Clinical Studies

The Effect of Guanethidine in the Treatment

of Hypertension

A Study of Twenty-Five Patients*

MAUDE STEVENSON, M.D., NELSON GOODMAN, M.D., DAVID FINKELSTEIN, M.D., F.A.C.C. and SAMUEL BELLET, M.D., F.A.C.C.

Philadelphia, Pennsylvania

T HE GANGLIONIC BLOCKING agents have been a valuable adjunct in the treatment of hy-

pertension which does not respond satisfactorily to the administration of less potent antihyper- tensive drugs. The untoward effects associated with parasympathetic blockade, however, have limited their usefulness in many patients with severe hypertension.

Guanethidine (SU-5864)t, one of a group of compounds synthesized by Mull and co- workers,’ was demonstrated to have a blood pressure lowering effect in hypertensive dogs with renal and neurogenic disease.2-4 These hypotensive effects are marked and prolonged following a single intravenous dose ; similar results have been obtained after oral admin- istration. More recently it has been demon- strated5 that guanethidine depletes the nor- epinephrine level in the hearts of rabbits and cats. It is believed that a similar effect takes place in the arteriolar wall; a depletion of norepinephrine at this site results in marked reduction in blood pressure without parasym- pathetic blockade. Recent investigations in human patients using guanethidine have .n- dicated that it is an antihypertensive agent of considerable promise.*p6J

The purpose of this study is to report our experience with twenty-five outpatients treated with guanethidine as the sole antihypertensive agent for periods ranging from six to twenty weeks. All of these patients had chronic hyper- tension and were referred for study after having been previously followed from several weeks to

t This drug was supplied by Ciba Pharmaceutical Products, Inc., Summit, New Jersey.

several years in the outpatient clinics of the Philadelphia General Hospital.

MATERIAL AND METHODS

Twenty-five patients with persistent diastolic hyper- tension were selected for study; fifteen were women and ten were men. Their ages ranged from thirty-one to seventy-three years; the average age was fifty-five years. The average known duration of the hyper- tension prior to treatment was five and a half years. Of these, twenty patients had essential hypertension, one had hypertension secondary to toxemia of preg- nancy and four had hypertension associated with chronic pyelonephritis. Recumbent blood pressures taken after other hypotensive medication had been discontinued for a period of at least two weeks were accepted as a baseline. These pressures ranged from 160 to 294 mm. Hg systolic and 100 to 160 mm. Hg diastolic; the mean systolic was 204 and the mean diastolic, 120 mm. Hg. Twelve patients had a diastolic pressure of 120 mm. Hg or greater, and thirteen had diastolic pressures between 100 and 120 mm. Hg prior to treatment. All patients had pre- liminary clinical examinations and laboratory studies which included roentgenogram of the chest, electro- cardiogram, urinalysis, blood urea nitrogen, phenol- sulfonphthalein and Fishberg concentration test as well as complete blood counts and liver function studies. When indicated, intravenous and retro- grade pyelography were performed. These tests were repeated at the completion of this study.

Depending on the basal blood pressure reading, an initial dose of 10 to 25 mg. of guanethidine was ad- ministered daily by mouth. The blood pressure was recorded weekly and the drug was increased by 10 to 25 mg. doses until a satisfactory fall in pressure was obtained or untoward effects ensued. Because of the initial small doses used and the variable responses to treatment, at least six weeks were required for an

* From the Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pennsylvania. This work was aided by a grant from the U. S. Public Health Service [H 141 (C-9)].

386 THE AMERICAN JOURNAL OF CARDIOLOGY

Effect of Guanethidine

-- weens

FIG. 1. Salutary effect of guanethidine in reducing the blood pressure in a fifty-seven year old woman (Case 4) with moderately severe hypertension. In this and the following figures the dotted line connects points representing the blood pressures in the erect position; the solid line, points representing supine pressures. Blood pressure has been plotted along the ordinate and weeks of study along the abscissa.

adequate dosage level and a satisfactory blood pres- sure response to be attained in many patients. There- fore, only those patients followed for a minimum period of six weeks were included in this report.

