Made in United States of America Reprinted from CIRCULATION Vol. II, No. 6, December, 1950 Experimental and Clinical Evaluation in Man of Hexamethonium (C6), A New Ganglionic Blocking Agent By FRANK ,4. FINNERTY, JR., M.D., AND EDWARD D. FREIS, M.D. In man, CG, a new ganglionic blocking agent (50 mg. intravenously) produced inhibition of the Valsalva, tiltback and cold pressor vasopressor responses. Marked increases in digital blood flow and skin temperature with inhibition of digital reflexes to "noxious" stimuli were consistently ob- served (room temperature TO F.). The increase in skin temperature was greater and more lasting than following Priscoline or tetraet,hylammonium chloride. Except for severe postural hypoten- sion, side effects were minimal. Clinically the drug may be useful in the evaluation of sympathetic vasoconstriction in peripheral vascular disease as well as in the treatment of acute neurogenic vasospasm. T HE SLJBSTAYCES which inhibit t,rans- mission of sympathetic vasoconst'rictor impulses may be divided int'o three main categories : (1) central blocking agents which int.erfere with sympathetic vasoconst'rictor re- flexes (cardioaortic, carotid sinus) through a central nervous system site of action, such as plasmochinl pentayuine" and the cent'ral block- ing component, of t,he DH alkaloids of ergot3; (2) adrenergic blocking agents which interrupt sympathetic nerve impulses peripherally and which also block or reverse the effects of in- jected epinephrine or norepinephrine, such as I>ibenamine4 and Priscoline"; and (3) ganglionic blocking agents of which tet,raethylammonium chloride (Etamon) is the best known example. The blocking agents inhibit t,ransmission through all aut,onomic ganglia including the parasympathetic as well as the sympa,thetic." In addition, t,hcy enhance rat#her than block t'he prcssor &c&s of epincphrine and norepineph- rine in both man' and animals.* - From the Department of Medicine, Georgetown University Hospit,nl and Georgetown University School of Medicine, and the Vet,er:lns Administr:rtion Hospital, Washington, D. C. This inv&igatiorl was supl)ortctl in part by tbe Squibb) Institute for Meciical Rcscarch, Xew Bruns- wick, Ncu- Jcrscy and Jlwin. Neisler & Co.: Decatur, Illinois. Hesamrt~honium was generously supplied by Mr. W. A. I,ott, Director, Division of Medicinal Chernistyy, of the Squibb Institute for Medical Re- search. Presented in part before t,hc national nleeting of the American E'ctler:ttion of Clinicnl Research: Atlan- tic Cit,,y, New *Jersey, May> 1950. Paton and Zaimisg recently have int'roduced a series of polymethylene bistrimethyl ammonium salts with interesting properties; the dccane derivatives (ClO) exhibit curariform activity while the pent,ane (C5) and hexane (CG) deriva- t,ives exhibit ganglionic blocking action. The lat'ter agents appeared to be five times as po- tent as tetraethylammonium salts. %udics in man by Arnold and his co-workers using C5" and by Burt and Graham using C5 and C6" suggest that these drugs produce a more com- plete and lasting ganglionic blockade with fewer side effects than any other agent used thus far. The purpose of the present report is to confirm and extend the observations of t'hcse British investigators on the effects of C6 in man. MATERIALS AND METHODS The subjects were ward and private patients at Georgetown University Hospital, the Veterans Atl- ministration Hospital and Gallinger Municipal Hos- pital, Washington, D. C. Fifty-five patients were studied. Many were considered norm:ll subjects in- sofar as their cardiovascular system was concerned while others were suffering from various types of peripheral vascular disease or from hypertension. The drug was given intravenously in dosages of 20 to 100 mg. of active substance dissolved in :t sterile solution of either isotonic benzyt alcohol or saline. It was also given intramuscularly in doses of 10 to 60 mg. For the hemodynamic studies of the vwopressor responses following the Valsalw maneuver, quick tilt,back, and immersion of the hand in icewater, an 18 gage needle was inserted into the brachial artery through novocainized skin. This was connected to a three-way stopcock which in turn was connected to a hlborn electromanometer. Heparin solution 828 Circulation, Volume II, Decemkr, 1950 F. A. FINNMITY AND E:. D. FREIS 829 was flushed through the stopcock intermittently to insure patency. 