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antihistamine (trade name Benadryl) used to treat allergic reactions involving the nasal passages (hay fever) and also to treat motion sickness (同)Benadryl

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/01/08 23:42:28」(JST)

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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-PPC (a division of Johnson & Johnson) 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 dimenhydrinate, its closest chemical relative, as well as orphenadrine, phenyltoloxamine, doxylamine, and halogenated diphenhydramine derivatives.^{[citation needed]}

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.^[5]^[6]

Diphenhydramine has been found to have a higher efficacy in treatment of allergies than some second-generation antihistamines (such as desloratadine)^[7] but a similar efficacy with others (such as cetirizine).^[8] 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.^[9]

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.^[10] Diphenhydramine can cause strong sedation and has also been used as an anxiolytic as a result.^[11] 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.^[12]

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, 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.^[13] Diphenhydramine can cause minor psychological dependence when used improperly.^[14]

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 meclozine, 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.^[15] Diphenhydramine also has local anesthetic properties, and has been used as such in patients allergic to common local anesthetics such as lidocaine.^[16]

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.^[17] 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.^[18] Diagnosis of toxicity is based on history and clinical presentation, and in general specific levels are not useful.^[19] 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.^{[citation needed]} No specific antidote for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia.^[19] Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in patients who are prone to these symptoms.^[20]

Some patients have an allergic reaction to diphenhydramine in the form of hives.^[21]^[22] However, restlessness or akathisia can also be a side effect made worse by increased levels of diphenhydramine, especially with recreational dosages.^[23] 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.^[24] These populations should be treated with second-generation antihistamines such as loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and azelastine.^[18] Due to its strong anticholinergic effects, diphenhydramine is on the "Beers list" of drugs to avoid in the elderly.^[25]

Diphenhydramine is category B in the FDA Classification of Drug Safety During Pregnancy.^[26] It is also excreted in breast milk.^[27] Paradoxical reactions to diphenhydramine have been documented, in particular among children, and it may cause excitation instead of sedation.^[23]

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.^[28]

Diphenhydramine can exacerbate restless legs syndrome.^[29]

Measurement in body fluids

Diphenhydramine can be quantified in blood, plasma, or serum.^[30] 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.^[30] Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for patients having ingested diphenhydramine.^[31] Quantification can be to used monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a death investigation.^[30]

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.^[32] It is a member of the ethanolamine class of antihistaminergic agents.^[18] 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.^[33]

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.^[34] 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.^[35] Diphenhydramine has also been shown to inhibit the reuptake of serotonin.^[36] It has been shown to be a potentiator of analgesia induced by morphine, but not by endogenous opioids, in rats.^[37]

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.^[3]

History

Diphenhydramine was discovered in 1943 by George Rieveschl, a former professor at the University of Cincinnati.^[38] In 1946, it became the first prescription antihistamine approved by the U.S. FDA.^[39]

In the 1960s, diphenhydramine was found to inhibit reuptake of the neurotransmitter serotonin.^[36] 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).^[36]^[40] A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.^[41]

Society and culture

Diphenhydramine is sometimes used recreationally as a deliriant, or as a potentiator of alcohol,^[42]^[43] opiates,^[44] 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.^[45] 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.^[46]^[47]

Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia,^[48] 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.^[49]

Recreational use

Diphenhydramine is sometimes used as a recreational drug, often by those without access to illegal drugs.^[50] 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^[51]

References

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^ Ritchie J (24 September 2007). "UC prof, Benadryl inventor dies". Business Courier of Cincinnati. Retrieved 14 October 2008.
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^ Barondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 39–40. ISBN 0-19-515130-5.
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^ Zimatkin SM, Anichtchik OV (1999). "Alcohol-histamine interactions". Alcohol Alcohol. 34 (2): 141–7. doi:10.1093/alcalc/34.2.141. PMID 10344773.
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^ Marinetti L, Lehman L, Casto B, Harshbarger K, Kubiczek P, Davis J (October 2005). "Over-the-counter cold medications-postmortem findings in infants and the relationship to cause of death". J. Anal. Toxicol. 29 (7): 738–43. doi:10.1093/jat/29.7.738. PMID 16419411.
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External links

Prescription Information (PDF)
Diphenhydramine University of Maryland Medical Center Medical References

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English Journal

A fast ultra high pressure liquid chromatographic method for qualification and quantification of pharmaceutical combination preparations containing paracetamol, acetyl salicylic acid and/or antihistaminics.