RESULTS

There was a fall in blood pressure in response to guanethidin.e in all twenty-five patients. This effect was more marked in the erect than the recumbent position (Table I). This is similar to findings previously reported.4P6p7 The pressures fell an average of 22 mm. Hg systolic and 14 mm. Hg diastolic in the recum- bent and 49 mm. Hg systolic and 24 mm. Hg diastolic in the erect position. There was no clear correlation between the initial blood pres- sure reading and the daily maintenance dose of the drug required to control the blood pressure. This maintenance dose varied from 5 to 200 mg. daily (average 80 mg.) and was adminis- tered either as a single dose or divided into two daily doses. Ten patients required from 10 to 50 mg. daily; five patients more than 50 mg. but less than ‘100 mg. ; and ten patients, 100 to 175 mg. daily to maintain satisfactory blood pressure levels.

Postural hypotensive ezects were noted as early as seventy-two hours after an effective dose and became troublesome if the dose was rapidly increased. The response to even a small in- crement in dosage could not be predicted. For example, case 4, a patient with moderately severe hypertension, manifested relatively fixed blood pressure over a wide range of doses (Fig. 1); then, a 25 mg. increment in daily dose resulted in symptoms of postural hypo-

Weeho

FIG. 2. Illustrates the effect of guanethidine in a pa- tient (Case 2) with mild hypertension, generalized arteriosclerosis and chronic congestive heart failure.

tension. Case 2 (Fig. 2), a fifty-nine year old man with mild hypertension, had a minimal response to 5 mg. of guanethidine daily but severe postural hypotension developed when the dose was increased to only 10 mg. daily. The patient became very dizzy on standing, and the dose was reduced again at the seventh week to 5 rng;; As the erect pressures began to rise another attempt to increase to 10 mg. daily at the tenth week was again followed by a severe drop in the erect pressure associated with syncope with essentially no change in the supine pres- sure. The erect pressures then rose slowly when the dose was decreased until a more marked increase in pressures occurred fairly rapidly between the seventeenth and nineteenth weeks. Dizziness on first arising in the morning and on standing was complained of by fourteen patients at some time during the course of treat- ment. In the majority of patients this was mild and was eliminated by lowering the dose. The action of the guanethidine was prolonged, a postural hypotensive effect being observed for periods up to five days after the drug was discontinued. Even more prolonged effects have been reported by others.4

The blood pressure changes at the end of the treatment period when taken in the recumbent position were not statistically significant. The mean systolic pressure dropped to 90.6 mm. Hg f 12.5 per cent of the control values; the mean diastolic pressure dropped to 89.4 f 9.2 per cent of the control values. The blood pressure changes when taken in the erect position were statistically significant. The mean systolic pres- sure was 77.6 f 9.9 per cent of the control values; the mean diastolic pressure fell to 80.7 f 10.7 per cent of the control values. The lowest erect blood pressure recorded during ther- apy was highly significant. The systolic pressure

388

Case No. Age Sex Diagnosis

1 60 Female 2 59 Male 3 58 Male 4 57 Female 5 58 Male 6 58 Female 7 54 Male 8 46 Male 9 55 Female

10 49 Female 11 63 Male 12 71 Female 13 31 Female 14 60 Female 15 64 Female 16 49 Female 17 73 Female 18 57 Male 19 37 Male 20 59 Female 21 44 Male 22 34 Female

23 54 Female 24 65 Female 25 48 Male

Average 55

Stevenson et al.

