December 2022 . live . https://web.archive.org/web/20221230073626/https://www.medicines.org.uk/emc/product/1476/smpc . 30 December 2022.
  3. Web site: Diphenhydramine- diphenhydramine hydrochloride injection, solution . DailyMed . 11 November 2019 . 18 May 2024.
  4. Web site: Showing Diphenhydramine (DB01075) . DrugBank . 5 September 2009 . live . https://web.archive.org/web/20090831145953/http://drugbank.ca/drugs/DB01075 . 31 August 2009.
  5. Garnett WR . Diphenhydramine . American Pharmacy . NS26 . 2 . 35–40 . February 1986 . 3962845 . 10.1016/s0095-9561(16)38634-0.
  6. Book: Ayd FJ . Lexicon of Psychiatry, Neurology, and the Neurosciences . 2000 . Lippincott Williams & Wilkins . 978-0-7817-2468-5 . 332 . live . https://web.archive.org/web/20170908214041/https://books.google.ca/books?id=ea_QVG2BFy8C&pg=PA332 . 8 September 2017.
  7. Web site: Diphenhydramine Hydrochloride . Drugs.com . American Society of Health-System Pharmacists . 6 September 2016 . 28 September 2016 . live . https://web.archive.org/web/20160915002404/https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html . 15 September 2016.
  8. Web site: Diphenhydramine Pregnancy and Breastfeeding Warnings . Drugs.com . 28 September 2016 . live . https://web.archive.org/web/20161002114958/https://www.drugs.com/pregnancy/diphenhydramine.html . 2 October 2016.
  9. Book: Dörwald FZ . Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds . 2013 . John Wiley & Sons . 978-3-527-64565-7 . 225 . live . https://web.archive.org/web/20161002085621/https://books.google.ca/books?id=YTeY9ZEfNccC&pg=PA225 . 2 October 2016.
  10. Web site: Benadryl . Ohio History Central . 28 September 2016 . live . https://web.archive.org/web/20161017192649/http://ohiohistorycentral.org/w/Benadryl?rec=2591 . 17 October 2016.
  11. Web site: The Top 300 of 2022 . ClinCalc . 30 August 2024 . 30 August 2024 . https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  12. Web site: Diphenhydramine Drug Usage Statistics, United States, 2013 - 2022 . ClinCalc . 30 August 2024 .
  13. Saran JS, Barbano RL, Schult R, Wiegand TJ, Selioutski O . Chronic diphenhydramine abuse and withdrawal: A diagnostic challenge . Neurology. Clinical Practice . 7 . 5 . 439–441 . October 2017 . 29620065 . 10.1212/CPJ.0000000000000304 . 5874453.
  14. Web site: Diphenhydramine Hydrochloride Monograph . The American Society of Health-System Pharmacists . Drugs.com . live . https://web.archive.org/web/20110615135322/http://www.drugs.com/monograph/diphenhydramine-hydrochloride.html . 15 June 2011.
  15. Brown HE, Stoklosa J, Freudenreich O . How to stabilize an acutely psychotic patient . Current Psychiatary . 11 . 12 . 10–16 . December 2012 . dead . https://web.archive.org/web/20130514183445/http://stg.currentpsychiatry.com/pdf/1112/1112CP_Freudenreich.pdf . 14 May 2013.
  16. Smith DW, Peterson MR, DeBerard SC . Local anesthesia. Topical application, local infiltration, and field block . Postgraduate Medicine . 106 . 2 . 57–60, 64–6 . August 1999 . 10456039 . 10.3810/pgm.1999.08.650.
  17. Web site: American Society of Health-System Pharmacists . Diphenhydramine Hydrochloride . Drugs.com . 2 August 2016 . live . https://web.archive.org/web/20160915002404/https://www.drugs.com/monograph/diphenhydramine-hydrochloride.html . 15 September 2016.
  18. Banerji A, Long AA, Camargo CA . Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: a literature review . Allergy and Asthma Proceedings . 28 . 4 . 418–26 . 2007 . 17883909 . 10.2500/aap.2007.28.3015 . 7596980.
