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Indoramin in the Treatment of Hypertension

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Indoramin in the Treatment of Hypertension SA MEDICAL JOURNAL VOLUME 63 26 FEBRUARY 1983 307 Indoramin in the treatment of hypertension A mini-review and update J. L. ARCHIBALD, P. TURNER prevent this reflex response; the mode of action of indoramin Summary reflects this approach.2 In the synthesis of indoramin,3 features of two types of mole­ The origins, pr-eclinical development a'nd clinical cule were combined. A series ofso-called bis-indoles4 had shown pharmacology of a new antihypertensive agent, good antihypertensive activity in which a-blockade was believed indoramin (Baratol; Wyeth), are briefly reviewed. ro have played an important part. Replacement of one indolyl­ Indoramin is a competitive postsynaptic a-adreno­ ethyl moiety of the bis-indole by a benzamido group gave ri e ro ceptor antagonist with a myocardial membrane­ indoramin, in which a resemblance to procainamide had been stabilizing component of action. These features are incorporated.; The extent to which an a-blocking action (as in believed to be responsible for its antihypertensive the bis-indole) and membrane-stabilizing action (as in procam­ efficacy. They may also explain the absence of prob­ amide) had been combined in the new molecule can perhaps be lems common to older a-blockers such as reflex judged from the following section. tachycardia and postural hypotension. Clinical ev~­ luation of a new agent such as indoramin in the management of hypertension is discussed in terms Preclinical development of efficacy, dosage regimen, tolerance, adverse effects, interactions, withdrawal syndrome, and Indoramin lowered blood pressure effectively in all species stu­ long-term influence on the complications of high 6 died. .? It also showed competitive a-adrenoceptor antagonism blood pressure. in a wide variety of in vitro and in vivo experiments, with for S Atr Med J 1983: 63: 307-309. instance a pA2 value against noradrenaline of 7,4 in the guinea­ pig aorta.s The hypotensive or antihypertensive activity was not accompanied by tachycardia, which suggested that the a­ blockade might indeed be accompanied by some action preven­ ting reflex stimulation ofheart rate. Many experiments indicated Following the introduction of indoramin (Baratol; Wyeth) for that this was a direct cardioregulatory property involving the treatment of essential hypertension in South Africa, it is myocardial membrane stabilization. For example, indoramin appropriate to provide a briefreview and update encompassing was shown to be a potent local anaesthetic agent9 and electrophy­ the origins, preclinical development, mode of action and thera­ siological studies on canine myocardial strips showed that at peutic use of the agent. therapeutic plasma concentrations there was a significant decrease in the rate of depolarization. 10 In vivo evidence of thiS direct effect on the heart fully supported the results in isolated Background and origins tissue," and indoramin has shown good antidysrhythmic activity in a variety of experimental situations.9 Increased peripheral vascular resistance is a major feature of Another factor contributing ro the lack oftachycardia can now essential hypertension, and since a-adrenocepror-blocking drugs be understood in terms of knowledge not available at the time reduce peripheral resistance it would theoretically be ideal to use indoramin was conceived. The discovery of presynaptic a­ them. for antihypertensive therapy. 1 In practice, older a-blockers receptors and negative feedback control ofnoradrenaline release were little used for this purpose. They tended to be poorly enabled us to appreciate that unselective a-blockers will inter­ absorbed after oral administration and to provoke gastro­ fere with this negative feedback control and thus allow greater intestinal disturbances, reflex tachycardia and postural hypoten­ stimulation of postsynaptic R-receprors in the heart and a­ sion. Alpha-blocker-induced reflex compensatorycardio-accele­ receptors in the blood vessels. This will contribute ro both an ration also increased cardiac output and therefore tended to increase in heart rate and the relative ineffectiveness of unselec­ offset any lowering of blood pressure in response to vasodilata­ tive a-blockers in lowering blood pressure. Indoramin avoids tion. If these drawbacks could be overcome, antihypertensive both of these drawbacks by acting specifically at postsynaptic efficacy would be increased and limiting side-effects avoided. a,-receptors. TypicalIX the ratio of post- to presynaptic poten­ One possible way to accomplish this would be to incorporate a cies is about I 000: 1. ' .13 component ofaction into an a-blocker that would counteract or Postural hypotension was another major drawback preventing widespread