Clinical Pharmacokinetics of Ketanserin

Abstract

Ketanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around 50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 L/kg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite. Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3 h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40 mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40 mg twice daily, steady-state concentrations fluctuate between 40 micrograms/L (trough) and 100 to 140 micrograms/L (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with beta-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations. In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Psilocybin links binocular rivalry switch rate to attention and subjective arousal levels in humans

“…After baseline "pretesting" of binocular rivalry, the ketanserin/placebo capsules were administered. Peak plasma levels of ketanserin are generally reached within 0.5 to 2 h (Perrson et al 1991). Therefore, to ensure occupancy of the 5-HT 2A receptor, the psilocybin/placebo capsules were not administered until 90 min after the ketanserin.…”

Effect of 5-HT2 Receptor Blockade on Cadmium-Induced Acute Toxicity

“…Ketanserin exerts a direct hypotensive effect on the arterial scale of circulation as well as on the portal venous system, but it is not totally clear if these actions are solely dependent on the blockade of 5-HT 2 receptors or if the weak α 1 -adrenergic receptor blocking capacity of ketanserin also participates in this [26]. Ketanserin has also been reported to exert a vascular protection effect through actions in the vascular smooth muscle and platelets, and this effect is also mediated through the blockade of 5-HT 2 receptors [47].…”

“…Ketanserin is a 5-HT 2 receptor antagonist with relatively weaker α 1 -adrenoreceptor and H 1 -receptor blocking properties [24,25] and it has been introduced as an antihypertensive agent as well as for the treatment of vasospastic disorders [26]. Ketanserin has the ability to reverse many of the physiological actions of serotonin mediated through the 5-HT 2 receptor type, and in addition to its vasoactive properties, it also blocks platelet aggregation and improves hemorrheological properties [26].…”

“…Ketanserin has the ability to reverse many of the physiological actions of serotonin mediated through the 5-HT 2 receptor type, and in addition to its vasoactive properties, it also blocks platelet aggregation and improves hemorrheological properties [26].…”

Ocular Hypotensive Action of a Novel Tetrahydroquinoline Analog in Rabbit: Physicochemical Evaluation

“…Both ketanserin 9-11 and trazodone 28 have shown to reduce IOP. Ketanserin, pharmacologically classified as a 5-HT 2 antagonist, 29 is the most widely studied serotonin antagonist for potential use to treat glaucoma. On the basis of the chemistry of these two compounds, we had previously identified two new primary pharmacophores, 30 1-phenylpiperidine and 4-phenylmorpholine, that lower IOP in rabbit eye by 24.6% and 22.8%, respectively, by a serotonergic mechanism.…”