CLINICAL TRIAL OF GUANETHIDINE, A NEW TYPE OF ANTIHYPERTENSIVE AGENT*? EDWARD D. FROHLICH, M.D. Fellow in Cardiooascular Research, Depavttnent oj Medicine, Georgetown Uniwsity Sclrool of Medicine EDWARD D. FREIS, M.D. Chief oj' Medical Semite, Veterans Administration (Mt. Alto) Uospital; Associate Projessor of Medicine, Georgetown Lbziaersity School (~,f Medicine AZ AXWELL and his associates', 2 liminary report describes the clinical effects of SW.5864 (guanethidine) in hypertensive patients. recently found in dogs that hexahydro-l-azep- inepropionamidoxime dihydrochloride (SU- 4029) lowered the blood pressure of neurogenic and renal hypertensive dogs, blocked the carotid occlusion pressor reflex, and eliminated the hypertension elicited by amphetamine and ephed- rine but enhanced the pressor responses to norepinephrine and epinephrine. Similar effects also were observed with the use of SU-5864 [2-(octahydro-1-azocinyl)-ethyl] guanidine sul- fate.3 Maxwell et al postulated that these drugs had a novel mode of action characterized by inhibition of efferent sympathetic nerve ac- tivity at an unknown peripheral site. This pre- * From the Veterans Administration Hospital; the Depart- ment of Medicine, Georgetmw University School of Medicine; and the Cardiovascular Research Laboratory, Georgetown University Hospital, Washington 7, D. C. t Sqqjorted in part by the Unitetl States PulAic Health Service Grant H-720 (National Heart Institute). MATERIALS AND METHODS Fifteen male patients were selected from the hypertensive clinic, and all antihypertensive drugs were discontinued for a period of 2 weeks. Following this control period SU-5864 was ad- ministered in an oral dose of 50 mg. once daily in the morning. The dosage was increased or decreased from that level depending on the patient's response. Patients were seen at least once weekly and their blood pressures deter- mined in the supine, sitting and erect positions after 15 minutes' rest. Approximately half of the patients recorded their blood pressure at home. The blood urea nitrogen and blood hemo- globin concentrations as well as the white blood count were determined prior to and at the conclusion of the study. 419 420 Antihypertensive gfects. SC-5864 produced pri- marily an orthostatic hypotension (table 1). The reductions of systolic and diastolic pres- sures averaged 7/4 per cent in the supine posi- tion, 18/14 per cent in the sitting posture, and 27/26 per cent in the erect position. There was considerable variation in different patients, how- ever, so that a few exhibited significant reduc- tions in supine blood pressure (table 1) while others showed no change or slight increases of Sew Type of Antihypertensive Agent-Frohlich and Freis AUGUST, 19.59 RESULTS blood pressure in the supine position. Some pa- tients who recorded the blood pressure at home noted diurnal fluctuations with low orthostatic levels on arising which rose progressively during the day. No evidence of tolerance or resistance to the antihypertensive effect was noted during the 4 to 9 weeks (mean 6 weeks) of treatment. Dose response pattern. Effective maintenance dosage varied widely from 12.5 to 1.50 mg. (average 50 mg.) per day. Antihypcrtensivc activity usually appeared 21 hours after an TABLE I Clinical Ejects of SF-5864 in Fijteelz Hypertensive Patiettts A. H. iv. E. J. W. R. J. H. F.t A. J. J. I?. W. B. 1~. M. s. s. N. B. E. G. S. B. treated (mm. H&T Sitting*, 260/13( 200/13( 180/14( 185/13( 126/96 160/10( 175/98 190/13c 220/131 , ) ) 1' 1 1 11 1 1 ) )I I 1 ) b - 12.1 12.1 75 2.5 50 50 .50 2.5 62. t 50 50 00 12.: 50 7s JO Blood Pressure on Treat- ment (mm. Hg-) Supine Sitting Erect 210/105 185/95 160/90 8 150/112140/110130/90 8 170/130138/108110/88 8 155/120 155/108 130/98 6 138/96 122/90 110/82 5 140/110128/98 98/72 5 210/130180/118150/101 6 190/126130/102 lOO/SO 6 200/130 185/120 155/10! 