811 test.s were carried out in a quiet room with the patient lying on a tilt-table. Skin temperature was measured using iron-con- stantan wire thermocouples taped 1ightlJ; to both big toes, both index fingers, umbilicus, right fore- arm, right upper arm and right shoulder. Two addi- tional thermocouples were used for recording room temperature. A graphic chart of all of these ten points was automatically recorded every five min- utes on a Leeds-Korthrup series G "Speedomas" equipped with a multiple point recorder. This method of registration permits continuous and auto- matic charting of skin temperature changes without disturbance to the patient by the examiner. Room temperature varied no more than 2 degrees F. in any experiment but testing was carried out in both cool (68 to 72 F.), moderate (74 to 78 F.) and warm (78 to 86 F.) environmental temperatures in differ- ent experiments. The patient reclined semiclothed on a comfortable bed. In all instances skin tempera- tures reached an equilibrium and remained constant for ab least 30 minutes prior to the administration of the drug. The period of observation after the drug was at least one hour. Digital plethysmography n7ts carried out using the Burch-Winsor plethysmographl* simultaneously with skin temperature measurements. A digital pneu- matic cuff was used for venous congestion of the digits at a congesting pressure of 50 mm. Hg. Blood flow was determined according to the method of Robertson, Farmer and Smithwick. RESULTS Inhibition of Sympathetic Vasoconstrictor Re- sponses Certain vasopressor responses, usually di- minished or abolished following surgical sym- pathectomy, mere completely blocked or defi- nitely inhibited after 50 mg. of CG administered intfravenously. These included : B. Valsalva l'asopressor Ovedoot. After in- t'ravenous administrat,ion of C6, the normal vasopressor overshoot of arterial pressure fol- lowing the Valsalva maneuve? was abolished in 4 out of 5 pat,ients, and markedly inhibited in the other (fig. 1). The effect appeared in 1 to 2 minut'es following injection and lasted 30 to 60 minut)es or longer. R. Cold Pressor Response. The cold pressor response was completely blocked in 6 and mark- edly inhibited in 2 of the 8 patients tested as compared w&h the hypertensive response be- fore administration of Cli (fig. 2). C. Postural Hypotension. All subject,s devel- oped a marked fall in arterial pressure in the upright, position, frequently to collapse levels. In addition, the usual vasopressor overshootI which occurs on tilting back quickly from the erect to the supine position was abolished. ARTERIAL PRESSURE :;; 200 MMHG 100 FIG. 1. Chart, of arterial pressure illustrating the abolition of the vasopressor "overshoot" following Valsalva maneuver in patient) IG. M., a 30 year old Negro woman with essential hypertension. See text for method of recording. Paper speed was 0.5 mm. per second. The elevation of the lower line indicates t,he IO-second period during which the patient blew out, forcibly into a closed tube. During the control period following release of the espiratory effort' a momentary elevation of both systolic and diastolic pressure occurred above the basal level. After C6 t,his "overshoot" was abolished. I 2 3 4 5 6 7 FIG. 2. Chart of t,he cold pressor responses before and after C6 in 7 hypert,ensive patients. Prior to the drug the per cent rise in mean systolic + diastolic 2 art)erial pressure on immersion of the hand in ice water varied between 10 and 52 per cent. Following the drug t,he rise in mean arterial prcssurc varied between 0 and 4 per cent,. D. Congestion Collapse. It has been demon- strated previously that after sodium nitrite or certain drugs which inhibit, sympathet)ic vaso- constrictor reflexes collapse will occur in the supine posit'ion following venous congest)ion of the limbs.15 This procedure was carried out by placing blood pressure cuffs proximally on both thighs and one upper arm and inflating them to pressures slightly below diastolic blood pres- 830 EXPERIMENTAL AND CLINICAL EVALUATION OF HlXSAIW~THOiYIL~M sure. Following C(i in all of 4 subjects examined a marked fall in arterial pressure wit'h collapse occurred within three minutes after congest'ing the limbs, whereas prior to the drug, similar congestion of the limbs for a period of five minutes produced insignificant changes in ar- terial pressure in the same subjects. drteriab Presswe, Supine The effect, of CG on art'erial pressure and pulse rate in the recumbent position was de- termined in 10 normot#ensive and 18 hyper- t,ensive pat,ients. In the normotensive group, there was a mean fall in systolic arterial pres- sure of 10 per cent (range 4 to 18 per cent) and a mean fall in diaafolic pressure of 7 per cent (range 0 to 20 per cent,). The decrease in arterial pressure began almost immediately fol- lowing injection and lasted one-half to one hour. An increase in heart rate averaging 21 beats per minute developed 1 to 2 minut'es after in- jection and lasted 20 t,o 40 minutes. In the hypertensive group the mean reduc- tion in systolic pressure was 34 per cent with a range of 12 to 63 per cent,. The average fall in diastolic pressure was 22 per cent (range 3 to 50 per cent). Thus, the reduction of bot'h sys- tolic and diast'olic pressure was much greater in the hypertensive than in t)he normotensive patients. Two hypertensive patients who es- hibit'ed reductions of mean arterial pressure of 52 and 53 per cent' respect'ively developed faint)- ness and nausea. These sympt,oms and the es- treme hypotension were relieved by tilting t'he bed into a head-down position. Skin Temperature and Digital Blood Flow The most, marked and consist#ent effects of CG were observed in the digits (fig. 3). Unlike the results obtained following dihydroergocor- nineI the percentage rise of digit,al skin temper- ature following C(i was greater in cool than in warm environments. Observations were made in 22 patient)s. Kinc patients were st'udied in cool environments (66 to 72 F.). Follo\l-ing CG in t,his group there was a mean rise of toe temperatures of 17 F. and an increase in finger temperatures of 11 F. Seven patient's were st'udied in moderate environments (72 to 80 F.); in this group the average rise in toe tempera- tures following CG was 9.3 F. In warm environ- ments (80.5 to 86.5 F.) the alTerage increase in toe t,emperatures in G patient's was 6.0 F. and TEMPERATURE DEGREES FAHRENHEIT 50%. I.V @-WFLW-MM? PER 5 CC PART PER SECOND , ,o 20 30 40 50 60 70 60 90 100 MINUTES FIG. 3. Chart illustrating the ctiects of C6 on toe temperature, blood flow and pulse volume in patient, F. A., a 28 year old woman, whose right lower est'rem- ity had been sympathectomized one year previouslp because of postphlebitic pain and edema. The room was maintained at a constant temperature of 70 F. throughout the experiment. In the right lower or sympathect,omizetl estremit,)- skin temperature re- corded from the second toe >vas approximately 91 degrees and equalled the umbilical temperature. In t,he left, lower (unsympathect~omized) extremity the toes were cold. However, following C6 the toe t)em- pernture on the unsympathectomized side rose from 68 to 92 F. with aboliiion of the skin temperature gradient. The rise in blood flow and pulse volume on the unsympathect,omized side paralleled the change in skin temperature. In the sympst,hectomized ex- tremity t,here was a slight rise in blood flow and pulse volume probably indicating that the sympnthectomy had not, been quit,e complete. in finger temperatures was 3.0 F. In all cases except, those who had organic obst'ruction of the larger arteries t,he t'emperat'ure gradient be- t,Iveen the toe and umbilical t'emperature was abolished, this response occurring in the cool as xell as in t,he warm room. F. A. FIKKI'RTY AND E. D. FREIS 831 As not,ed previously by Burt and Graham" the rise in toe t#emperature usually was of greater degree and of longer duration than the elevation in finger temperature. Occasionally, however, t,he rise in finger temperature appros- imated the toe temperature and in 2 subjects who had an exceptionally marked vasoconstric- tar response in the fingers to cold, t#he eleva- tion of finger temperature exceeded that in t,he toes by 10 and 12 F. respect,ively. The rise in digital skin t,emperat#ure began in 2 to 10 minut,es aft,er int,ravenous inject)ion, reached a peak in 15 to 30 minutes and then gradually subsided to pre-injection levels over a period of 2 to F hours. Patients often exper- ienced a feeling of warmt,h in the t)oes and absence of sweating of the feet' which some- t,imes persisted for as long as C, hours. In contrast to the poor correlation observed in subjects in warm rooms it is generally rec- ognized that changes in digital skin tempera- t,ure usually reflect changes in digit'al blood flow when the subject is examined in a cool room.`" Nevertheless, plethysmographic meas- urements of digital blood flow were carried out in 6 subjects before and after the in- travenous injection of .50 mg. of CG. In all cases the digital blood flow doubled and in some inst,ances rose much higher (fig. 3). In addition, there was a marked increase in pulse volume (fig. 4) and inhibit*ion or abolition of the vasoconstrictor response to "noxious" stim- uli such as a deep breath and ice applied to the face. The increase in pulse volume and blood flow usually was greater and of longer duration in the toes than in the fingers. Compa,rison with TEA and Priscoline The marked and consist'ent effects of CA on digital blood flow especially in t'he toes sug- gested that a promising clinical applicat'ion of the drug might be in t)he field of peripheral vascular disease. It seemed advisable, therefore, to compare CG with other agents used clinically in the diagnosis and treat,ment of peripheral vasospast'ic disorders. The response of digital skin temperature in a cool environment was used as the basis of comparison. Patients were given different drugs on consecutive days, the room temperature being maint,ained at t'he same level each day. FIG. 4. Chart showing cuttings t,aken from the plet,hysmographic record of pat)ient F. A. (fig. 3). On t,he sympat,hectomized side there was a moderate in- crease in pulse volume in the tot after C6. In the unsympathectomized or normal limb prior to C6 there are no perceptible pulse waves due to the marked vasoconstrict,ion in the cool room. However, after C6 there was a marked increase in pulse volume. ELEVATION OF TOE TEMPERATURE - DEGREES FAHRENHEIT 25- 20 :I 5 0 I t. 2 3 cl- * PRISCOL )! 4 5 FIG. 5. Chart showing elevation of toe temperature in 6 patients given either Priscoline 50 mg. intrave- nously or C6,50 mg. intravenously, on alternate days. Room t,emperat,ure vas maintained at t,he same level each day (70 degrees F. in most, esperimenb). In cases 2 and 4 the rise in toe temperature following Priscoline equalled that, follow-ing C6 but. in the other 4 patients the elevation of toe temperature following C6 was significantly greater than that following Pris- coline. Six patients were given 50 mg. of Priscoline intravenously (fig. 5). Following intravenous Priscoline the duration of the rise in skin tem- perat'ure was somewhat shorter than the tem- perature rise following CA. In all cases the in- 832 EXPERIMEXTAL AND CLINICAL EVALUATIOS OF HIXAMETHOSIL~M ject.ion was followed by parasthesias, palpita- tion, flushing of the skin, nasal stuffiness and in 4 instances by shivering. The rise of digital skin temperature in this cool environment was significant in some patient#s a,nd insignificant or absent, in others. In cases 1 and 3 (fig. a), the rise in toe temperature following C6 ex- ceeded t'hat following Priscoline by 15 and 20 F. respectively, in case 5 by 12 F. and in case 6 by 9 F. In cases 2 and 4 the rise in toe tem- perature after Priscoline equalled that follow ing the injection of C6 but in these 2 cases the rise in finger temperatures was 11 and 13 degrees greater respectlively following C6. In I 3 FIG. 6. Chart showing elevation of toe tempera- ture in 6 patiemts given either tetraethylammonium chloride, 400 mg. intravenously, or, C6, XI mg. intra- venously, on alternate days. Experimental condi- tions similar to those described for figure 5. In every case the elevation of toe temperature following C6 was significantly greater than that following TEA. another patient' with far advanced arterioxcle- rosis obliterans of the left leg, neither C6, intravenous or intraarterial Priscoline nor lum- bar paravert'ebral block induced wit,h procaine resulted in any significant rise in the tempera- ture of the toes. Similar comparisons were made between the effects of 50 mg. of CC; given intravenously as compared t,o 400 mg. of t'etraet,hylammonium given by t)he same route. In all of the 6 pa- tients &died a significantly greater rise in digit,al skin temperat,ure occurred following CG as compared to TEA (fig. 6). In cases 2 and G (fig. 6), the rise in the toe temperature aft,er the drug exceeded that! following TEA by 20 and 18 F. respectively. In cases 1 and 3 the increase was 8 degrees greater, in case 4 it was 14 degrees and in case 5 the rise in toe temper- ature was 7 degrees higher following CG than that observed after TEA. The rise in digital skin t'empemture following TEA was fleeting in character, lasting only 15 to 20 minut,es, as compared with a duration of at least, one hour following C6. Accompanying the inject,ion of TEA all of the 6 patients studied complained of unpleasant' parest'hesias, a met)allic tast,e and palpitation. These side effects were not noted after the administrat#ion of C6. Site of Action Paiton and ZaimiG demonstrated in ani- mals that CG produces its effect's by blocking transmission through all autonomic ganglia. PosititFe proof of ganglionic inhibition cannot, be determined readily in man. However, a similar site of action in the human is strongly suggested by t#he following observations: (1) the injection of small doses (12 mg.) of Pris- coline intraarterially in 3 subjects resulted in a significant elevation of skin t'emperature in the injected limb as compared with the con- tralateral limb. However, intraarterial injec- tion of 10 to 20 mg. of CG in the same subjects resulted in no significant increase in the skin temperat'ure of the injected limb. Thus, C6 appeared t,o have no peripheral vasodilating action in man. (2) True ganglionic block- ing agents paralyze transmission of impulses through all autonomic ganglia including the parasympathetic as well as the sympathetic. Therefore, following C6 the parasympathetic or vagal influence on the heart should be abol- ished so t,hat subsequent injection of atropine would be without effect on cardiac rat,e. Three pat'ient#s were given 60 mg. of C6 intravenously following which the heart rate increased by 20 to 30 beats per minute. After attaining a steady state an atropinizing dose (1 mg. of atropine sulfate) was injected int,ravenously following which in no instance was there any further change in heart, rate. (3) In cont'rast t,o drugs which inhibit t#ransmission of sympathetic nerve impulses at, other sit,es the ganglionic blocking agents increase the pressor effects of F. B. FINNERTY BND E. D. FREIS 833 epinephrine and norepinephrine.7 In 3 normal subjects epinephrine (1 ,ug. per cc.) and nor- epinephrine (1.5 pg. per cc.) were given al- ternately by continuous intravenous infusion. Following C6 the same doses of epinephrine and norepinephrine produced significantly greater rises in arterial pressure after as compared Do before the drug. These various observations strongly suggest that the site of action of C6 is at the autonomic ganglia in man as well as in animals. Dosayr and Routes of Administration During t'he early phases of this investigation doses of 20 to 30 mg. were given intravenously, but at' this dosage the abolit'ion of sympathetic reflexes was inconstant. Hence, the dosage was raised to 50 mg. Intravenous doses as high as 100 mg. have been given but these seemed t#o be no more effective than the 50 mg. dose. The drug was also active in 50 mg. doses following intramuscular injection. However, oral and sub- lingual doses as high as 500 mg. were completely inact,ive. Thus, it' would appear that for diag- nostic studies or ot'her instances in which a rapid effect is desired an int'ravenous dose of 50 mg. is well tolerated and effective, whereas for continuous administration the drug may be given intramuscularly in similar dosage at, intervals of 3 to 4 hours. Side Effects and Tolerance Except for the development of severe pos- tural hypotension the side effect,s following C6 were few and of minor consequence. Most pa- tients noted no subjective sensations. Slight dilat'at,ion of t,he pupils frequently occurred and 12 patients complained of blurred vision which usually persisted no longer than 10 min- utes. A few patients noted a dry mouth; 6 patients complained of drowsiness and 3 of transient nausea. However, there were no in- stances of vomit,ing, parest,hesias, flushing, na- sal stuffiness or palpitation. The more complete the ganglionic blockade the more readily mill postural collapse result. Following C6 post,ural hypotension persisted for as long as two hours in some patients. In a few cases tested in the supine position it was necessary to elevate the foot, of t'he bed slightly in order to combat a steady fall in arterial pressure. C6 has been reported to produce col- lapse in anesthetized individualsI and prob- ably should never be used in patient,s who have suffered recent blood loss since the drug effectively blocks compensatory vasoconstric- t'or mechanisms.15 In 2 patients with hyper- tension, coronary artery disease and angina pectoris a marked fall in arterial pressure in the supine position precipitated a bout of an- gina. Both the hypotension and the angina were relieved by elevating and passively ex- ercising the lower extremities. Although studies of the effect of continued treatment with C6 are still in the preliminary stages, observations in 2 patients who mere given daily injections of the drug did not indi- cat,e the development of any significant, degree of tolerance. For example, in a patient, with thrombophlebitis 50 mg. of CG was adminis- tered daily for eight days. On the eight,h day a rise of toe temperature of 17 F. following t'he drug was as great as the rise following t'he first injection. In a similar paGent' 30 mg. of C6 was administered daily for four days and every other day for six days with no evidence of development of tolerance t'o the drug. It, has not yet' been determined whether tolerance develops when the drug is administered at, more frequent, intervals. DISCUSSION As a ganglionic blocking agent CG differed from tetraethylammonium, the prototype of such drugs, in several important respects: (1) C6 appeared to be more potent than TEA in man since 50 mg. doses appeared t'o produce maximal effects. (2) The durat'ion of action of the drug was approximately five time longer than TEA, the effects of C6 lasting 1 to 2 hours as compared with 15 to 20 minutes in the case of TEA. (3) The injection of CG was not attended by the dist,urbing and unpleasant' side effects of TEA such as met'allic t)aste, generalized tingling and other parest)hesias. The most striking vasomotor effect of the drug was the marked elevat'ion of skin tem- perature and blood flow in t,he digits, partic- 834 EXPERIMl2NTAL BND CLINICAL EV.4LU.4TION OF HES4METHONIUM ularly in the toes. In evaluating sympathetic blocking agents it is important that the skin t'emperat'ure measurements be carried out in a cool although not excessively cold environ- ment. First, digit,al skin temperature and blood flow changes parallel each ot'her only under such conditions12; and, second, sympathetic vasoconstrictor nerves to the digits are ac- tivated in cool rather than in warm environ- ments. In fact, a hot environment may effectively abolish vasoconstrictor tone.18 The importance of controlling room temperat#ure was demonstrated in studies with dihydroergo- cornine,16 where it was found that the drug produced a rise in digital skin temperature in warm but not in cool environments. Similarly, Priscoline mill abolish t,he temperature gradi- ent bet'ween the toes and t.he umbilicus at' environmental temperatures of ii F.5 but,, as shown in these studies, will not do so uni- formly at room temperatures of 68 to 72 F. As suggested by Burt' and Graham" the reason that C6 usually produced a greater rise of skin temperature in the toes as compared with the fingers might be due to t'he greater in- herent vasoconstrictor tone in the lower limbs.16 This explanation is supported by the observa- tion that in 2 pat#ient,s wit#h abnormally cold hands the rise in finger temperature exceeded that in t'he toes. The regular occurrence of a marked rise in toe temperat'ure in a cool room following C6 suggests that sympathetic vaso- constrictor impulses to this area were markedly inhibit'ed if not completely abolished. Studies are in progress to determine the extent of sympathetic block using as an index the in- crease in blood flow in the foot after CG as compared with the effect,s of lumbar para- vertebral block.lg The failure of TEA to bring about a com- parable rise in skin t'emperature may be re- lated more to the short duration of action of the drug