A Clinical Appraisal of Pentapyrrolidinium (M&B 2050) in Hypertensive Patients By EDWARD D. FREIS, M.D., EDWARD A. PARTENOPE, M.D., LAWREKCE: S. LILIENFIELD, M.D., AND JOHN C. ROSE, M.D. The new ganglionic blocking agent, pentnpyrrolidinium or M&B 2050, appears to have several distinct advantages over hesamethonium in the treatment of severe hypertension. These advantages include longer duration of action, greater potency, less tolerance, less interference with intestinal motility, and, most important, a more uniform response from day to day on oral :&ninistration. However, critical adjustment of dosage is necessary and side effects are not infrequent, the most disturbing being post'ural faintness and impotence. T HE advantages as well as t'he deficiencies of hexamethonium in t)he trcat,ment of hypertensive patient,s'n 2 have stimulat)ed interest in the development of ganglionic blocking agents which will retain the desirable effects of hexamethonium and eliminate its undesirable qualities. By the very nature of its action it can be expected that a,ny drug whicsh acts by inhibiting t,ransmission through au- tonomic ganglia will exhibit, many of t,he side effects of such blockade. However, it, seems possible t,hat t'here may bc differences in the predilection of various compounds for certain ganglia as compared with ot'hers; and also t)hat other advantages might be gained, such as longer duration of a&on, lessened t,olerance, greater and more predictable absorption from the gastrointestinal t,ract, which would decrease From The Cardiovascular Research Laboratory, Georgetown University Hospital, the Department of PI?Iedicine, Gcorget,ow-n University School of Medicine, and t,he Veterans Administration Hospital, Wash ington, I). C. Supported in part by rcscarch grants from the National Heart Instit.utc of the Kntional Institutes of He&h, T'ublic Healt~h Service (Grant H-720), and t'he Squibb Institute for i\lcdical Rcscnrch, Nca Brunswick, N. J. Pentapq-rrolidiniuln bitartratc was supplied by May & Baker Ltd., &glarld and by Wyeth Labora- tories, Philadelphia, I'a. Sponsored (in part) by the Veterans Adminis- tration and published with the :tpproval of the Chief Medical Director. The statements and conclusions published by the authors are a result, of their own study and do not nwwsarily reflect t.he opinion or policy of the Veterans Administration. the hazards and inconveniences att,endant upon hexamcthonium administration. Recently, a new ganglioni? blocking agent, pentamethylene 1: 5-bis-( 1 -mcthyl-pyrrolidin- ium bitartrate) (pentapyrrolidinium or 3f&B 2030) has been synthesized by T&man, Pain and Slack.3 Detailed pharmacologic studies in animals have been carried out by Wein and Mason.3 Preliminary clinical trials by Campbell and Maxwell suggested that the new drug was more potent, longer-acting, and produced a more predictable response on oral administration than hexamet1honium.5 Smirk found that pentapyrrolidinium administered orally was more effective and better tolerat)ed by hypcr- tensive patients than was hex:imethonium.6 The purpose of the present report is t,o describe the cxperienccs in this clinic w&h t,his IWV agent in hypert'cnsive patients. For t'he sake of clarity all dosage of both hexamethonium and M&B 2050 will be referred to in terms of the amount of ion. Hexamcthonium was admin- istered in the form of the chloride and M&B 2050 as the bitartrate salt. POTENCY AND DURATION OF ACTION OF M&B Four hospitalized hypertensive patients were given hexamet,honium intravenously in an amount sufficient to produce a signific,ant, re- duction of arterial pressure. Several days later pentapyrrolidinium was inject,ed slowly int'ra- venously until the fall of blood pressure was similar to that, produced by the hosameth- FREIS, PARTENOPE, LILIEKFIELD AND ROSE 541 T.ARI,E 1 .-Conlparison of Single Intravenous Dosages of Hexamethonictm ((26) and rentap?Jrrolidiniurn (Al&:-R 2050) c. n. 195/120 R. c. 220/145 A. 5. 