Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Remedica Ltd., Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Pharmacotherapeutic group: Antihistamines for systemic use
ATC Code: R06AA02
Diphenhydramine is a potent antihistamine and antitussive with concurrent anticholinergic and sedative properties. 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.
Menthol has mild local anaesthetic and decongestant properties. The mechanism by which menthol may act as an antitussive may be related to a strong stimulate effect on cold receptors in the larynx in the absence of cold air. It has been noted that substances which produce a hot sensation in the airway may stimulate the cough reflex, while method, which produces a cold sensation, has the opposite effect.
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.
Menthol is highly lipid soluble and, when taken orally, is rapidly absorbed from the small intestine.
There is insufficient data on the distribution of menthol.
In humans, menthol is partially metabolized to menthol glucuronide by rapid conjugation. Animal studies in rats have demonstrated that menthol then undergoes extensive enterohepatic recirculation after being cleaved from the glucuronide conjugate and reabsorbed in the small intestine. The reabsorbed menthol is then subsequently metabolized by oxidative processes it he liver. There is support for this model in humans as well because menthol has been shown to be oxidized y CYP2A6 in human liver microsomes.
A study in humans has demonstrated that approximately 50% of a menthol dose is excreted in the urine as menthol glucuronide. Other studies in rats have shown that menthol glucuronide is excreted in both the bile containing the majority of menthol glucuronide and with the urine also containing various oxidation products.
The results of a range of tests suggest that neither diphenhydramine nor menthol have mutagenic potential.
There is insufficient information to determine the carcinogenic potential of diphenhydramine or menthol, although such effects have not been associated with these drug in animal studies.
The results of a number of studies suggest that the administration of either diphenhydramine or menthol 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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