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PubMed1989

Prevention of atherosclerotic complications: controlled trial of ketanserin. Prevention of Atherosclerotic Complications with Ketanserin Trial Group.

STUDY OBJECTIVE: To determine whether ketanserin, an antagonist at the serotonin receptor, prevents important vascular events such as death, myocardial infarction, major stroke, and amputation of a leg in patients with claudication. DESIGN: Double blind, randomised, placebo controlled trial after a single blind run in period of placebo treatment for one month. SETTING: One hundred and forty seven outpatient clinics in 14 countries. PATIENTS: Total of 3899 patients over 40 years old who had had documented intermittent claudication for at least two months and in whom the ratio of systolic blood pressure in the ankle to that in the arm was less than or equal to 0.85 in both arteries of at least one foot. INTERVENTION: After the one month placebo run in period patients were randomly allocated to take 20 mg ketanserin three times daily for the first month and 40 mg three times daily thereafter or to take the same number of placebo tablets. Five months after the onset of the trial, on the recommendation of the ethical and safety committee, four patients stopped taking ketanserin and two stopped taking placebo because they had a corrected QT interval greater than 500 ms. Four months later the committee recommended that all patients taking diuretics should stop receiving trial treatment (167 of those taking ketanserin and 144 of those taking placebo). END POINT: The first primary event after randomisation. Primary events were definite myocardial infarction, major stroke, amputation above the ankle, excision of ischaemic viscera, and death due to other vascular causes. MEASUREMENTS AND MAIN RESULTS: There were 136 study end points in the 1930 patients treated with ketanserin, who were followed up for 2063 patient years, and 132 study end points in the 1969 patients treated with placebo, who were followed up for 2129 patient years. A harmful interaction of ketanserin and potassium losing diuretics resulted in an increase in the number of deaths. After patients taking potassium losing diuretics or antiarrhythmic agents were excluded [corrected] a secondary analysis showed that there were 65 end points in 1514 patients taking ketanserin and 87 in 1557 patients taking placebo, a reduction of 23% in the number of study end points in those taking ketanserin. CONCLUSIONS: Ketanserin can prolong the corrected QT interval, and the combined use of ketanserin and potassium losing diuretics can be harmful. A secondary analysis suggested a protective effect of ketanserin against cardiovascular complications in patients with claudication.

Adult↗
PubMed1990

Incidence and clinical relevance of QT prolongation caused by the new selective serotonin antagonist ketanserin. Multicenter Ketanserin Research Group.

Efficacy and safety of ketanserin was studied prospectively in a randomized and double-blind trial involving 221 patients treated for hypertension and/or coronary artery disease. Since ketanserin has been suggested to cause QTc prolongation, we investigated the incidence and severity of this effect, as well as its influence on the incidence of malignant ventricular arrhythmias during Holter monitoring. After a 1-week run-in-period, all patients were examined, measuring blood pressure, electrocardiogram (ECG) and 24-hour Holter ECG. Two thirds of the patients (n = 147) were then randomized to ketanserin, 1 week 20 mg b.i.d. followed by 3 weeks 40 mg b.i.d.; one third of the patients (n = 74) received placebo b.i.d. for 4 weeks. After 4 weeks of treatment, blood pressure, ECG and 24-hour Holter ECG were performed. In hypertensive patients, ketanserin resulted in a significant reduction of systolic (mean reduction: -17 +/- 2 mm Hg; p less than 0.0001) and diastolic blood pressure (-12 +/- 1 mm Hg; p less than 0.0001) as compared to baseline, and to the placebo group (p less than 0.005 for systolic and diastolic blood pressure). The QTc interval was prolonged with ketanserin (mean value: 400 to 418 ms; p less than 0.01) but not with placebo (399 vs. 402 ms). In the ketanserin group 30% of patients and in the placebo group 8% of patients had QTc prolongation greater than 30 ms (p less than 0.01). QTc was not prolonged to greater than 500 ms in any patient. During Holter monitoring 128/147 patients (ketanserin group) and 61/74 patients (placebo group) had ventricular premature beats; in 42 (ketanserin group) and 13 patients (placebo group) ventricular pairs and tachycardia were documented. Incidence and severity of the ventricular arrhythmias after 4 weeks of treatment were not different between the ketanserin and placebo groups. No sustained ventricular tachycardia occurred in any patient after ketanserin treatment. Thus, though ketanserin prolonged QTc in one third of the patients, the drug was not arrhythmogenic or antiarrhythmic.