acceptance of older a-blockers for the treatment of hypertension. In contrast, the incidence ofposrural hypotensIOn with indoramin is minimal. Probable reasons for this include the Wyeth Laboratories, Taplow, Maidenhead, Berkshire, UK competitive nature of the antagonism, the apparently greater J. L. ARCHIBALD, PH.D., FRS.C. potency in resistance than in capacitance vessels,S and the lack of Department of Clinical Pharmacology, St Bartholomew's Hospital, London antagonism of postsynaptic a 2-receptors. Animal experiments P. TURNER, M.D., FR.C.P. involving additional falls in blood pressure on 90° head-up tilt were fully in accord with clinical experience in this ~espect. Dare received: I November 1982. Unlike most other antihypertensive agents studied, indoramin 308 SA MEDIESE TYDSKRIF DEEL 63 26 FEBRUARIE 1983 caused no such additional falls in blood pressure on head-up tilt, methyldopa. 18 A small reduction in dose may lead to its dis­ except at the highest dose tested, which was many times the appearance without reduction in blood pressure control. maximum human therapeutic dose.2 Other less frequent adverse effects include weight gain and Indoramin is well absorbed when orally administered, does fluid retention, headache and depression. not cause gastro-intestinal disturbances and does not provoke No other significant adverse effects have appeared with pro­ tolerance. In addition, its vasodilator and bronchodilator proper­ longed use of indoramin. In particular it does not appear to ties will allow it to be used on patients for whom some other produce an increase in antinuclear factor or a systemic lupus antihypertensive treatments are contraindicated, as discussed in erythematosus-type syndrome. Nevertheless, as with all drug the clinical part of this review. treatment vigilance is required to identify previously unrecog­ nized adverse effects associated with long-term use, particularly if they are limited to certain groups of patients at special risk. Clinical pharmacology of indoramin The following factors should be considered when evaluating a Interactions with other drugs .. new drug such as indoramin in the management ofhypertension: Several important interactions between antihypertensive and (i) efficacy; (ii) dosage regimen; (iii) tolerance; (iv) short- and other drugs are recognized. Drugs that inhibit monoamine reup­ long-term adverse effects; (v) interactions; (vi) withdrawal syn­ take can antagonize the hypotensive effects of those blocking drome; and (vii) long-term influence on the complications of adrenergic neurons and of clonidine, but do not appear to in­ high blood pressure. fluence the action of indoramin.20 The efficacy of B-adrenergic blocking drugs and ofdiuretics can be reduced by non-steroidal anti-inflammatory drugs,21 but this has not yet been studied with Efficacy ofindoramin indoramin. The systemic clearance of some B-adrenoceptor­ Although in preliminary single-dose studies in normal sub­ blocking drugs is reduced by treatment with cimetidine,22 but it jects indoramin produced an increase in heart rate in association is not yet known whether a similar interaction occurs between with a fall in systolic and diastolic blood pressures,14 long-term indoramin and cimetidine. studies in hypertensive patients have demonstrated clinically important falls in blood pressure without any increase in heart rate,15.16 so confirming the results of animal studies already Withdrawal syndrome described. The abrupt withdrawal ofsome drugs may be associated with Twenty-four-hour records ofintra-arterial ambulatory blood l7 the appearance ofa characteristic syndrome, the most important pressure after 6 weeks' treatment ofhypertensive patients with among antihypertensive drugs being that following sudden twice-daily indoramin demonstrated significant reduction in withdrawal of clonidine.. Se~eral inve~~i90a~ors.have ab.ruptly blood pressure throughout the whole 24-hour period, including dlscontmued treatment with mdoramm .-. Without eVidence the early-morning phase of rising blood pressure just prior to of withdrawal hypertension or any other adverse clinical effects. awakening. Comparative studies ofindoramin against otherantihyperten­ sive drugs are generally lacking, but Yajnik er al. 18 found no significant difference between indoramin and methyldopa in 89 Long-term influence on complications of patients in a controlled trial. hypertension There is now good evidence that long-term control of mode­ rate and severe hypertension, and probably of mild hyperten­ Dosage regimen sion, is associated with a fall in morbidity and mortality caused Patient compliance is assisted by once- or twice-daily rather by high blood pressure,24 and it is probable that indoramin will than more frequent administration of a drug. The studies of have a similar beneficial effect, although
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