Therapy with modern hypotensive drugs

Therapy

with Modern A Report EUGENE BAR~TH,

Hypotensive

from Budapest*

M.D.

and PONGR~CZ TARJAN,

Budapest,

the adrenergic transmission in postganglionic sympathetic fibers without affecting the action of circulating adrenaline or noradrenaline and without blocking parasympathetic impulses. Experiments with radioactive isotopes showed that the drug has a specific affinity for sympathetic nerve endings where it accumulates in a concentration that is sufficient to block Chemically, the adrenergic nerve impulses. bretylium tosylate is N-o-bromo-benzyl-N-ethylNN - dimethylammonium - p - toluene sulphoThis drug considerably nate (Darenthin@). lowers the systolic and diastolic blood pressure when taken in a single oral dose of 200 mg. Side effects rarely occur and are less severe than with ganglion-blocking agents. This drug does not possess any central depressant action like rauwolfia alkaloids. We have studied its effects in 108 patients, mostly advanced cases with severe alterations in the eyegrounds. Eject on Blood Pressure: The action of bretylium tosylate was first studied in a preliminary The patients received 200 mg. investigation. on an empty stomach in the morning. On subsequent days hexamethonium, chlorisondaand mecamylamine were mine, pempidine, After administered under similar conditions. the administration of the tablets, blood pressure, pulse rate and oscillometric tracings were studied at hourly intervals for eight hours. The blood pressure was measured in the recumbent and standing positions. These and other experiments showed that bretylium tosylate exerted a powerful lowering action on blood pressure in nearly all cases. This action can be compared to that of the There was ganglion-blocking agent, pempidine. no change in pulse rate, or a slight decrease; oscillometric tracings remained unaltered. The fall of blood pressure usually began three to four hours after the administration of the drug

P

GANGLION-BLOCKING AGENTS These agents have been introduced in recent years for the treatment of severe, advanced hypertension (hexamethonium, cases of chlorisondamine, pempidine, and mecamylamine). They act by blocking the synaptic transmission of nerve impulses in the ganglia of the autonomic nervous system, and suppression of sympathetic-adrenergic impulses results in a considerable reduction of blood pressure. A disadvantage in this form of therapy is that not only are sympathetic-vasomotor impulses suppressed but also parasympathetic (choAs a consequence, unlinergic) impulses. desirable side effects appear, such as disturbance of accommodation, gastric and intestinal atony Recent investigations show and constipation. that ganglion-blocking agents cannot be chemically modified so that cholinergic transmission is no longer inhibited. A pathologically increased transmission of impulses from the postganglionic fibers on the effector organ seems to play an important part in causing some forms of hypertension. Therefore recent experimental research endeavored to find drugs that exert their action exclusively on postganglionic sympathetic nerve endings, as such drugs would be free from the undesirable side effects of ganglion-blocking agents. SYMPATHETIC BLOCKERS BRETYLIUM TOSYLATE a drug which inhibits

* From the Hypertension

M.D.

Hungary

ROGRESS OF MODERN drug therapy of hypertension has advanced in three stages. (1) The discovery and successful use of ganglion(2) The discovery of new symblocking agents. pathetic blockers. (3) An advancement of therapy by the introduction of combined antihypertensive therapy.

Boura et al.’ discovered

Drugs

Clinic of the Jdnos Hospital, 848

Budapest, THE

Hungary.

AMERICAN

JOURNAL

OF CARDIOLOGY

Therapy

with Modern

and lasted for eight to ten hours. In 72 preliminary trials, the average fall of blood pressure was as follows: in the recumbent position: in the standing position: 53/20 mm. Hg; 64/26 mm. Hg ; and the average fall in pulse rate was eight beats per minute. Because of the rapid and powerful Dosage: action of bretylium tosylate, variations in blood pressure are very pronounced in some patients who develop a feeling of weakness and dizziness. It is therefore important to increase dosage cautiously to the required amount. After an initial testing dose of 100 mg. (i/z tablet) we increased each dose by 100 mg. to a maximal total daily dose of 600 to 800 mg. In rare cases we gave doses above 1,000 mg. It seemed to us that our patients were more sensitive to the drug than hypertensive patients in Great Britain. Perhaps this can be explained by the lower weight and the smaller build of the Hungarians. In the evaluation of good and moderate results we did not attach much importance to a fall of diastolic pressure to below 105 mm. Hg.2s3 Some elderly hypertensive patients experienced severe disturbances although the diastolic pressure was below 100 mm. Hg. Advantages: Treatment with bretylium tosylate constitutes important progress in the therapy of hypertension. Because of the pronounced variations in blood pressure, however, it is often difficult to establish the right dosage for each patient. In our opinion, daily doses above 1,000 to 1,200 mg. are excessive. If the blood pressure can be lowered only by the administration of such high doses, we prefer to use combined therapy (see below). One great advantage of bretylium tosylate is that side effects are rare and mild (vertigo, diarrhea and swelling of the parotid gland). Absence of the side effects observed after the use of ganglion-blocking agents, such as visicn disturbances and severe constipation, is of great value. Nevertheless, it is necessary to combine bretylium tosylate and ganglion-blocking agents in some cases where gastric distress or symptoms of peptic ulcer are present due to the blocking of the sympathetics. GUANETHIDINE This drug was first investigated by Page and Dustan. It has an inhibitive action on sympathetic nerve endings and thereby causes a pronounced fall of blood pressure. Chemically, guanethidine is (2-) octahydro-1 ‘-azocinylJUNE 1962

