bol. 12, No. 2. SINGAPORE MRDIC:AL JOURNAL 106 April. 1971 DEBRISOQUINE SULPHATE -A NEW ANTIHYPERTENSIVE AGENT WITH MINIMAL SIDE -EFFECTS

By Beatrice T. M. Chen, M.B., M.R.n.C.N. (Sen Registrar, :Medical Unit II, General Hospital, Singapore)

Methyldopa and gua net hid inc are the com- over 70 per cent of the drug is excreted in the monly used antihypertensive agents in the manage- urine, partly unchanged and partly in the form of ment or moderate to severe hypertension. In three metabolites. From 10 to 15 per cent of the general, they are very effective drugs. However, drug is excreted in the faeces. Hacmodynamic there remains a small group of patients who studies show that there is only a small reduction either develop intolerable side -effects to these of cardiac output in the supine position and a drugs, or who are unresponsive to them, singly or marked reduction occurs when the patient is in in combinations. Lt was therefore decided to the erect position. Renal blood flow and glomerular conduct a trial on debrisoquine sulphate (Declinax) filtration rate are not altered in the supine position. which has been shown to be as effective as guane- There is, however, marked reduction in the renal thidine in the management of hypertension but blood flow in the erect posture whereas glomerular with fewer side -effects (Gent and Bacon, ,1967; filtration rate is not affected (Abrams et al, 1964; Kitchin and Turner, 1966; Athanassiadis et al, Onseti et al, 1966). 1966). MATERIAL AND METHOD PHARMACOLOGY Between December 1968 and October 1969, Debrisoquine sulphate (3-4 dihydro-2 (IH) patients with diastolic blood pressure of 120 mm. isoquinoline carboxamine sulphate) (Fig. I) is a Hg. or more on 2 consecutive days were given the drug. These included patients seen for the first i time in Medical Unit IL, General Hospital, Singa- NH pore and patients who had been under treatment in the same unit for some time but whose blood N -C . H2SO4 pressures were not responding to available anti - N H2 hypertensive agents, either singly or in various combinations. Patients with blood urea of more Fig. I. than 70 mg. % were not included in the trial. relatively new antihypertensive agent first syn- All patients were admitted to the hospital when thesised in 1961 and has been made generally the drug was started. No drug was given for two available since 1966. It blocks post -ganglionic days after admission and the blood pressure was outflow without interfering with parasympathetic measured in the supine and erect postures twice activity and has therefore a similar action to that a day to obtain baseline readings. Routine in- of guanethidine although chemically they arc not vestigations done prior to treatment were: full related. haematological investigations, urinalysis, blood Like guanethidine, ìn anaesthesised dogs and urea, serum uric acid, serum electrolyte, creatinine in hypertensive patients, a single intravenous dose clearance and intravenous pyelogram. Haemato- of debrisoquine sulphate will produce an initial logical investigations and creatinine clearance were rise of blood pressure lasting l to 4 hours, followed repeated at the end of 6 months of therapy. The by a hypotensive effect lasting more than 4 hours. blood pressure was measured in the supine and Abrams and his colleagues (1964) found no pressor erect postures twice daily and body weight was effect with oral administration although Luria recorded before breakfast. Side -effects were asked and Freis (1965) found that a large oral dose every day and recorded when present. could produce an initial pressor effect. The initial dose of debrisoquine sulphate was After oral administration, debrisoquine sul- 10 mg. twice a day. This was increased by 5 mg. phate is rapidly absorbed and a hypotensive effect increment per dose every 2-3 days. When the occurs lasting 8 to 12 hours. The blood pressure blood pressure was relatively well controlled, the fall is found to be more marked in the erect than patients were discharged to be followed up as in the supine position. Within 24 hours of ingestion, out -patients, weekly at first for one month and H)r SINGAPORE. MEDICAL JOURNAL.

subsequently fortnightly or monthly. Chloro- TABLE I thiazide 0.5 gm. daily was given if the patient DURATION OF THERAPY IN 20 PATIENTS showed progressive increase in body weight and his pressure not blood controlled. 4 months - I The aim of treatment was to reduce the blood 6 months - - 3 pressure to as normal a level as possible without 7 months - - 2 side -effects. The criteria of response was based on 8 months - - - 2 that of Dollery el al (1962). A sustained fall of 9 months - - - 2 10 diastolic pressure to 100 mm. Hg. or less either months - - - 2 in the lying or standing position was regarded as 11 months - - - 4 good response; a fall of diastolic pressure of 12 months - - 5 20 mm. Hg. or more but above 100 mm. Hg. as Average follow-up period 9.55 months fair. Responses of less than 20 mm. Hg. in diastolic pressure were considered to be poor.