rather than to its lack of potency. The skin temperature changes following C6 occurred slowly, maximum values being at- tained after 10 to 30 minutes. Since the dura- tion of action of TEA is brief it is possible that the ganglionic inhibition produced by t'his drug was wearing off before maximum skin temperature changes could occur. Because of t#he drug's potent effect on dig- ital blood flow and skin temperature C6 may be useful in the evaluation of patients with peripheral vascular disease. In such cases the intravenous injection of C6 may provide a rapid and simple method of assessing the role of the sympathetic vasoconstrictor mechanisms without discomfort to the patient. For example, in a case of causalgia of the right hand follow- ing an old injury to the wrist, C6 effectively relieved bhe pain and hyperesthesia for sev- eral hours. Sympathectomy was performed sub- sequently with complete relief of pain. In an- other patient wit,h Raynaud's phenomenon characDerist,ic color changes developed in the fingers whenever the hands mere placed in cold water. This cold-induced attack was corn- pletely, although only temporarily, blwked following the injection of C6. The drug also may be useful in t'he t#reat- ment of acute peripheral vascular disorders such as acute thrombophlebit'is, or t8hrombosis or embolism of peripheral arteries whenever it, is desirable to abolish the effect's of reflex vase- spasm. In the present st,udy 3 cases of acute thrombophlebitis have been treated \\rith daily injections of 50 mg. of C6. As judged by relief of pain and improvement in color and temper- ature of t,he involved foot the results seemed comparable t'o t'hose usually obtained wit'h lumbar paravertebral block induced wit-h pro- caine. However, evaluation of these suggested clinical applications of C6 must' await exten- sive studies in a large series of patients. SUMMARY AND COKCLUSIONS Hexamethonium (C6), a new ganglionic blocking agent', was administered in doses of 50 mg. intravenously to a heterogeneous group of 55 individuals including normal subjects and patients with various diseases of t'he vas- cular system with the following results: 1. Sympat,hetic vasopressor reflexes includ- ing the hypertensive overshoot t#o the Val- salva maneuver and the tiltback overshoot were inhibited or abolished. The cold pressor response was markedly inhibited, as were the reflex vasoconstrictor responses in the digits to "noxious" stimuli. 2. A significant increase in digital skin tem- F. A. FINNERTP AKD E. D. FREIS 835 perature, usually with abolition of the temper- ature gradient, occurred in cool as well as in warm environments. The response was more marked in the toes than in the fingers except, when the latter exhibited abnormal vasocon- striction. The rise in digital skin temperat'ure was accompanied by simultaneous increases in digit,al blood flow and pulse volume as meas- ured plethysmographically 3. In the same subjectIs studies in compar- able environmental t'emperatures (room tem- perature approximately TO F. and stat'ionary) the rise in digital skin temperature after CG was usually great,er and more prolonged than that achieved following either Priscoline (50 mg. intravenously) or tetraethylammonium (400 mg.). 4. The redu&ion in supine arterial pressure frequently was minimal in normot'ensive sub- ject,s while, although variable in degree, it, was somet,imes marked in hypertensive patient's. Because of the inhibition of sympathetic vaso- constriction, a severe postural hypot'ension was a regular occurrence. For this reason the drug may precipitate vasomotor collapse in the erect or sitting position or after moderate degrees of blood loss. Occasional severe hypotensive reactions occurring in t,he supine position could be prevented or t)reated by slightly elevating the foot of the bed. 5. When injected intravenously the dura- tion of action of t,he drug was I t,o 2 hours. CG was effect,ive by all routes of parenteral ad- ministration but was inactive aft'er oral or sublingual administration. 6. Adverse subjective sensat'ions such as paresthesiax, palpitation, flushing, nausea, lvere complet~ely absent,. However, post,ural hy- potenxion was severe and 2 pat,ients with an- gina pect)oris developed a,nginal attacks during selrere hypotensive reactions. Preliminary dat'a suggest that t,he drug may be used clinically in the evaluation of the sympat hctic vasoconstrict~or component, in cases of peripheral vascular disease as well as in the t)reat'ment of acut,e peripheral vascular disorders associat'ed with neurogenic vaso- spasm. ACKNOWLEDGMENT The authors wish to thank RIessrs. Raymond E. Flath and Henry G. Gillem for valuable technical assistance. ADDENDUM Since preparation of this paper, Turner (Lancet 2: 353, 1950j has reported that doses of 1.5 to 5 Gm. of hexamethonium bromide are effective by t,he oral route of administration. Thus it would appear that, the effective oral dose is approximately 50 to 100 times greater than the effective parenteral dose. REFERENCES 1 MOE, G. K., AND SEICVERS, M. H.: Central im- pairment of sympathetic reflexes hy plasmochin. Federation Proc. 5: 193, 1946. ~RICHARDSON, A. P., WALKEH, H. A., APED ~IILLER, B. S.: Effect of pentaquine on cardiovascular system of unanesthetized dogs. Proc. Sot. Expel. Biol. 8: Med. 65: 258, 1947. 3 ROTHLIN, E.: The pharmacology of the natural and dihydrogenated alkaloids of ergot. Bull. schweiz. Akad d. med. Wissensch. 2: 249, 1947. 4N~~~~~~~~, &I., AND N~M~GUCHI, G. M.: Locus of the adrenergic blocking action of Dibenamine. J. Pharmacol. & Exper. Therap. 93: 40, 1948. 5 CHESS, D. AND YOXKM~N, F. F.: Adrenolytic and sympatholytic actions of Priscol (benzyl-imi- dazoline). Proc. Sot. Exper. Biol. & Med. 61: 127, 1946. 6 ACHESON, G. H., AND MOE, G. K.: The action of tetraethyl-ammonium ion on the mammalian circulakion. J. Pharmacol. & Exper. Therap. 87: 220, 1946. ~FREIS, E. D., MACKAY, C. J. AND OLIWR, I\-.: The effect of drugs which inhibit transmission through the sympathetic nervous system on the cardiovascular responses to epinephrine and nor- epinephrine in man. Circulation. In press. SMUT, G. K.: Potentiation of pressor action of epinephrine by tetraethyl ammonium. J.A.1I.A. 137: 1115,1948. g PATON, w. D. A%., -m-D ZAIMIS, E. J.: Clinical potentialities of certain bisquaternary salts caus- ing neuromuscular and ganglionic block. Nat,ure 162: 810, 1948. 'OARXOLD, P., GOETZ, R. H., ,~ND ROSI~:NHI!XM, M. L.: Effect of pentamethonium on the pe- ripheral circulation. Lancet 2: 408, 1949. "BURT, C. C., .mD GRAHAM, A. J. P.: Pentame- thonium and hexamethonium iodide in investi- gation of peripheral vascular disease and hypw tension. Brit. M. J. 1: 455, 1950. I2 BURCH, G. E.: A new sensitive portable plethys- mograph. Bm. Heart J. 33: 48, 1947. I3 ROBERTSON, C. IV., FARMI!X, D. A., .~ND &mm- WICK, R. H.: A simplified venous occlusion method of digit blood flow estimation using tile 836 EXPERIMENTAL AND CLINICAL EVALUBTION OF HIXAMETHONI~M Burch-Winsor plethysmograph. J. Lab. & Clin. Med. 34: 1718,1949. "WILKINS, R. Iv., AND CULBERTSON, J. W.: The effects of surgical sympathectomy upon certain vasopressor responses in hypertensive patients. Tr. A. Sm. Physicians 60: 195, 1947. I~FREIs, E. D., ST~KTON, J. R., FIKNERTY, F. A. JR., RATH, C. E., AND WILKINS, R. W.: The phenomenon of "congestive collapse." Its patho- genesis and significance. Program Sot. for Clin. Investigation, Atlantic City, May 1, 1950. la--, STANTON, J. R., LITTER, J., CULBERTSON, J. W,, HALPERIN, M. H., MOI~PER, F. C., AND WILKINS, R. W.: The hemodynamic effects of hypotensive drugs in man. II. Dihydroergo- cornine. J. Clin. Investigation 28: 1387, 1949. 17 HUNTER, A. R. : Hexamethonium bromide. Lancet 1: 251, 1950. I8 PICKERIh-G, G. Iv., AND HESS, W.: Vasodilation in hands and feet in response to warming the body. Clin. SC. 1: 213, 1933. ~~HOOBLER, S. W., MALTON, S. D., BALLANTINE, H. T., JR., COHEN, S., NELIGH, R. B., PEET, 31. >I., AND LYONS, R. H.: Studies on vasomotor tone. I. The effect of tetraethyl ammonium ion on the peripheral blood flow of normal subjects. J. Clin. Investigat.ion 28: 638, 1949. ~OFREIS,E. D., STANTON, J.R., CULRERTSON, J. W., LITTER, J., HALPERIN, 1~1. H., BURNlYrT, C.H., -44~~ WILKINS, R. W. : The hemodynamic effect,s of hypotensive drugs in man. I. Veratrum viride. J. Clin. Investigation 28: 353, 1949. 21 GRIMSON, K. S., REIIRDON, 31. J., MARGORI, F. A., AND HENDRIX, J. P.: The effects of priscol (2-benzyl-4,5-imidazoline HCl) on peripheral vascular diseases, hypertension and circulation in patients. rlnn. Surg. 27: 968, 194X.