Chemical formula: C₁₇H₂₁NO Molecular mass: 255.355 g/mol PubChem compound: 3100
Diphenhydramine is a potent antihistamine and antitussive with concurrent anticholinergic and sedative properties.
Diphenhydramine is effective in reducing sleep onset (i.e., time to fall asleep) and increasing the depth and quality of sleep.
Experiments have shown that the antitussive action is discrete from H1-receptor blockade and is located in the brain stem. The duration of activity of diphenhydramine is between 4 and 8 hours.
The sedative mechanism for diphenhydramine is thought to result from antagonism of central histamine and cholinergic receptors. The time course for sedation following a 50 mg oral dose was associated with higher plasma concentrations, and was significantly different from placebo during the first three hours following administration. The pharmacodynamics of sedation was correlated from placebo during the first three hours following administration. The pharmacodynamics of sedation was correlated with peak concentration of drug occurring during absorption and the alpha distribution phase.
Diphenhydramine is well absorbed from the gastrointestinal tract, reaching peak plasma concentrations from 47-153 ng/ml between 1.5 hours and 4 hours after a single 50 mg dose in adults. After multiple oral doses of 50 mg diphenhydramine hydrochloride four times during each day to four subjects, minimum diphenhydramine plasma concentrations at steady state on the third day ranged from 57-150 ng/ml.
Diphenhydramine is widely distributed throughout the body, including the CNS. The pharmacokinetics of diphenhydramine follows a two-compartment model in which the distribution or alpha phase is apparent over the first eight to ten hours. The volume of distribution adjusted by body weight is large for diphenhydramine at 14.0 l/kg (38%) for adults, 16.0 (32%) for adolescents, and 19.5 (28%) for children. Diphenhydramine is highly protein bound with free drug concentrations of 24.0 ± 1.9% ng/ml and 14.8 ± 1.5% ng/ml measured in Asian and Caucasian plasma. In adults with liver disease, protein binding is lower, although the volume of distribution is comparable to healthy adults.
Diphenhydramine undergoes extensive first pass metabolism with an absolute bioavailability of 72% ± 8%. It is extensively metabolized in the liver by demethylation to N-demethyl diphenhydramine (DMDP), and the extent of DMDP measured in plasma is highly correlated with the clearance of diphenhydramine. DMDP is subsequently demethylated too N,Ndidemethyl diphenhydramine. Because only the latter, minor metabolic pathway of N,Ndidemethylation appears to be mediated by cytochrome P450 2D6, diphenhydramine disposition in humans is not determined by CYP2D6 activity. Rather, clinical pharmacokinetics data to suggest that diphenhydramine may be an inhibitor of CYP2D6 without being extensively metabolized by this cytochrome P450 isozyme. N,Ndidemethyl diphenhydramine is further metabolized by oxidative deamination to diphenylmethoxyacetic acid.
Mean beta elimination half-life from 8.5 and 11.5 hours in adults have been reported in studies in which blood is sampled up to 24 to 72 hours. The half-life is increased to 13.6 ± 4.2 h in the elderly and to 15.2 ± 1.5 h in adults with liver cirrhosis. Little unchanged drug is excreted in the urine.
Mean oral clearances for adults after a 25 and 50 mg dose are 1041 and 1029 ml/min, respectively having coefficients of variation of 40% and 35%. Oral clearance is about 50% lower in elderly adults. Oral clearance is 691 ml/min (32%) for children ages 2 to 11 years, and is 1251 ml/min (43%) for adolescents' ages 12 to 17 years.
Pharmacokinetic studies indicate no major differences in distribution or elimination of diphenhydramine compared to younger adults.
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.
Diphenhydramine hydrochloride has a well-established safety profile.
The results of a range of tests suggest that diphenhydramine does not have mutagenic potential.
There is insufficient information to determine the carcinogenic potential of diphenhydramine, although such effects have not been associated with this drug in animal studies.
The results of a number of studies suggest that the administration of diphenhydramine does not produce any statistically significant teratogenic effects in rats, rabbits and mice.
There is insufficient information to determine whether diphenhydramine has the potential to impair fertility, although a diminished fertility rate has been observed in mice in one study.
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