Some Clinical Pharmacological Studies with Indoramin, with Observations on Its Therapeutic Usefulness

Postgrad Med J: first published as 10.1136/pgmj.50.590.729 on 1 December 1974. Downloaded from

Postgraduate Medical Journal (December 1974) 50, 729-733.

Some clinical pharmacological studies with indoramin, with observations on its therapeutic usefulness

C. DE B. WHITE R. B. RoyDs M.R.C.P. M.R.C.P. P. TURNER M.D., F.R.C.P. Department of Clinical Pharmacology, St Bartholomew's Hospital, London

Summary (Briant, Reid and Dollery, 1973), is impaired by In the treatment of fifteen patients with essential treatment with tricyclic antidepressant drugs. Since hypertension, in open trial indoramin caused a mean depression is not uncommon in patients who are being blood pressure fall from 180/115 mmHg to 159/98 treated for essential hypertension, these interactions mmHg. No reversal of antihypertensive effect was are of importance. Simpson and Waal-Manning seen in four patients after additions of the tricyclic (1971) suggested that in these circumstances a thiazide antidepressant drug desipramine. Blood pressure did diuretic combined with a P-adrenoceptor blocking not begin to rise in these four patients for at least 5 drug is the regimen of choice, but pointed out the Protected by copyright. weeks after stopping indoramin. The implications of lack of alternatives if those drugs were not effective these findings are discussed. or suitable. It seemed reasonable, therefore, to investigate the Introduction interaction of indoramin with a tricyclic antidepres- Indoramin (3-[2-(4-benzamidopiperid-1-yl)ethyl] sant drug. The results ofsuch a study in four patients indole) has been shown in animal experiments to are described in this paper, together with a review combine competitive a-adrenoceptor blocking pro- of our clinical experience with indoramin in the perties with cardioinhibitory, local anaesthetic, treatment of essential hypertension. antihistamine and anti-5-hydroxytryptamine activity (Alps et al., 1972; Collis and Alps, 1973). Its competitive a-adrenoceptor blocking activity has been Methods confirmed in studies of human isolated smooth Open study: indoramin in essential hypertension muscle and Fifteen patients were treated with indoramin in strips (Variava Turner, 1973). Royds, clinical trial. The had either not Coltart and Lockhart (1972) showed that in healthy open patients http://pmj.bmj.com/ volunteers a single oral dose produced a significant previously been treated for hypertension, or their fall in blood pressure when compared with placebo, blood pressure had not been adequately controlled and that after intravenous infusion of indoramin the with conventional treatment. In each case the pressure response to noradrenaline showed a parallel diagnosis of essential hypertension was established time-related shift to the right. Indoramin also pro- by finding a raised diastolic blood pressure ofgreater duced a dose-dependent reduction in histamine- than 105 mmHg on at least two occasions after induced skin weals, but did not influence critical supine rest for 5 min. Known causes of hypertension flicker frequency in doses which had a-adrenoceptor were excluded. Some patients, including patients 1 on September 27, 2021 by guest. blocking and antihistamine activity. Boakes, Prichard and 2 (Table 1), had repeated blood pressure readings and Teoh (1972) found considerable positional falls as day patients in hospital. in blood pressure after intravenous and oral dosing. Preliminary clinical studies of indoramin in Influence ofdesipramine on the antihypertensive effect patients with essential hypotension indicated that ofindoramin it might have a therapeutic effect in this condition Of the patients who responded to indoramin, four (Royds, 1972), although not all patients responded were selected with mild degrees of depression. The favourably in a recent study (Lewis, George and addition of a medicine affecting mood was discussed Dollery, 1973). with them, pointing out that although it might affect The hypotensive action of several established their blood pressure control they would be kept antihypertensive drugs, including bethanidine and under close observation. Consent was freely given guanethidine (Mitchell et al., 1970) and clonidine by each subject. Postgrad Med J: first published as 10.1136/pgmj.50.590.729 on 1 December 1974. Downloaded from 730 C. de B. White, R. B. Royds and P. Turner

0 .2 2 0 o 0

.a co

0 E oZZ , 0oZ Zo oo o

o E

0 0 0 0 000 000000 N0000 0 - 0o o oooooo oocoooo o ^o r 8. " 0 in00 0 W) 6 4C6 4) E E:EE EC = m t0 0 00000000000 0 0 ^ > ° WI CC = 2 e2 222ese°o e WIo2 t e 2 2 cOO Protected by copyright. en W

0. oo o3 5'§ . or»* 0 o - . -uo ^oN'c0 e o o1 oo o ) * Eg 0

en WI

l 4) " (ien"' o as W) I en Ch -- -t-, i c http://pmj.bmj.com/ on September 27, 2021 by guest.

