ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The association between antihypertensive medications and depression has been recognised for over 40 years. More recently, our understanding of the role of neurotransmitters in the aetiology of depression has helped us understand how antihypertensive drugs cause depression. Biogenic amine depletion is now believed to underlie the organic nature of depression, and many of the drugs used to treat hypertension interfere with this system.There is now compelling evidence that both reserpine and &agr;-methyldopa can induce or worsen depression through their actions on the central nervous system. &bgr;-Blockers have also been implicated, but the data supporting the link between these drugs and depression are not as certain. Guanethidine, clonidine, hydralazine, and prazosin appear to pose little risk in causing depression, although rare occurrences have been reported. Diuretics, calcium channel blockers, and angiotensin converting enzyme (ACE) inhibitors appear to have the lowest association with depression and are therefore the drugs of choice when depression is a risk.Physicians should know which drugs introduce the risk of causing or worsening depression. The wide array of medications now available to treat hypertension offers alternatives that pose low risk. All patients receiving medication to treat hypertension should be evaluated periodically for depression, and if depression occurs, medication should be suspected as playing a role in its aetiology.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Available information indicates that about 78 new molecules belonging to the class of angiotensin converting enzyme (ACE) inhibitors are under investigation, and that at least 11 or 12 of the newer ACE inhibitors will be available for clinical use. The newer ACE inhibitors can be classified, according to the zinc ion ligand of ACE, into 3 main chemical classes: sulfhydryl-, carboxyl- and phosphoryl-containing ACE inhibitors.All the newer sulfhydryl-containing ACE inhibitors differ from captopril since they are prodrugs, and among them alacepril and probably moveltipril (altiopril, MC 838) are convertedin vivoto captopril. When compared with captopril, they show a slower onset and a longer duration of action, and obviously the same route of elimination. Zofenopril, a prodrug that is convertedin vivoto the active diacid, shows a greater potency, a similar peak time and a longer duration of action than captopril and, unlike captopril, partial elimination through the liver.The newer carboxyl-containing ACE inhibitors are prodrugs which are convertedin vivoto active diacids. Like enalaprilat, they are excreted via the kidney; the exception is spirapril, which is totally eliminated by the liver. Compared to enalapril, benazepril shows an earlier peak time and a slightly shorter terminal half-life, cilazapril and ramipril have an earlier peak time and even longer terminal half-life, perindopril shows similar peak time and terminal half-life, while delapril, quinapril and spirapril show an earlier peak time and a shorter half-life. The phosphoryl-containing ACE inhibitors belong to a new chemical class. Fosinopril is a prodrug which is converted to the active diacidin vivo, shows a relatively late peak time, a long terminal half-life, and is eliminated partially by the liver. SQ 29852, the only newly developed ACE inhibitor which is not a prodrug, seems to be more effective than captopril, with a much longer lasting effect and elimination through the kidney.When the differences in potency between these drugs are compensated by dosage adjustment, all the newer ACE inhibitors are expected to exert a similar amount of inhibition of circulating ACE, and therefore to inhibit to a similar extent the generation of circulating angiotensin II and the breakdown of bradykinin. Obviously they may differ in timing and the duration of circulating ACE inhibition according to their pharmacokinetic properties. With regard to the possibility that they may stimulate prostaglandin synthesis, it is suggested that this action, which does not seem to be specific to this drug class, plays only a minor role in their antihypertensive action; the hypothesis that the sulfhydryl group exerts an additional stimulating action remains to be proved.Experimental data, however, indicate that ACE inhibitors are able to inhibit tissue ACE, that each drug may differ in the amount and duration of ACE inhibition in different tissues, and that tissue bioavailability seems to be the major determinant of these differential effects. These findings raise the theoretical possibility that newer ACE inhibitors might be designed with preferential affinity to various organs, with different therapeutic profiles.As with the systemic humoral effects, it is expected that all the newer ACE inhibitors will exert similar systemic haemodynamic actions. However, the question of whether the different tissue penetration and/or inhibition of the tissue renin-angiotensin system will differentiate the newer ACE inhibitors in terms of regional haemodynamics remains to be answered.The usefulness of the newer ACE inhibitors in the treatment of hypertension and of congestive heart failure is under clinical investigation. Whether these drugs can offer the same or additional advantages or disadvantages as their parent drugs is still in the future.