Clinical Pharmacokinetics of H1-Receptor Antagonists (The Antihistamines)

Abstract

This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents. Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours. Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine. Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days]. They also have relatively large apparent volumes of distribution in excess of 4 L/kg. In children, the elimination half-lives of chlorpheniramine and hydroxyzine are shorter than in adults. In patients with alcohol-related liver disease, the elimination half-life of diphenhydramine was increased from 9 to 15 hours, while in patients with chronic renal disease that of chlorpheniramine was very greatly prolonged. Little, if any, published information is available on the pharmacokinetics of these drugs in neonates, pregnancy or during lactation. The relatively long half-lives of a number of the older H1-receptor antagonists such as brompheniramine, chlorpheniramine and hydroxyzine suggest that they can be administered to adults once daily.

Ebastine: the effect of a new antihistamine on psychomotor performance and autonomic responses in healthy subjects.

“…This was shown by its lack of effect on autonomic responses under parasympathetic control such as resting heart rate and salivary production (Tyrer, 1976), and the standing-tolying test (Bellavere & Ewing, 1982). This absence of anticholinergic actions may also contribute to its lack of sedative effects at least in therapeutic doses (Paton & Webster, 1985). In addition, the absence of a significant effect on the blood pressure or heart rate also suggests that ebastine does not impair the function of the sympathetic nervous system.…”

“…In experimental pharmacology and preliminary clinical investigations ebastine appears to be a potent long-acting drug with no apparent sedative properties in the antihistamine dose range (Roberts et al, 1987). Antihistamines have been used for over 30 years but impairment of psychomotor performance, sedation and anticholinergic effects have been associated with most earlier compounds (Peck et al, 1975;Carruthers et al, 1978;Clarke & Nicholson, 1978;Nicholson & Stone, 1982, 1986Paton & Webster, 1985). Antihistamines without sedation or psychmotor impairment constitute an important clinical development.…”

Cardiac arrest caused by diphenhydramine overdose

“…Peak serum levels of DPH are reached approximately 2–3 h after ingestion, and elimination half‐life is approximately 4 h. Because DPH is liposoluble and its volume of distribution is large (3–7 L/kg),2 its elimination by hemodialysis and hemoperfusion is difficult. Although DPH is considered as a relatively safe drug with a large therapeutic range, it causes dose‐dependent toxicity.…”

The pharmacokinetics, antihistamine and concentration‐effect relationship of ebastine in healthy subjects.

“…The disparity in the individual correlations is not clear but could result from variability in responsiveness to histamine (Bain, 1949;Huther et al, 1977), the presence of other active metabolites in varying concentrations in different individuals which could influence concentration-effect relationships (Paton & Webster, 1985), variability in the metabolism of ebastine by the liver (Brodie et al, 1981) or a combination of these factors. A similar significant correlation had been described for astemizole (Richards et al, 1984) and diphenhydramine (Bilzer et al, 1974;Carruthers et al, 1978).…”

“…A limiting factor in the acceptability of most conventional antihistamines is their sedative and anticholinergic effects (Nicholson & Stone, 1982;Paton & Webster, 1985;Levander et al, 1985). Recently, a new generation of antihistamines which do not appear to show sedative properties in their clinically useful antihistamine dose-range, have been introduced.…”