Hypotensive

Drugs

849

(-ethyl)guanidine - sulphate (Ismelin@). Its pharmacologic action is similar to that of bretylium tosylate. However, the onset of The initial daily dose is 10 action is slower. to 25 mg. and is later increased to 20 to 60 mg. In a preliminary trial, as previously described, the fall in blood pressure was relatively late ; a pronounced fall of blood pressure often occurred only after five to six days of treatment. An advantage of guanethidine is that its action does not begin too quickly and that small doses are sufficient to maintain a low level of blood presAfter cessation of treatment the blood sure. pressure often remains low for another two or three days. It is rarely necessary to exceed daily doses of 100 mg. Orthostatic and Other Effects: The greatest fall in blood pressure usually occurs in the standing position and during walking and may be so pronounced that the systolic pressure falls as much as 70 to 80 mm. Hg and the diastolic pressure 30 to 40 mm. In such cases weakness and dizziness are often experienced but can be alleviated by administration of epinephrine or norepinephrine. However, if moderate doses are used these side effects rarely occur. Diarrhea is sometimes observed and is a sign of overdosage that usually occurs when blood pressure is lowest. At the same time there is a pronounced slowing of the pulse rate. Sympathetic inhibitors such as bretylium tosylate and guanethidine should be administered in small doses in the morning and in larger doses in the evening to patients who work. If the fall in blood pressure is too pronounced, it is advisable to discontinue treatment for two to three days. Guanethidine, too, is often indicated for combined therapy. Since March 1960 we have used the drug in 69 patients, mostly severe cases. Good and moderate results were obtained in 67 per cent. COMBINED TREATMENT ANTIHYPERTENSIVE DRUGS PLUS THIAZIDE DERIVATIVES Chlorothiazide and hydrochlorothiazide are powerful saluretic agents which play an important part in the treatment of hypertensive patients. Combined therapy with these drugs was recommended by Barath and Tarj6n.5 For basic therapy Gijmijri et al.6 preferred rauwolfia alkaloids that could be combined with various antihypertensive drugs. Martos and Kiss7 and Barhth and Tarjan

850

Bara’th and TarjAn

250

200

f50

fO0

70 ; FIG. 1.

A 48 year

old patient

with

have shown that chlorothiazide and hydrochlorothiazide possess a powerful diuretic action, and at the same time they considerably lower the systolic and diastolic blood pressure. A good hypotensive action can be obtained when these drugs are combined with other agents such as bretylium tosylate, guanethidine, pempidine and mecamylamine. Moderate doses of these saluretic agents (50 mg. of hydrochlorothiazide or 0.5 to 1 .O gm. of chlorothiazide) provoke a pronounced increase in urine flow up to 2,000 to 3,000 ml. and an increased elimination of sodium chloride up to 10 to 15 gm. daily. A great advantage of the new diuretic agents is that, if they are combined with ganglion-blockers or sympathetic inhibitors, only 60 to 70 per cent of the daily doses of the latter drugs is necessary to obtain a satisfactory result. The incidence of side effects is thereby also reduced. On days when the patients take saluretic drugs, a total daily amount of 3 to 4 gm. sodium chloride is allowed in the diet. A further advantage of combined therapy is that saluretic agents often cause a considerable weight loss, a favorable effect in obese hypertensive patients. We administer the saluretic agents in the morning and at midday so as not to disturb the

hypertension

and cardiorenal

sclerosis.

