Diphenhydramine

Absorption

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 .

Toxicity

Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others . Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes . Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse . Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow .
Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk . This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant .
Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults . Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects . Avoid use in elderly patients with confusion .
The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR) .
After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease . However, the mean plasma clearance and apparent volume of distribution were not significantly affected .
LD50=500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death.

Description

Diphenhydramine is one of the main representatives of antihistamine drugs that block H1 receptors. Besides antihistamine activity, diphenhydramine exhibits a local anesthetic effect, relaxes smooth muscle, and has sedative and soporific action.

Originator

Benadryl,Parke Davis,US,1946

The Uses of Diphenhydramine

Diphenhydramine also reduces muscle rigidity and general stiffness, and has a relatively minor effect on tremors.

The Uses of Diphenhydramine

Antihistaminic.

The Uses of Diphenhydramine

Diphenhydramine is used for symptoms of allergies, for treating hives, hay fever, serum sickness, and other allergic illnesses, and also as a sedative and soporific drug as an independent as well as in combination with other drugs. Synonyms of this drug are dimedrol, benadryl, allergina, valdren, and many others.

Background

Diphenhydramine - perhaps known most commonly as its brand name formulation Benadryl - is a first-generation H1 receptor antihistamine that is used extensively for the treatment of seasonal allergies, insect bites and stings, and rashes . However, it also has antiemetic, antitussive, hypnotic, and antiparkinson properties . As histamine receptors exist both peripherally and in the central nervous system, diphenhydramine has been shown to cause sedation due to its competitive antagonism of histamine H1 receptors within the central nervous system . While its use in allergy therapy can sometimes fall out of favor due to its sedative effect, diphenhydramine has been repurposed for use within many non-prescription over-the-counter sleep aids and cough-and-cold medications that have been marketed for "night time" use .
Diphenhydramine is also used in combination with 8-chlorotheophylline as the anti-nausea drug Dimenhydrinate where it is utilized primarily for its antagonism of H1 histamine receptors within the vestibular system .
Diphenhydramine has also been shown to be implicated in a number of neurotransmitter systems that affect behaviour including dopamine, norepinephrine, serotonin, acetylcholine, and opioid . As a result, diphenhydramine is being investigated for its anxiolytic and anti-depressant properties.

Indications

Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea .
Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for: i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated ; ii) the active treatment of motion sickness ; and iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents .

Definition

ChEBI: Diphenhydramine is an ether that is the benzhydryl ether of 2-(dimethylamino)ethanol. It is a H1-receptor antagonist used as a antipruritic and antitussive drug. It has a role as a H1-receptor antagonist, an antiemetic, a sedative, an anti-allergic agent, a muscarinic antagonist, an antiparkinson drug, an antipruritic drug, a local anaesthetic, an antidyskinesia agent, an antitussive and a oneirogen. It is an ether and a tertiary amino compound.

Manufacturing Process

As described in US Patent 2,421,714: (a) benzhydryl
omide is first prepared as follows: 840 parts by weight of diphenylmethane is heated to 130°C with stirring. In the presence of a 200 watt electric light 6 inches from the flask, 880 parts of
omine is added slowly. Liberation of H
occurs and addition requires 1 hour and 45 minutes. The temperature is maintained at 130°C for an additional 30 minutes. A fine stream of air is blown in to remove H
and
2 while the reaction mixture cools. Benzene (180 parts) is added and the solution used immediately in (b) below.
If pure benzhydryl
omide is desired the above reaction mixture is dissolved in ether, washed with water, sodium carbonate solution and finally with water. The ether is removed, benzene added and distilled off and the benzhydryl
omide distilled in vacuo. Yield 85%.
(b) 490 parts β-dimethylaminoethanol and 530 parts of anhydrous sodium carbonate are heated to 110°C with stirring. The addition of the benzenebenzhydryl
omide mixture is then begun. The temperature is raised to 120°- 125°C. As reaction takes place carbon dioxide is evolved, the addition requires1? hours. The mixture is kept at 125°C for 5 hours additional time. After cooling, 3,000 parts of water is added and the mixture stirred until the inorganic salts are dissolved. The mixture is transferred to a large separatory funnel and 1,500 parts of ether added. The ether solution is washed several times with water and then the ether layer extracted with 1 to 4 hydrochloric acid. The acid solution is treated with 30 parts of Darco and 30 parts Filter-Cel and filtered.
The free base is liberated from the acid solution with 20% sodium hydroxide solution and taken up in ether. The ether layer is washed with water, saturated with NaCl and then shaken with solid potassium hydroxide. The ether is removed by distillation, 200 parts of benzene added and distilled off. The residue is distilled in vacuo and the fraction 150°-165°C/2 mm is collected and amounts to 433 parts. The hydrochloride salt is prepared by dissolving the free base in anhydrous ether and slowly adding an alcoholic solution of hydrogen chloride. The solid is recrystallized from absolute alcohol-ether mixture or isopropanol-ether mixture and has a MP of 161-162°C.

Therapeutic Function

Antihistaminic

Trade name

Benadryl (Parke-Davis)

Contact allergens

This antihistaminic drug with sedative properties is mainly sold over the counter. It can be used both topically (treatment of pruritis) and orally for its antiallergic, antiemetic, sedative, and anticough properties. Allergic or photoallergic contact dermatitis and fixeddrug eruption seem to be rare.

Pharmacokinetics

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 .

Safety Profile

Deadly human poison by an unspecified route. Poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Experimental reproductive effects. Human systemic effects by ingestion: somnolence, alteration of operant conditioning, changes in psychophysiological tests. Human mutation data reported. When heated to decomposition it emits toxic fumes of NO,. See also ETHERS.

Synthesis

Diphenhydramine, 2-diphenylmethoxy-N,N-dimethylamine (10.2.5), is synthesized by the esterification of 2-dimethylaminoethanol with benzhydrylbromide [35¨C37].

Environmental Fate

Diphenhydramine is fairly stable in the environment although it does undergo photodegradation. Conjugates of diphenhydramine such as diphenhydramine-N-glucuronide may be converted back to the parent compound, diphenhydramine, through enzymatic cleavage during sewage treatment process. Diphenhydramine is removed poorly through wastewater treatment processes and is found in significant concentrations in aquatic organisms downstream from such plants.
Diphenhydramine has significant risk for bioaccumulation, particularly in water downstream from wastewater and sewage treatment facilities.

Metabolism

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 .

Solubility in water

One gram of diphenhydramine is soluble in 1 mL of water, 2 mL of ethanol, 2 mL of chloroform, or 50 mL of acetone; the compound is very slightly soluble in benzene or ether.

Toxicity evaluation

The toxicity of antihistamines is related to their anticholinergic (antimuscarinic), antihistamine, and serotonergic activation. The action of acetylcholine at the muscarinic receptors is blocked, resulting in signs and symptoms of anticholinergic poisoning. Diphenhydramine may produce direct toxicity unrelated to its anticholinergic properties including inhibition of cardiac fast sodium channels and at higher concentrations, the drug may inhibit potassium channels, which can result in QT prolongation. Diphenhydramine also blocks the reuptake of serotonin and has been reported to cause serotonin syndrome in some individuals during overdose. The action of diphenhydramine at H-1 receptors causes sedation.