Aged↗
PubMed1988

Identification of nonserotonergic [3H]ketanserin binding sites associated with nerve terminals in rat brain and with platelets; relation with release of biogenic amine metabolites induced by ketanserin- and tetrabenazine-like drugs.

In mammalian striatal tissue and cat platelets, [3H]ketanserin labels besides serotonin-S2 receptors nonserotonergic saturable binding sites. The sites have been distinguished and characterized in [3H]ketanserin binding assays by selective inhibition with tetrabenazine (Ki = 4 nM), a monoamine depleting agent. In rats, the nonserotonergic ketanserin sites were enriched in the striatum (KD = 12.4 +/- 0.3 nM, maximal number of binding sites = 53.2 +/- 11.8 fmol/mg of tissue at pH 7.7, 37 degrees C) and nucleus accumbens. The sites were decreased by 65 to 78% after 6-hydroxydopamine lesions, suggesting an association with dopaminergic nerve terminals. In in vitro superfusion experiments using [3H]dopamine, [3H]norepinephrine and [3H]serotonin loaded rat brain tissue and [3H]serotonin loaded human platelets, 5 min superfusion with 10(-6) M ketanserin, tetrabenazine and reserpine caused instantaneously a marked increase in tritium efflux. The effect was attenuated by the monoamine oxidase inhibitor, pargyline, in brain slices but not in platelets. High-performance liquid chromatography analysis of endogenous catecholamines, serotonin and metabolites in superfusates from striatal slices revealed that stimulation with these drugs provoked mainly release of 3,4-dihydroxybenzeneacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Potencies of a series of ketanserin derivatives, benzoquinolizine derivatives and a variety of drugs affecting neurotransmission were assessed in the in vitro release test using [3H]dopamine loaded striatal slices, and in [3H]ketanserin binding assays to nonserotonergic sites in the striatum and to serotonin-S2 receptors in brain tissue. Activities of drugs in the release test correlated strongly with their binding affinities for nonserotonergic ketanserin sites (rs = 0.83, n = 30, P less than .001). High potency in the latter two tests was confined to few close structural congeners of ketanserin and tetrabenazine. Distinct structural activity relationships for interaction with nonserotonergic ketanserin sites and serotonin-S2 receptors were found. It was concluded that nonserotonergic ketanserin sites mediate release of oxidated metabolites of biogenic amines from nerve endings and of serotonin from platelets. Hence release of biogenic amine metabolites or of cytoplasmic amines is probably not a mere diffusion process but involves specific membranous molecules. Unlike tetrabenazine, ketanserin caused no obvious depletion of central catecholamine and indoleamine stores. Implications of these findings for the mechanism of action of the drugs are discussed.

Animals↗
PubMed1986

Pharmacokinetics of ketanserin and its metabolite ketanserin-ol in man after intravenous, intramuscular and oral administration.

The pharmacokinetics of ketanserin (R 41 468), a novel serotonin S2-receptor blocking agent widely investigated for its effect on acute and chronic hypertension, has been studied in 10 healthy male subjects. They received single 10 mg doses i.v. and i.m., and 20, 40 and 60 mg solutions of ketanserin by mouth, in a five-way cross-over design. The model-independent kinetics of i.v. ketanserin were characterized by a terminal half-life of 14.3 +/- 4.4 h, a moderate plasma clearance (CL = 565 +/- 57 ml/min) and a large tissue distribution (Vss = 268 +/- 71 l, Vz = 703 +/- 204 l; mean +/- SD). Following i.m. administration, peak levels of nearly 200 ng/ml were attained within 10 minutes and the absolute bioavailability was 112 +/- 23%. After oral dosing, peak levels of ketanserin were reached within 1 h. The peak level and AUC increased in proportion to the dose. The absolute bioavailability was 46.8, 50.4 and 55.5% for 20, 40 and 60 mg doses and they conformed to the predicted bioavailability based on i.v. clearance data. The terminal half-life of 17 h and the urinary excretion of parent drug (about 0.7% of the dose) were similar after oral and parenteral dosing. The kinetics of ketanserin-ol, the major metabolite of ketanserin formed by ketone reduction, was also studied. Because of its negligible pharmacological activity, the contribution of ketanserin-ol to the overall therapeutic effect of ketanserin is small, in spite of its 1.6-times (parenteral) to 3.2-times (oral) higher plasma level than that of ketanserin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Antihypertensive efficacy of ketanserin alone or in combination with a beta-blocker or a diuretic: the Swiss Ketanserin Study.