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The advent of potent new bisphosphonates (diphosphonates) now makes it possible to restore and maintain normal bone turnover in many patients with Paget's disease of bone (osteitis deformans). This has necessitated a reappraisal of the indications for treatment, the ways in which disease activity and response are assessed, as well as the place of existing therapies.Measurements of urinary hydroxyproline and serum alkaline phosphatase remain the most useful markers of disease activity. Pyridinium crosslinks may prove to be more specific than hydroxyproline in the assessment of bone resorption but osteocalcin has been disappointing in monitoring the effect of treatment on bone formation.Etidronic acid (disodium etidronate), the first bisphosphonate introduced for clinical use, is a potent inhibitor of osteoclastic bone resorption but its potential is limited by the development of defective mineralisation with high dosage (10 to 20 mg/kg/day). The newer bisphosphonates, clodronic acid (clodronate) and pamidronic acid (pamidronate, APD), are free from this problem and appear able to control a wide range of disease activity. A small number of patients appear resistant to the agents but the underlying mechanism is unclear. The efficacy and safety of these bisphosphonates makes it likely that the threshold for treating asymptomatic patients will fall in the hope of preventing long term complications.These developments will lead to a reappraisal of the role of calcitonin which can now be administered by both the parenteral and intranasal routes. One focus of interest will be on the quality of the bone laid down during treatment. Meticulous radiographic studies have shown that calcitonin improves bone architecture and this may have particular relevance to the treatment of lytic disease. The relative merits of the different forms of therapy for Paget's disease need further evaluation, particularly with respect to the identification of specific advantages of individual drugs.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Atrial fibrillation (AF) is a common cardiac arrhythmia which is particularly prevalent among the elderly. In patients with AF of recent onset, restoration of sinus rhythm may be feasible and this can be achieved by DC cardioversion, or by the use of one of a number of drugs including amiodarone, flecainide or propafenone. Neither digoxin nor the calcium antagonists facilitate the restoration of sinus rhythm. Recurrence of AF is common after successful cardioversion and, although long term antiarrhythmic drug therapy may help to maintain sinus rhythm, all such drugs are potentially toxic and can have important proarrhythmic actions. In patients with chronic AF, restoration of sinus rhythm is rarely possible and treatment is directed towards control of the ventricular response rate, which may be achieved with digoxin and/or a rate-limiting calcium antagonist such as verapamil or diltiazem; &bgr;-blockers may also be used although they appear to impair effort tolerance. In addition, long term anticoagulation may be indicated to reduce the risks of systemic embolisation, even in patients with ‘nonrheumatic’ AF; antiplatelet drugs are of no apparent value in this context. A minority of patients present with AF associated with ventricular pre-excitation; in these individuals both digoxin and the calcium antagonists are contraindicated and the ventricular response rate should be controlled with flecainide, amiodarone or propafenone.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Sore throats are most commonly due to infections, many of which are viral and do not require specific treatment. Symptoms and signs of the common cold, influenza or croup, the occurrence of conjunctivitis in some adenoviral infections, generalised lymphadenopathy and splenomegaly in glandular fever or the presence of vesicles characteristic of herpangina (Coxsackie A virus) or of herpes simplex infection, occasionally enable a clinical diagnosis and avoid the need for antibiotic therapy. In the case of treatable conditions a typical membrane may suggest diphtheria, a scarlatiniform rash infection due toStreptococcus pyogenesor toCorynebacterium haemolyticum, and a cherry-red epiglottisHaemophilus influenzaetype b. Associated atypical pneumonia suggests infection withMycoplasma pneumoniaeorChlamydia pneumoniae. Pharyngitis due toNeisseria gonorrhoeaemay be accompanied by infection at other sites or by other sexually transmitted diseases. Candidal infection, in the appropriate clinical circumstance, should suggest HIV infection. Surgical drainage is required in the case of peritonsillar or retropharyngeal abscess. Noninfectious cases of sore throat, e.g. thyroiditis, are relatively uncommon considerations in the differential diagnosis of acute febrile pharyngitis. The most common problem is to recognise streptococcal pharyngitis, which requires antibiotic treatment for 10 days to avoid the risk of rheumatic fever.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisRemoxipride is a substituted benzamide of the same class as sulpiride, and has a pharmacodynamic profile consistent with central antidopaminergic activity. It is a weak, but relatively selective, central dopamine D2-receptor antagonist and appears to have preferential affinity for extrastriatal dopamine D2-receptors. It also has marked affinity for central sigma receptors. Clinical data from noncomparative and comparative studies show that remoxipride has antipsychotic activity in patients with chronic schizophrenia, and acute exacerbation of chronic schizophrenia, with activity on both positive and negative symptoms. Its overall efficacy in these studies was similar to that of haloperidol. Importantly, however, remoxipride produced a substantially lower incidence of extrapyramidal effects than haloperidol. Further long term