  19. Book: Humphries RL, Stone CK . CURRENT Diagnosis and Treatment Emergency Medicine . Seventh . LANGE CURRENT Series . McGraw–Hill Professional . 2011 . 978-0-07-170107-5 . Chapter 11: Shock . Young WF.
  20. Sheikh A, ten Broek VM, Brown SG, Simons FE . H1-antihistamines for the treatment of anaphylaxis with and without shock . The Cochrane Database of Systematic Reviews . 1 . CD006160 . January 2007 . 2007 . 17253584 . 10.1002/14651858.CD006160.pub2 . 6517288.
  21. Web site: Diphenhydramine Topical . . 9 October 2020 . live . https://web.archive.org/web/20201010221833/https://medlineplus.gov/druginfo/meds/a601044.html . 10 October 2020.
  22. Book: Katzung B, Masters S, Trevor A . Basic & Clinical Pharmacology . 12th . 2012 . The McGraw-Hill Companies, Inc. . 978-0-07-176401-8 . 483–500 . Aminoff MJ . Chapter 28. Pharmacologic Management of Parkinsonism & Other Movement Disorders.
  23. Web site: Benadryl Addiction . eMedTV . Monson K, Schoenstadt A . 8 September 2013 . usurped . https://web.archive.org/web/20140104053402/http://allergies.emedtv.com/benadryl/benadryl-addiction.html . 4 January 2014.
  24. Dinndorf PA, McCabe MA, Friedrich S . Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses . The Journal of Pediatrics . 133 . 2 . 293–5 . August 1998 . 9709726 . 10.1016/S0022-3476(98)70240-9.
  25. News: Is it wrong to drug your children so they sleep on a flight? . Crier F . The Telegraph . 2 August 2017 . subscription . 13 April 2020 . live . https://ghostarchive.org/archive/20220111/https://www.telegraph.co.uk/travel/family-holidays/is-it-ok-drug-babies-toddlers-children-sleep-flight-antihistamines/ . 11 January 2022.
  26. News: Morris R . Should parents drug babies on long flights? . 3 April 2013 . BBC News . 13 April 2020 . live . https://web.archive.org/web/20210308034544/https://www.bbc.com/news/magazine-21977785 . 8 March 2021.
  27. Web site: Swanson WS . 25 November 2009 . If It Were My Child: No Benadryl for the Plane . Seattle Children's . 13 April 2020 . dead . https://web.archive.org/web/20210225070641/https://seattlemamadoc.seattlechildrens.org/if-it-were-my-child-no-benadryl-for-the-plane/ . 25 February 2021.
  28. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL . Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline . J Clin Sleep Med . 13 . 2 . 307–349 . February 2017 . 27998379 . 10.5664/jcsm.6470 . 5263087.
  29. De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A . Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis . Lancet . 400 . 10347 . 170–184 . July 2022 . 35843245 . 10.1016/S0140-6736(22)00878-9 . free . 11380/1288245 . free . 250536370.
  30. Flake ZA, Scalley RD, Bailey AG . Practical selection of antiemetics . American Family Physician . 69 . 5 . 1169–74 . March 2004 . 15023018 . 10 March 2016 . live . https://web.archive.org/web/20160324141234/http://www.aafp.org/afp/2004/0301/p1169.html . 24 March 2016.
  31. Spencer JP, Gonzalez LS, Barnhart DJ . Medications in the breast-feeding mother . American Family Physician . 64 . 1 . 119–26 . July 2001 . 11456429.
  32. October 2020 . Diphenhydramine . Drugs and Lactation Database (LactMed) Internet . Bethesda (MD) . National Library of Medicine (US) . 30000938.
  33. , which cites
    • Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G . ABH gel is not absorbed from the skin of normal volunteers . Journal of Pain and Symptom Management . 43 . 5 . 961–6 . May 2012 . 22560361 . 10.1016/j.jpainsymman.2011.05.017 . free.