In the Swiss Ketanserin Study the antihypertensive efficacy and tolerability of ketanserin (given in 20 or 40 mg doses twice daily) was investigated, after a placebo run-in phase, as monotherapy (n = 68) as well as in combination with either atenolol (100 mg/day) (n = 30) or the potassium-sparing diuretic hydrochlorothiazide (50 mg/day) and amiloride (5 mg/day) (n = 26) in 124 patients with essential hypertension, aged 41 to 82 years. With the addition of ketanserin, diastolic blood pressure fell by 8 +/- 8, 8 +/- 8, and 7 +/- 9 (+/- SD) mm Hg, respectively (p less than 0.05 for all) in the three treatment groups; heart rate remained unchanged or fell slightly. Ketanserin had no effect on body weight, or biochemical variables, including total serum cholesterol and triglycerides, with the exception of a minor increase in apolipoprotein B. Using a patient self-assessment questionnaire (30 items), the addition of ketanserin was associated with a reduction of most of the symptoms encountered in the placebo phase, including sleep disturbances, general feeling of weakness, headaches, nervousness, and fatigue, but there was a tendency toward increases in stuffy nose and dry mouth. In patients older than 60 years, the antihypertensive efficacy of ketanserin was greater, with 59% achieving a diastolic pressure less than or equal to 95 mm Hg versus 45% in the younger patients. This age trend also emerged when ketanserin was combined with either atenolol or the diuretic.

Adrenergic beta-Antagonists↗
PubMed1986

Long-term safety and efficacy of ketanserin in essential hypertension: ketanserin versus or in combination with metoprolol.

The long-term safety and efficacy of ketanserin in the treatment of essential hypertension was assessed in monotherapy or in combination with the beta-blocker, metoprolol. In an initial double-blind phase, 40 patients were randomized and treated for 12 weeks with either ketanserin or metoprolol. When compared with baseline placebo values, both drugs were significantly effective in reducing blood pressure levels. The antihypertensive action of ketanserin was more gradual than that of metoprolol. The incidence of side-effects was lower with ketanserin: six cases of mild bradycardia were noted with the beta-blocker. Following this phase, all patients received ketanserin therapy during a 12-month period in an open study. Those patients not controlled by monotherapy [i.e. diastolic blood pressure (DBP) greater than 90 mmHg] were treated by a combination of both drugs. Twenty-two patients receiving ketanserin monotherapy were successfully controlled for all of the period of observation [mean supine systolic blood pressure (SBP)/DBP = 142/88]. Side-effects were minimal, with no significant changes observed in biochemical or haematological measurements during the year-long open phase. The results of this study document the efficacy and safety of long-term treatment of essential hypertension with ketanserin.

Adult↗
PubMed1985

Antihypertensive mechanism of action of ketanserin and some ketanserin analogues in the spontaneously hypertensive rat.

Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of alpha 1-adrenoceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker alpha-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked alpha 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced. It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.

Animals↗
PubMed1986

Pharmacokinetic approach to equilibrium between ketanserin and ketanserin-ol.

The metabolic reduction-oxidation equilibrium between ketanserin and ketanserin-ol was studied after oral dosing of both substances to two healthy volunteers. Comparison of plasma Cmax and AUCs indicated that the equilibrium was shifted towards ketanserin-ol. There is evidence that ketanserin-ol elimination is the slowest step dictating the terminal half-life of ketanserin.