night’s rest by prolonged diuresis. Patients who would be disturbed in their daily professional activity by abundant diuresis are advised to take the drugs on Saturdays or Sundays. It is usually sufficient to administer 2 doses daily on two or three days of the week. It is advisable that the patients eat fruit and potatoes on such days, in order to counterbalance the potassium loss. Figure 1 illustrates the results of combined therapy with 3 tablets of 200 mg. bretylium tosylate and 3 half-tablets (37 mg.) of hvdrochlorothiazide daily. When the administration of bretylium tosylate is discontinued, a considerable rise in blood pressure occurs. Upon subsequent simultaneous administration of bretylium tosylate and hydrochlorothiazide, again there is a remarkable lowering of the blood pressure. The hypotensive action of the saluretic agents may be caused by a considerable loss of sodium chloride. As long ago as 1929, Kor&i8 and Widals drew attention to the hypotensive action of sodium chloride depletion. There is, however, no agreement on the mode of action of the new diuretic agents. Probably chlorothiazide and hydrochlorothiazide do not act by inhibition of carbonic anhydrase like some THE

AMERICAN

JOURNAL

OF

CARDIOLOGY

Therapy

FIG. 2. Regulatory Longitudinal section. TarjAn, P. ct al.14

with Modern

mechanism in a small Low magnification.

artery. From

:

of their predecessors. Possibly, the saluretic agents inhibit the tubular reabsorption of sodium chloride, thereby provoking a diminution of plasma volume and a lowering of blood pressure. ANTIHYPERTENSIVE IODINE

DRUGS

PLUS

INTRAVENOUS

THER.4pY

Even 25 years ago, Barath recommended the intravenous administration of an iodine solution for the treatment of patients suffering from high blood pressure. In forms of hypertension that are accompanied by aortic dilatation with an accentuated second sound, this form of therapy may be indicated in view of the possible syphilitic etiology. Barath and Tarjan’O recommended combined treatment with hypotensive agents such as veratrum alkaloids and ganglion-blocking agents together with iodine therapy. Iodine is administered in a 10 per cent solution of sodium iodide in doses increasing from 6 to 10 ml.; the injections are given daily or every second day until a total amount of 15 to 16 gm. has been administered. The patients tolerate injections very well; elderly arteriosclerotic patients become more lively; headaches and vertigo soon disappear. Often a remarkable improvement is noted in sclerotic vascular changes in the eyegrounds. Iodine therapy has also been found of value in peripheral vascular disease (intermittent claudication). Our experience shows that iodine therapy can give excellent results if combined with hypotensive agents. Recent investigations by Martos et al.” show that intravenous iodine therapy produces biochemical changes in the blood, resulting in a lowering of serum cholesterol and lipoproteins. JUNE1962

Hypotensive

Drugs

Intravenous iodine therapy is contraindicated in the presence of hyperthyroidism, nervous overexcitation with marked tachycardia, recent myocardial infarction, cerebral hemorrhage and all other recent hemorrhages. Side effects are rare; they consist of nasal congestion, acne, marked salivation and swelling of the sublingual gland. Iodine therapy by injection can be combined with veratrum alkaloids, hexamethonium, mecamylamine, bretylium tosylate or guanethidine on alternate days. The dosage of the latter agents can be reduced by 30 to 40 per cent. A repetition of the iodine treatment sometimes becomes necessary after four to five months. The long term results of combined therapy arc quite favorable. I~~PORTANCE

OF PERIPHERAL

REGULATORY TREATMENT

CIRCULATORY

MECHANISMS OF HYPERTENSIVE

IN THE DISEASE

In the smallest arterioles and venules certain cell proliferations are found which constitute mechanisms. regulatory Recent studies’“-I4 underlined the importance of these structures. The regulatory mechanisms are “cushion-like” in form and contract and dilate rhythmically; they probably exert a “lock-like” action.15 ClaraI described these structures as arteriovenous anastomoses. The part played by these mechanisms is still little understood. It seems, however, that these structures which some investigators have described as epithelioidal cell agglomerations can accumulate water and sodium chloride and might also have some hormonal activities. Bar&h and Temesrtk&i13 first pointed to the possibility of investigating the physiologic and pharmacologic behaviour of these “lock-like” mechanisms in normal and hypertensive persons by excision of small pieces of nasal and buccal mucosa before and after the administration of various drugs, and by histological examination. They found that chlorisondamine and hexamethonium caused an initial swelling and a subsequent shrinking of these structures, resulting in an acceleration and improvement in peripheral blood flow. Figure 2 shows such a “lock-like” structure in low magnification. Figure 3 shows the shrinking of the “cushions” and an open lumen after the administration of iodine and reserpine. Our recent investigations have led us to believe that these mechanisms probably play an important part in the regulation of peripheral