215/115 I'. D. 185/135 in 1 Reduction of Blood Pressure mm. Hg After After M&B ?ifter C6 2050 C6 28/22 48/35 65/30 72/m M/27 92128 60/20 50/30 - onium. These patients had received no prior therapy \vith &her agent. On the basis of t,hese acute comparative studies M&B 2050 nas approximat#cly five (range four to seven) times more potent than hex~~met,honium (t,able 1). The average dura- tion of action of M&I3 2030 also was 42 per cent (range 40 to 40 per rent) longer than that of hexamethonium. During a,n intravenous t,itration with hexa- met,honium the blood pressure falls rapidly when t)he effective dose has been reached. When M&B 2050 is administered intrave- nously, however, the reduction in the blood pressure proceeds more gradually over a period of 10 minutes or more following an effective dose. Thus, intravenous Ctration with M&B 2030 is mow difficult' t,han wit,h hexamet'h- onium since t>hc effective dose may be exceeded. This could 1~ avoided in some measure by inj&ing the drug quite slowly with t,he patient sitSting on t,hc side of the bed, since postural hypotension appears before supine hypot,en- sion. I~ELATION BI;T\VEEN EFFECTIVE PAR~TERAL FolloCng int~ravenous t,it,ration 10 hyper- tensive paticnt)s wrc t#reated with M&B 2050 subcut,ancously twice daily either in the hos- pitSal or, owasionally, in the home. If treatment was on an ambulat~ory basis, t,hc blood prcssurc was recorded five t,imcs daily in the home. At, the end of one wck parcnteral t'herapy was discontinued aild the drug administered orallJ7 every eight, hours. The dosages were increased every other day unt'il the average daily blood pressure approsimat,ed that achieved during parenteral therapy. `ypertensive Patients Change in Heart / DOX, Kate Beats Min. rnC. of Ion After M&B 2050 C6 0 -1 1s +16 +I8 50 -4 -4 20 +1s +16 12 Duration of Effect In Hours Ch M&B 2050 10 10 11 9 The mean effect,ive parcnteral dose of M&B 2050 was 15 mg. per day, lvhereas the mean daily oral dose was 280 mg. Thus, the effective oral dose was approximately 20 t,imes as great as t*hc effective parenteral dose. This relation- ship between oral and parentcral dosage is similar to that previously observed with hexamcthonium.7 It also agrees in general w&h urinary recoveries of M&B 2050 in animals, which indicated t,hat less than 20 per cent of an orally administered dose is absorbed.8 I'ent'apyrrolidinium given orally differed from hexamet,honium administ,ered orally in one import,ant' respect,. The onset of action was far more prcdict*able t,han with hexamcthonium, beginning approximat,ely one hour aft,er an ef- fective dose. There also n-as less variation from day to day in the response to a given dose of M&B 2050 t,han had previously been cx- perienced with t)he response t)o hexamethonium.? However, as will be discussed later, many cx- traneous factors influenced t,he response to M&B 2050 so that the extent of blood pressure reduction was not completely uniform from one day to another. The improvement in pre- dictability of response after XI&B 2050 as compared wit,h hexamethonium was one of de- gree, therefore, rather than being an absolute qualitative difference. 'rOLER.4NCE TO M&B 2050 During one meek of therapy w&h M ~3% 2050, administered subcutaneously t\vice daily to 10 hypert,ensive patients, t'here was no evidence of development of t,olcrancc. In five of thcsc listed in table 2 at t,hc end of the week the mean effective dose of M&R 2050 was 0.5 times less (range - 1.8 to + 1 .G times) t,han the initial titrating dose. Five of these patients previously 542 PENTAPYRROLIDINIUM IN HYPERTENSION had been under continuous therapy with hexamethonium for periods of 6 to 19 months. Review of their records showed t,hat at t,he end of the first week of therapy with hexamcth- onium given subwtancously, dosages had been raised progressively t'o a mesn dose which was 1.9 times (range 1.5 t)o 2.5 times) the initial titrating dose. Thus, during this short period of observation t,he degree of tolerance induced by M&B 2050 administered subcutaneously was