Reprinted from the A. M, A. Archives of IuternaJ &ledicine May 1956, Vol. 97, pp. 551-561 Copyright 1956, by American Medical dssociation Experimental and Clinical Evaluation EDWARD D. FREIS, M.D. and WE M. WILSON, M.D., Washington, D. C. Stone and his co-workers * have reported recently on certain unusual pharmacological properties of mecamylamine (3-methylam- inoisocamphane) hydrochloride. This com- pound, a secondary amine, produces a marked and prolonged degree of blood pressure reduction and ganglionic blockade in animals. Blecamylamine also is well absorbed from the gastrointestinal tract, the L. D.so being approximately the same whether the drug is adminished subcutane- ously or orally. By contrast, previously suc- cessful ganglion-blocking agents, which are tertiary amines, are poorly absorbed from the gastrointestinal tract. The ratio of oral Submitted for publication Sept. 28, 1955. Mecamylamine was supplied under the trade name of Inversine by John R. Beem, M.D., Sharp & Dohme. From the Cardiovascular Research Laboratory, Georgetown University Hospital, the Department of Medicine, Georgetown University School of Medi-. tine, and the Veterans -4dministration Hospital. Supported in part by research grants from the National Heart Institute, U. S. Public Health Service ; the Squibb Institute for Medical Research, New Brunswick, N. J. ; Irwin, Neisler & Company, Decatur, Ill., and Sharp & Dohme, Division of Merck Sr Co., Inc., Philadelphia. * Stone, C. A.; Torchiana, M. L.; O'Neill, G. P., and Beyer, K. H.: Ganglionic Blocking Proper- ties of 3-?ifethylaminoiso-Camphane Hydrochloride (Mecamylamine), a Secondary Amine, read before the American Society for Pharmacology and Ther- apy, Iowa City, Sept. 7, 1955. to subcutaneous hypotensive dosages of the Iatter drugs in man is approximately 1.5 : 1.f In patients under treatment with ganglion- blocking agents it is possible that some of the difficulties of clinical management, such as irregular fluctuations of blood pressure and gastrointestinal atony, may be due to the poor absorption and, hence, large local accu- mulations of the previously available com- pounds in the gastrointestinal tract. `It seemed worth while, therefore, to evaluate the use of mecamylamine, a readily absorbed blocking agent, in hypertensive patients. JIa4TERIALS AXD METHODS The subjects for the experimental studies were pa- tients from the wards of the Georgetown University and the Veterans Administration Hospitals, Wash- ington, D. C. The methods of investigaiion used were similar to those published in a previous com- munications Mecamylamine was administered in sterile water containing 1.0 mg. of active substance per milliliter. In the clinical studies the patients were chosen from the wards and hypertensive clinics of the above hospitals. They represented a mixed group of severe hypertensives, white and Negro, representing all varieties of social and economic classes. ESPERI3IENTAL RESULTS COMPARISON OF INTR~~EXO~X AED ORAL DO~ACES The blood pressure response in both the supine and erect positions was followed in nine patients given single intravenous doses of 15 to 20 mg. of mecamylamine. The next day the same patients were given an oral dose which was 5 to 10 mg. less than the previous intravenous dose. Following all doses there was a significant reduction of supine blood pressure and a marked postural hypotension, which was as great after oral as after intravenous administration (Table I ). These results, in marked contrast to the rela- tively large oral dosages required with other t References 1 and 2. 2 TABLE 1 .