    • Weschules DJ . Tolerability of the compound ABHR in hospice patients . Journal of Palliative Medicine . 8 . 6 . 1135–43 . December 2005 . 16351526 . 10.1089/jpm.2005.8.1135.
  34. "Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 21 November 2018.
  35. Web site: Diphenhydramine Side Effects . Drugs.com . 9 November 2024 . 3 October 2024.
  36. Book: Aronson JK . Meyler's Side Effects of Cardiovascular Drugs . 2009 . Elsevier . 978-0-08-093289-7 . 623 . 4 March 2020 . live . https://web.archive.org/web/20210308005242/https://www.google.com/books/edition/Meyler_s_Side_Effects_of_Cardiovascular/oeBgU3UwgZkC?hl=en&gbpv=1&dq=Diphenhydramine+QT+prolongation&pg=PA623 . 8 March 2021.
  37. Heine A . Diphenhydramine: a forgotten allergen? . Contact Dermatitis . 35 . 5 . 311–312 . November 1996 . 9007386 . 10.1111/j.1600-0536.1996.tb02402.x . 32839996.
  38. Coskey RJ . Contact dermatitis caused by diphenhydramine hydrochloride . Journal of the American Academy of Dermatology . 8 . 2 . 204–206 . February 1983 . 6219138 . 10.1016/S0190-9622(83)70024-1.
  39. de Leon J, Nikoloff DM . Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports . CNS Spectrums . 13 . 2 . 133–5 . February 2008 . 18227744 . 10.1017/s109285290001628x . 10856872.
  40. Web site: Restless Legs Syndrome Fact Sheet . National Institute of Neurological Disorders and Stroke . 27 August 2019 . live . https://web.archive.org/web/20170728021833/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet . 28 July 2017.
  41. Salahudeen MS, Duffull SB, Nishtala PS . Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review . BMC Geriatrics . 15 . 31 . 31 . March 2015 . 25879993 . 10.1186/s12877-015-0029-9 . free . 4377853.
  42. Web site: Does Benadryl help with or cause anxiety? . Drugs.com . 9 November 2024 . 27 July 2023.
  43. Book: Sicari V, Zabbo CP . Diphenhydramine . 2021 . StatPearls . Treasure Island (FL) . StatPearls Publishing . 30252266 . 27 December 2021 . live . https://web.archive.org/web/20220528171459/https://www.ncbi.nlm.nih.gov/books/NBK526010/ . 28 May 2022.
  44. Book: Huynh DA, Abbas M, Dabaja A . Diphenhydramine Toxicity . 2021 . 32491510.
  45. Encyclopedia: Diphenhydramine overdose . MedlinePlus Medical Encyclopedia . U.S. National Library of Medicine . live . https://web.archive.org/web/20130530074604/http://www.nlm.nih.gov/medlineplus/ency/article/002636.htm . 30 May 2013.
  46. Book: Manning B . Olson K . Poisoning & Drug Overdose . 6th . 2012 . McGraw-Hill . 978-0-07-166833-0 . Chapter 18. Antihistamines . http://www.accessmedicine.com/content.aspx?aID=55974020. . 19 March 2013.
  47. Khalifa M, Drolet B, Daleau P, Lefez C, Gilbert M, Plante S, O'Hara GE, Gleeton O, Hamelin BA, Turgeon J . Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine . The Journal of Pharmacology and Experimental Therapeutics . 288 . 2 . 858–65 . February 1999 . 9918600.
  48. Cole JB, Stellpflug SJ, Gross EA, Smith SW . Wide complex tachycardia in a pediatric diphenhydramine overdose treated with sodium bicarbonate . Pediatric Emergency Care . 27 . 12 . 1175–7 . December 2011 . 22158278 . 10.1097/PEC.0b013e31823b0e47 . 5602304.
  49. Web site: Diphenhydramine and Alcohol / Food Interactions . Drugs.com . live . https://web.archive.org/web/20130217152320/http://www.drugs.com/food-interactions/diphenhydramine.html . 17 February 2013.