far less than t,hat, experienced previously wlbh hexamethonium. If oral administration was begun without any preceding period of parenteral therapy, there frequently was a tra,nsient hypotensive response lasting one to several days and occur- ring at a level vonsidorahly below the final effective maint'cnancae dose. Following this, the increase in tolerance t'o t,he drug was very slight. For example, in 15 patients t,reated with oral M&B 2030 alone for periods varying from three to six weeks, t,he mean effective dose at the beginning of therapy was 232 mg. (range 45 to 518 mg.) per day of the ion; while at the end of t'he abore period t,he average effective dosage was 275 mg. (range 1,35 to 5U mg,) per day. CROSS TOLERAN~I~: ISKTWEFX M&R 2050 AND HEXAMKTHONIUM The degree of cross tolerance existing be- tween M&B 2050 and hcxamethonium seemed to be wry small. This was estimated in five patients who had been t'reated continuously with hcxamet)honium, subcutaneously admin- TABLE 2.-Effect of Hemn~efhonitcm and Pentapy rolidinium in the Same l'ntients Showing LIcnelop ment of Tolerance to Each and Degree of Cross Tolerance IIelamethorlium Ion, ElIertive Pentapyrrolidillium Dose (mg.) Ion, ELTrctive Uose img. 1 Patient lp A. S. -I-~ 20 2 1.5 II. B. 30 100 11 10 c. P. 75 1,s 3 0. H. 30 45 00 11 11 J. C. 50 100 120 20 11 ' istered for periods of six months to t\vo years (table 2). When comparison is made between t)he initial effective dose of hesamethonium obtained by intravenous titration (prior to any previous therapy with ganglionic blocking agcnt,s) and the initial cffect#ive titrating dose of M&B 2050 (aft>er prolonged therapy with hexamcthonium) the dat,a indicate that M&B 2050 was approximately 2.5 times more active (range 0 to 4 times) than hexamcthonium. Thus, in these hexamethonium-treated pa- tients, the relat~ive potency of M&B 2050 was only half as great as in pat)iellt,s previously un- treated wit,h gnnglionic blocking agents. However, \vhen comparison was made in these same patients between the init,ial t&m- tion dose of M&R 2050 and tho dosage of hexamethonium required after prolonged thcr- spy with t,he lat,ter drug, the mean relat,ive pot'ency of M&B 2050 was 13.5 times (range 5 to 35 times) that of hexumnthonium. It would appear, thcrcfore, that' the degree of cross tolerance between the two drugs is so slight that for practical clinicAa1 purpows one may consider that, tolerance to hesamethonium does not induce significant t~olernnce to M&B 2050. FACTORS POTEYIYATING THE HYPOTENSIVE ~LK+JWNSE TO M&B 2050 Since the majority of the pat&& under treatment \I-ith M&B 2050 recorded their blood pressures at home, it was possil)le to study in some dct,ail the various ext~ranwus factors whicah influenwd the blood pressure. These were as follows: Postuml l$Jwls. (1) When the patiwt was up and about a smaller dosage usually was necessary to lower the blood pressure than when he n-as supine. IIenvc, a larger dose usually was required at bedtime. (a) SC\-ere postural hypotcnsion lvith faintness owurrcd more frequently after the morning dose than at ot'her timcls. (3) Some of the patients not,iccd increased noct#uria ac~companicd by dcweascd urinary frequency during t,hc day. Ac~ditiw l~[~rcts oj 0th l'asodilntiny Ir~jh- cwcs. (1) The ingest'ion of alcoliol frequently was followd by marked potcntiation of t,hc hypotcwsirc action of RI&B 2030. The amount FRlX3, PARTENOPE, LILIENFIELD AND ROSE 543 of al~~)hol need not be large since one or two "coc~ktnils" was sufficient to induce significant additional reductions of blood pressure. (2) The ingest)ion of a large meal at times acted as a pot,entiating factor. (3) Vigorous exercise such as pushing a law-n mower n-as followed at limes by an additional fall of blood pressure. This \vns in cont,rast, to the untreated individual \vhose blood prcssurc uswlly increases with exercise. (4) During t#he hot, summer weather the dosage of X16-S 2050 frequent,ly had to be wduced because of marked hypotcnsion. The incidence