RESULTS TABLE II

Between December 1968 and October 1969, CLINICAL DATA OF 20 PATIENTS 22 patients with a diastolic blood pressure of 120 mm. Hg. or more on two consecutive days New cases - - II were started on debrisoquine sulphate. They Old cases - - 9 included 13 patients with hypertension seen for the first time and 9 patients who failed to respond Sex: to available antihypertensive therapy for a period Male - - 9 4 from months to 5 years. Female - 11 Two of the 13 new cases died at 2 weeks and Age: 3 months after starting treatment because of acute 30 - 39 - - - - 3 myocardial infarction and cerebral haemorrhage 40 - 49 - - - - 7 respectively. They were not included this series 50 - 59 - - - - 6 because of inadequate follow-up, and in the case Over 60 - - - - 4 of the second patient, irregularity in taking his medicine. Race: Chinese - - - - - 15 Altogether 20 patients were treated with Malay - - - - 3 debrisoquine sulphate for a period of 4 months to Indian - - - - - 2 one year (Table I). Table II gives a summary of clinical data of these 20 patients. Diagnosis: The 9 old cases had been followed in our Essential hypertension - - - 13 Chronic out -patient clinic for a period ranging from 4 glomerulonephritis- - 6

Chronic - 1 months to 5 years (average 25.5 months). Their pyelonephritis - blood pressure were not controlled with the Fundal Grading: available antihypertensive agents in maximal Grade 1 - - - - - 0 doses using reserpine, guanethidine, methyldopa Grade Il - - - - - 16 and mecamylamìne (Table Ill), and diuretics Grade Ill - - - 1 such as chlorothiazide, frusemide and clorexolone. Grade IV - - - - - 3 The initial controlling dose ranged from 20 mg. to 70 mg. per day in two divided doses, with an average of 4625 mg. per day (Table IV). Twelve TABLE itt patients obtained good control of blood pressure, 4 had fair control and 4 failed to respond. Of the PREVIOUS ANTI HYPERTENSI VE THERAPY 4 patients who did not respond, 3 were old cases in whom the dose of debrisoquine sulphate were Drug No. of Patients increased to more than 200 mg. per day before they were taken off the drug. The remaining one Guanethidine - - 9 patient, a new case, failed to respond at a dose of Methyldopa - 9 100 mg. per day and therapy was changed at this Reserpine - - - 4 stage -because he developed severe diarrhoea. Of Mecamylamine 1 the 16 patients with Grade II retinopathy, 10 APRIL, 1971 108

TABLE 1V patient did not respond to treatment at all. Two DOSE OF DEBRISOQUINE SULPHATE FOR patients developed diarrhoea; in one of them it was severe enough to warrant withdrawal of the INITIAL CONTROL drug. fhe other patient had mild diarrhoea only; (mg. per day) in addition he also complained of feeling cold while on the drug. He, too, did not respond to the 20 _ 2 50 - 3 a dose 220 day. - 3 drug at of mg. per Five patients 30 - L 60 had no side -effects at all. 40 - 5 70 - 2

Mean: 4625 mg. per day TABLE VIE SIDE -EFFECTS TO DEBRISOQUINE responded well, 3 fairly well and 3 did not respond. SULPHATE The one patient with a Grade TIL retinopathy the 3 patients with obtained good response. Of Fluid retention - 9 was malignant hypertension, the response equally Postural hypotension 8 distributed in each category (Table V). Blocked nose - 2 2 Diarrhoea - TABLE. V Lethargy - FUNDAL GRADING AND INITIAL Weakness - 1 Feeling cold - - 1 RESPONSE No side -effects 5

At the end of 6 months, none of the 19 patients Good response 10 developed any haematological disorders, including Fair response 3 o autoimmune haemolytic anaemia such as which Poor response 3 o occurs in some patients on methyldopa. There was also no appreciable changes in creatinine clearance The time taken to obtain control of blood in these patients at the end of 6 month therapy. pressure in the 16 patients ranged from one week to 4 months (Table VI). As the trial progressed, DISCUSSION it was found that some patients required an increase sulphate is a sympathetic block- in dose to maintain a response. Debrisoquine ing agent similar in action but different in structure that guanethidine. The onset of action is, TABLE VI to of however, rapid and it is therefore quicker to TIME FOR CONTROL OF BLOOD PRESSURE achieve control of blood pressure with this drug than with guanethidine. An optimal initial response l week 6 can be obtained within one week although some 2 weeks cases may take as long as 4 months. Like guane-

3 weeks 1 thidine, the controlling dose varies widely- between 20 and 70 mg. per day with an average 4 weeks 3 of 4625 mg. in this series. Other authors have 5 weeks reported a wider range (l0 to 120 mg. per day 6 weeks l with an average of 45 mg.; Kitchin and Turner,