Administration, Oral↗
PubMed1987

Comparative antihypertensive effects of ketanserin and a ketanserin-hydrochlorothiazide combination administered once daily.

The effects of monotherapy with once-daily ketanserin (40 mg) were compared to those of ketanserin (40 mg) plus hydrochlorothiazide (25 mg) once daily in 21 patients with mild essential hypertension. After a placebo run-in period of 4 weeks, medication was randomly allocated. The study was double-blind and the double-dummy technique was used. The measurements of blood pressure during the 3-month treatment period showed a tendency for progressive decreases of the variable. Supine and erect blood pressure mean values were significantly reduced, between pretreatment and the end of week 12, by 17 and 12 mm Hg with ketanserin therapy and by 19 and 16 mm Hg with combination treatment, respectively. A mathematical model used for studying the evolution of erect diastolic blood pressure over time revealed that the combination lowered blood pressure at a higher rate than did ketanserin alone in the first week of treatment, but that thereafter the velocity of change was higher for ketanserin alone. Both treatments had equally effective antihypertensive effects after 12 weeks, although differences existed in the time courses of blood pressure changes. More prolonged studies are required in order to distinguish further between the medications used.

Blood Pressure↗
PubMed1990

Acute respiratory and cardiovascular effects of inhaled ketanserin in chronic obstructive pulmonary disease. A comparative study with intravenously administered ketanserin.

In a double-blind, crossover study, nebulized ketanserin, a 5-HT2 receptor antagonist, and a placebo were given to eight patients with moderate to severe nonasthmatic COPD. Intravenous ketanserin had rapid onset of action and induced a longer lasting bronchial response than inhaled ketanserin. These results confirm that ketanserin acts as a mild bronchodilator in patients with COPD and demonstrate that the inhaled route has no advantage over the intravenous route in terms of effectiveness. Thus, 5-HT may play a role in bronchomotor tone, at least in patients with chronic airway obstruction.

Administration, Inhalation↗
PubMed1988

Distinct autoradiographic labelling of serotonin 5-HT2 receptors, alpha 1-adrenoceptors and histamine-H1 receptors and of tetrabenazine-displaceable ketanserin binding sites in rodent brain with [125I]7-amino-8-iodo-ketanserin.

[125I]7-Amino-8-iodo-ketanserin ([125I]AMIK) binding was assayed in rat and guinea-pig horizontal brain sections and was analysed by autoradiography. The use of selective displacers allowed the identification of four distinct receptors in rat and guinea-pig brain. In rats, 5-HT2 receptors were detected in cortical areas and in caudate putamen, alpha 1-adrenoceptors were found in cortical areas and several thalamic nuclei, tetrabenazine-displaceable ketanserin binding sites involved in the release of biogene amine metabolites occurred in caudate putamen, periaqueductal grey matter and septal nuclei. Histamine-H1 receptors could be identified in the guinea-pig cerebellum.

Animals↗
PubMed1988

Pharmacokinetics and tissue distribution of ketanserin in rat, rabbit and dog.