  50. Zimatkin SM, Anichtchik OV . Alcohol-histamine interactions . Alcohol and Alcoholism . 34 . 2 . 141–7 . 1999 . 10344773 . 10.1093/alcalc/34.2.141 . free.
  51. Web site: PDSP Ki Database . Psychoactive Drug Screening Program (PDSP) . Roth BL, Driscol J . Bryan Roth . University of North Carolina at Chapel Hill and the United States National Institute of Mental Health . 14 August 2017 . live . https://web.archive.org/web/20190420130325/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=diphenhydramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query . 20 April 2019.
  52. Tatsumi M, Groshan K, Blakely RD, Richelson E . Pharmacological profile of antidepressants and related compounds at human monoamine transporters . European Journal of Pharmacology . 340 . 2–3 . 249–58 . December 1997 . 9537821 . 10.1016/s0014-2999(97)01393-9.
  53. Krystal AD, Richelson E, Roth T . Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications . Sleep Medicine Reviews . 17 . 4 . 263–72 . August 2013 . 23357028 . 10.1016/j.smrv.2012.08.001.
  54. Tsuchihashi H, Sasaki T, Kojima S, Nagatomo T . Binding of [3H]haloperidol to dopamine D2 receptors in the rat striatum . J. Pharm. Pharmacol. . 44 . 11 . 911–4 . 1992 . 1361536 . 10.1111/j.2042-7158.1992.tb03235.x . 19420332.
  55. Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG . Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes . Bioorganic & Medicinal Chemistry . 14 . 19 . 6640–58 . October 2006 . 16782354 . 10.1016/j.bmc.2006.05.077.
  56. Gantz I, Schäffer M, DelValle J, Logsdon C, Campbell V, Uhler M, Yamada T . Molecular cloning of a gene encoding the histamine H2 receptor . Proceedings of the National Academy of Sciences of the United States of America . 88 . 2 . 429–33 . 1991 . 1991PNAS...88..429G . 1703298 . 10.1073/pnas.88.2.429 . free . 50824.
  57. Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG . Cloning and functional expression of the human histamine H3 receptor . Molecular Pharmacology . 55 . 6 . 1101–7 . June 1999 . 10347254 . 10.1124/mol.55.6.1101 . 25542667.
  58. Liu C, Ma X, Jiang X, Wilson SJ, Hofstra CL, Blevitt J, Pyati J, Li X, Chai W, Carruthers N, Lovenberg TW . Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow . Molecular Pharmacology . 59 . 3 . 420–6 . March 2001 . 11179434 . 10.1124/mol.59.3.420 . 123619.
  59. Bolden C, Cusack B, Richelson E . Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells . The Journal of Pharmacology and Experimental Therapeutics . 260 . 2 . 576–80 . February 1992 . 1346637.
  60. Suessbrich H, Waldegger S, Lang F, Busch AE . Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole . FEBS Letters . 385 . 1–2 . 77–80 . April 1996 . 1996FEBSL.385...77S . 8641472 . 10.1016/0014-5793(96)00355-9 . free . 40355762.
  61. Khilnani G, Khilnani AK . Inverse agonism and its therapeutic significance . Indian Journal of Pharmacology . 43 . 5 . 492–501 . September 2011 . 22021988 . 10.4103/0253-7613.84947 . free . 3195115.
  62. Book: Brunton L, Chabner B, Knollmann B . Brunton L . Goodman & Gilman's The Pharmacological Basis of Therapeutics . 12e . 2011 . McGraw Hill . 978-0-07-162442-8 . 242–245 . Chapter 32. Histamine, Bradykinin, and Their Antagonists.
  63. Web site: Lopez AM . Antihistamine Toxicity . WebMD LLC . Medscape Reference . 10 May 2010 . live . https://web.archive.org/web/20101013230957/http://emedicine.medscape.com/article/812828-overview . 13 October 2010.
  64. Kim YS, Shin YK, Lee C, Song J . Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine . Brain Research . 881 . 2 . 190–8 . October 2000 . 11036158 . 10.1016/S0006-8993(00)02860-2 . 18560451.