TABLE I

Effects of Guanethidine on Twenty-Five Patients with Hypertension

HCVDt

CPZ HCVD HCVD CP HCVD CP HCVD HCVD CP HCVD HCVD HCVD HCVD HCVD HCVD HCVD HCVD HCVD HCVD HCVD HCVD

(toxemia) HCVD HCVD HCVD

13 6 6 months

10 5

15 4

9 13

4 months 20

2 months 2 2 1 month 4 2 3 4 2 3

180/106 15 160/100 14 220/l 40 12 210/140 19 180/120 8 195/100 12 185/125 16 230/150 28 210/120 14 260/160 15 220/130 17 200/100 12 186/130 8 220/100 8 218/116 10 185/116 12 294/l 12 12 230/l 30 8 180/115 9 180/117 11 180/108 9 180/112 11

10 160/118 8 6 months 235/120 13 3 170/120 6

5.5 204/120 12

Known Duration of Hypertension

(Years)

Blood Pressure before

Therapy (mm. Hg)

Duration of Treatment

(Weeks)

* In order to indicate the efficacy of guanethidine in reducing the blood pressure recorded in a standing position the lowest recorded value is included in the table. In many instances the symptoms accompanying the postural hypo- tension made it advisable to decrease the dose of guanethidine. This is reflected in the higher blood pressures recorded at the end of therapy. In some cases the recorded values do not reflect the maximum reduction in pressure because

was 71.3 mm. Hg f 10.5 per cent of the con-

trol values and the diastolic pressure fell to 75.0 f 9.1 per cent of the control values.

Toxic and Side JCfects: The blood counts, liver and renal function tests enumerated previously were studied during the course of and at the end of treatment. The results were unaltered, indicating that the drug has no demonstrable toxic effects on the parameters studied. Roent- genograms of the chest and electrocardiograms obtained before and after treatment showed no essential change. In all cases the pulse rate fell an average of 16 to 20 beats per minute. In one patient with marked impairment of renal function the level of blood urea nitrogen rose in spite of cautious lowering of blood pressure.

This later fell below the initial level, suggesting a renal hemodynamic readjustment. Further cautious lowering of blood pressure in this pa- tient was then obtained. On the basis of this experience and that of Richardson and Wyso,G it appears that when impairment of renal func- tion is marked, extreme caution must be exer- cised in the use of this drug to avoid renal decompensation. Gastrointestinal symptoms were relatively mild ; nausea or vomiting oc- curred in four patients and diarrhea in two. No other side effects were noted. The accum- ulation of edema fluid during treatment with guanethidine has been previously described,4 but this was not noted in the cases in our series.

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Effect of Guanethidine

TABLE I Continued

389

Final Daily Maintenance

Dose of Guanethidine

(mg.)

Blood Pressure at End of Treatment Period

(mm. Hg) Toxic Effects _.

_. Recumbent Erect

Lowest Erect Blood Pressure* Recorded during

Therapy

(mm. Hg)

60 180/104 160194 126/86 None 10 156/90 106/70 110/60 Dizziness 37.5 160/114 142/108 136/94 None

125 178/108 158/100 132/100 Nausea, diarrhea, dizziness 25 170/110 164,‘llO 150/100 Dizziness 20 175/90 155/88 120174 Dizziness

100 164/106 140/92 140/92 Nausea 75 210/l 30 170/94 136/84 Nausea

150 164/100 150/94 150194 Dizziness 125 156/94 150/90 142/90 Dizziness 175 198/110 148/86 148/86 None

10 176/96 152194 146180 Nausea, dizziness 125 170/118 164/110 136/88 Dizziness 100 214196 180/86 168/86 Diarrhea

75 186/96 146184 150186 None 75 180/110 158/110 158/100 Dizziness

37.5 280/125 220/108 140/70 Dizziness 75 180/120 176/112 144/90 Dizziness 75 150/95 140/95 140/95 None 25 180/110 155195 150185 Dizziness 50 170/105 150/100 140/95 None

150 180/105 140/100 140/100 Dizziness

50 100

50

80

205/115 160/100 160/100 None 180/100 140/80 140/80 Dizziness 180/115 160/110 140/105 None

182/106 l55/96 143/89 . .