) 0-H Postgrad Med J: first published as 10.1136/pgmj.50.590.729 on 1 December 1974. Downloaded from Some clinical pharmacological studies with indoramin 731 Two control blood pressure readings were made thiazide diuretics which were continued unchanged in the week before starting the study. Desipramine throughout. In some patients who were not well con- 25 mg 8 hourly or an identical placebo were added trolled with indoramin alone, a thiazide diuretic to the antihypertensive therapy in double blind was later found to have a marked additive effect. manner in each patient for a period of 10 days. The response to indoramin was variable. The mean There was then a wash-out period of 4 days before reduction in standing blood pressure from pretreat- crossover of medication and the commencement of ment values for all patients was from 180/115 mmHg the second 10-day treatment course. Two patients to 159/98 mmHg (Table 1). Continued increase in received desipramine first and the other two placebo. dosage where necessary was often limited by seda- All four patients were assessed on days 1, 2, 4, 7, tion and on one occasion by intolerable nasal 10, 14, 15, 18, 21, 24 and 28 of the investigation, at stuffiness. Other side effects were dry mouth, weight the same time of day. On each occasion, the blood gain, shortness of breath (two cases), ankle oedema pressure was measured with a London School of (one case) and failure of ejaculation (one case). Hygiene sphygmomanometer after 5 min supine rest Sedation was usually seen at doses higher than 150 and again after 3 min standing. The pulse rate and mg/day, but was reported after a single dose as low any volunteered side effects were also recorded. as 12-5 mg in one patient. Mean blood pressures (diastolic+ 1/3 pulse No patient complained of palpitations while pressure) during the two treatment periods were taking indoramin, though an increase in heart rate subtracted from the control pressures taken before ofup to 8 beats/min was often observed after starting the addition of antidepressant or its placebo. The therapy. difference between the means of changes in both treatment periods was calculated and compared Influence ofdesipramine on the antihypertensive effect

using Student's 't' test for differences between means. of indoramin Protected by copyright. Table 2 shows that the blood pressure of the four Effect ofsubstitution ofindoramin by placebo patients in this study was well controlled by indor- At the end of the study, active drug treatment amin. The addition of desipramine to the treatment was abruptly withdrawn from the four patients to regimen did not adversely affect the action of indor- confirm the diagnosis of hypertension. Indoramin amin. The mean blood pressure during treatment therapy was replaced by identical placebo in a single with indoramin plus desipramine in fact fell slightly blind fashion. The blood pressure was monitored at by 7-9 mmHg in the supine position and 11.7 mmHg twice weekly and later at weekly intervals. when erect. With indoramin plus placebo the mean blood pressure fell by 4*4 mmHg in the supine and Results 4-1 mmHg in the erect position. None of these Open study: indoramin in essential hypertension changes was significantly statistically different from The details of the patients and responses to treat- the blood pressure on indoramin alone. ment are given in Table 1. The treated blood pressure Mean pulse rates for the four subjects during the values are the means of at the dose with indoramin and the readings optimal placebo period desipramine http://pmj.bmj.com/ of indoramin as quoted for each patient, the only period were 86 beats/min and 89 beats/min standing change in treatment being the addition of indoramin. and 82 beats/min in both periods lying down. The Some patients had previously been stabilized on only side effects reported were of marked dryness of

TABLE 2. Blood pressures of four patients before and during treatment with indoramin, indoramin plus desipramine, and indoramin plus placebo

