Research paper by Rex N. Brogden, Eugene M. Sorkin

Indexed on: 18 Nov '12Published on: 18 Nov '12Published in: Drugs


Ketanserin is a 5-HT2 receptor antagonist without partial agonist properties which also possesses weak α1-adrenoceptor antagonistic activity, which may explain its antihypertensive mechanism of action in patients with essential hypertension. It also inhibits the effects of serotonin on platelets in cardiovascular disease, inhibits vasoconstriction caused by the amine, and when administered intravenously improves some haemorheological indices in patients with ischaemic diseasesThe antihypertensive effect of oral ketanserin 40mg twice daily is comparable with that of total daily doses of metoprolol 200mg, propranolol 160mg, captopril 100mg, enalapril 20mg, hydrochlorothiazide 50mg, or α- methyldopa 1000mg and is achieved without adverse effect on plasma lipoproteins or carbohydrate metabolism in patients with concomitant diabetes mellitus. Evidence from prospective studies suggests a greater antihypertensive efficacy in the elderly than in younger patients. In patients with intermittent claudication, results have been inconsistent in small studies, while a large study showed no improvement in pain-free walking distance but fewer amputations compared to placebo. In Raynaud’s phenomenon symptomatic improvement relative to placebo was achieved in larger trials. Its role in preventing atherosclerotic complications requires further investigationKetanserin is reasonably well tolerated, the frequency of adverse effects being comparable with that of other antihypertensive drugs in controlled trials. Dizziness, tiredness, oedema, dry mouth and weight gain are the most commonly reported effects. Ketanserin prolongs QT interval in a dose-related manner, and when given in certain predisposing circumstances ventricular arrhythmias and syncope may occurAdministered intravenously, ketanserin 10mg followed by an infusion of 2 to 4 mg/h controls moderate to severe pre-and postoperative hypertension in most patients, acting as a balanced vasodilator, lowering cardiac pre-and afterloadAlthough the arrhythmogenic potential of ketanserin in patients receiving potassiumdepleting diuretics requires suitable precautions, it appears that its antihypertensive activity is suited to the elderly provided plasma potassium concentrations are normal at the start of treatment and are maintained within the normal rangeKetanserin is a serotonin antagonist that primarily binds to 5-HT2 receptors, to α1-adrenergic and H1-histaminergic receptors at higher concentrations, and possesses no partial serotonin agonist properties. Administered intravenously or orally, single doses of ketanserin generally have a minimal effect on heart rate or blood pressure in healthy volunteers, but blood pressure and peripheral vascular resistance are lowered in hypertensive patients. In patients studied after coronary artery surgery, intravenous ketanserin 5 or 10mg every 2 minutes for 6 doses decreased right atrial pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. Stroke volume and cardiac index were unchanged. Maximal effects were observed at around 15 minutes. Oral administration of ketanserin 40mg daily for 2 weeks reduced renal vascular resistance substantially more than systemic vascular resistance. Mean blood pressure decreased by 8% while cardiac index, heart rate, and vascular resistance in the forearm and liver were unchanged. Intra-arterially administered ketanserin 50 ng/kg/min reversed the vasoconstriction induced by high doses of serotonin in healthy volunteers, but did not influence vasodilatation caused by low doses of serotonin. Intravenously administered ketanserin had minor haemodynamic effects in healthy volunteers. It improved leg perfusion in patients with obstructive arterial disease of the legs, and blood inflow and tissue perfusion in Raynaud’s disease. In other circumstances ketanserin increased low cardiac output, while leaving low resistance states unchanged; lowered pulmonary artery pressure and pulmonary vascular resistance; lowered elevated pulmonary shunt fraction; lowered renal vascular resistance; and increased skin blood flow while dilating skin capillaries. The circulatory effects of orally administered ketanserin have been less apparent than after parenteral administration, but were demonstrable in some studiesKetanserin inhibits serotonin-induced platelet aggregation in vitro and ex vivo with a more pronounced effect in patients over 55 years during prolonged administration. Ketanserin also inhibits the second phase of aggregation induced by critical concentrations of adenosine diphosphate (ADP) or l-epinephrine (adrenaline) and in some studies interfered with secondary recruitment of platelets subsequent to a release reaction induced by ADP or collagen. The irreversible serotonin-induced platelet aggregation observed in patients with cardiovascular diseases was inhibited by ketanserin and placebo in 50% and 4% of patients, respectively. Plasma concentrations of β-thromboglobulin and platelet factor 4 were significantly decreased by chronic treatment with ketanserin in patients in whom