디펜히드라민

Pharmaceuticals

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

log Kow = 3.27

3.4

150-165 °C at 2.00E+00 mm Hg

BP: 165 °C at 3 mm Hg

BP: 150-165 °C at 2.0 mm Hg

161-162

Crystals from absolute alcohol + ether; mp: 166-170 °C; bitter taste; pH of 1% aqueous solution about 5.5; 1 g dissolves in: 1 mL water, 2 mL alcohol, 50 mL acetone, 2 mL chloroform; very slightly soluble in benzene, ether. Slowly darkens on exposure to light. Stable under ordinary conditions. /Diphenhydramine hydrochloride/

168 °C

9.1

9.1

8.98

pKa = 8.98

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P264+P265, P270, P280, P301+P317, P302+P352, P305+P351+P338, P321, P330, P332+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 6 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

REACH registered substance: Diphenhydramine (EC: 200-396-7)

Ethanamine, 2-(diphenylmethoxy)-N,N-dimethyl-: Does not have an individual approval but may be used under an appropriate group standard

Antiemetic active ingredients. The active ingredient of the product consists of the following when used within the dosage limits established for each ingredient in section 336.50(d): Diphenhydramine hydrochloride. /Diphenhydramine hydrochloride/

Nighttime sleep-aid active ingredients. The active ingredient of the product consists of the following when used within the dosage limits established for each ingredient in section 338.50(d): Diphenhydramine hydrochloride and diphenhydramine citrate. /Diphenhydramine hydrochloride and diphenhydramine citrate/

Antihistamine active ingredients. The active ingredient of the product consists of the following when used within the dosage limits established for each ingredient: Diphenhydramine hydrochloride and diphenhydramine citrate. /Diphenhydramine hydrochloride and diphenhydramine citrate/

Antitussive active ingredients. The active ingredients of the product consist the following when used within the dosage limits and in the dosage forms established for each ingredient in section 341.74(d): Diphenhydramine hydrochloride and diphenhydramine citrate. /Diphenhydramine hydrochloride and diphenhydramine citrate/

For more FDA Requirements (Complete) data for DIPHENHYDRAMINE (7 total), please visit the HSDB record page.

Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Diphenhydramine hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. /Diphenhydramine hydrochloride/

Hygiene measures: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Diphenhydramine hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Diphenhydramine hydrochloride/

Diphenhydramine hydrochloride topical solution contains a flammable vehicle, and the solution should not be exposed to an open flame or ignited materials (e.g., a lighted cigarette).

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Diphenhydramine hydrochloride/

Hand protection: Handle with gloves. /Diphenhydramine hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Diphenhydramine hydrochloride/

Skin and body protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Diphenhydramine hydrochloride/

Eye protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Diphenhydramine hydrochloride/

There is no specific antidote for diphenhydramine toxicity, but the anticholinergic syndrome has been treated with physostigmine for severe delirium or tachycardia. Benzodiazepines may be administered to decrease the likelihood of psychosis, agitation, and seizures in patients who are prone to these symptoms.

Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines/

Concurrent use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. /Antihistamines/

Concurrent use /with alcohol or other CNS depression-producing medications/ may potentiate the CNS depressant effects of either these medications or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamines/

Anticholinergic effects may be potentiated when /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines/

For more Interactions (Complete) data for DIPHENHYDRAMINE (8 total), please visit the HSDB record page.

EC50; Species: Danio rerio (Zebra Danio) age 4 hr postfertilization embryo, wild-type; Conditions: freshwater, static, 25 °C, pH 6.8-8, hardness 217-235 mg/L CaCO3, dissolved oxygen >80%; Concentration: 0.35 mM for 20 hr; Effect: abnormal development /formulation/

EC50; Species: Danio rerio (Zebra Danio) age 4 hr postfertilization embryo, wild-type; Conditions: freshwater, static, 25 °C, pH 6.8-8, hardness 217-235 mg/L CaCO3, dissolved oxygen >80%; Concentration: 0.14 mM for 44 hr; Effect: abnormal development /formulation/

EC50; Species: Danio rerio (Zebra Danio) age 4 hr postfertilization embryo, wild-type; Conditions: freshwater, static, 25 °C, pH 6.8-8, hardness 217-235 mg/L CaCO3, dissolved oxygen >80%; Concentration: 0.15 mM for 68 hr; Effect: abnormal development /formulation/

EC50; Species: Danio rerio (Zebra Danio) age 4 hr postfertilization embryo, wild-type; Conditions: freshwater, static, 25 °C, pH 6.8-8, hardness 217-235 mg/L CaCO3, dissolved oxygen >80%; Concentration: 0.02 mM for 140 hr; Effect: abnormal development /formulation/

For more Ecotoxicity Values (Complete) data for DIPHENHYDRAMINE (7 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 380(SRC), determined from a log Kow of 3.27(2) and a regression-derived equation(3), indicates that diphenhydramine is expected to have moderate mobility in soil(SRC). The pKa of diphenhydramine is 8.98(4), indicating that this compound will exist almost entirley in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Diphenhydramine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2014).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 380(SRC), determined from a log Kow of 3.27(2) and a regression-derived equation(3), indicates that diphenhydramine is expected to adsorb to suspended solids and sediment(SRC). The pKa of diphenhydramine is 8.98(4) which indicates diphenhydramine will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces and bioconcentration are not expected to be an important fate processes. Biodegradation data in water were not available(SRC, 2014).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diphenhydramine, which has an estimated vapor pressure of 5.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase diphenhydramine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.13 days(SRC), calculated from its rate constant of 1.3X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase diphenhydramine may be removed from the air by wet and dry deposition(SRC). Diphenhydramine does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Signs and Symptoms of Overdose

Diphenhydramine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding.

/AQUATIC SPECIES/ 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 multiple modes of action (MOA) targeting the histamine H1, acetylcholine (ACh), and 5-HT reuptake transporter receptors, and as such is used in hundreds of pharmaceutical formulations. The primary objective of this study was to develop a baseline aquatic toxicological understanding of DPH using standard acute and subchronic methodologies with common aquatic plant, invertebrate, and fish models. A secondary objective was to test the utility of leveraging mammalian pharmacology information to predict aquatic toxicity thresholds. The plant model, Lemna gibba, was not adversely affected at exposures as high as 10 mg/L. In the fish model, Pimephales promelas, pH affected acute toxicity thresholds and feeding behavior was more sensitive (no-observed-effect concentration = 2.8 ug/L) than standardized survival or growth endpoints. This response threshold was slightly underpredicted using a novel plasma partitioning approach and a mammalian pharmacological potency model. Interestingly, results from both acute mortality and subchronic reproduction studies indicated that the model aquatic invertebrate, Daphnia magna, was more sensitive to DPH than the fish model. These responses suggest that DPH may exert toxicity in Daphnia through ACh and histamine MOAs. The D. magna reproduction no-observed-effect concentration of 0.8 ug/L is environmentally relevant and suggests that additional studies of more potent antihistamines and antihistamine mixtures are warranted.

/AQUATIC SPECIES/ Ceriodaphnia dubia were tested to evaluate the acute and chronic interactive effects of diphenhydramine and sertraline. Observed effects were compared with 2 reference toxicity models, the concentration addition model and the independent action model. Results indicate that the 2 drugs exhibit additive toxicity in C. dubia. In some cases, individually sublethal concentrations of the chemicals resulted in 100% mortality when combined, demonstrating the potentially severe impact of trace environmental contaminants.

EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; See the data in Chemical Explorer/[USEPA; ICSS Dashboard Application; Available from, as of March 28, 2014: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. /Diphenhydramine hydrochloride/[Available from: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=147-24-0]

Antiemetic active ingredients. The active ingredient of the product consists of the following when used within the dosage limits established for each ingredient in section 336.50(d): Diphenhydramine hydrochloride. /Diphenhydramine hydrochloride/

Nighttime sleep-aid active ingredients. The active ingredient of the product consists of the following when used within the dosage limits established for each ingredient in section 338.50(d): Diphenhydramine hydrochloride and diphenhydramine citrate. /Diphenhydramine hydrochloride and diphenhydramine citrate/

Antihistamine active ingredients. The active ingredient of the product consists of the following when used within the dosage limits established for each ingredient: Diphenhydramine hydrochloride and diphenhydramine citrate. /Diphenhydramine hydrochloride and diphenhydramine citrate/

Antitussive active ingredients. The active ingredients of the product consist the following when used within the dosage limits and in the dosage forms established for each ingredient in section 341.74(d): Diphenhydramine hydrochloride and diphenhydramine citrate. /Diphenhydramine hydrochloride and diphenhydramine citrate/

For more FDA Requirements (Complete) data for DIPHENHYDRAMINE (7 total), please visit the HSDB record page.