Mean blood pressure (diast.+ 1/3 pulse) (mmHg) on September 27, 2021 by guest. Controlled Indoramin Indoramin Before indoramin on indoramin* + placebot + desipraminet Patient Supine Erect Supine Erect Supine Erect Supine Erect 1 131-0 136-0 107-7 99.3 104-7 94.3 100-7 96-0 2 119-3 129-0 91-3 83-3 95-3 88-7 92-0 76-7 3 154-6 151-3 124-7 120-6 111-3 110-3 122-3 109-7 4 152-0 150-3 128-0 127-7 122-7 121-3 105-0 101-7 Average 139-2 141-6 112-9 107-7 108-5 103-6 105-0 96-0 ±s.e.m. ±8-49 ±5-48 ±8-47 ±10-13 ±5-76 ±7-45 ±6-37 ±7 03 * Average of two readings. t Average blood pressure over 10-day period. Postgrad Med J: first published as 10.1136/pgmj.50.590.729 on 1 December 1974. Downloaded from 732 C. de B. White, R. B. Royds and P. Turner the mouth (two subjects), which ceased 5 days after with desipramine in a dose of 25 mg 8 hourly. More- stopping the desipramine, and drowsiness 2-3 hr over it was seen in every patient so treated. Four or after taking the tablets (one subject). five patients on clonidine showed reversal within a week of the introduction ofdesipramine (Briant et al., Effect ofsubstitution ofindoramin by placebo 1973). When patients treated for long periods with It may be argued that, since there was no change indoramin had placebo substituted for this drug, in blood pressure of the patients for at least 5 weeks blood pressure tended to remain low for prolonged following withdrawal of indoramin, it is unlikely intervals. that a reversal by desipramine would be seen within In patient 2, mean lying and standing blood 10 days. However, a prolonged period of normo- pressures were 94 and 96 mmHg respectively after tension follows withdrawal of guanethidine in many 20 weeks of placebo substitution. Patients 1 and 4 cases (Dollery, 1967) although reversal with desi- maintained satisfactory mean pressures for 7 and 9 pramine is rapid. While the possibility of a later weeks respectively on placebo. The mean standing reversal of indoramin's hypertensive effect has not blood pressure of patient 1 rose to 112 mmHg at been excluded, this study suggests that, where a week 10 and that of patient 4 to 146 mmHg at week patient with essential hypertension requires treat- 15, when both were restarted on indoramin there ment with a tricyclic antidepressant drug, indoramin were subsequent falls to mean pressures of 106 mmHg may be of value in the control of hypertension. for patient 1 and 132 mmHg for patient 2. The mean The delay in relapse of hypertension in all our standing blood pressure of patient 3 remained con- patients studied after withdrawal of effective indor- trolled for 4 weeks on placebo, then rose from 123 amin treatment illustrates an important question in mmHg to 145 mmHg by the seventh week, when the assessment of antihypertensive drugs. This effect has been reported in extensive studies with longProtected by copyright. active antihypertensive therapy was required. established antihypertensive agents with different modes ofaction (Page and Dustan, 1962; Perry et al., Discussion 1966; Thurm and Smith, 1967) and ap-adrenoceptor- The place of oc-adrenoceptor blocking drugs in blocking drug (Persson and Ulrich, 1973). the treatment of essential hypertension is not yet It is unlikely that there is prolonged receptor established. Brownlee (1966) pointed out that, blockade following indoramin withdrawal as other logically, drugs acting in this way ought to provide evidence of adrenergic blockade, such as impaired the most effective means of lowering blood pressure, sexual function, disappears within a few days of but that most known oc-blocking drugs had other discontinuation. Baroreceptor resetting has been pharmacological actions which prevented their long- demonstrated in dogs with renogenic hypertension term use in this condition. Although indoramin has (McCubbin, Green and Page, 1956) and Page and important pharmacological properties apart from Dustan (1962) suggested that this mechanism could its a-adrenoceptor-blocking activity, it has been account for their findings of a persistent effect in possible to treat some patients with essential hyper- nine out of the twenty-seven patients whose drug tension for many months without untoward effects treatment was discontinued in their study. Prichard http://pmj.bmj.com/ and with satisfactory blood pressure control. How- and Gillam (1969) suggested that the antihyperten- ever, although sedation did not occur with single sive effects of P-adrenoceptor blocking drugs might 20 mg oral doses of indoramin (Royds et al., 1972), be due in part to a change in baroreceptor activity. a proportion of patients on higher and continuous Such a long term change would by its very nature be dosage reported this symptom. difficult to confirm, but the time course of indor- The controlled investigation of the effects of amin's action would be consistent with it. That the desipramine suggest that the interaction demon- effect is dependent on the previous duration of on September 27, 2021 by guest. strated with guanethidine, bethanidine (Mitchell treatment with indoramin received some support et al., 1970) and clonidine (Briant et al., 1973) in from the finding, in patient 3, that withdrawal of which a marked reversal of the antihypertensive indoramin after 8 weeks' effective treatment was effect occurs, does not arise with indoramin. In fact followed by a rise in blood pressure to pretreatment there was a slight additive effect