they were initially elevatedParenterally administered ketanserin decreased whole blood viscosity, red cell transit time, clogging particles and the red cell deformability index: this may improve the flow properties of bloodOral administration of ketanserin 40 to 80mg daily usually decreased total cholesterol and tended to reduce triglycerides. HDL rose in some studies and LDL decreased with a corresponding change in HDL/LDL ratio, although others reported a neutral effect on lipid profiles with a possible modest beneficial effect. Ketanserin did not adversely affect glucose metabolism in diabetic patients with concomitant hypertensionParenterally administered ketanserin did not influence prolactin release induced by a variety of stimuli, but impaired the prolactin response to hypoglycaemia and attenuated the reduction in plasma adrenocorticotrophic hormone. Plasma aldosterone was decreased by intravenous ketanserin in patients with primary aldosteronism but not in healthy volunteers, while plasma renin activity was unaffected in both groups. Oral administration of ketanserin over several weeks generally had little effect on plasma concentrations of aldosterone and angiotensin II, and plasma renin activity. Similarly, the effects of orally or intravenously administered ketanserin on plasma concentrations of norepinephrine (noradrenaline) and epinephrine varied between studies. Generally, concentrations of these catecholamines were increased during exercise by ketanserin, but not at restKetanserin dose-dependently increases corrected QT interval (QTc) at dosages of 40mg twice daily or more. However, QTc seldom exceeds 500 msec when ketanserin is used alone and clinically important complications have occurred only in patients receiving concomitant potassium-wasting diuretics or antiarrhythmic drugs, or with pathological bradycardiaThe mechanism of the antihypertensive effect of ketanserin remains unclear. While combined 5-HT2 and α1-adrenoceptor antagonism has been suggested, the relative contribution of these or other possible mechanisms is still the subject of debateThe pharmacokinetic properties of ketanserin, and of its major metabolite ketanserinol, have been studied in healthy volunteers, hypertensive patients and those with hepatic or renal impairment. After single dose oral administration, mean maximum plasma concentrations were 71, 198 and 287 µg/L after 20, 40 and 60mg, respectively. This linearity was also evident from area under the plasma concentration-time curve (AUC) values at steady-state. Systemic availability has consistently been about 50%, with about half the dose being extracted and eliminated by first-pass hepatic metabolism. Ketanserin is 95% protein bound, principally to albumin, and this binding is independent of plasma drug concentrations between 1 and 10 000 µg/L. Orally administered ketanserin is extensively metabolised in humans, with ketone reduction to ketanserinol and oxidative N-dealkylation to the acid metabolite being the main pathways. Ketanserinol, the formation of which is particularly involved in first-pass metabolism, does not directly contribute to the pharmacological effects of ketanserin, but its oxidative regeneration to ketanserin may contribute to the relatively long elimination half-life of ketanserin of about 14 hours (average) after a single dose and 29 hours at steady-state. Urinary radioactivity accounted for 68% of the orally administered dose of 14C-ketanserin over 96 hours which was almost entirely due to metabolites; unchanged drug represented less than 1% of an oral dose. Total plasma clearance was around 33 L/h after intravenous administrationIn patients with cirrhosis, AUC was 2-to 4-fold that reported in nonelderly healthy volunteers, due probably to reduced first-pass metabolism. Other variables were generally similar to those reported in healthy volunteers, as they were in patients with renal impairment. However, elimination half-life was shorter in patients with cirrhosis, and tended to increase in patients with chronic renal insufficiency. Systemic availability of ketanserin appeared to be increased in elderly volunteersThe antihypertensive effect of ketanserin has been assessed in over 25 000 patients. The effect of 40 to 80mg daily in two divided doses is superior to that of placebo in patients with mild to moderate essential hypertension. In double-blind studies, ketanserin in fixed dosages of 20mg twice daily during the first 2 weeks and 40mg twice daily thereafter, was of similar efficacy to metoprolol 100mg twice daily or propranolol 80mg twice daily in numerous trials, and to pindolol 10mg, atenolol 100mg daily, or hydrochlorothiazide 50mg daily in a few studies. When the dosage of ketanserin and of propranolol was adjusted according to response, goal blood pressure or a decrease of 20/ 10mm Hg was achieved in about two-thirds of patients treated with either drugThe relative antihypertensive efficacy of ketanserin and nifedipine has varied between studies when each was administered with one or more other antihypertensive drugs. Ketanserin 40 to 80mg daily was similar in efficacy to prazosin 2 to 4mg or captopril 50 to 100mg