comparative studies are required to ascertain the relative suitability of remoxipride for preventing relapse in psychotic patients, and to determine whether tardive dyskinesia occurs in remoxipride recipients - the latter has not been reported with remoxipride to date.Thus, while further experience (particularly of a long term comparative nature) is needed, at present remoxipride appears to offer an important tolerability advantage over haloperidol.Pharmacodynamic PropertiesCompared with the standard antipsychotics, remoxipride is a weak, but relatively specific central dopamine D2-receptor antagonist, with minimal effect on central cholinergic, serotonergic, histamine, muscarinic or &agr;1-adrenergic receptors. Remoxipride appears to have little affinity for dopamine D1-receptors, as demonstrated byin vivoreceptor binding studies and a lack of effect on dopamine-stimulated adenylate cyclase activity. However, remoxipride also has marked affinity for sigma receptors.While there is a need for caution with regard to extrapolation fromin vitrostudies to humans, observations that remoxipride induces differential increases in dopamine turnover in specific areas of rat brain indicate a preferential affinity for extrastriatal dopaminergic systems. This specificity for particular central dopaminergic systems is also demonstrated by the wide separation of doses of remoxipride effective in animal behavioural models for induction of catalepsy, which is believed to be mediated by striatal dopaminergic systems, and the antagonism of dopamine agonist-induced hyperactivity, thought to be mediated through the mesolimbic system. Remoxipride transiently increases plasma prolactin levels in humans; however, fewer remoxipride than haloperidol recipients had trough plasma prolactin levels outside normal limits during short term studies.Pharmacokinetic PropertiesRemoxipride is almost completely absorbed following oral administration in healthy subjects: absorption rate is limited only by the dissolution rate of the preparation. Bioavailability is greater than 90%, and distribution is rapid, with peak plasma levels reached within 1 to 2 hours of oral administration. Approximately 80% of the absorbed dose is bound to plasma protein. There is a dose-proportional relationship for maximum and steady-state plasma concentrations of remoxipride. The half-life of remoxipride is between 4 and 7 hours. Most of an oral dose is excreted in the urine; 10 to 40% is excreted unchanged and the remainder as metabolites.Elimination may be impaired in elderly patients, patients with severe renal dysfunction or severe liver disorders, and in patients who are slow debrisoquine metabolisers. Decreases in urinary pH increase both the elimination rate and the percentage of remoxipride excreted unchanged in urine.Therapeutic UseShort term noncomparative studies in patients with mainly chronic schizophrenia have shown that individualised doses of remoxipride provide an effective replacement for previous antipsychotic treatment. Over 75% of patients display moderate or marked symptomatic improvement at doses up to 600 mg/day. Both positive and negative symptoms appear to respond well to remoxipride. Improvements have been reported for the positive symptoms of thought disturbance, hostility/suspiciousness and hallucinations, and the negative symptoms of emotional withdrawal and motor retardation.Most studies reported to date have compared the efficacy of remoxipride with haloperidol. In terms of overall therapeutic efficacy, remoxipride appears to be similar to both thioridazine and haloperidol but, importantly, it appears to produce a lower incidence of extrapyramidal symptoms. Data from a 6-month placebo-controlled trial show that doses of 150 to 300 mg/day were significantly superior to placebo in preventing relapse. However, the high withdrawal rate in the placebo group complicates interpretation of this study. In addition, data from 1 study comparing remoxipride with chlorpromazine and placebo suggest that remoxipride has a greater efficacy than placebo in patients responsive to treatment with other antipsychotics. Further studies with other antipsychotics are needed to extend these initial findings and confirm the place of remoxipride in the therapy of schizophrenia.TolerabilityExtrapyramidal symptoms are frequently associated with antipsychotic drug treatment and were present in the majority of patients before treatment with remoxipride. During treatment with remoxipride many of these patients showed a decrease in severity of such symptoms. There are relatively few reports of extrapyramidal effects attributable to remoxipride treatment. Few data are available on the effect of remoxipride on pre-existing tardive dyskinesia: preliminary results indicate either improvement or no effect on existing symptoms. The incidence of tardive dyskinesia with remoxipride, if any, has yet to be determined in longer term studies.Occasional cardiovascular effects, including postural hypotension, have been reported during remoxipride administration, but in most patients these would not be clinically important. Other miscellaneous reported adverse reactions occurred with a similar incidence in placebo and remoxipride recipients. Only a small number of patients were withdrawn from therapy due to adverse effects.Dosage and AdministrationOral administration of remoxipride should start with a dose of 300mg daily, in 2 divided doses, and the dosage should be adjusted to achieve maximum control of symptoms. The initial dosage should be halved for elderly patients. The majority of patients initially respond to doses of 300 to 450 mg/day although some require up to 600 mg/day. For long term treatment, the lowest effective maintenance dose (usually 150 to 300 mg/day) should be administered.