The plasma kinetics and tissue distribution of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468) were studied in the rat, rabbit and dog. The studies were performed utilizing 3H- and 14C-labelled ketanserin and appropriate techniques to measure levels of radioactivity, unchanged drug and a major metabolite ketanserin-ol in plasma and tissues. Following intravenous administration to male rats and dogs (10 mg/kg), plasma levels could be described by a two-compartment model. The plasma clearance (C1) averaged 3.8 and 19.2 ml/min/kg and the volume of distribution (Vdss) 0.67 and 4.7 l/kg in male rats and in dogs, respectively. Following oral administration (10-40 mg/kg), ketanserin was rapidly and completely absorbed in all species studied. The absolute bioavailability of oral ketanserin was more than 80% in both rats and dogs. Due to the high clearance of the metabolites in rats, ketanserin was the main component of the plasma radioactivity. In dogs, the fraction of the metabolite ketanserin-ol was more pronounced than that of ketanserin. The apparent elimination half-life of ketanserin was 1.5 h in rabbits, 2-5 h in rats and 3-15 in dogs. The pharmacokinetics of ketanserin were dose-related after single and chronic intravenous and oral dosing. Distribution studies in rats after intravenous and oral administration (10 mg/kg) demonstrated an almost immediate equilibrium between plasma and tissues, resulting in slightly higher tissue than plasma concentrations in the well perfused tissues, and similar or slightly lower levels in the remaining tissues. Ketanserin was the main component of tissue radioactivity. The drug crossed the blood-brain barrier only to a slight extent, brain levels of the unchanged drug being similar to the free fraction in plasma. Ketanserin disappeared from tissues with a similar half-life to that in plasma. On repeated dosing, a small fraction of metabolites was more slowly eliminated. The excretion of the urinary and faecal metabolites after repeated dosing was very similar to that after a single dose. Placental transfer of ketanserin in the rat was limited. On average 0.3% of the maternal radioactive dose, preferentially metabolites, was recovered from the combined foetuses. In dogs orally treated with doses of up to 40 mg/kg/d for 12 months, no undue accumulation or retention of ketanserin or ketanserin-ol was found in any tissue. In lactating dogs orally dosed at 10 mg/kg, preferentially metabolites were excreted in the milk. Concentrations of ketanserin and ketanserin-ol in the milk were respectively 2 and 4 times higher than plasma levels.

Animals↗
PubMed1992

[Cerebral effects of ketanserin. The influence on hemodynamics and brain metabolism].

Ketanserin, a 5HT2- and alpha 1-receptor antagonist, decreases blood pressure by decreasing systemic vascular resistance without causing reflex cardiac stimulation, while cardiac output remains unchanged. To date, little is known about the effects of ketanserin on cerebral haemodynamics and cerebral metabolism. According to a recently published study, ketanserin seems not to impair cerebral blood flow autoregulation in man. The present study was designed to investigate the influence of ketanserin on cerebral circulation and metabolism, and the cerebrovascular response to CO2 in man. METHODS. Twenty male patients between 44 and 67 years of age who were scheduled for coronary artery bypass surgery were randomly allocated to one of two groups. In group 1 measurements were performed after induction of anaesthesia during normocapnia (p(a) CO2 approximately 40 mm Hg) and hypocapnia (p(a) CO2 approximately 30 mm Hg). Then, ketanserin was given at a bolus dose of 0.3 mg.kg-1 followed by an infusion of 0.06 mg.kg-1.h-1 and measurements were repeated under hypocapnic and normocapnic conditions. Patients of group 2 were hyperventilated at first, then normoventilated. Afterwards, ketanserin was administered at the above-mentioned dose and measurements were again performed during normocapnia and hypocapnia. Cerebral blood flow (CBF) was measured using the argon wash-in technique. Cerebral venous blood was obtained from a catheter in the superior bulb of the right internal jugular vein. Cerebral perfusion pressure (CPP) was calculated by subtracting jugular bulb pressure from mean arterial pressure and cerebral vascular resistance (CVR) by dividing CPP by CBF. Cerebral metabolic rates of oxygen, glucose, and lactate were calculated by multiplying the arterial-cerebral venous oxygen and substrate differences by CBF. RESULTS AND DISCUSSION. Ketanserin decreased CPP by 16% to about 60 mm Hg. Cerebral blood flow remained unchanged as a result of an insignificant decline in CVR. Hyperventilation increased CVR by 32%, while CBF decreased by 27% to the same value that had been obtained during hypocapnia without ketanserin. The percentage changes in CBF per mm Hg change in CO2 were 1.45%/mm Hg (group 1 and 2.91%/mm Hg (group 2), respectively, without ketanserin and 1.98%/mm Hg and 2.22%/mm Hg with ketanserin. As CO2-responsiveness with ketanserin was higher in group 1 but lower in group 2 than without ketanserin, the direction in which ventilation was changed rather than ketanserin was responsible for these changes in CO2-responsiveness. Neither during normocapnia nor during hypocapnia did ketanserin have any effects on cerebral metabolic activity. Thus, it can be concluded that ketanserin does not impair CBF regulation and metabolism and that cerebral vascular responsiveness to hypocapnia is preserved.