-.

the patients were advised to discontinue or reduce their medication if severe symptoms occurred. By the time of their visits to the outpatient clinic, the blood pressures recorded in the standing position had frequently increased to the point where symptoms were no longer present.

t HCVD = hypertensive cardiovascular disease ; $ CP= chronic pyelonephritis.

COMMENTS Mechanism qf Action: Guanethidine mani-

fests a definite hypotensive action. The mech- anism of blood pressure reduction is incom- pletely understood but pharmacologic studies in the dog have indicated that the locus of ac- tion is probably at peripheral sympathetic receptor sites.

Burn and Rand8 have suggested that “sym- pathomimetic amines may be divided into two classes,” one class consisting of substances like norepinep:hrine, epinephrine and neosyne- phrine which act on vessel walls directly, causing a pressor response which is enhanced in animals pretreated with reserpine; the second group of substances, including tyramine, ephedrine

MARCH 1961

and amphetamine, are ineffective in produc- ing a vasopressor response in animals treated with reserpine. Since there is evidence that reserpine may deplete stores of norepinephrine in vessel walls, the first group of substances which act directly on the arteriolar wall is presum- ably more effective if the few receptor sites normally occupied by resting levels of norepine- phrine are freed of this hormone by reserpine and can be stimulated anew. The second group of substances is thought to produce sympatho- mimetic effects by facilitating the release or action of norepinephrine at end organ sites. These substances cannot produce such effects if the wall is depleted of norepinephrine.

It has been similarly demonstrated by Page

Stevenson et al.

FIG. 3. This sixty-five year old man (Case 11) with moderately severe hypertension had a gradual fall in erect and supine pressures with increasing doses of guanethidine (first to tenth weeks).

and Dustan that the pressor response to norep- inephrine, angiotensin, vasopressin and metar- amino1 is augmented by prior administration of guanethidine and the response to tyramine, amphetamine, mephentermine and ephedrine is reduced. They have noted the resemblance of these effects to those described with reserpine and have further observed a reserpine-like quieting effect of intravenous guanethidine in dogs. It has been demonstrated also that al- though it abolishes the carotid sinus pressor reflex, guanethidine does not affect parasym- pathetic efferent transmission and postgang- lionic sympathetic action potentials. These observations have led previous investigators to conclude that the hypotensive action of guane- thidine is similar to that of reserpine in block- ing either the release, action or distribution of norepinephrine at peripheral sympathetic end organs.3,4

Hemodynamic Efects: With regard to the hemo- dynamic aspects of blood pressure reduction, Richardson and WysoG observed that in some of their patients treated with guanethidine there was a reduction in glomerular filtration rate and renal plasma flow and a rise in blood urea nitrogen, especially if azotemia was pres- ent prior to treatment. These authors also noted a fall in cardiac output of about 10 per cent in the supine position and 20 per cent in the erect position, associated with reduction in blood pressures and attributed to venous pooling in the legs.

Development of Tolerance: Guanethidine has an advantage over the ganglionic blocking agents in that symptoms of constipation, dry

mouth, urinary retention and pupillary changes are not observed. The optimum dosage of the drug, however, is difficult to ascertain because of marked individual variations in response. In all but mild degrees of hypertension, toler- ance appears to develop to a dose which initially produced a satisfactory hypotensive effect, necessitating further increase in dosage. The development of such tolerance is illustrated by Case 11 (Fig. 3), a patient who had a satisfactory response to 150 mg. of guanethidine daily but gradually had an increase in blood pressure over the ensuing six weeks until a further increment in dosage was necessary. If the dose is increased rapidly, however, symp- toms of postural hypotension become trouble- some and slow gradual increases necessitate frequent visits to the outpatient clinic.