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisNitroglycerin (glyceryl trinitrate) has been used for many years via the sublingual route for treating acute anginal attacks. In recent years transdermal delivery of nitroglycerin has gained popularity for prophylaxis against angina. However, nitrate tolerance appears to be a therapeutic problem with all long-acting nitrates regardless of delivery mechanism, and it occurs in most patients with stable angina treated with continuous 24-hour application of nitroglycerin patches. Since continuous 24-hour plasma concentrations of nitroglycerin do not appear to be desirable, alternative approaches to therapy are needed. A simple method to minimise tolerance with transdermal nitroglycerin patches is to remove the patch at bedtime and reapply a new patch in the morning. Such intermittent therapy allows a patch-free period during the night, when most patients experience few angina attacks, but optimises nitrate sensitivity during the daytime. However, the place of intermittent nitroglycerin patch therapy in the treatment of stable angina needs clarification with further study, particularly comparisons with other long-acting forms of nitrates. There are insufficient data to recommend the use of transdermal nitroglycerin patches in the treatment of patients with unstable angina or congestive heart failure.In conclusion, transdermal nitroglycerin patches offer a convenient and cosmetically acceptable dosage form which has potential use in stable angina if administered as an intermittent regimen providing a patch-free period each night.Pharmacological ProfileThe numerous formulations of nitroglycerin patches, while using different technologies in their manufacture, essentially achieve the same pharmacological end-point at equivalent doses, i.e. the constant release of the drug across the skin into systemic circulation for 24 hours which achieves constant steady-state plasma concentrations of nitroglycerin.The primary anti-ischaemic mechanism of action of nitroglycerin is believed to be relaxation of vascular smooth muscle. The biochemical events leading to vascular relaxation remain unknown, but are thought to include effects on cyclic guanosine monophosphate production to induce contractile protein relaxation, and the possibility that nitrates may be physiological substitutes for endothelium-derived relaxing factor (EDRF). Nonetheless, consequent vasodilatation leads to a reduction in preload and cardiac oxygen demand. A number of other mechanisms have been hypothesised, with recent evidence strongly suggesting an additional direct anti-ischaemic effect produced by improved coronary blood flow. In patients with congestive heart failure the higher doses that are generally used may produce a reduction in afterload from arteriolar dilatation, as well as the more important reduction in preload.Systemic bioavailability of nitroglycerin is about 75 to 90% following patch administration. The drug is detected in plasma 30 to 60 minutes after application, steady-state plasma concentrations persist from 2 to 24 hours, and no drug is measurable in plasma within 1 hour of patch removal. Mean steady-state plasma concentrations are about 0.2 &mgr;g/L after a patch dose of 0.4 mg/h and are directly proportional to the dose administered. There may, however, be wide intra- and interindividual variation; up to 10-fold differences have been noted. This is probably related to the large volume of distribution (3 L/kg); plasma nitrate probably accounts for no more than 1% of the total body nitrate pool. The site of patch application does not affect absorption, but exercise or sauna may increase the rate of absorption from nitroglycerin patches. A phasic release nitroglycerin patch has recently been developed which delivers about 75% of the dose in the first 12 hours and only 10 to 15% in the last 6 hours.Metabolism of nitroglycerin is rapid (half-life of a few minutes): the action of glutathione-organic nitrate reductase yields 1- and 2-mononitrates, 1,2- and 1,3-dinitrates, and glycerol which are mainly excreted renally. Relatively high dinitrate concentrations may be achieved in plasma and may contribute to the pharmacological activity of the drug.Therapeutic UseControlled clinical trials of the continuous application of nitroglycerin patches throughout each 24-hour period indicate that tolerance may develop to the antianginal and anti-ischaemic effects of the drug in the majority of patients with stable angina. Attenuation of the response occurs as early as 8 to 12 hours after patch application, and opinion is divided whether any benefit is gained during long term continuous therapy. Therefore, as indicated by recent studies ‘intermittent’ therapy may provide a more rational approach to therapy. Removal of the patch for 10 to 12 hours in each 24-hour period provides a patch-free period which may allow the re-establishment of sensitivity to nitroglycerin. Use of a phasic-release nitroglycerin patch, which provides a ‘nitrate-low’ interval in each 24-hour period, may reduce the likelihood of developing tolerance. Comparisons with continuous patch application in fact do show improved maintenance of therapeutic effect with intermittent therapy. Longer term studies in larger numbers of patients are therefore required with ‘intermittent’ and phasic-release patch therapy to define more precisely the clinical efficacy of their anti-ischaemic and antianginal action, in particular compared with other established long-acting