-Comfwative Hypotensive Effects of Single Intravenous and Single Oral Doses of Mecamylamine Intravenous OrIll C- Arterial Pressure, BIm. , r , Hg Arterial Pressure, Mm. Hg r `Before > r , After Before After Case . %? n 7iiz-GT Dose, xx. 5&ic-xz 5lzr-ez 1 w lW/l20 100/125 130/w @wJ 10 170/115 160/115 l.?5/90 109/75 4 15 130/110 lsq110 130135 no/70 10 W/92 146/92 120/35 w/70 3 15 19o/L20 lw/lW 140/1@5 120/93 10 190/130 190/130 170/110 lsO/llP 4 20 190/115 190/12n 140195 115190 10 170/122 l&3/124 146/192 146/1C2 5 w 240/160 230/160 180/140 150/129 10 NO/140 lea/130 16o/llS w/110 6 w 200,mo lss/l3S 15qlM) 130190 10 295/125 7 20 200/115 MO/135 160/110 15O/lMl NO/120 Itlo/ 140/9Q 10 170/110 169~115 140/W no/70 8 w 220/115 ZOO/l20 16ojlOO 102/75 15 210/120 169/1ca 145/&W ww 10 no/120 9 160/110 18/90 115/&l w 230/120 2oO/lW 160/109 100/60 15 21O/lcCJ l50/109 loo/70 ww 10 2QO/llO 170(110 lX@O 90(70 5 2~/110 160/110 155/100 lW/.SO ganglion-blocking agents, provided clear evi- dence that mecamylamine is well absorbed from the human gastrointestinal tract. FoIlowing intravenous administration, the blood pressure began to fall gradually several minutes after injection, reaching minimum values in one-half to one hour. It remained at the lowest level for several hours or, in others, began to rise after one hour reaching control values in all cases by 6 to 12 hours. ARTERIAL PRE~uRE MMHG 2 soy MECAMYLAMINE ISMG ORALLY 0123456? HOURS Fig. L-Charts showing characteristic blood pres- sure response to 20 mg. of mecamylamine intra- venously (above) and 15 mg. orally (below) in a 62-year-old man with essential hypertension. The tests \vere carried out on successive days. The broken vertical columns indicate the blood pressure in the erect position. See text for further details. The postural hypotension usually followed a similar time pattern (Fig. 1) . Following oral dosage, the blood pressure began to fall after 1 hour, reached minimum values at approximately 2 hours, and re- turned gradually to control values in 4 to 12 hours. The more profound the reduction of blood pressure the longer the duration of the response. Postural hypotension sometimes persisted for several hours after the blood pressure in the supine position had returned to control levels. EFFECT OF MECAMYLAYISE OK SYMPATHETIC VASOCO~STRKTOR REFLEXES Previous studies with the ganglion-block- ing agent hexamethonium demonstrated a marked inhibition or abolition of homeostatic vasoconstrictor reflexes.3 Postural hypoten- sion alone does not indicate such inhibition, since peripheral vasodilators acting directly on blood vessels, such as sodium nitrite, may induce a postural fall of blood pressure. Four criteria were used to measure the reactivity of the sympathetic vasoconstrictor responses and the effect of mecamylamine thereon. These were the hypertensive over- shoot following the Valsalva maneuver,i the cold pressor test, 5 the skin temperature gra- dient bet\veen the digits and the umbilicus in patients exposed in a cold constant-tempera- ture room,O and refles vasoconstrictor re- sponses as revealed by digital plethysmog- raphy.l (n) The Yalsnlva Maneuver.--If a patient blows out forcibly into a closed tube for 10 3 TABLE 2.-Vaso@essor Responses to the Vakalva Maneuver Bejore and Ajfer i/w Intravenous Administration of Mecamylamine Control After Xeeamplamino * L I 1 r Arterial Pressure, Mm. Hg Time Arterial Pressure, Mm. Hg h , , Over- After r , Over- $y, After shoot; DE:. After shoot; Case Basal va1va1sa % Basal `Salsaloa % 1 20 263/14? 288/142 . 20 10 2W1!?3 253/160 15 40 240&Q 260116? 9 lo 9 ~-~ 4 20 201/99 240/125 IS X0/63 174j95 8 40 162?;W li3/98 7 7 20 22~jlll 253/160 20 2 210/s 23?/110 12 30 1Wl.a mEa 6 3 15 1411110 290/100 47 10 1m)nr !z;136 22 40 mill4 2l8/135 22 2 15 x%8:90 196/98 11 10 1*7/s? 133/76 0 40 14OIeO 13U74 0 5 20 2621160 310/M 18 10 2Zjl45 2il/li? 34 30 215/1x 2?@/184 29 50 Z?/160 ZiO/li$ 17 120 210/1;0 23?jl35 7 v Calculated from the mean (one-half the sum of the systolic and diastolic) pressure. seconds, intrathoracic pressure is markedly increased and the blood pressure will fall. I\:hen the expiratory effort suddenly is released there is a transient overshoot of blood pressure above the basal level. Wilkins has presented evidence that the pressor over- shoot is due primarily to reflex vasoconstric- tion mediated over sympathetic pathways.4 After lumbodorsal splanchnicectomy 4 or cer- tain "sympatholytic" agents $ the overshoot is abolished. The Valsalva overshoot was determined in six patients before and periodically for one hour after intravenous mecamylamine, with use of direct continuous recording of arterial pressure 3 (Table 2). The overshoot was abolished in one of the six cases and reduced by 50% to 70% in the remaining subjects. (b) The Cold Pressor Test.-The blood pressure response during one minute of im- mersion of the patient's hand in ice water was $ References 3 and 5. determined before and one-half hour after intravenous mecamylamine. -After the drug the cold pressor response ivas signilicantly reduced in only two of the six patients (Table 3). (c) The Skin Temperature Gmdient.- Nine hypertensive patients, who had no evi- dence of peripheral vascular disease, were exposed to room temperatures of 63 to 71 C. In any one experiment the room temperature was kept constant within a range of 3 C. The skin temperature of the digits and umbilicus was recorded every three minutes. After one hour mecamylamine was given intravenously and the skin temperature and blood pressure values were recorded for an additional hour. The results follolved no consistent pattern (TabIe 4). In three patients there was a $g- nificant elevation of toe temperature ; in four, a partial rise, and in two there was no sig- nificant change. There was a significant rise TABLE J.-Effect of Intravenous hlecamylamine on the Responses to the Cold Pressor Test __- Arterial Pressure, Control Arterial Pressure After Xecamylamine* I * \I , Peak Peak Response Response Basal, to Ice, Case Basal, to Ice. Increase,t Mm. Hg Mm. Hg lnerre*+ Mm. Hg Xm. Hg % 1 262/142 300/x34 I.5 232p*" 264/166 12 : 19-L/98 218/112 13 It%/95 1a,n10 14 232/1W 240/108 5 210/41 nsp3 3 3 ljijS8 188/108 17 1;1/110 19?p26 9 2 138/100 256/138 32 l&,M 214,a?0 28 5 2741156 230/x% 3 `*57/L% 225,`156 0 o The post-treatmert tests were carried out approximately one-half hour after administration of mecamglamine. For dosages see Table 1. t See footnote, Table I. 4 TABLE 4,Changes in Skin Temfwratures After the Intravenous Administration of Meca~nylamine Control After bfecamylamine .A r 3 P 1 Bloo&Presure Blood Pressure, Dose* 5izz%z r Skin Temp., F* Mm. Hg Skin Temp.. F" case Ng. R U T F --zzFxz 7r-rb-T 10 15 195/ll5 190/115 68 94 69 72 166jlO9 140/98 68 91 71 67 ll 10 lW/llO NO/l10 69 94 69 74 Ijo: m/90 70 St 76 88 9 20 23o/l20 200/115 63 90 77 64 160/1@8 llO/sO 65 67 87 64 l2 20 190/135 lEt?/120 68 88 68 70 166/12n la/113 68 82 82 69 13 18 19op25 190/12O 70 95 77 77 158jlO8 14OojlW 70 94 86 83 14 28 240/K% 236/12U ii 91 76 79 liO/llO 130/120 70 92 69 15 16 18OJUO 180/108 86 73 84 130/105 130/100 71 88 79 iii 16 12 X+0/90 130/K! 67 93 68 74 115/W 16QJsO 67 Sl 78 W 17 15 120175 120175 n 833 73 85 l&i/i2 We n 86 88 95 `R, room temperahIre: U. umbilicus temperature: T, toe temperature: F. 5nger temperature. in finger temperature in five cases and an insignificant change in four. (a) Digital Plethysmography.-Following a deep inspiration there is normally a sharp decrease in the volume of the digit and the digital pulse, indicating vasoconstriction. This reflex vasoconstriction, which can be detected readily in the digital plethysmo- graph, is abolished after sympathetic dener- vation `I and after hexamethonium.s During the period of observation, which lasted 30 to 60 minutes following intravenous mecamylamine, there was a partial inhibition of the vasoconstrictor response to a deep inspiration in two cases and no change in four (Table 5). To one of these patients hexamethonium, 50 mg., was given intrave- nously, with an immediate abolition of the vasoconstrictor reflex (Fig. 2). Because of the possibility that insufficient time was allowed to permit the development of sym- pathetic blockage, three patients under con- tinous oral administration of mecamylamine were studied. These showed a persistence of digital refiex vasoconstriction despite signifi- cant reductions of blood pressure and marked postural hypotension. DECP BREATH AFTER 20 MO. MECAMYLAMINE AFTER 20 MO. MECAMYLAMINE DE DE 5 5 P BREATH P BREATH AFTER 50 MO. HEXAMETHONIUM AFTER 50 MO. HEXAMETHONIUM Fig. Z.-Tracings of the digital plethysmograph in a 39-year-old man with essential hypertension. The upper tracing shows an active vasoconstrictor re- sponse following deep inspiration 40 minutes after 20 mg. of mecamylamine. The lower tracing was taken 10 minutes after SO mg. of hexamethonium in the same patient. The vasoconstrictor response is completely blocked, the fluctuations in base line being due to respiratory movement. CLISICtlL RESULTS EFFECT OF CONTINVUOUS ORAL ADMINISTRATION ON BLOOD PRESSURE Thirty-six patients with "fixed" moder- ately severe to severe hypertension were TABLE S.-Effect of Mecamylamine on Digital Vasoconstrictor Reflexes Control After Mecemylamine =Ose, z&ic-%z Case Ng. 10+ 20 200/130 170/130 18 10 160/110 160/110 19 20 190/120 190/12ci 29 18 190/125 190/120 2l 20 12OJXl 120/75 22 5 lOOj65 lOO/ffi Vasocon- strictor Reflexes -f&+-t +;+++ +z I, Blood Pressure, Vasoconstrietor Reflexes, Mm. HP Time After Drua. Nin. -. * , +;>$ 343 60 +++ . . . . . . +++ +++ . . . . . . . . . . . . +++ wm 95j50 ++ +++ o Hexamethonium, 50 mg. intravenously, while producing DO further reduction of supine blood pressure, completely abolished the vssoconstrictor response in this patient. 5 treated continuously with oral mecamylamine for periods varying from one to four months (average, 2.8 months). The Keith, Wagener, and Barker classification of the optic fundi ' in these patients prior to any treatment was as follows : Grade IV, S patients ; Grade III, 15 patients ; Grade II, 13 patients, and Grade I, no patients (Table 6). For the group as a whole the mean pre- treatment blood pressure was 217/129 mm. Hg. -4fter treatment the mean blood pres- sure was 167/108 in the supine position and 153/101 in the erect position. This repre- sented a reduction of 21% systolic and 16% diastolic in the supine position and of 27% systolic and 2070 diastolic in the erect posi- tion. In every case the control and post- treatment blood pressure values were the average of many obtained in the hospital, by the patient's families in the home, and in the clinic. DOSAGE The average total daily dose was 29 mg. (range, 3 to 90 mg.) . In general, this was divided into three doses per day, generally at 8 a. m., 2 p. m., and 10 p. m. However, some patients exhibited such a prolonged effect from the drug and were so sensitive to it in the morning hours that the dose taken the night previously controlled their blood pressure until the early afternoon. In such cases, only two doses per day were required, at noon and at bedtime. Other patients exhibited resistance to the drug during the evening hours and so required an extra dose at 5 or 6 p. m. TABLE 6.-Average Blood Pressure Before and After Treatment with Mecamylamine in Thirty-Six Hypertensive Patients CWS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 la 19 20 21 29 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Nlerm Age, Yr. 57 41 42 39 59 43 39 30 45 61 47 3a 59 62 43 37 45 65 51 62 29 49 53 45 31 58 56 40 48 39 59 45 59 5; 55 5s Sex N Y 51 M N M M M BI N Bl 51 Bf N N N N N N N M F N F F N Bf F N F N N Bf N F N Optic Fundi, Grade III III II III II III III III II III II II IV III III II III III II IV IV II II IV III IV II II IV II II III III IV III IV Control IhkPGg 2001135 200/130 180/120 220/130 iao~l20 240/136 200/130 2cw135 190/120 198/125 220/135 la.?/130 220/140 2cu/m 200/135 NO/135 no/120 200/140 21O.fl15 220/130 200/150 230/130 2oQ/l20 230/130 250/140 2301130 2101120 220/120 210/120 264f150 220/140 220/150 235/138 230/130 230/120 240/130 2171129 Daily DWll. Dose, tion, Ng. MO. 3 3 32.5 3.5 5 2.5 3 3.5 32.5 3 25 2.5 25 2.5 20 3.5 25 3 40 3.5 27.5 4 30 3.5 55 4 a.5 3 10 3.5 27.5 3 27.5 2.5 25 2.5 3 1 40 1.5 32.5 2 40 3 50 3.5 15 3.5 25 3.5 50 2 35 2 30 4 10 3.5 40 3 22 3.5 90 2 47.5 1 15 1 80 3 40 1 29 2.3 Post-Treatment Per Cent Decrease Blood Pressure, ,- I > Mm. Ek SUPlIE Erect L I- ' Supine 16o/loj 150/110 m/110 145/110 140/95 172/116 laofloa no/120 160/105 150/100 w/115 no/120 2fJojll5 lao/llO 170/m 140/102 no/112 ljo/llO m/98 205/m lao/115 170/100 16a/llO x70/105 155/lOQ lao/llO li5f 110 ljs/loa lzJ/loil 160/105 190/115 m/112 2oo/llO 170/110 165/9a 150/100 x7/108 " Systolic DiastolidrSystolic DIastollB Erect 150/102 130/100 154/1oo 125/105 120/w 152/m 170/100 140/115 150/m 120/W 170/110 lsojll5 170/110 170/m 150/110 135/100 1701115 150/110 135/W 197/105 170/110 16olloo 160/108 164J/lc0 