daily, while fixed doses of ketanserin 80mg produced a comparable decrease in blood pressure to enalapril 20mg daily or α-methyldopa 1000mg daily. Studies of the effect of ketanserin plus other antihypertensive drugs have not been ideally designed to demonstrate the increase in efficacy resulting from the additional drug(s), although a further reduction in blood pressure has been observed following combined administration of a β-adrenoceptor antagonist, ACE inhibitor, or a diuretic and ketanserin, relative to that obtained with either drug alone. During long term oral administration of ketanserin for up to 2 years there was no evidence of tolerance to its antihypertensive effectAn association between age and antihypertensive effect has been demonstrated with the response to ketanserin being greater in the elderly than in younger patientsIn clinical situations unsuited to oral administration, intravenously administered ketanserin successfully reduced blood pressure. A bolus of 10mg, usually followed by infusion at an appropriate rate, controlled hypertension associated with pre-eclampsia, vascular surgery, sternotomy or cerebrovascular accident, and in patients with severe primary or secondary hypertension, without causing adverse haemodynamic effectsSince serotonin may have a role in initiating and maintaining vascular spasm and constriction, the efficacy of ketanserin has been studied in Raynaud’s phenomenon and intermittent claudication. Placebo-controlled trials in small numbers of patients with Raynaud’s phenomenon have recorded inconsistent results with symptomatic improvement relative to placebo in some but not others. However, a significant decrease in attack frequency, and improvement in global evaluations in favour of ketanserin occurred in a definitive large multicentre trial. Despite clear haemodynamic improvement after intravenous administration of ketanserin this was seldom demonstrable when given orally. Studies in patients with intermittent claudication have also produced variable results, with the most positive results from a larger multicentre studyIn a large study designed to determine whether ketanserin 40mg three times daily could prevent atherosclerotic complications, a 23% reduction was observed in primary and secondary cardiovascular events in a secondary analysis subgroup of patients not also receiving potassium-losing diuretics or antiarrhythmic drugs, but these findings should be interpreted cautiously. There is some additional clinical evidence for vascular protection based on apparent prevention of occlusion and early restenosis following percutaneous angioplasty and reduction in cardiac ischaemic episodes relative to aspirin in patients awaiting this procedureThe frequency of adverse effects during oral therapeutic use of ketanserin has been assessed in over 100 placebo-controlled trials conducted over periods of 1 week to 3 months. In the largest of these trials, which involved 4000 patients, symptoms reported more frequently with ketanserin than placebo were dizziness (9.7 vs7.3%, respectively), tiredness (9.4 vs5.9%), oedema (4.7 vs2%), dry mouth (3.5 vs0.8%) and weight gain (2.8 vs0.9%). Comparisons with placebo in patients with mild to moderate essential hypertension have frequently noted a similar incidence of adverse effects in each group. In studies comparing ketanserin with metoprolol, pindolol or atenolol, prazosin, nifedipine and α-methyldopa the incidence of adverse effects was usually comparable between groups although the type of adverse effect could differ depending on the drug being studied. A trend towards more frequent adverse effects with ketanserin in some studies and with propranolol in others has been noted in comparisons of these drugs. An analysis of ketanserin-induced QTc prolongation demonstrated a dose-related effect at dosages of 40mg daily and above. Arrhythmogenic effects appear most likely to occur in patients with electrolyte imbalance (particularly hypokalaemia) or in those receiving drugs with arrhythmogenic potential or with pathological bradycardia and are particularly likely when QTc interval exceeds 500 msec. In a large multicentre study ketanserin 120mg daily accentuated an underlying harmful effect of potassium-losing diuretics, increasing mortality. Thus, ketanserin must not be administered with a potassium-losing diuretic, if there is severe bradycardia or to patients with a pretreatment QTc ⩾ 500 msec, hypokalaemia or hypomagnesaemiaThe usual initial oral dose in the treatment of mild to moderate hypertension is 20mg twice daily. If response is not satisfactory after 1 month dosage should be doubled. If response remains inadequate a β-adrenoceptor antagonist, an ACE inhibitor, or a potassium-conserving diuretic should be added: if a diuretic is given, a potassium-conserving agent should always be included. Usual intravenous or intra-arterial dosage is 10mg initially and should be titrated individually according to blood pressure response up to a maximum of 30mg. Initial response can be maintained by a continuous infusion of 2 to 6 mg/h. In patients with hepatic insufficiency, dosage should not exceed 20mg twice daily