852

BarAth and TarjAn

FIG. 3. Regulatory mechanism in a small artery. A, before administration administration of reset-pine, showing pronounced shrinkage of the regulatory of the wssels.

blood flow and respond to pharmacologic actions. For instance, iodine and reserpine can cause a pronounced stagnation and swelling in the folds of the nasal mucosa. This phenomenon could explain the rhinitis and nasal congestion provoked by iodine and reserpine and also by ganglion-blocking agents and sympathetic inWe believe that these pharmacohibitors. histologic methods of investigation constitute a

of reserpine. B, after cells in an open lumen

remarkable progress in the study of pharmacologic actions, as well as of allergic reactions and of some experimental pathologic problems. Similar investigations may contribute to our understanding of the mechanisms of action of various drugs in the therapy of hypertension.

SUMMARYAND The

discovery THE

CONCLUSION

of adrenergic AMERICAN

JOURNAL

inhibitors OF

such

CARDIOLOGY

Therapy

with Modern

as bretylium tosylate and guanethidine is clearly a major advance in the treatment of severe hypertension. A very important enrichment of therapy is the introduction of combined therapy with new saluretic drugs as well as the combined treatment with 10 per cent sodium iodide solution, administered intravenously in doses of 6 to 10 ml. This form of therapy is recommended for the treatment of the advanced sclerotic stage. The results are often dramatic. Further progress seems to be in the discovery of peripheral regulatory mechanisms in the smallest arterioles and venules. These “locklike” mechanisms can be investigated by excision of small pieces of nasal and buccal mucosa before and after administration of various drugs. We believe that these pharmacohistologic methods of investigation constitute remarkable progress in the study of pharmacologic actions, as well as of allergic reactions and some experimental problems. REFERENCES 1. BOURA, A. L. A., GREEN, A. F., MCCOUBREY, A., LAURENCE,D. R., MOULTON, R. and ROSENHEIM, M. L. Darenthin, hypotensive agent of new type. Lancet, 2: 17, 1959. 2. HURLEY, R. E. and PAGE, I. H. Bretylium tosylate as an antihypertensive drug. JA.M.A., 172: 2081, 1960. 3. DOLLERY, C. T., EMSLIE-SMITH, D. and McMICHAEL, .I. Bretylium tosylate in the treatment of hypertension. Lamet, 1 : 296, 1960. 4. PAGE, I. H. and DUSTAN, H. P. A new potent

JUNE 1962

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5.

6.

7.

8.

9. 10.

11.

12.

13.

14.

15.

16.

Drugs

antihypertensive drug. J.A.M.A., 170: 1265, 1959. BAR~TH, E. and TARJAN, P. Experimental investigations on the antihypertensive action of a new diuretic agent (dihydrochlorothiazide). OIVOSi H&l@, 100: 1962, 1959. GBMBRI, P., GLAz, E. and SZAB~, 2. Some actual problems of the hypertensive disease. Orvosi H&lap, 101: 361, 1960. MARTOS, K. and KISS, .I. Dihydrochloride-treatment of hypertensive patients. Oruosi Hetitap, 100: 1555, 1959. KORANYI, A. V. Pathologie und Therapie der Nieren-Krankheiten, pp. 292, 140. Berlin, 1929. J. Springer. WIDAL, P. cit. Korbnyi, ref. 8. BARATH, E. and TARJAN, P. Eine nene Methode znr medikamentijsen Behandlung der Hochdruckkrankheiten. Cardiologia, 30: 253, 1952. MARTOS, K., MAJLATH, J., KBNIG, M. and BARITH, E. Experimental investigations upon the alterations of the blood-lipids and proteins after intravenous sodium iodide treatment. Oruosi H&lap, 99: 597, 1958. R&NYI, L., BARATH, E., KISS, F. and B~LINT, J. Neue Betrachtungs-weise der Entstehung van Cholecystopathien auf grund klinischer und anatomischer Untersuchung. Acta Med. Acad. SC. Hung., 7: 333, 1955. BARATH, E. and TEMESR~KASI,D. Experimental investigations upon the role of occlusion mechanisms of the peripheral vascular system. Oruosi H&lap, 99: 1337, 1358. TARJAN? P., B;\LINT,J. and BARATH, E. Pharmacological responses of the occlusion mechanisms in the vascular system. Lecture. Scientific Session, Oct. 1958. J&OS Hospital, Budapest. BARATH, E. Pharmacological response in occlusion mechanisms of the terminal vascular system. Therap. Hung., 7: 1, 1959. Die arteriovenijsen CLARA, M. Anastomosen. Wien, 1956. J. Springer.