nitrate treatments such as isosorbide dinitrate. In addition, with intermittent therapy a decreased exercise capacity to angina onset has been noted prior to patch application with long term treatment compared with placebo, raising the possibility of a rebound haemodynamic phenomenon. The clinical relevance of this observation is unknown. Until this has been investigated further, patients should be monitored carefully for any increase in angina frequency or severity during the patch-free period of intermittent therapy.Studies of transdermal nitroglycerin in other therapeutic areas, including unstable angina and congestive heart failure, have been relatively few, but have generally indicated that continuous patch application is unlikely to be of use.Adverse EffectsThe adverse effect profile of nitroglycerin is well established and results from the drug's vasodilatory properties. Unwanted effects usually occur early in therapy and may disappear spontaneously or with a dosage reduction. They occur in about 20 to 30% of patients, leading to withdrawal in about 5 to 10% of patients. Headaches account for about three-quarters of all reported effects. This is followed less frequently by cutaneous reactions and postural hypotension (dizziness, weakness, rare syncope, and reflex tachycardia with occasional worsening of angina). Other adverse effects include bradycardia, flushing, nausea and vomiting. Cutaneous reactions usually involve mild erythema but may on occasions involve severe macular erythematous lesions usually related to the nitroglycerin itself and occasionally some component or excipient of the patch.Dosage and AdministrationThe suggested starting dose of transdermal nitroglycerin in patients with angina is between 0.2 and 0.4 mg/h. Doses of between 0.4 and 0.8 mg/h have shown continued effectiveness for 10 to 12 hours/day for at least one month of intermittent administration. Although the minimum nitrate-free interval has not been defined, a nitrate-free interval of 10 to 12 hours in each 24-hour period, usually at night, limits the potential for tolerance. Thus, an appropriate dosing schedule for nitroglycerin patches would include a daily ‘patch-on’ period of 12 to 14 hours and a daily ‘patch-off’ period of 10 to 12 hours.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisKetanserin is a 5-HT2receptor antagonist without partial agonist properties which also possesses weak &agr;1-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 diseases.The 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 &agr;-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 investigation.Ketanserin 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 occur.Administered 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 afterload.Although 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 range.Pharmacodynamic PropertiesKetanserin is a serotonin antagonist that primarily binds to 5-HT2receptors, to &agr;1-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. Intraarterially 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 studies.Ketanserin inhibits serotonin-induced platelet aggregationin vitroandex vivowith 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) orl-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 &bgr;-thromboglobulin and platelet factor 4 were significantly decreased by chronic treatment with ketanserin in patients in whom they were initially elevated.Parenterally 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 blood.Oral 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 hypertension.Parenterally 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 rest.Ketanserin 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 bradycardia.The mechanism of the antihypertensive effect of ketanserin remains unclear. While combined 5-HT2and &agr;1-adrenoceptor antagonism has been suggested, the relative contribution of these or other possible mechanisms is still the subject of debate.Pharmacokinetic PropertiesThe 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 &mgr;g/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 &mgr;g/L. Orally administered ketanserin is extensively metabolised in humans, with ketone reduction to ketanserinol and oxidativeN-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 of14C-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 administration.In 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 volunteers.Therapeutic EfficacyThe antihypertensive effect of ketanserin has been assessed in over 25000 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 drug.The 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 &agr;-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 &bgr;-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 effect.An association between age and antihypertensive effect has been demonstrated with the response to ketanserin being greater in the elderly than in younger patients.In 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 effects.Since 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 study.In 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 procedure.Adverse EffectsThe 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 (9.7vs7.3%, respectively), tiredness (9.4vs5.9%), oedema (4.7vs2%), dry mouth (3.5vs0.8%) and weight gain (2.8vs0.9%). 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 &agr;-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 hypomagnesaemia.Dosage and AdministrationThe 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 &bgr;-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.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS