Reprinted from ChtcuL.4TIo~ Vol. V, No. 1, January 1952 Printed ~7i C.S.A. The Treatment of Hypertension with Hexamethonium By EDWARD D. FREE, M.D., FRANK -4. FINNERTY, JR., M.D., HAROLD W. SCHNAPER, M.D., AND CAPTAIN ROBERT L. JOHNSOK, M.C., U. S. A. F. Hexamethonium by subcutaneous injection in doses of 10 to 75 mg. of the ion every 8 or 12 hours produced significant reductions of arterial pressure and symptomatic improvement in a high per- centage of patients with benign or malignant hypertension. Methods for preventing tolerance and undesirable side effects are presented, and the advantages as well as the limitations of hexamethon- ium therapy are discussed. - I N 1948 Paton and Zaimisl introduced a series of polymethylene bistrimethylam- monium compounds of which the decame- thonium (ClO) member exhibited curariform properties while the penta- and hexametho- nium (C5 and C6) compounds produced a blockade of all autonomic ganglions. Arnold, Goetz and Rosenheim* and Burt and Graham3 demonstrated the marked vaso- dilator and hypotensive properties of penta- methonium in man. Kay and Smith4 noted a marked reduction of gastric acidity after hexamethonium in patients with peptic ulcer, this effect apparently being due to inhibition of the parasympathetic nervous system. Favor- able reports5-8 have appeared concerning the use of C5 and/or CG in the treat,ment' of essen- tial hypertension. Previous studies in this laboratory indicated that hexamet'honium, C6, produced greater vasodilatation in the toes thaneither tetraethyl- ammonium or Priscoline.g Quantitative meas- urements of the increase in foot blood flow From The Cardiovascular Research Laboratory, Georgetown University Hospital and the Department of Medicine, Georget,own University School of Medi- cine, the Georgetown Medical Division, Gallinger Municipal Hospital, and the Veterans Administration Hospital, Washington, D. C. Supported in part by research grants from the National Heart Inst,itute, U. S. Public HealthService; The Squibb Inst.itute for Medical Research, New Brunswick, K. J.; and Irwin, Neisler and Company, Decatur, Ill. Hexamet,honium dibromide (Bistrium) was sup- plied by H. Sidney Newcomer, M.D., E. R. Squibb and Sons, New York, N. 1'. after 50 to 100 mg. of C6 ion in normal subjects suggested that t'his compound produced nearly complete blockade of the sympathetic outflow to the footlo and was, therefore, considerably more potent, than previously known vasodilator agents." The present communication outlines our experience to date wit,h C6 in the treat- ment of hypertension. The dosages of hexa- methonium given in this paper refer to the amount of C6 ion rather than of the salt hexa- methonium dibromide. TIME-DOSE RELATIONSHIPS Following the intravenous administration of 5 to 50 mg. of C6 ion (9.6 to 96 mg. of hexa- methonium dibromide) the cardiovascular ef- fects of the drug appeared within t,wo to three minutes and quickly reached a maximum within 10 minutes or less. These effect,s con- sisted of a reduction of blood pressure and increase of heart rate, both of variable degree, as well as a consistent marked postural hypo- tension. Following the larger doses t,here also was a marked increase of foot blood flow and digit'al skin temperature. The peak of these effects usually lasted 15 minutes after which there was a gradual waning over a period of 5 to 10 hours. The heart rate usually in- creased only slightly and at times actually decreased. By the int,ramuscular and subcutaneous routes responses occurred at 15 to 30 minutes following injection and persisted for a period similar to that observed after intravenous ad- ministration. 20 Czrculation, v"lume v, January, 1956 FREIS, FINNERTY, SCHNAPER, AND JOHNSON 21 EFFECT OF ORAL ADMINISTRATION OF HEXAMETHONIUM A previously untreated 49 year old man with essential hypertension was given 25 mg. of C6 intravenously with a reduction of blood pres- sure from 220/120 to 160/95 and a further fall to 110/70 on sitting up in bed. The next day he was given 0.5 Gm. of CB ion orally in the form of the dibromide salt. One hour later the blood pressure had fallen from 225/125 to 190/115 with a further reduction to 150/110 on standing upright. Two hours later the blood pressure rose to the control values and the postural hypotension had disappeared. The next morning the patient was given 0.8 Gm. of C6 ion aft'er breakfast. There was no significant reduction of arterial pressure unt'il three hours after the dose had been taken when the blood pressure was unchanged with the patient in the supine position but in the erect position it fell from 210/130 to 160,015. At five hours the patient complained of feeling cold (a reaction we have not'ed when the in- crease in peripheral blood flow is int'ense). The blood pressure was 170/115 supine and 120/90 erect. At eight hours he felt weak and listless and was unable t'o stand without faintness. The blood pressure was 160/110 supine and 110/80 on sitting up in bed. At 10 hours the blood pressure supine was 130/80 and the pa- tient developed nausea and vomiting. Follow- ing this the blood pressure rose gradually and at 24 hours it was 180/100 with no postural hypotension. Thus, a dose of 0.5 Gm. had produced only a transient and minimal response whereas the next day a dose of 0.8 Gm. had resulted in a delayed and profound degree of autonomic blockade. Similar unpredictable responses were seen in two other cases who were given single daily doses of C6 orally. Three hospitalized patients who had ex- hibited satisfactory hypotensive responses to parenteral C6 in doses varying from 10 to 25 mg. twice daily were given the drug orally in amounts varying from 0.25 to 1.0 Gm. of C6 ion every 12 hours for periods ranging from five days to two weeks. In all of these patient's the hypotensive response usually was consider- ably less marked and more fleeting than after parenteral dosages. It was apparent that these large oral doses were insufficient, suggesting that almost the entire amount had been de- stroyed in the gastrointestinal tract. However, on occasion marked reductions of blood pres- sure occurred accompanied by severe postural hypotension suggesting that the rate of destruc- tion and absorption was sporadic and, hence, unpredictable. TOXIC REACTIOKS The "toxic reactions" to the drug appeared to be due entirely to the blockade of autonomic ganglions. In hypertensive, elderly and de- bilitated patients sudden and profound reduc- tions of blood pressure to collapse levels have occurred even when the patients were in the supine position. Parenteral doses as small as 10 mg. may precipitate these marked hypo- tensive reactions. Almost always they occurred after the init'ial injection and, when dosages were repeated several times per day, the blood pressure reduction was more moderate. How- ever, if the drug was discontinued for four or five days or longer an injection of CB might be followed again by a marked fall of art'erial pressure. In general, the greater the interval between injections of C6 the more marked and long lasting the reduction of blood pressure following each injection. All patients exhibited marked postural hypo- tension which persisted for four to six hours or even longer but was severe only during the first three hours after the drug. During con- tinued administration of C6, particularly if the drug was given at frequent intervals (four to six hours apart) the postural effect diminished in intensity. With less frequent administration (8 to 12 hour intervals) con- siderable but not disabling postural hypoten- sion was retained for as long as our observations have been carried out (five months). Approximately two-thirds of the hyperten- sive patients complained of constipation. In addition, in four cases a condition resembling paralytic ileus occurred during the first week of treatment which was manifested by disten- tion, obstipation, absence of peristaltic sounds on auscultation of the abdomen and nausea. In 22 TREATMENT OF HYPERTENSION WITH HEXAMETHONIUM one instance fluid levels were seen in t'he small bowel by roentgenography. The constipation and il&s apparently were due to the marked inhibition of gast'rointestinal tract motility produced by the blockade of the autonomic nervous system, part'icularly the parasympathetic system.12 For this reason we have used more recently, to rest'ore bowel motility, parasympathomimetic agents, the most satisfactory of which has been the urethane of p-methylcholine (Urecholine) in doses of 5 to 20 mg. (average dose 10 mg.) under t,he t,ongue two to three times per day. If constipat,ion cont,inued despite tolerated doses of this drug, laxatives such as mineral oil and magnesium hydroxide were used in addition. However, since Urecholine has been used no further cases of ileus have been en- countered. The drug also prevented the dryness of the mouth complained of in a few patients. Four hypertensive patients complained of urinary retenhion. This difficulty also occurred early in treatment and disappeared following temporary reduction of dosage. It probably also is due t)o parasympathetic blockade and has not been observed since the introduction of parasympathomimetic agents into the treat- ment regimen. DOSAGE ADJUSTMENT In all cases over the age of 40 and in all debilitated or hypertensive patients the initial dosage level was determined as follows: while the blood pressure was being recorded once per minute in the opposite arm, the patient being propped up slightly in bed, C6 was injected at a rate of 1 mg. of t,he ion per min- ute until a total of 10 mg. had been adminis- tered. If there was no significant fall of blood pressure the rate of administration was in- creased to 2 mg. per minute until an additional 10 mg. had been given and then at a rate of 5 mg. per minute to a t'otal of 50 mg. As soon as a slight reduction of blood pressure occurred the injection was temporarily halted for two to three minutes in order to determine whether a further fall of pressure would occur. If, at any time during this trial period, there was a profound fall of blood pressure, the pillow was removed from beneath the patient's head and he was placed in a head-down position by tilting the foot of the bed on shock blocks. The lower extremities were elevated and passively exercised. If this failed to restore the blood pressure the intravenous administration of 2 to 5 mg. of phenylephrine hydrochloride (P\`eo- synephrine) intravenously quickly elevated the blood pressure to normal levels. These severe hypotensive reactions occurred prior to the instit,ution of the method for determining the initial dosage outlined above. They were suffi- ciently frequent to make it obligatory that a physician administer the first dose of t'he drug and t,hat an assistant follow t,he blood pressure response in order to arrive at, a dose level that was safe for the particular case. When these precautions were taken severe collapse reactions have been avoided. After the effective dose had been determined, this amount was administered every 8 to 12 hours by subcutaneous inject#ion since shorter intervals between doses seemed impractical for chronic therapy of hypert'ension. The ini- tial dosage level seldom was effective beyond several days so that it was necessary to in- crease each dose by an amount, of 5 to 15 mg. and further increases were made as necessary to a total of 50 mg. of the ion. Even larger doses have been used in occasional resistant cases. In such instances ldrger doses not only produced a greater but also a more prolonged reduction of blood pressure. In some patients, however, the hypot'ensive effect did not persist beyond six hours. In such cases various drugs were used in an attempt to maintain t,he hypotensive response, t,he most, effective of which was 1-hydrazinophthalazine (C-5968)* given orally midway between the doses of C6. The initial dose of C-5968 was 25 mg. and this was increased at intervals of 24 hours by increments of 25 mg. until the pat,ient manifested a significant hypotensive response or until side effects such as severe palpitation occurred. The effective dose of C-5968 usually varied between 50 and 150 mg. Like C6 this drug usually could not be given more often than every 12 hours without the appearance of side effect,s, particularly head- * Generously supplied by Frederick Yonkmann, M.D., Ciha Pharmaceut,icals, Summit, N;. J. FREIS, FIiYNERTY, SCHNAPER, AND JOHNSON 23 aches, as well as the development of tolerance. A complete description of t,he result,s obtained with C-5968 will be reported elsewhere.13 RESULTS IIT HYPERTENSIVE DISEASES Thirty-t,wo patients have been treated for periods varying between one and five mouths. All except one were hospitalized prior t)o aud at, the onset, of treatment. Fourteen of t)hese cases exhibited malignant, hype&ension, two had chronic glomerulonephritis, while the remaining patients had varying degrees of sustained diast,olic blood pressure of 110 mm. Hg or higher. The two patients with chronic glomerulonephritis and uremia exhibited re- ductions of blood pressure and t,emporary symptomatic improvement, but died within one and two months respectively of their uremia. Of the 14 cases of malignant hypertension, six showed a good result following the use of C6, four exhibit,ed remissions using C6 and C-5968 in combination*3 and four, three of whom had advanced reual failure, had a poor result). All except oue of these patients also were administered diet>s containing 200 t,o 500 mg. of sodium per day. However, this probably was not necessary in all cases and in each pa- tient, it, was possible to demonstrate the hypo- tensive effect, of hexamet,honium in the results obtained. Case 1, R. II., a 52 year old housewife, was first seen lvith malignant hypertension one year pre- viously. Treatment with a diet containing 200 mg. of s&urn per day and Anatensol* resulted in a remission lasting approximately eight months. The malignant phase then gradually rsturned despite treatment and in November 1950 the patient onre again exhihit,ed marked neuroretinitis. The blood pressure, recwrded three times daily- either by the patient's husband or a visiting physician. was rela- tively fixed at 2.5O/l-i0. There was weight loss from 110 to 91 pounds, anorexia, nausea and vomiting, constant headache, and nocturia five to six times. The blood nonprotein nitrogen was 39 mg. per 100 cr. Hexamethonium was begun on Kov. 2, 1950, 25 mg. every six hours, with an immediat,e fall * Purified extract of verat,rum viride. K. R. Squibb & Sons, New York, N. Y. of blqod pressure to approximate levels of 190/ 120 (fig. 1). The dose was reduced to 25 mg. every 12 hours, but because of elevations of pressure in the morning, the frequency of doses was increased to every eight hours. During the first two weeks there was severe obstipation, nausea, vomiting and faint- ness. However, all symptoms began to regress and within two months the fundi had cleared completely except for residual scars. After 14 weeks the num- ber of inject,ions was reduced to two a day, but the dose was increased to 3X mg. with maintenance of reduced levels of blood pressure (fig. 1). After five months of treatment with C6. the pa- tient had a good appetite and weighed 106 pounds. The nocturia, headaches and nausea disappeared. Following each injection of C6 she found it neces- sary to remain supine for one to two hours herause * * I QIFFKJ? I2 I' I6 I 12 i* FIG. 1. Chart of the average arterial blood pressure and dosage of hexamethonium in case 1, It. D., a white woman, aged 52 years, with malignant hyper- tension. Each point in the chart of arterial pressure represents the average of at least 28 separat,e deter- minat,ions, all being recorded with the patient in the supine position. See t,ext for further details. of t,he postural hypotension. Throughout treatment the blood pressure levels fluctuated, markedly drop- ping one-half to one hour after each inject,ion and then slowly rising until the next d,lse of C6. Even after five months, during a sing12 day it was not unusual for the recorded pressures to vary between 160/95 to 210/130 mm. Hg. Becausz of persistent constipation, laxatives daily and enemas several times per week were required until rrecholine plus mild laxation were introduced. Case 2. T. M. a 52 year old man, was admitted with a blood pressure of 260/170. There was ex- tensive neuroretinitis with many hemorrhages and exudates in the fundi. The blood nonprotein nitro- gen was 48 mg. per 100 cc. The patient was placed on a 200 mg. low sodium diet and was given 10 mg. of C6 intravenously on the day of admission. Within five minutes after the drug had been given the blood pressure fell from 260/170 to lOO/SO supine. Despite this sudden and profound hypot'ensive response the patient noted only a moderate sensation of faint- ness. When this dose was repeated every four hours 24 TREATMENT OF HYPERTENSION WITH HEXBMETHONIU?VI the blood pressure rose and, despite elevation of dosage to 25 and even 50 mg. repeated every four hours, the general level of blood pressure returned to nearly control values (fig. 2). The interval be- tween doses was then increased to 12 hours and this was followed by a fall in pressure to normotensive levels. After three weeks the blood pressure fell to SO/SO and the patient complained of marked faint- ness, Hexamethonium was discontinued and the patient was given 1000 cc. of saline intravenously. He improved immediately, the blood pressure rising to 130/100. The sodium content of the diet was in- creased to 500 mg. per day. C6 was omitted for the next 10 days and the blood pressure gradually rose ARTERIAL PRESSURE- MM HG 26or h HEXAMETHONIUM - MG PER DOSE 50 25 I 2 3 4 3 c 7 8 DAYS FIG. 2. Chart of the arterial pressure and dosage of hexamethonium in case 2, T. M., a white man, aged 52 years, with malignant hypertension. All blood pressures were recorded with the patient in the supine position. Note (1) the marked hypertensive response to a small initial dose of C6, (2) the apparent develop- ment of tolerance when doses were administered at frequent intervals, (3) the return of a significant hypotensive effect when the doses of C6 were separated by an interval of 12 hours, and (4) the typi- cal marked fluctuations of blood pressure during each day while under treatment. See text for further de- tails. to a level of 170/120. The drug was again given in doses of 10 mg. every 12 hours, the blood pressure falling to average values of 140/100, where it re- mained for the succeeding month. The hemorrhages and exudates disappeared from the optic fundi although slight papilledema still remained. At the end of the next month the papilledema had cleared completely, the nonprotein nitrogen was 36 mg. per 100 cc. and the patient was ambulatory and felt considerably improved. Hypertension Other Than Malignant There were 16 paGents in this group, of whom 10 exhibited a continued, average reduc- tion of blood pressure greater than 25 mm. Hg systolic and 10 mm. Hg diastolic. Of this number seven exhibited sustained reductions of average pressure varying between 40 and 60 mm. Hg systolic, and six of these maintained reductions of diastolic pressure varying between 20 and 40 mm. Hg. Two of the patients who had a good result exhibited grade III changes in the fundi; all of the others being grade II. Of the patients who exhibited a poor response, three exhibited grade III changes, two grade II, and one manifested grade I fundi. Thus, there was no relationship between the severity of the hypertension and the therapeutic result obtained. Some of the cases manifesting poor results were treated in t,he earlier stages of t#he inves- tigation. They were failures either because resistance to the hypotensive effects developed quickly, or the duration of the hypotension was brief or was insignificant in the supine position. Several of the more recently treated patients, who appeared to be resistant to C6 alone, have exhibited a satisfactory hypoten- sive response when the dosage was raised and/ or when C-5968 was added to the treatment regimen.13 DISCLBSION The results obtained to date with the use of hexamethonium in the treatment of hyper- tension are in essential agreement with the prior observations of Smirk14 and other in- vestigators.5-8 The combined experience of these various studies leaves little doubt that hexa- methonium provides a method for reducing blood pressure in a large percentage of hyper- tensive patients, and that this reduction fre- quently is accompanied by relief of some of the signs and symptoms associated with the disease. The ability to induce a significant therapeutic response in 10 of the 14 cases of malignant hypertension either with C6 alone or in com- bination with a low sodium diet and/or C-5968 represents in our experience a higher percentage of remissions than would be anticipated with other known methods of treat'ment. The advantages of C6 are its ability to pro- duce and to maintain for long periods a signifi- cant hypotensive response in a high percentage of patients, its rapidity of action and simplicity of administration. The disadvantages are (1) FREIS, FINNERTY, SCHNAPER, AND JOHNSOX 25 the danger of severe hypotensive reactions due to injudicious dosage administration in the early phases of treatment, (2) the frequent development of constipation and occasionally paralytic ileus, and (3) the inability to obtain a stable level of hypotension throughout the 24 hour period in many pat,ients. Finally, unless the technic of administering oral therapy can be improved, the necessity for continued hypodermic injections imposes a hardship on the patient. Recent evidence suggests that large amounts of hexamet,honium dichloride (0.5 to 2.0 Gm. of the ion) given as a single daily oral dose administered at bedtime may be more effective than divided oral dosage.15 The most dangerous of the `%oxic" reactions is the extreme hypotension that may follow the initial dose of the drug. A fatality has been reported after C616 and serious hypotension has occurred also following the less potent and shorter acting ganglionic blocking agent, tetraethylammonium. I7 In both of these re- ported cases, epinephrine was used to combat the hypotension. Epinephrine has a vasodilator component and, after the pressor response has subsided, t'he blood pressure does not fall directly to normal, but rather there is a period of hypotension. l8 Epinephrine also induces marked vasodilation in skeletal muscle*g and, in contrast to norepinephrine and related drugs, produces a decrease rather than an increase in total peripheral resistance.20 In addition, the ganglionic blocking agent' t,etraethylammonium increases the sensitivity of the myocardium to epinephrine-induced arrhythmias in dogs under cyclopropane anesthesia.21 As a result of their study, Stutzman and his co-workers*l concluded that "epinephrine is contraindicated as a pressor agent after t'etraet,hylammonium chloride." They recommend t'hat phenyl- ephrine (Neosynephrine) be used for this pur- pose. The most successful and the safest procedure for t,reating the collapse reactions following the administration of C6 was to elevate the foot of the bed in order to maintain the cerebral circulat'ion. In addition, further elevation and passive exercise of the lower extremities facili- tated diversion of blood into the central circu- lation. These severe hypotensive responses almost always occur only after the initial injection. Hence, if care is used at this time such reac- tions should be avoidable. Since we have uti- lized the method of administration outlined in the "dosage adjustment" se&ion of this paper, severe collapse reactions have not been encount,ered. The importance of determining the effective initial dose in each case is empha- sized by the observation that one patient ex- hibit,ed a significant hypotensive response after only 3 mg. of C6 ion had been administered intravenously. If 5 or 10 mg. had been injected the patient almost certainly would have had a severe hypotensive reaction. On the other hand some cases have exhibited little hypo- tensive response in the supine position after an init,ial dose of 50 mg. The concomitant administration of a para- sympathomimetic agent to alleviate t'he con- stipation, ileus, dry mouth and difficulty in urination produced by C6 represents one ap- plication of the general principle of circum- venting undesirable side effects by utilizing antagonistic pharmacologic agents which, how- ever, do not int'erfere with t'he desired thera- peutic a&ion. Since parasympathomimet'ic agents have vasodilator properties they may be expected t'o enhance t'he hypotensive effect of C6. The therapeutic regimen of alternating doses of C6 and C-5968 also seems representa- tive of another principle of hypotensive drug therapy. In our experience all vasodepressor agents produce varying degrees of tolerance. By utilizing alternately agents with different loci of action the development of tolerance tQ any single agent may be considerably delayed. Smirk has taught his patients to self-ad- minister hexamethonium by injection in the home.14 This procedure has been applied suc- cessfully in the present study, and, in addition, in many instances a member of the family or t'he patient has been taught to record the blood pressure. By such frequent measurements of arterial pressure under varying condit,ions a far more precise indication of the effect of treatment has been obtained. It should be emphasized that the results of treatment with C6 reported herein are of a 26 TREATMENT OF HPPERTFXSION WITH HEXAMETHONIUM preliminary nature since none of the patients have been treated continuously for longer than five months. In addition, the most' effective method of administering the drug or of com- bining it wit'h other hypotensive procedures cannot be considered to be finally set'tled. Finally, because the method of administra- tion outlined herein requires repeated hypo- dermic injections and frequent observation of the pat,ient, at least in the initial phases of t,reat,ment, it would seem to be indicated only in the more severe and resist#ant cases of hypertension. SGMMARP AND CONCLUSIONS Hexamrthonium has been administered con- t,inuously for periods of one to five months by subcutaneous injection to a series of 32 hyper- tensive patients with the following results: I. In 11 cases of malignant hypertension, six have undergone a remission of t,he malig- nant, phase while four others have exhibited remissions with the addition of l-hydrazino- phthalazine (C-5968) administered orally mid- way between the doses of CG. Four patients, three of whom had advanced renal failure, did not, respond to CO; alone or in combination with other drugs. Two additional patients who had advanced chronic glomerulonephrit,is exhibited hypotension and symptomatic improvement but died of progressive uremia. 2. In I6 patients with less severe degrees of sustained hypertension, six have shown sus- tained redu&ions of arterial pressure after hexamethonium alone, four have responded to a combination of C6 and C-5968 while six others failed-.-to. maintain a sustained hypotensive fe:espoilSe. Most. of t,he latter cases were treated in the early stages of this investigation when the doses were t,oo frequent, and too small. 3. The effective hypotensive dose of CB ion by subcutaneous injection varied bet)ween 10 and 100 mg. Small doses usually lowered the blood pressure after the initial injection hut gradually increasing doses were required over a period of days or weeks to att.ain a stable ef- fective dosage level. C6 was administered at intervals of 8 or 12 hours. 4. Undesirable reacbtions consisted of (1) occasional severe reductions of blood pressure occurririg almost entirely only after the initial injection of C6, (2) postural hypotension diminishing in severity with prolonged treat- ment, (3) gast,rointestinal atony producing constipation occasionally with paralytic ileus and, rarely, (4) difficult,y in urination. Met,hods for circumvent,ing most of these reactions are described. 5. Hexamet'honium administered orally in doses up to I .O Gm. of the ion t'o a few patients appeared to be less effective and more unpre- dictable than parenteral administrat,ion. 6. The most effective and best' tolerated treat'ment for t'he largest number of hyper- tensive patients was the following: (1) paren- teral administration of C6 at int,ervals of 12 hours in doses of 10 t'o 75 mg. of t#he ion de- pending upon the patient's response, (2) oral ingestion of 50 to 150 mg. of C-5968 midway between the doses of CG and (3) a diet con- taining 200 to 500 mg. of sodium per day. ADDENDUM After 10 months of continuous treatment all the cases in this series who had responded favorably are maintaining a significant hypotensive effect and they remain clinically improved, except for one patient with malignant hypertension who died suddenly due to a coronary occlusion. In some cases it has been necessary to elevate dosages to as high as 150 mg. of C6 ion in order to overcome toleranre but this has been accomplished without adverse side effects. REFERENCE8 ' I'~ToP~, 11'. D. M., ,4ND ~/IAIMIs, ti:. G.: Clinical potentialities of certain bisquaternary salts causing neuromuscular and yanglionir block. Xature 162: 810, 1968. "ARNOLD, I'., GOETZ, R. H., AND ROSENHEIM, M. L. : Effect of pentamethonium on the periph- eral circulation. Lancet, 2: 408, 1949. 3~u~17, C. C., AND GRAHAM. A. J. I'.: Pentame- thonium and Iie~amet'llorlium iodide in inves- tigation of peripheral vascular disease and hy- pertension. TM. 11. J. 1: 455, 1950. 1 SCOTT, L. D. W., KAY-, A. IT-., O'HARE, AI. M., AND SIMPSON, J. A. : Hesamethonium bromide in duodenal ulcer. I&it. 11. ,J. 2: 13i0, 1950. 5 REYTALL, P. A., AND ~?MIRK, F. H.: The treat- ment of hypertension with hesamethonium. New Zealand 11. J. 49: 206, 1950. 6 TURNER, R. : "Medical s~mp"tliect,oI11~" in hy- pertension. T,ancet P: 353, 1950. ' SAVILLIC, 9. : Pwtame thonium in hypertension. LancPt 2: 35S, 195P. FREIS, FINNERTY, SCHNAPER, AND JOHNSON 27 8 CAMPBELI,, rl., AND ROBERTSON, E.: Treatment of severe hrpert.ension with hexamethonium bromide. Brit. M. J. 2: 804, 1950. g FINNXRTY, F. A., JR., BND FREIS, E. D.: Experi- mental and clinical evaluation in man of hesa- methonium (C6), a new ganglionic blocking agent. Circulation 2: 828, 1950. lo SCHNAP~~IZ, H. W., JOHNSON, R. L., TOUHY, E. B., AND FREIS, E. D.: The effect of hexamethonium as compared to procaine regional block on blood flow to the foot of normal subjects. J. Clin. Investigation 30: 786, 1951. I1 HOOBLER, S. W., MALTON, S. D., BALLANTINE, H. T., JR., COHEN, S., NELIGH, R. B., PEET, N. X., END LYONA, R. H.: Studies on vasomo- tor tone. I. The effect of tetraethylammonium ion on the peripheral blood flow of normal subjects. J. Clin. Investigation 28: 638, 1949. I? Kay, A. J17., AND SMITH, A. K.: Effect of hesa- methonium iodide on gastric secretion and mo- tility. Brit. >I. J. 2: 460, 1950. I3 JOHNSON, R. L., FREIS, E. D., SCHNAPER, H. W., AND FINNXRTY, F. A., JR. : The effect of L- hydrazinophthalozine (C-5968) in hypertension with special reference to combined therapy using hexamethonium. To be published. I4 SMIRR, F. H.: Letter to the editor. Lancet 2: 4ii, 1950. I5 FREIS, E. D., SCHNAPER, H. W., AND JOHNSON, R. L. Unpublished data. I6 HIRSON, C., AND KELSALL, A. R.: Letter to the editor. Lancet 1: 585, 1951. I7 FRIEDLICH, A. J., JR., CHAPMAN, IV. P., AND STaNIXJRG, J. B.: A severe reaction to tetra- ethylammonium chloride. New England J. Med. 238: 629, 1948. I8 GOODMAN, L., AND GILMAN, A.: The Pharma- logical Basis of Therapeutics. New York, Mac- millan, 1941. I9 ALLEN, W. S., BARCROFT, H., AND EDHOLM, 0. G.: On the action of adrenaline on the blood vessels in human skeletal muscle. J. Physiol. 106: 255, 1946. 2o GOLDENBERG, M., PINES, K. L., BALDWIN, E. DEF., GREENE, D. G., AND RAH, C. E.: The hemodgnamic response of man to nor-epi- nephrine and its relation to the problem of hy- pertension. Am. J. Med. 5: 792, 1948. `l STUTZMAN, J. Iv., PETTINGA, F. L., FRUGGIERO, E. J. AND MAISON, G.L.: Enhancement of epinephrine induced cardiac arrhythmias by tetraethylammonium chloride (Etamon). Proc. Sot. Esper. Biol. & Med. 68: 686, 1948.