Combined Pharmaco-EEG and Pharmacopsychological Study to Estimate CNS Effects of Ketanserin in Hypertensive Patients

Abstract

When developing a new compound, potential side effects on the central nervous system (CNS) should be systematically investigated to determine the drug’s safety, e.g., in respect of operating machinery or driving a car. The present study investigated CNS effects of ketanserin, a newly developed S2-serotonergic antagonist, in hypertensive patients. A multidimensional research strategy was used combining pharmaco-EEG and pharmacopsychological methods. The investigation consisted of two separate double-blind, randomized, and placebo-controlled studies, which were, however, planned together and in part included the same patients. The first study was carried out in 2 × 24 patients receiving chronic treatment with 2 × 20 mg ketanserin for 2 weeks, followed by 2 × 40 mg for a further 3 weeks. The second study was performed in 2 × 20 patients after subacute administration of 20 mg twice daily for six days. A multidimensional research strategy was employed to investigate CNS effects on functional and performance measures. Vigilance-related parameters, such as the alpha slow wave index and the absolute delta power, were assessed with pharmaco electroencephalography. Critical flicker-fusion frequency served as a measure of central sedation. Psychomotor performance and concentration tests were used to detect CNS effects which might impair car-driving ability. In addition, subjective well-being and adverse drug reactions were recorded. Ketanserin proved to be a safe drug to lower blood pressure. Only after chronic treatment were there slight indications that ketanserin could have a sedating and inhibiting action on the CNS. However, the differences between placebo and the ketanserin group, and the alterations within each group, were so minimal that they were not considered clinically relevant. A negative effect of ketanserin on car-driving ability is not very likely. The results show that the model was sensitive enough to detect CNS effects with sufficient certainty.

Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

“…This effect on RT accords with the known effects of ketanserin. When given orally, 20 mg of ketanserin may reduce sustained attention (Wingen et al, 2007) or alertness (Koudas et al, 2009), although the clinical effect of ketanserin on arousal is not profound (Herrmann and Baumgartner, 1986). Further, at this dose, ketanserin does not significantly effect cerebral blood flow (Olsen et al, 1992).…”

Serotoninergic mechanisms in hypertension. Focus on the effects of ketanserin.

“…138 In a psychoperformance study in 24 elderly patients with essential hypertension, treatment with ketanserin (40 mg twice daily for 5 weeks) caused a slight reduction of vigilance, without electroencephalographic changes and without impairment of visuomotor coordination; momentary well-being expressed on a mood scale was significantly better with ketanserin treatment than with placebo treatment. 260 In studies comparing ketanserin (40 mg b.i.d.) treatment with that of other antihypertensive agents, the incidence of complaints and the dropout rate for side effects was similar between ketanserin and the reference drugs (see Tables 4 and 5).…”

“…266 In humans, the sedation and sleepiness observed after high intravenous doses of ketanserin 117 and the transient sedation and alterations in the electroencephalogram following oral administration indicate that the drug reaches the brain. 259 - 260 Experiments in the dog 267 and the cat 268 also suggest that a centrally mediated inhibition of sympathetic nerve activity contributes to the hypotensive action of ketanserin. Furthermore, a single dose of ketanserin reduces sympathetic nerve activity in rats 8 -106 and cats.…”

Comparison of ketanserin, buspirone and propranolol on arousal, pupil size and autonomic function in healthy volunteers

“…It is also an α 1 adrenergic and histamine receptor antagonist (Dollery 1999). Ketanserin 20 mg has been reported to reduce critical flicker fusion frequency (CFFF; Graham et al 2002) and sustained attention (Wingen et al 2007) and it is considered a sedative drug (Dollery 1999) although clinically, its effects on arousal may not be as profound (Herrmann and Baumgartner 1986). Propranolol is another widely used antihypertensive agent with sympatholytic properties via peripheral beta adrenoceptor blockade on the vascular bed.…”