170/100 160/100 135/80 170/100130/100135/80 190/110180/108158/90 190/110135/90 112/70 175/112 140/100145/10( 170/120155/120150/12( Heart Rate on Treat- ment (per minute) Supine* 50/20 50/18 10/o 30/10 +8/+6 t20/+1 i-30/+1 tlO/+6 j/+1 lO/lO 10/+5 o/20 30/20 3X/8 l-20/+ 11 12/4 Sitting 75/35 60/20 42/32 30/22 4/6 32/2 o/2 50/18 20/o 20/10 15/+2 10/22 x5/40 60/45 52 56 68 70/52 58 62 76 50/37 56 68 84 16/18 60 62 64 62/28 50 58 76 30/12 44 52 60 SO/SO 64 76 82 45/20 56 60 62 45/30 52 76 76 40/18 72 80 80 32j40 68 72 76 7X/70 50 58 64 65/20 60 68 68 -lO/+SSZ 64 64 50/32 ,57 65 71 Side-etlects Orthostatic faint- ness Nasal stuffiness Nasal stuffiness Fatigue, weakness None Wcakncss, impo tence Nasal stuffiness Drooping eyelids Drooping eyelids, blurred vision Weakness, imp- tence Diarrhea Diarrhea, weak- ness, impotence Orthostatic faint- ness, diarrhea, blurred vision None Impotence, ortho- static syncolx, diarrhea, blurretl vision * Although not reported because of minimal differences from sitting B.P. the control supine and erect pressures were used in calculating B.P. changes after treatment. t Sympathectomy-transthoracic 8 years ago. 1 Reduction in blood pressure unless otherwise indicatetl. VOL. XXVIII, NO. 8 Medical Anfzals of the District of Columbia 421 effective dose level and often progressed over the succeeding 2 or 3 days. Because of this cumulative effect severe orthostatic hypoten- sion and other side-effects such as diarrhea could be precipitated by raising the dosages too rapidly. The duration of the orthostatic anti- hypertensive effect lasted as long as 1 days to 1 week after discontinuation of oral dosage. This was observed when drug administration was stopped because of severe postural hypotension or other side-effects. The prolonged duration of action probably contributed to the cumula- tive action of W-5864. Brad~cardic eflect. Unlike the adrenergic blocking agents, SU-5864 produced a decrease in heart rate to an average level of 57 (range 44 to 68) beats per minute with the patient in the supine position. Reflex increase in heart rate was not blocked, however, since the average rate increased to 65 in the sitting posture and 71 beats per minute in the erect position (table 1). Side-eJects. In addition to the bradycardia certain other side-effects suggested parasympa- thetic stimulation or at least parasympathetic effects unopposed by sympathetic activity. These side-effects included nasal stuffiness in 3 pa- tients, drooping of the upper eyelids in 2, and diarrhea in 5. The diarrhea was severe and ac- companied by abdominal cramps in 3 of these cases. It was readily controlled by methanthe- ine bromide (Ranthine), 50 to 100 mg. once or twice daily. Four patients complained of impotence. Un- like the impotence experienced after ganglionic blocking agents, libido and ability to obtain an erection were not impaired. However? ejacula- tion could not be consummated, a reaction simi- lar to the sexual impairment caused by lumbar sympathectomy. Orthostatic weakness and faint- ness were experienced regularly when the dosage was increased beyond tolerable limits, and 1 patient developed syncope. Dosage manipula- tion was necessary to achieve the optimal degree of orthostatic hypotension. Several patients com- plained of mild intermittent blurring of vision, although their pupils were neither dilated nor unresponsive to light or accommodation. This complaint disappeared in all patients after several weeks of treatment. No significant changes were noted in the hemogram or the blood urea nitrogen level. DISCUSSION The presence of orthostatic hypotension and failure of ejaculation suggest a specific sympa- thetic blocking action of SU-5863 consistent with the pharmacologic studies in animals.3 The presence of diarrhea and bradycardia, and the absence of dryness of the mouth or disturb- ance in pupillary accommodation indicate that the parasympathetic nervous system is not inhibited. The absence of tachycardia is in- consistent with the action of adrenergic blocking drugs such as tolazoline or dibenzyline. The ability of SU-5864 to produce an ortho- static hypotension comparable to that achieved with the ganglionic blocking drugs but without the side-effects of parasympathetic inhibition makes this agent worthy of further study. The diarrhea produced by SU-5864 could be con- trolled with parasympathetic blocking drugs. The disturbance of sexual function is less com- plete and, therefore, less objectionable to the patients than that produced by ganglionic block- ade. The disadvantages of SC-5864 include the predominantly orthostatic antihypertensive effect leading to postural faintness and even syncope, and the necessity for critical dosage adjustment. These disadvantages are similar to those experienced with the ganglionic blocking drugs. The prolonged duration of action of SU-5864 is an additional inconvenience and possible potential danger, since severe ortho- static hypotension may persist for several days after the drug has been withdrawn. Preliminary clinical evidence suggests that the following measures may facilitate treatment with this agent: (1) gradual increase in dosages beginning at a level of 12.5 mg. once daily for 422 New Type of Antihypertensive Agent-Frohlich and Freis AUGUST, 1959 the first week and increasing by increments of 12.5 mg. at weekly intervals, and (2) daily home blood-pressure recordings taken with the patient in the erect position and with instruc- tions that the patient discontinue the medication if the blood pressure falls below a given level. Preliminary evidence suggests that administra- tion of chlorothiazide as an adjunct seems to dampen out the wide diurnal swings of blood pressure seen in some of the patients. SU-5864 probably should be restricted to the more severe and resistant cases in which the blood pressures are not controlled with chlorothiazide alone or chlorothiazide with small doses of hydralazine and/or reserpine. Although no serious toxic effects have yet appeared following SU-5864, it is still too early to be certain that they will not occur with further exhibition of the drug. SUMMARY Guancthidine, a new type of sympathetic nervous system inhibitor, was given orally in single daily dosages to 15 hypertensive patients for periods varying from 4 to 9 weeks. The aver- age effective dose was 50 mg. per day (range 12.5 effective dose was 50 mg. per day (range 12.5 to 150 mg.). The response was characterized by a potent, orthostatic, antihypertensive effect similar to that seen with the ganglionic blocking drugs but without the side-effects of parasym- pathetic blockade. However, some of the dif- ficulties associated with ganglionic blocking drugs such as the need for careful dosage adjustment also characterized SU-5864 and were even aggra- vated by the prolonged duration of action of the drug. Side-effects included diarrhea, failure of ejaculation, and bradycardia. BIBLIOGRAPHY 1. ~~AXWELL, R. A., ROSS, S. I>., A?JD PLUMMER, iz. J.: Phar- macology of hexahydro-1-azepinepropionamidoxime di- hydrochloride (SC-4029). J. Pharmacol. & Exper. Therap., 1958, 123, 128. 2. MAXWELL, R. A., AND OTHERS: Concerning the mechanisms of the cardiovascular actions of hexahydro-l-azel)inel,ro- pionamidoxime @U-4029). Ibid., 1958, 124, 127. 3. MAXWELL: I<. A$., MULL, Ii. P., AI'CD PLUblMER, 11. J.: [2-(Octahydro-1-azocinyl).ethyl]-guanidine sulfate (SU- 5864), a new synthetic antihypertensive agent. Ex- perientia, in press.