  65. Carr KD, Hiller JM, Simon EJ . Diphenhydramine potentiates narcotic but not endogenous opioid analgesia . Neuropeptides . 5 . 4–6 . 411–4 . February 1985 . 2860599 . 10.1016/0143-4179(85)90041-1 . 45054719.
  66. Horton JR, Sawada K, Nishibori M, Cheng X . Structural basis for inhibition of histamine N-methyltransferase by diverse drugs . Journal of Molecular Biology . 353 . 2 . 334–344 . October 2005 . 16168438 . 10.1016/j.jmb.2005.08.040 . 4021489.
  67. Taylor KM, Snyder SH . Histamine methyltransferase: inhibition and potentiation by antihistamines . Molecular Pharmacology . 8 . 3 . 300–10 . May 1972 . 4402747.
  68. Paton DM, Webster DR . Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines) . Clinical Pharmacokinetics . 10 . 6 . 477–97 . 1985 . 2866055 . 10.2165/00003088-198510060-00002 . 33541001.
  69. Wang C, Paul S, Wang K, Hu S, Sun CC . 2017 . Relationships among Crystal Structures, Mechanical Properties, and Tableting Performance Probed Using Four Salts of Diphenhydramine . Crystal Growth & Design . 17 . 11 . 6030–6040 . 10.1021/acs.cgd.7b01153.
  70. Rao DD, Venkat Rao P, Sait SS, Mukkanti K, Chakole D . 2009 . Simultaneous Determination of Ibuprofen and Diphenhydramine Citrate in Tablets by Validated LC . Chromatographia . 69 . 9–10 . 1133–1136 . 10.1365/s10337-009-0977-3 . 97766056.
  71. Rao DD, Sait SS, Mukkanti K . April 2011 . Development and validation of an UPLC method for rapid determination of ibuprofen and diphenhydramine citrate in the presence of impurities in combined dosage form . Journal of Chromatographic Science . 49 . 4 . 281–286 . 10.1093/chrsci/49.4.281 . 21439118.
  72. Chan CY, Wallander KA . February 1991 . Diphenhydramine toxicity in three children with varicella-zoster infection . DICP . 25 . 2 . 130–132 . 10.1177/106002809102500204 . 2058184 . 45456788.
  73. Kamijo Y, Soma K, Sato C, Kurihara K . November 2008 . Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support . Clinical Toxicology . 46 . 9 . 864–868 . 10.1080/15563650802116151 . 18608279 . 43642257.
  74. Web site: Diphenhydramine Hydrochloride . PubChem . U.S. National Library of Medicine.
  75. Web site: Diphenhydramine citrate . PubChem . U.S. National Library of Medicine.
  76. Web site: 28 August 2023 . Diphenhydramine Hydrochloride vs Citrate: What's the difference? . drugs.com . Pope C.
  77. Krystal AD . A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice . Sleep Med Rev . 13 . 4 . 265–74 . August 2009 . 19153052 . 10.1016/j.smrv.2008.08.001.
  78. Book: AHFS Drug Information . 1990 . Published by authority of the Board of Directors of the American Society of Hospital Pharmacists . 9 October 2017 . live . https://web.archive.org/web/20230114195325/https://books.google.com/books?id=WR0NAQAAMAAJ . 14 January 2023.
  79. Simons KJ, Watson WT, Martin TJ, Chen XY, Simons FE . Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children . Journal of Clinical Pharmacology . 30 . 7 . 665–71 . July 1990 . 2391399 . 10.1002/j.1552-4604.1990.tb01871.x . 25452263.
  80. Scavone JM, Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI . Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers . J Clin Pharmacol . 38 . 7 . 603–9 . July 1998 . 9702844 . 10.1002/j.1552-4604.1998.tb04466.x . 24989721.
  81. Gelotte CK, Zimmerman BA, Thompson GA . Single-Dose Pharmacokinetic Study of Diphenhydramine HCl in Children and Adolescents . Clin Pharmacol Drug Dev . 7 . 4 . 400–407 . May 2018 . 28967696 . 10.1002/cpdd.391 . 5947143.
  82. Book: Smith RK, Bogusz MJ . Pragst F . Forensic Science (Handbook of Analytical Separations) . 2nd . Elsevier Science . Amsterdam . 2007 . 978-0-444-52214-6 . 471 . Chapter 13: High performance liquid chromatography in forensic toxicological analysis . 6.
  83. Rogers SC, Pruitt CW, Crouch DJ, Caravati EM . Rapid urine drug screens: diphenhydramine and methadone cross-reactivity . Pediatric Emergency Care . 26 . 9 . 665–6 . September 2010 . 20838187 . 10.1097/PEC.0b013e3181f05443 . 31581678.
  84. News: Hevesi D . 29 September 2007 . George Rieveschl, 91, Allergy Reliever, Dies . The New York Times.
  85. Book: Sneader, Walter . Drug Discovery: A History . 23 June 2005 . John Wiley & Sons . 978-0-471-89979-2 . 405.
  86. Web site: Ritchie J . UC prof, Benadryl inventor dies . 24 September 2007 . Business Courier of Cincinnati . 14 October 2008 . live . https://web.archive.org/web/20081224055505/http://www.bizjournals.com/cincinnati/stories/2007/09/24/daily52.html . 24 December 2008.
  87. Domino EF . History of modern psychopharmacology: a personal view with an emphasis on antidepressants . Psychosomatic Medicine . 61 . 5 . 591–8 . 1999 . 10511010 . 10.1097/00006842-199909000-00002.
  88. Awdishn RA, Whitmill M, Coba V, Killu K . Serotonin reuptake inhibition by diphenhydramine and concomitant linezolid use can result in serotonin syndrome . Chest . October 2008 . 134 . 4 Meeting abstracts . 4C . 10.1378/chest.134.4_MeetingAbstracts.c4002 . 19 March 2013 . live . https://web.archive.org/web/20160311054736/http://journal.publications.chestnet.org/article.aspx?articleid=1094281 . 11 March 2016.
  89. Book: Barondes SH . 2003 . Better Than Prozac . 39–40 . New York . Oxford University Press . 978-0-19-515130-5 . registration.
  90. News: 2 December 1975 . FDA Orders Sominex 2 Withdrawn From Market . . 125 . 336 . 2 . . 16 April 2024.
  91. Web site: Childrens Benadryl Allergy (solution) Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division . Drugs.com . 26 November 2019 . live . https://web.archive.org/web/20200729221548/https://www.drugs.com/otc/110643/childrens-benadryl-allergy.html . 29 July 2020.
  92. News: Is P&G Preparing to Expand ZzzQuil? . 10 February 2017 . live . https://web.archive.org/web/20170211081209/http://adage.com/article/cmo-strategy/p-g-preparing-expansion-zzzquil/293998/ . 11 February 2017.
  93. Book: January 2023 . Mother To Baby Fact Sheets [Internet] . Diphenhydramine . . 35951938 . https://www.ncbi.nlm.nih.gov/books/NBK582675/ . 16 April 2024.
  94. Food and Drug Administration, HHS . Labeling of diphenhydramine-containing drug products for over-the-counter human use. Final rule . Federal Register . 67 . 235 . 72555–9 . December 2002 . 12474879 . live . https://web.archive.org/web/20081105004602/https://www.fda.gov/OHRMS/DOCKETS/98fr/120602a.htm . 5 November 2008.
  95. Marinetti L, Lehman L, Casto B, Harshbarger K, Kubiczek P, Davis J . Over-the-counter cold medications-postmortem findings in infants and the relationship to cause of death . Journal of Analytical Toxicology . 29 . 7 . 738–43 . October 2005 . 16419411 . 10.1093/jat/29.7.738 . free.
  96. Book: Baselt RC . Disposition of Toxic Drugs and Chemicals in Man . Biomedical Publications . 2008 . 489–492 . 978-0-9626523-7-0.
  97. Web site: DOC . List of prohibited and controlled drugs according to chapter 96 of the laws of Zambia . The Drug Enforcement Commission ZAMBIA . 20 March 2013 . dead . https://web.archive.org/web/20131116010729/http://www.gctrips.org/documents/IllegaldrugsinZambia.docx . 16 November 2013.
  98. Web site: Zambia . Country Information > Zambia . Bureau of Consular Affairs, U.S. Department of State . 17 July 2015 . live . https://web.archive.org/web/20150721232323/http://travel.state.gov/content/passports/english/country/zambia.html . 21 July 2015.
  99. Thomas A, Nallur DG, Jones N, Deslandes PN . Diphenhydramine abuse and detoxification: a brief review and case report . Journal of Psychopharmacology . 23 . 1 . 101–5 . January 2009 . 18308811 . 10.1177/0269881107083809 . 45490366.
  100. Web site: Atypical Drugs of Abuse . Forest E . 27 July 2008 . Articles & Interviews . Student Doctor Network . live . https://web.archive.org/web/20130527231559/http://studentdoctor.net/2008/07/atypical-drugs-of-abuse/ . 27 May 2013.
  101. Halpert AG, Olmstead MC, Beninger RJ . Mechanisms and abuse liability of the anti-histamine dimenhydrinate . Neuroscience and Biobehavioral Reviews . 26 . 1 . 61–7 . January 2002 . 11835984 . 10.1016/s0149-7634(01)00038-0 . 46619422 . 23 December 2017 . dead . https://web.archive.org/web/20200802230007/https://www.queensu.ca/psychology/sites/webpublish.queensu.ca.psycwww/files/files/Faculty/Richard%20Beninger/Beninger_prp_25.pdf . 2 August 2020.
  102. Gracious B, Abe N, Sundberg J . The importance of taking a history of over-the-counter medication use: a brief review and case illustration of "PRN" antihistamine dependence in a hospitalized adolescent . Journal of Child and Adolescent Psychopharmacology . 20 . 6 . 521–4 . December 2010 . 21186972 . 10.1089/cap.2010.0031 . 3025184.
  103. Dilsaver SC . Antimuscarinic agents as substances of abuse: a review . Journal of Clinical Psychopharmacology . 8 . 1 . 14–22 . February 1988 . 3280616 . 10.1097/00004714-198802000-00003 . 31355546.
  104. Mumford GK, Silverman K, Griffiths RR . Reinforcing, subjective, and performance effects of lorazepam and diphenhydramine in humans . . 1996 . 4 . 4 . 421–430 . 10.1037/1064-1297.4.4.421.
  105. Web site: TikTok Videos Encourage Viewers to Overdose on Benadryl . TikTok Videos Encourage Viewers to Overdose on Benadryl . 9 October 2020 . live . https://web.archive.org/web/20201008114600/https://www.checkupnewsroom.com/tiktok-videos-encourage-viewers-to-overdose-on-benadryl/ . 8 October 2020.
  106. Web site: 28 August 2020 . Dangerous 'Benadryl Challenge' on Tik Tok may be to blame for the death of Oklahoma teen . KFOR.com Oklahoma City . 9 October 2020 . live . https://web.archive.org/web/20210802073032/https://kfor.com/news/local/dangerous-benadryl-challenge-on-tik-tok-blamed-for-the-death-of-oklahoma-teen/ . 2 August 2021.
  107. Web site: 25 September 2020 . Teen's Death Prompts Warning on 'Benadryl Challenge' . medpagetoday.com . 9 October 2020 . live . https://web.archive.org/web/20200929121653/https://www.medpagetoday.com/pediatrics/generalpediatrics/88816 . 29 September 2020.
  108. Web site: 23 April 2023 . What is the Benadryl challenge? New TikTok challenge that's left 13-year-old dead . The Independent . 23 April 2023.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Diphenhydramine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2025, A B Cryer, All Rights Reserved. Cookie policy.