with the addition levels within 1 week. A similar rise after discon- of desipramine, which may be due to its c-adreno- tinuation took 7 weeks to occur when the same ceptor-blocking activity (McCullough and Story, patient had been maintained on the drug for 6 1972). months. Mitchell et al. (1970) found that the reversal of If such periods of prolonged normotension do in the antihypertensive effects occurred within 2 days fact follow effective antihypertensive drug therapy, in patients on guanethidine, and within a few hours then the use of crossover designs in the assessment on bethanidine and debrisoquinone, when treated of new agents, such as one recently used to assess Postgrad Med J: first published as 10.1136/pgmj.50.590.729 on 1 December 1974. Downloaded from Some clinical pharmacological studies with indoramin 733 indoramin (Lewis et al., 1973), must be questioned. COLLIS, M.G. & ALPS, B.J. (1973) The evaluation of the It is evident that if the criterion for a-adrenoceptor blocking action of indoramin, phentol- antihypertensive amine and thymoxamine on the rat and guinea-pig isolated efficacy is to be based on the difference between the mesenteric vasculature and aortic spiral preparations. effect of active drug and identical placebo, periods Journal of Pharmacy and Pharmacology, 25, 621. of active treatment must be followed by prolonged DOLLERY, C.T. (1967) Drugs and the regulation of blood wash-out intervals. The duration of such pressure. In: Modern Trends in Pharmacology and Thera- placebo peutics, Volume 1, p. 310. Butterworths: London. wash-out must be determined separately for each LEWIS, P.J., GEORGE, C.F. & DOLLERY, C.T. (1973) Clinical patient by an increase in blood pressure towards evaluation of indoramin, a new antihypertensive agent. pretreatment levels. European Journal of Clinical Pharmacology, 6, 211. A therapeutic implication of the effect, as pointed MCCUBBIN, J.W., GREEN, J.H. & PAGE, I.H. (1956) Barocep- out and Dustan is that after tor function in chronic renal hypertension. Circulation by Page (1962), long Research, 4, 205. periods ofeffective treatment regular attempts should MCCULLOUGH, M.W. & STORY, D.F. (1972) Antagonism of be made to reduce or stop antihypertensive drugs noradrenaline and histamine by desipramine in the and thereby avoid untoward effects. isolated artery of the rabbit ear. British Journal ofPharma- In conclusion, clinical experience with indoramin cology, 46, 140. has demonstrated that blockade with MITCHELL, J.R., CAVANAUGH, J.H., ARIAS, L. & OATES, J.A. oc-adrenoceptor (1970) Guanethidine and related agents. III Antagonism indoramin may be of value in the management of by drugs which inhibit the norepinephrine pump in man. essential hypertension. The absence of troublesome Journal of Clinical Investigation, 49, 1596. tachycardia may be due to the drug's associated PAGE, T.H. & DUSTAN, H.P. (1962) Persistence of normal cardioinhibitory activity (Alps et al., 1972). blood pressure after discontinuing treatment in hypertensive sedation at doses patients. Circulation, 25, 433. Although antihypertensive PERRY, H.M., SCHROEDER, H.A., CATANJARO, F.J., MOORE- limited its use in some patients, the lack of reversal D. & of its effects treatment with JONES, CAMEL, G.H. (1966) Studies in the control of antihypertensive by hypertension. VIII Mortality, morbidity and remissions Protected by copyright. desipramine for a 10-day period suggests that it may during twelve years of intensive therapy. Circulation, 33, be a valuable drug in hypertensive patients requiring 958. tricyclic PERSSON, I. & ULRICH, J. (1973) Treatment of hypertension antidepressant therapy. with a new .3-blocking agent, pindolol (Visken). European Journal of Clinical Pharmacology, 6, 217. Acknowledgments PRICHARD, B.N.C. & GILLAM, P.M.S. (1969) Treatment of We thank John Wyeth & Brother, Ltd, for financial support hypertension with propranolol. British Medical Journal, 1, and supplying indoramin, and Geigy Pharmaceutical, Ltd, for 7. providing desipramine. ROYDS, R.B. (1972) Initial clinical experience with indoramin, a new antihypertensive agent. British Journal of Pharma- References cology, 44, 379. ALPS, B.J., HILL, M., JOHNSON, E.S. & WILSON, A.B. (1972) ROYDS, R.B., COLTART, D.J. & LOCKHART, J.D.F. (1972) Quantitative analysis on isolated organs of the automatic Pharmacological studies of indoramin in man. Clinical blocking properties of indoramin hydrochloride (Wy Pharmacology and Therapeutics, 13, 380. 21901). British Journal of Pharmacology, 44, 52. SIMPSON, F.O. & WAAL-MANNING, H.J. (1971) Hypertension BOAKES, A.I., PRICHARD, B.N.C. & TEOH, P.C. (1972) a- and depression: interrelated problems in therapy. Journal inhibition from indoramin in man. British of The Royal College London, 14. Adrenoceptor of Physicians of 6, http://pmj.bmj.com/ Journal of Pharmacology, 44, 378. THURM, R.H. & SMITH, W.M. (1967) On resetting of 'baro- BRIANT, R.H., REID, J.L. & DOLLERY, C.T. (1973) Interaction stats' in hypertensive patients. Journal of the American between clonidine and desipramine in man. British Medical Medical Association, 201, 301. Journal, 1, 522. VARIAVA, D.H. & TURNER, P. (1973) The a-adrenoceptor BROWNLEE, G. (1966) Drugs which lower blood pressure. blocking effect of indoramin on human isolated smooth Transactions of the Medical Society ofLondon, 82, 103. muscle. Journal of Pharmacy and Pharmacology, 23, 629. on September 27, 2021 by guest.