Clinical Applications: Because of the marked variation in the dose required for effective reduction of blood pressure, the unpredictability of an increment in dose, the severe postural hypotensive effect and the apparent develop- ment of tolerance, guanethidine seems to have little place in the treatment of patients with mild hypertension because more satisfactory drugs are available. Chlorothiazide, reserpine and their analogues have proved effective in lowering the pressure in this group of patients with relatively few serious side effects. Guane- thidine seems to act similarly to reserpine but manifests a greater peripheral and relatively less central hypotensive effect. It would seem in- advisable to use guanethidine as the initial form of therapy in previously untreated patients with hypertension. It should probably not be used alone in therapy. The aforementioned regi- men would eliminate the need for the ganglionic blocking agents in therapy. It would appear from our own experience and that of others that guanethidine has a role in the treatment of patients with more severe hypertension who do not respond to the rauwolfia derivatives and chlorothiazides alone. In the latter group it would seem advisable to add guanethidine in small and gradually increasing doses to the chlorothiazides instead of and occasionally in addition to reserpine.

It should be stated that because of the rela- tively small group of patients investigated, our views are to be considered tentative and may be subject to revision as larger series are studied. Studies are now in progress on the use of guane- thidine in combination with other forms of antihypertensive therapy.

THE AMERICAN JOURNAL OF CARDIOLOGY

Effect of Guanethidine

SUMMARY

Twenty-five patients with chronic hyper- tension have been treated with guanethidine for periods ranging from six to eight weeks. The blood pres,sures fell an average of 22 mm. Hg systolic and. 14 mm. Hg diastolic in the re- cumbent and 49 mm. Hg systolic and 24 mm. Hg diastolic in the erect position. The hypo- tensive action of the drug appears to be similar to that of reserpine in blocking either the release, action or distribution of norepinephrine at sympathetic end organs. The maintenance dose has ranged from 5 to 17.5 mg. daily; there has been marked variation between subjects in their response to a given dose. Occasionally tolerance seemed to develop. Postural hypo- tension was observed in all patients. Dizziness on standing was noted in fourteen patients, nausea or vomiting in four and diarrhea in two. Guaneth:idine has the advantage over the ganglionic blocking agents in that parasym- patholytic effects are not observed.

It is concluded that guanethidine may be a useful supplement to other hypotensive agents

but has little place in the treatment of hyper- tension when used alone.

REFERENCES

1. MULL, R. P., MAXWELL, R. A. and PLUMMER, A. J. Antihypertensive activity of hexahydro-l-azepine- proprion-amidoxime. Nature, 180: 1200, 1957.

2. MAXMTELL, R. A., Ross, S. D. and PLUMMER, A. J. Pharmacology of hexahydro-1 -azepineproprion- amidoxime dihydrochloride (SU-4029). J. Phar- macol. @ Expel. Therap., 123: 128, 1958.

3. Ciba: Orientation on SU-5864 (revised May, 1959). Summit, New Jersey.

4. PAGE, I. H. and DUSTAN, H. P. A new, potent anti- hvnertensive drug. J.A.M.A.. 170: 1265. 1959.

5. CA,: R., KUNTZM~N, R. and BRODIE, B.‘B. Nor- epinephrine depletion as a possible mechanism of action of guanethidine (SU-5864), a new hypo- tensive agent (25702). Proc. SOL Exper. Biol. G3 Med., 103: 871, 1960.

6. RICHARDSON, D. W. and WYSO, E. M. Effective re- duction in blood pressure without ganglionic blockage. Virginia Med. Monthly, 86: 377, 1959.

7. FROHLICH. E. D. and FRIES. E. D. Clinical trial of guanetkdine, a new type of antihypertensive agent. M. Ann. District of Columbia, 28: 419, 1959.

8. BURN, J. H. and RAND, M. J. The action of sympa- thomimetic amines in animals treated with rcser- pine. J. Physiol., 144: 314, 1958.

MARCH 1961