D04AA32

R - Respiratory system

D - Dermatologicals

QR - Respiratory system

QD - Dermatologicals

Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain.

Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response. Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center. Furthermore, H1 receptors are similar to muscarinic receptors. Consequently, diphenhydramine also acts as an antimuscarinic. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication. Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties.

Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. Antihistamines antagonize, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa. /Antihistamines/

H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects mediated by activation of H1 receptors on endothelial cells (synthesis/release of NO and other mediators). /H1 Receptor Antagonists/

H1 antagonists suppress the action of histamine on nerve endings, including the flare component of the triple response and the itching caused by intradermal injection. /H1 Receptor Antagonists/

The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H(1) receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K(+) channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC(50) (12.5 and 48.1 microM, respectively) is within the range of drug concentrations detected in poisoned patients (30-300 microM). Both drugs shifted the I-V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1-4 and heteromeric KCNQ3/Q5 currents. Moreover, mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, mepyramine reduced the M type K(+) current in a concentration-dependent manner and led to marked membrane potential depolarization. It is likely that these effects may be involved in the adverse neuroexcitatory effects observed in patients experiencing an overdose of antihistamines.

The first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild. Three known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 +/- 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 microM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine > cetirizine approximate to hydroxyzine > fexofenadine > loratadine > diphenhydramine. The rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine approximate to fexofenadine > loratadine > desloratadine > or = hydroxyzine > or = diphenhydramine.

The elimination half-life ranges from 2.4-9.3 hours in healthy adults. The terminal elimination half-life is prolonged in liver cirrhosis.

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg. ... The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. ...

The terminal elimination half-life of diphenhydramine has not been fully elucidated, but appears to range from 2.4-9.3 hours in healthy adults. The terminal elimination half-life reportedly is prolonged in adults with liver cirrhosis.

Diphenhydramine undergoes rapid and extensive first-pass metabolism. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite). Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged. The metabolites are further conjugated with glycine and glutamine and excreted in urine. Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine.

Diphenhydramine is rapidly and apparently almost completely metabolized. Following oral administration, the drug apparently undergoes substantial first-pass metabolism in the liver. Diphenhydramine appears to be metabolized principally to diphenylmethoxyacetic acid, which may further undergo conjugation. The drug also undergoes dealkylation to form the N-demethyl and N, N-didemethyl derivatives. Diphenhydramine and its metabolites are excreted principally in urine.

Diphenhydramine is widely used as an over-the-counter antihistamine. However, the specific human cytochrome P450 (P450) isozymes that mediate the metabolism of diphenhydramine in the range of clinically relevant concentrations (0.14-0.77 microM) remain unclear. Therefore, P450 isozymes involved in N-demethylation, a main metabolic pathway of diphenhydramine, were identified by a liquid chromatography-mass spectrometry method developed in our laboratory. Among 14 recombinant P450 isozymes, CYP2D6 showed the highest activity of diphenhydramine N-demethylation (0.69 pmol/min/pmol P450) at 0.5 uM. CYP2D6 catalyzed diphenhydramine N-demethylation as a high-affinity P450 isozyme, the K(m) value of which was 1.12 +/- 0.21 uM. In addition, CYP1A2, CYP2C9, and CYP2C19 were identified as low-affinity components. In human liver microsomes, involvement of CYP2D6, CYP1A2, CYP2C9, and CYP2C19 in diphenhydramine N-demethylation was confirmed by using P450 isozyme-specific inhibitors. In addition, contributions of these P450 isozymes estimated by the relative activity factor were in good agreement with the results of inhibition studies. Although an inhibitory effect of diphenhydramine on the metabolic activity of CYP2D6 has been reported previously, the results of the present study suggest that it is not only a potent inhibitor but also a high-affinity substrate of CYP2D6. Therefore, it is worth mentioning that the sedative effect of diphenhydramine might be caused by coadministration of CYP2D6 substrate(s)/inhibitor(s). In addition, large differences in the metabolic activities of CYP2D6 and those of CYP1A2, CYP2C9, and CYP2C19 could cause the individual differences in anti-allergic efficacy and the sedative effect of diphenhydramine.

Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were grown in Sabouraud dextrose broth and screened for the ability to metabolize the ethanolamine-type antihistamine diphenhydramine. Based on the amount of parent drug recovered after 7 days incubation, both C. elegans strains metabolized approximately 74% of the diphenhydramine, 58% of this being identified as organic extractable metabolites. The organic extractable metabolites were isolated by reversed-phase high-performance liquid chromatography and identified by analyzing their mass and nuclear magnetic resonance spectra. Desorption chemical ionization mass spectrometry (DCIMS) with deuterated ammonia was used to differentiate possible isobaric diphenhydramine metabolites and to probe the mechanisms of ion formation under ammonia DCIMS conditions. C. elegans transformed diphenhydramine by demethylation, oxidation, and N-acetylation. The major metabolites observed were diphenhydramine-N-oxide (3%), N-desmethyldiphenhydramine (30%), N-acetyldidesmethyldiphenhydramine (13%), and N-acetyl-N-desmethyldiphenhydramine (12%). These compounds are known mammalian metabolites of diphenhydramine ... .

Diphenhydramine has known human metabolites that include Diphenhydramine N-glucuronide and N-Desmethyldiphenhydramine.

Hepatic and renal Route of Elimination: Little, if any, is excreted unchanged in the urine; most appears as the degradation products of metabolic transformation in the liver, which are almost completely excreted within 24 hours. Half Life: 1-4 hours

8GTS82S83M

DIPHENHYDRAMINE

Mechanisms of Action [MoA] - Histamine H1 Receptor Antagonists

Established Pharmacologic Class [EPC] - Histamine-1 Receptor Antagonist

Diphenhydramine is a Histamine-1 Receptor Antagonist. The mechanism of action of diphenhydramine is as a Histamine H1 Receptor Antagonist.

DIPHENHYDRAMINE

Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate.

Drugs used to prevent NAUSEA or VOMITING.

Drugs used to induce SLEEP, prevent SLEEPLESSNESS, or treat SLEEP INITIATION AND MAINTENANCE DISORDERS.

Drugs that selectively bind to but do not activate histamine H1 receptors, thereby blocking the actions of endogenous histamine. Included here are the classical antihistaminics that antagonize or prevent the action of histamine mainly in immediate hypersensitivity. They act in the bronchi, capillaries, and some other smooth muscles, and are used to prevent or allay motion sickness, seasonal rhinitis, and allergic dermatitis and to induce somnolence. The effects of blocking central nervous system H1 receptors are not as well understood.

Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety.

Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475)

Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour. The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.

The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine. Only about 1% of a single dose is excreted unchanged in urine. The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites.

Diphenhydramine is widely distributed throughout the body, including the CNS. Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg.

Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min.

Distribution of diphenhydramine into human body tissues and fluids has not been fully characterized. Following IV administration in rats, highest concentrations of the drug are attained in the lungs, spleen, and brain, with lower concentrations in the heart, muscle, and liver. Following IV administration in healthy adults, diphenhydramine reportedly has an apparent volume of distribution of 188-336 L. Volume of distribution of the drug reportedly is larger in Asian (about 480 L) than white adults.

The drug crosses the placenta and has been detected in milk, although the extent of distribution into milk has not been quantitated.

Anesthetics, Local; Anti-Allergic Agents; Antiemetics; Histamine H1 Antagonists; Hypnotics and Sedatives

MEDICATION

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >2500

For the treatment of symptoms associated with Vertigo/Meniere's disease, nausea and vomiting, motion sickness and insect bite.

(1976) 4.10X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1978) 4.40X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1976) PROBABLY GREATER THAN 9.08X10+5 GRAMS

(1978) PROBABLY GREATER THAN 9.08X10+5 GRAMS

By heating diphenylbromomethane, beta-dimethylamino-ethanol, and sodium carbonate in toluene. After distilling off the toluene, the purified diphenhydramine is converted to the hydrochloride with hydrogen chloride. /Diphenhydramine hydrochloride/

Table: Diphenhydramine Hydrochloride Preparations [Table#4378]

Benadryl, Benocten, Nytol, Sedopretten, Sominex, Unisom Sleepgels. /Diphenhydramine hydrochloride/