of post'ural faintness or frank syncopal att)acsks itwreased at t,he onset, of a period of unusually hot weat,her. Salt Depiction. (I ) When patient,s I\-ere placed on diets rigidly rest,ricted in sodium the hypo- tensire effect, of M&R 2030 was exaggerated. Such individuals became unusually susceptible to postural hypotrnsion, n-hilt t,he margin widened bet\\-een the level of blood pressure in t,he erect position as compared n-it,h the supine position. For this reason it swmed advan- tageous to permit a moderate salt, intake in all of the nouc~ardiac~ patients. In this way dosages could be raised to the point of influ- encing the supine pressure without, inducing post)ural syncopc. (2) Mercurial diuretics were sdministcrcd at t.imcs to the cardiac patients in order to control the signs of congestive heart failure although the necessity for using them usually dccwased greatly after the inst,it,ution of hypot)ensive therapy. It \\-as noted that as the edema accumulated t>he dosages of M&R 2050 became progressively less effective. However, immediat,ely following the mercwrial-induced diuresis markrd reductions of blood pressure occurred. For this reason it, was necessary in some instances to reduce t)hc dosage of M&B 2030 for a day or t,wo follo\ving the mercurial injection. (3) The potentiating a&on of hot weather dcscribcd nbo\-c may have been due in part to excessive salt loss. TH EIZ.WEUTIC RESULTS Tnent,y-sewn patients were treated with M&B 20,iO orally as the sole medication for periods varying from t,\\o t,o six months. All could be classified as having severe, "fixed" hypertension. Twel\-c had grade 11: hyperten- sion with papilledema or had shown evidence of papilledema in the recent past (21 of the total group ha.d received previous therapy with other drugs), nine had grade III and six had grade II hypertension." Dosages of the drug were administered as close to every eight hours as possible, the first dose being taken immediately after arising in the morning. Because of its long durat,ion of action, the dosages of M&B 2050 should be widely spaced in order t,o avoid the additive effect of one dose overlapping on another.`j Following the initial period of adjustment the mean daily effective dose was 300 mg. (range 135 to 630 mg.) of the ion. This was divided as follows: the average morning requirement was 03 mg., t,he afternoon dose 86 mg., and the mean bedtime dose was 122 mg. The larger dosage at night was well tolerated and usually was required to lower the blood pressure while the patient was in the supine position. The results are based on the means of many home and clinic readings taken with the pa- tient in the sitting position (t,able 3). Record- ings taken with the patient in the supine position were somewhat higher, and those taken in the erect position were somewhat lolvcr. The control value in each case was t'he level of blood pressure taken prior to any therapy after 38 hours or more of rest in bed in the hospital. The average pretreatment blood pressure for the ent,ire group was 230/135 (range 180/l 10 to 26O/l(iO) mm. Hg; the mean post-treatment TABLE X.-Mean Reduction of Blood Pressure in $7 HypertensiLle Patients Treuted with Penfapyr- rolidinium. Basis of Comparison Is Hospital Control Rlood Pressure Prior to Any Form of Drug Therapy - Reduction of Blood Presure NO. % Systolic (iOmm.IIgormore. 15 55 40 mm. Hg 01' ~OTC. 2P 81 20 mm. Hg OT more. 2F 96 Less than 20 mm. IIg. ., 1 4 Diastolic 30 mm. IIg or more. 14 52 20 mm. Hg or more 23 85 15mm.Hgormore 21 89 Less than 15 mm. Hg 3 11 .