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Pharmacology: Pharmacodynamics: Diphenhydramine HCl is an ethanolamine antihistamine with anticholinergic (antimuscarinic), antitussive, anti-emetic, anti-vertigo, and sedative and hypnotic properties.
Antihistamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1-receptor sites on effector cells, thus preventing but not reversing responses mediated by histamine alone.
The antitussive effect of diphenhydramine is due to a central mechanism involving suppression of the medullary cough center.
The anti-emetic and anti-motion sickness effects of diphenhydramine result from its central anticholinergic and central nervous system (CNS) depressant properties. Likewise, its activity on parkinsonian syndrome and drug-induced extrapyramidal reactions are related to its central anticholinergic effects.
Anti-vertigo action is by central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the mid brain.
The exact mechanism for CNS depressant action is not known, but it is thought to cause indirect reduction of stimuli to the brain stem reticular formation.
Pharmacokinetics: After oral administration, diphenhydramine HCl is well absorbed from the gastrointestinal (GI) tract. The drug appears in plasma within 15 minutes and peak plasma concentrations are attained within 1 to 4 hours.
After single oral doses of 50 and 100 mg in healthy adults, peak plasma concentrations of 37 to 83 ng/mL and 81 to 159 ng/mL, respectively, have been reported. After oral administration of diphenhydramine at dosages of 2.5 mg every 4 hours or 50 mg every 6 hours, peak steady-state plasma concentrations of the drug were 55 to 85 ng/mL, respectively, and minimum steady-state plasma concentrations were 27.5 or 30 ng/mL, respectively.
Diphenhydramine is widely distributed throughout the body, including the CNS. The drug crosses the placenta and has been detected in milk, although the extent of distribution into milk has not been quantified. Diphenhydramine is approximately 80 to 85% bound to plasma proteins in vitro. Less extensive protein binding of the drug has been reported in healthy Asian adults and in adults with liver cirrhosis.
In a study among Caucasian and Asian patients, diphenhydramine 50 mg given orally caused greater peak plasma concentrations among Asians compared with Caucasians. Plasma protein binding was 85.2% in Caucasians and 76% in Asians. Asians had higher mean volumes of distribution and mean clearance values.
Diphenhydramine is rapidly and almost completely metabolized. After oral administration, the drug undergoes substantial first-pass metabolism in the liver and only about 40 to 60% of an oral dose reaches systemic circulation as unchanged diphenhydramine. Diphenhydramine appears to be metabolized principally to diphenylmethoxyacetic acid, which may further undergo conjugation. The drug also undergoes dealkylation to form the N-demethyl N, N-didemethyl derivatives. Diphenhydramine and its metabolites are excreted principally in urine.
Plasma concentrations of diphenhydramine appear to decline in a monophasic manner, although some pharmacokinetic data suggest a polyphasic elimination. The terminal elimination half-life of diphenhydramine has not been fully-explained, but appears to range from 2.4 to 9.3 hours in healthy adults.