Aged↗
PubMed1994

Differences in the chronic hypotensive mechanism of action of ketanserin in spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: To investigate the hypotensive effect and mechanism of action of chronic administration of ketanserin in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. METHODS AND RESULTS: SHR and WKY rats were given chronic ketanserin infusions via osmotic minipumps to minimize fluctuations in drug concentrations and receptor responsiveness. In SHR treated with intravenous infusions of 3.0 (n = 9) or 6.0 mg/kg per day (n = 8) ketanserin for 7 days, significant dose-dependent falls in systolic blood pressure (SBP) were observed during the infusion period. Heart rate did not change in either the vehicle- or the ketanserin-treated groups of SHR. In WKY rats intravenously infused with 3.0 (n = 9) or 6.0 mg/kg per day (n = 10) ketanserin, dose-dependent falls in SBP were also observed during the infusion period, with the changes reaching statistical significance at the 6.0 mg/kg per day dose. The changes in heart rate were not different from those in control rats. Pressor responses to the type 2 5-hydroxytryptamine (5HT2)-receptor agonist (+/-)-alpha-methyl-5-hydroxytryptamine (5.0-125.0 micrograms/kg), as assessed on day 7, were reduced dose-dependently in all ketanserin-infused rats. alpha 1-Adrenoceptor responses to 1.0-10.0 micrograms/kg intravenous phenylephrine were attenuated in only the WKY rats infused with 6.0 mg/kg per day ketanserin. In the SHR treated with ketanserin there was no change in the pressor responsiveness to phenylephrine. Baroreflex sensitivity on day 7 was significantly greater in the ketanserin-infused SHR than in their respective controls. Changes in baroreflex sensitivity were not significantly different in WKY rats following ketanserin infusion. CONCLUSIONS: These results show that chronic administration of ketanserin lowers blood pressure in both SHR and WKY rats. In SHR the alpha 1-adrenoceptor-blocking effects of ketanserin are compensated for, and the reduction in blood pressure by day 7 is maintained predominantly by, 5HT2-receptor blockade. In WKY rats ketanserin-induced hypotension is associated with concomitant blockade of 5HT2- and alpha 1-receptors. The present study therefore suggests a differential mechanism of action of ketanserin in hypertensive and normotensive rats during chronic treatment.

Animals↗
PubMed1987

Pharmacokinetics of ketanserin in patients with essential hypertension.

The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%. During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy. The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy. Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.

Administration, Oral↗
PubMed1990

Ketanserin pharmacokinetics in patients with renal failure.

1. The pharmacokinetics of ketanserin and its major metabolite ketanserin-ol were investigated after a single oral dose of 40 mg and after chronic oral administration of 20 or 40 mg twice daily for 10 days in 12 patients with chronic renal insufficiency of whom six were on intermittent haemodialysis. Plasma protein binding of ketanserin was measured in these 12 patients and in eight healthy volunteers. 2. In both dialysis and non-dialysis patients the terminal half-life of ketanserin (mean +/- s.d.) was prolonged compared with that reported previously for healthy volunteers (28 +/- 4 h vs 18 +/- 4 h). This may be explained by a lowered renal clearance of ketanserin-ol from which ketanserin is partly regenerated. 3. In patients with chronic renal insufficiency plasma ketanserin concentrations were similar to those found in healthy subjects after the same dose. Plasma ketanserin-ol concentrations were elevated, resulting in a raised AUC ratio of ketanserin-ol to ketanserin as compared with healthy individuals (7.3 +/- 4.0 vs 3.2 +/- 0.7). 4. Urinary excretion of ketanserin was negligible in both dialysis and non-dialysis patients, and ketanserin-ol excretion was markedly lowered. 5. The plasma protein binding of ketanserin was slightly reduced in comparison with healthy volunteers (93.7 +/- 1.0% vs 95.0 +/- 0.2%). 6. A dose regimen of 20 mg twice daily appeared to be well tolerated in spite of less plasma binding in renal failure.

Adult↗