~ 544 PENTAPYRROLIDINIUM IN IIYPERTENSIOPi blood pressure was 170/110 (range 130/95 to 210/130) mm. Hg. Slightly more than ,50 per cent of the patients exhibited a reduction of 60 mm. IIg or more in sy&olic pressure snd of 30 mm. Hg or more in the diast'olic pressure. Twenty-two, or 81 per rent, showed systolic reductions of 40 mm. Hg or more and 23, or 85 per cent exhibited diastolic reductions of 20 mm. Hg or more. The hypotcnsive response to M&B 2050 was somewhat more predictable than t,hc response to hexamcthonium and once a main- tenance dosage level had been established, t,he necessity for constantly modifying it was not nearly as great. h'cverthelcss, variability pro- duced by the extraneous additive factors pre- viously discussed or by unknown causes was sufficient to be an ever-present potential source of inconvenience and even hazard to many patients. For example, patient, C. I'., a $2 year old, white, male teacher with "malignant" hyper- tension in therapeut'ic remission was taking 3 doses per day of 100, 150 and 350 mg. of M&B 2050 in the morning, afternoon and at bedtime, respectively. On arising in the morning his blood pressure usually was 190/110 mm. Hg; this fell after t,he morning dose to 140/95 mm. Hg. It t,hen rose gradually to 190/120 mm. Hg at 2 p.m. but fell again aft'er the 2 p.m. dose to lGO/llO mm. Hg. During the evening the blood pressure rose gradually t'o 190/120 mm. Hg. Two hours after his morning dose on a hot July day he walked up a steep hill to the hos- pital for his regular office visit. When he ap- peared in the clinic hc was pale and on t'he TABLE 4.-Incidence of Side EJeec1.s Produced by Perltapyrrolidiniuln in 27 Hypertensive Patients Side Effect A-o. 9; Irqmired visual :tccommod:t- tion. 14 5'2 Dry mouth.. 13 40 Constilx~tion of any degrw 11 40 Not cout,rolled by neostyg- mine. 4 15 Enemas rrquid.. ~ 0 0 Posturd faintness X 30 Postural syncope. 1 4 Impoteiice.. : 8 30 verge of syncope. His blood pressure sit,ting in a chair was 90/75 mm. Hg. lmmediatcly after lying down t)he pressure rose t'o 165jllS mm. Ilg, and after rest,ing supine for an hour the patient \vas able to go about his usual day's activities. SIDE EFFMTH The so-called side effect,s of M&B 2050 were similar to those experienced with hexameth- onium; all could be accounted for on the basis of ganglionic blockade. The most prominent of these \vere postural faintness, dry mouth and loss of visual accommodat,ion (table 4). These side effects were most pronounced when the blood pressure was the lowest. Many of the patients required reading glasses with positive lenses for occupat,ions requiring accommoda- tion for near vision and t'inted glasses to war in bright sunlight bwausc of the failure of pupillary constrictioil. In contrast, t,o t)ho lack of conxtipat,ion in patients treated wit,h parenteral R&U 2050, oral ingestion of the drug was awompanied by some degree of constipat)ion in many inst,ances (table 4). It, was not as sevcrc as that observed in patients taking hexamethonium and in most inst'ances responded to oral ncontigmine in doses of 15 to 45 mg. In a few instancLes irritant cat,hart,ics also were newssary. Paralyt~ic ileus and sevcrc obstipat,ion did not cwur. One of t,he patient,s \cho suft'crcd S~VVI'C huts of awte gastric dilatat'ion whci~ t,akilig parctntc~ral hexamethonium sufrewtl a similar attack on oral M&B 2050. Impotence n-as a frequent and troublesome side cffwt in the male. In general the middle aged and elderly patients suffered wmplete impot,ence during the t>lltire period of treat- ment whereas most of the younger pnt,icnts were only partially inc~apacitatcd. The urethane of p-methylcholine (Urecbholinej, 10 mg. muler the tongue every hour for three hours preceding sexual intcrc~ourw, scemcd to beiwfit some of t,he pat)itnts, but it, is impossible> to sny \Vlicttiel the effect of T~rwholinc was real or psychogcwic. A few patients c~ompltlined of (Bhilly sctisa- tions in a cold cnvironmc~tlt probal)ly due to failure of reflex vauoc,oli~tric,tion in t,hc skin. This recluiwd that' they dress warmly during F'ltl51S, I'ARTEKOl'E, LILIIGNFIlCLD ASD ROSE 54!5 cooler \\cather in order to conserve body heat. Now of t,hc patit:nt8s taking RI&IS 2050 suf- f'cwd from inability to empty the urittary blad- dor; otw of t,hcse patients had lwn unable t,o t,akc hexamcthonium bccauso of this side ef- icct. Cr>rtain side react~iotis, particularly dryness of the mout,h and frequent postural faintness, were most prominent during t,he early stages of treatment but, tcttded to diminish as trcat- mcnt progressed, \vherens ot,her side clf'ccts such as impotence remained unchnngcd during the cnt,irc period of tJreatjment, `l'hc purposes of this study ww t,wofold: t.o d&~rmine, first, whether h4 kR 2050 pos- sessed thc~rapcutio ad\vant)ages over hcsameth- ottium attd, swontl, whether it wuld bc given safely and cffwti\-cly by the oral rout,e of ad- ministration. Our findings in gmeral are in agrccmcnt \\-ith those of Smirk." In regard to the first question M&T3 2030 appeared t,o be superior to hc~s:tmethonium in several rc- qmt s: 1. Tlw tlrgwe of tolrranw induced by M&B 2050 dcfittitt~lv \vas less t ban that observed \\+th hr~snnlc,tllottittm. The wgligiblc degree of cross tolcr:uicc: \vas of thtwret~ic~ as ~~41 a8 of ptwti(~al importattw. The reason for the de- ~~c~lopment, of "tolCranw" to the hypotensivc cfi'ects of ltex:~mc~tlionium has not, lIeen clear. It Jvas unknown whether this wpresentcd a trite drug tol(~ratiw or \vlictliclr, despite czon- t,iuuccl gattglionic bloc~kadr, some ot,her hyper- tcttsive mcchattism operating humorally, or in some other way not dq~endent upott transmis- sion of impulses through aut'omatic ganglia, had bcctl acati\,atrd to r&ore the hypertension. The fact, that after tlic> de\-elopment of tolerance to Itc~s~~tnc~tllottium th(J patients remained setnsi- tivc to rclnti~~t~ly small tloscs of M&H 2050 s11ggwts strongly that. the resistance to hexamc~thoniutn reprcwnted true drug t'oler- awe. From the prac%ical point, of view the lesser d~~grw of tolerattw experienwd with M&U 2050 pcrmittcd managcmettt' of the pa- tient Jvith 1~s:: frcqucwt nwd for dosage read- justment. 2. When compared with hexamct~honium, t)he duration of action of pentapyrrolidinium was longer than that of hcxamcthonium and permitt'ed less frequent administ,ration. 3. The response following oral administ,ration of M&R 2050 was more predictable than t,hat observed after hcxamcthonium. The effective dosage range was not as \\ide and the variat,ions of blood pressure response on a given dose from day to day not' as great. The greater pre- dict,ahility of response may have hccn related at' least in part to the lesser effect, of M&B 2050 on intestinal motility t,han that produced by hexamethonium. The degree of constipation and skis in t,he gastrointestinal tract' produced by oral M&R 2050 could be controlled usually by simple measures such as the administration of oral neostygminc. As a result accumulation of t,he drug in the gut seldom occurred. In the case of oral hexamethottium such accumulat,ion of the drug may be followed by absorption of largt: dosages over a long period of t'ime leading to severe and persistent, hypotensive reactions. Alt,hough xyncopal attwks owurred after M&B 2050, the prolonged caollapso react'ions often ac~ompanicd by ileus \vert: not seen as they had hecn with hoxamethotrium. Nevertheless, oral therapy with M&B 2050 left, much to bc desired. Some of t,he pnt,icnt,s were c*ontrolled, \vit,h minimal side effects, but in the majorit,y carit,ical dosage adjustmenC was required, slight cxcwses produring hypotcnsive reactions and slight under-dosage failing to induce a significant hypotJensivc response. In addition, in order to lower t)hc blood pressure, it usually was nwessary t,o elevate dosage to a point where side &"wts \vere frequent, par- ticularly during the early weeks of adjustment. During t,he tJrcat,ment period it was observed frequently that vasodilat,or influences such as heat,, alcohol, exert% and food, which ordi- narily would have no eflect on blood pressure, produced a significant hypotensive effect in the paGent treated wit,h M&B 2050. I-ndcr normal conditions such vasodilator influences are opposed immediately by homcost,atic vaso- const,rirtor responses mediated over the sym- pathetic nervous system. These reflexes produce vasoconstric%ion in other vascular arcas thereby preventSing any appreciable fall iti total peripheral vascular rcsistancc. IIowevcr, M&B 2050, by producing ganglionic blockade, prc- vents these homeost,atic adjust,ments. Thcre- fore vasodilat8ion in one vascular area will be unopposed by vasoconstriction in ot,her regions, and, if the dilated area is large, the syst'cmic blood pressure \vill fall. These considerations provide a rational basis for combining the ganglionic blocaking agclnts with other vaso- dilat,ing drugs. The effect,s of combining pents- pyrrolidinium with other hypotcnsive agent>s will be discussed in a suweeding paper.`" SUMMARY AND CONCLUSIOhT I. Comparisons were mudc between the ef- fects of hexamethonium and pertt,apyrrolidin- ium (M&B 2050) in hypcrt,onsive patients. The following differences were noted : (a) M&B 2030 was approximately five times more potent than hexa,methonium. (b) The durat'ion of the hypotensive effect, MM 40 per cent longer. (c) Less tolerance owurred after M&B 2030. Cross tolerance bet~w-rc~t~ this drug and hcxamet'h- onium was very slight,. (d) Less const,ipation was produced by M&l3 2050 and there was no interference with empt,ying of t,he urinary bladder. The c~onstipat~ion could be controlled with oral ncost,ygmine and/`or irrit,ant cat,har- tics. (e) On oral udministrat,ion a more prc- dictable hypotensive response was obtained. 2. The ot,her side effects of ganglionic block- ade were similar to those observed with hexamethonium. 3. Various extraneous fact,ors such as pos- tural changes, ingestion of alcohol or a heavy meal, exercise, hot weather and sa,lt depletion intensified the hypotensive effect of M&B 2050. 4. Unlike hexamet'honium it was possible to lower the blood pressure significant,ly in the major&y of patients with oral administrat,ion of M&B 2050 without producing prolonged collapse reactions or paralytic ileus. I-Iowcver, critical adjust,ment of dosage was necessary and side effects were not, infrecjuent, the most disturbing being post,ural faintness and im- potence. For t,hese reasons M &rZ 2050 swms to bc of greatest value in those cases of severe hypcrtcnsiott whic~h cwtnot be controlled by simpler measures. SUM.\IUO ESP.'I%OL El micvo agentme bloc~ucador gatigliotiar, peittapyi~roliditiiiim 0 31 &H 2030 npxrcnta t,erier cicrt,as v(ltitajns dist.incti\w sotwc cl hexamet,hottittm cn el t,rutatnicnt.o de la hiper- tcttsi(jti se\wa. E&s \witujas itic~luycn una accicitt m:is prolongada, m:byor potcttcia, menor toleraticiaI mcnos int~erferctic~ia wt1 la movili- dad intestinal y rnus importatrt,e atin, una respuest,a mas uniformc de dia cti dia a la admitiisttwitin oml. Sitieml)argo, utt ajuste critic0 de la posologia fu6 iiwwario $- 10s cfwtos no deseablcs no fueroti itifrtc~uetites, cl m:is alarmant,c siendo cl dcsfallec~imic~ttt,[) post'ural y la impot,en&. 1 RI~~AJ,L, I'. .\., AND SMIRIC, F. H.: The tJC:bt,llleJJt of h~~lwtensiott with Ile~~trncthor~itIrn. New %eal:mrl RI. J. 49: 20F, 1950. z E'RI~;Is, F:. I)., $~-NICRTY, F. -\., Jtt., $:CHNAPtGR, H. \V., AI-D JOHNSON, It. I,.: The tJdmeJlt Of hypertension with IlestLtuethorliurll. Circu- lation 5: 20 1952. *LILlM,4N, 1). il., PAIS, 1). I,., AA-D SLACK, It.: Some bisqunrter~nat~y salts. .J. Chcrn. Sot. 430: 2305, 1952. 4 \~IGK, It., AND h'f.4SOS, 1). F. J.: ~`h'nl:trO~Ogy Of M&R 2050. IAtlc:et 1: 151, 1953. 5 ~Jaxwtsr,r., R. J>. II., AND CAMPUELL. ~1. J. $1.: New s,wn~~ut~hal~t~i~ agents. T,nncrt 1: 455, 1953. 6 SMIRK, F. IT.: z\c+iotl of a new ntethoniurn cotn- pouiitl in arterial hypertension Pentatnethylene 1 :5-bis-N-(h'-metl~~l-~~~~~olitlirliu~~~ bitnrtrate) (MM3 2050 ~1). Lnncet 1: 457, 1953. 7 &~LSE, G. Il., AND OLEESKY, s.: AF\hsorption of I-les:~met,honiurl1. JIrit. R. J. 2: 17i, 1951. 8 WIEN, It.: Personal cot~lmunicntian t,o the authors. 9 KEITH, N. M., 117.4~~~~~, II. I'., AP;D J~ARXI,:R, N. W.: Some different types of esscnt,inl hyper- tension: Their course nrltl pr'ogt'ess. A\t~~. ,J. hf. SC. 197: 332, 1939. lo FREIR, R. I)., LILIENJ~II~LD, I,. S., Paiwssore, E. -I., :IND E'JNNI~K~Y, F. -I., JR.: In I,reparntion.