Deconinck E, Sacre PY, Baudewyns S, Courselle P, De Beer J.SourceDepartment of Pharmaco-Bromatology, Section Medicinal Products, Scientific Institute of Public Health (IPH), J. Wytmansstraat 14, 1050 Brussels, Belgium.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2011 Sep 10;56(2):200-9. Epub 2011 May 19.
A fully validated UHPLC method for the identification and quantification of pharmaceutical preparations, containing paracetamol and/or acetyl salicylic acid, combined with anti-histaminics (phenylephrine, pheniramine maleate, diphenhydramine, promethazine) and/or other additives as quinine sulphate,
PMID 21665401

Effects of the antihistamine diphenhydramine on selected aquatic organisms.

Berninger JP, Du B, Connors KA, Eytcheson SA, Kolkmeier MA, Prosser KN, Valenti TW Jr, Chambliss CK, Brooks BW.SourceInstitute of Biomedical Studies, Baylor University, Waco, Texas, USA. jason_berninger@baylor.edu.
Environmental toxicology and chemistry / SETAC.Environ Toxicol Chem.2011 Sep;30(9):2065-72. doi: 10.1002/etc.590. Epub 2011 Jul 13.
In recent years pharmaceuticals have been detected in aquatic systems receiving discharges of municipal and industrial effluents. Although diphenhydramine (DPH) has been reported in water, sediment, and fish tissue, an understanding of its impacts on aquatic organisms is lacking. Diphenhydramine has
PMID 21647947

Japanese Journal

Membrane Transport Mechanisms of Quinidine and Procainamide in Renal LLC-PK1 and Intestinal LS180 Cells

Masago Miki,Takaai Mari,Sakata Jumpei,Horie Asuka,Ito Toshikazu,Ishida Kazuya,Taguchi Masato,Hashimoto Yukiya
Biological & Pharmaceutical Bulletin 33(8), 1407-1412, 2010
… The rank order of the inhibitory effects of hydrophobic cationic drugs on the uptake of procainamide in LS180 cells was imipramine>quinidine>diphenhydramine≈pyrilamine>procainamide, which was consistent with that on the uptake of quinidine. …
NAID 130000300368

Hypnotic and Sleep Quality-Enhancing Properties of Kavain in Sleep-Disturbed Rats

TSUTSUI Ryuki,SHINOMIYA Kazuaki,TAKEDA Yasuhiro,OBARA Yoshihito,KITAMURA Yoshihisa,KAMEI Chiaki
Journal of pharmacological sciences 111(3), 293-298, 2009-11-20
… The present study was performed to investigate the effects of kavain on the sleep-wake cycle in comparison with that of rilmazafone and diphenhydramine using sleep-disturbed rats. … On the other hand, significant shortening of the sleep latency was observed following the administration of diphenhydramine, while no effects were observed on the awake and non-REM sleep time. …
NAID 10026154277

Related Pictures

★リンクテーブル★

リンク元	「ジフェンヒドラミン」「diphenhydramine laurylsulfate」
拡張検索	「diphenhydramine citrate」「diphenhydramine salicylate」「diphenhydramine hydrochloride」「diphenhydramine methylbromide」

「ジフェンヒドラミン」

Diphenhydramine
Systematic (IUPAC) name
	2-(diphenylmethoxy)-N,N-dimethylethanamine
Clinical data
Trade names	Benadryl, Unisom, Sominex, ZzzQuil,
AHFS/Drugs.com	monograph
MedlinePlus	a682539
Pregnancy cat.	AU: A; US: B;
Legal status	AU: Pharmacy Only (S2); Over-the-counter;
Dependence; liability	Very low
Routes	Oral, parenteral (IM and IV), topical, suppository
Pharmacokinetic data
Bioavailability	40–60%
Protein binding	98–99%
Metabolism	Various cytochrome P450 liver enzymes: CYP2D6 (80%), 3A4 (10%)
Half-life	8 hours (children); 9 to 12 hours (adults); 17 hours (elderly)
Excretion	94% through the urine, 6% through feces
Identifiers
CAS number	58-73-1
ATC code	D04AA32 D04AA33, R06AA02
PubChem	CID 3100
IUPHAR ligand	1224
DrugBank	DB01075
ChemSpider	2989
UNII	8GTS82S83M
KEGG	D00669
ChEBI	CHEBI:4636
ChEMBL	CHEMBL657
Chemical data
Formula	C17H21NO
Molecular mass	255.355 g/mol
	SMILES O(CCN(C)C)C(c1ccccc1)c2ccccc2;
	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 ; Key:ZZVUWRFHKOJYTH-UHFFFAOYSA-N ;
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