3 months 2 1966). 4 months The greatest advantage of this drug over the available antihypertensive agents such as methyl - Mean: 3.3 weeks dopa and guanethidine is the notably fewer and less severe side -effects. Of the 20 patients in this Side -effects were minimal and seldom dis- series, 5 were completely free from any side -effects. abling (Table VII). Nine patients showed pro- One of them was particularly pleased with the gressive increase in weight due to fluid retention drug because it did not cause impotence and and had to be given chlorothiazide. Eight patients failure to ejaculate, a side -effect which he had had postural hypotension but only 2 complained experienced with other antihypertensive agents., of giddiness relating to posture. Only 2 patients Nine patients had to be given chlorothiazide complained of stuffy nose and one of them also because of steady weight gain during each visit; complained of weakness and lethargy. This latter in one of them fluid retention was so severe that 109 SING A PORE MEDICA L JOURNAI

he exhibited signs of early heart failure which of having remarkably few side -effects. It was also required digitalisation. The only other series in found to be effective in cases not responsive to which. fluid retention causing signs of early heart other antihypertensive agents. Although in some failure was recorded was that of Athanassiadis centres (Gent and Bacon, 1967), it is considered et al (1966), and fluid retention was not a major the agent of choice in the management of hyper- complication in the series of 45 patients reported tension, it is the author's Opinion that this drug by Kitchin and Turner (1966). Unlike other should be regarded only as an useful addition reports (Gent and Bacon, 1967), there was no and alternative to the array of antihypertensive necessity to reduce the dose of debrisoquine agents available. For as with all conditions for sulphate when a diuretic was added to the regime which more than one drug is available for manage- of treatment. As with other series, postural hypo- ment, it is better for the physician to be familiar tension is one of the commonest side -effects. In with one drug and to change only when this drug addition, exertional dizziness has been recorded fails to achieve the desired result. in cases no exhibiting postural hypotension (Gent and Bacon, 1967; Athanassiadis et al, 1966); SUMMARY this was not present in the present series. None of Twenty patients our patients complained of exertional muscle were given debrisoquine sul- phate (Declinax) a pain, blurred vision or nocturia (Athanassiadis for period of 4 months to one year. Good was obtained in 16 et at, 1966; Kitchin and Turner, 1966). Diarrhoea control patients, fair control in 4 and poor control in 4. Six of the was said to be severe in 4 out of 7 patients de- 9 patients who had not responded scribed by Athanassiadis et al (1966) but Kitchin previously to other antihypertensive agents responded to de- and Turner (1966) reported only 2 patients with brisoquine sulphate. mild diarrhoea. In this series, 2 patients had diarrhoea and in only one of them was this severe The drug is as effective as guanethidine and enough to warrant withdrawal of the drug. How- methyldopa in the management of moderate to ever, both of these patients did not achieve good severe hypertension. It has, however, the distinct control of blood pressure, even though in one of advantage over the latter in producing remarkably them the close of debrisoquine sulphate was few side -effects. pushed up to 220 mg. per day. The patient who had mild diarrhoea also complained of feeling ACKNOWLEDGEMENTS cold, a side -effect which has not been reported in I wish to thank Professor O. T. Khoo for per- the literature reviewed. None of the 20 patients mission to publish this paper, and Roche Far East developed any haematological disorders including Research Foundation, for their generous supply autoimmune haemolytic anaemia, had depression of Declinax for this trial. or showed appreciable deterioration of glomerular filtration rate at the end of 6 months of treatment. REFERENCES This is in agreement with all reports reviewed. I. Abrams, W. B., Pocclinko, R., Klausner, M., Hanauer, Like guanethidine, some degree of tolerance L. and Whitman, E. N. (1964): "Clinical Pharma- to debrisoquine sulphate developed, i.e., an in- cological Studies with Debrisoquin Sulfate-A New Antihypertensive Agent." J. New Drugs, 4, 268. crease in doses over that achieved for initial con- 2. Athanassiadis, D., Cranston, W. I., Juei-Jensen, B. P. was trolled required in some patients as the trial and Oliver, D. O. (1966): "Clinical Observation on the progressed. This is in accordance with the findings Effects of Debrisoquine Sulphate in Patients with High of Kitchin and Turner (1966) and Athanassiadis Blood Pressure." Brit. Med. J., Vol. II, 732. 3. Dollery, C. T. and Harrington, M. (1962): el al (1966) but at variance the "Methyldopa with report of in Hypertension. Clinical and Pharmacological Studies." Gent and Bacon (1967). Lancet, Vol. I, 759. Of the 9 cases who did not respond to available 4. Gent, A. E. and Bacon, A. P. C. (1967): "Debrisoquine- A Hypotensive Drug with Minimal Side -Effects." The antihypertensive agents in various combinations Practitioner, 198, 673. and diuretics, 5 patients obtained good response 5. Kitchin, A. H. and Turner, R. W. D. (1956): "Studies on and one a fair response. The remaining 3 did not Debrisoquine Sulphate." Brit. Med. J., Vol. II, 728. respond. Athanassiadis et al (1966) also reported 6. Luria, M. H. and Frcis, E. D. (1965): "Treatment of Hypertension with Debrisoquin Sulfate (Declinax)." response to debrisoquine sulphate in patients who Curr. Then. Res., 7, 289. failed to respond to methyldopa and guanethidine. 7. Onseti, G., Laschiazza, D., Brest, A. N. and Moyer, J. H. (1966): "Cardiac and Renal - Debrisoquine sulphate is therefore an effective Haemodynamic Effects of Debrisoquin Sulfate in Hypertensive Patients." antihypertensive agent with the added advantage Clin. Pharmacol. Titer., 7, 17.