m/98 160/105 m/105 150/110 150/95 155(100 180/110 20 22 25 24 24 15 35 23 6 8 14 16 34 15 43 19 22 20 33 25 28 14 36 21 10 17 15 23 15 11 30 15 16 13 21 17 24 20 39 26 la 15 22 19 8 7 14 19 9 la 23 21 10 4 15 9 15 11 25 19 26 23 28 26 19 6 19 4 25 21 26 21 28 Xi 35 22 6 19 10 19 10 23 lb 27 26 23 30 23 16 8 W 10 26 19 31 23 33 28 40 30 n 15 30 19 24 8 27 13 28 10 31 a 26 17 28 20 38 30 40 33 14 17 la 21 17 2.5 23 28 14 19 11 17 26 15 43 27 28 la 47 33 37 23 45 27 21 16 27 20 6 There also was evidence for some cumula- tive effects of mecamylamine. It was not uncommon on discontinuing the drug to observe a gradual disappearance of the hypo- tensive effects over a period of 24 to 72 hours. 1Vhen dosages were being adjusted it often was found that the maximum effect from an elevation of dosage would appear on the second day of treatment at the new level, suggesting that some cumulation had oc- curred from the previous day. On the basis of these experiences we are at present beginning therapy with a dose of essential in determining the need and extent of such modifications.g OTHER CLINICAL EFFECTS (a) Optic Fun&.-Of the eight patients who exhibited Grade IV changes in the optic fundi prior to treatment, two reverted to Grade III and six to Grade II. In the group of 15 patients with Grade III fundi, 1 re- mained Grade III, 13 reverted to Grade II, and 1 reverted to Grade I. In the Grade II cases seven remained Grade II and six reverted to Grade I. Fig. 3.-Roentgenograms of the chest taken before and three months after treatment with mecamylamine in a 57-year-old Negro man with malignant hypertension. Digitalis and mercurial diuretics were not used in treating this patient. 2 mg. after breakfast, at 2 p. m., and at bed- time and then increasing the dosage by 2 mg. every 4s hours, until a hypotensive effect is obtained. At this point the three doses dur- ing the day are individually raised or 1owere.d. as the occasion demands so as to obtain the least diurnal fluctuation of blood pressure within the limits of tolerable side-effects. An additional dose may be given at 5 or 6 p. m. if the evening pressures are high, or the morning dose may be sharply reduced or omitted if the blood pressure is extremely low at that time. A running record of the supine and erect blood pressure values in the hospital and later at home was found to be (b) Cardiac Stu.tzls.-Cardiac size was measured roentgenographically before and after treatment in 31 cases. Only changes. of 1 cm. or more in the transverse diameter of the heart were considered significant, since the depth of inspiration and other factors may influence the apparent size. Three cases showed an increase in transverse diameter ranging between 1.5 and 2.0 cm. (mean, l.S cm.). Twenty-one exhibited no change, while seven showed a decrease varying between 1 and 3 cm. (mean, 1.7 cm.) (Fig. 3). Electrocardiographic changes were fol- lowed in 30 cases. Left ventricular hyper- trophy was indicated in the electrocardio- III aVR aVF BEFORE TREATMENT AFTER 2 MONTHS OF TREATMENT Fig. 4.-Cuttings taken from electrocardiograms of a 45year-old man with essential hyper- tension. After two months of treatment with mecamylamine the pattern of left ventricular hyper- trophy disappeared. grams of 2s patients. Of this number, 23 were unchanged, 4 reverted to normal (Fig. 4), and 1 exhibited changes toward normal. Two patients with normal electrocardiograms before treatment showed no change after therapy. cc) Red Ftrnction.-Albuminuria tended to lessen after treatment in the patients who showed the greatest amounts of albumin be- fore therapy (Table 7). In the patients with lesser degrees of albuminuria the changes were variable. In the 28 cases in ,which albuminuria was measured, II exhibited im- provement, 11 were unchanged, and 6 showed a greater degree of albuminuria than before treatment. There were no significant changes in specific gravity or in the urinary sediments. 8 In 22 cases the excretion of phenolsul- urinary stream. In two cases there was in- fonphthalein (PSP) dye was measured in ability to empty the bladder completely, a sample collected 15 minutes after the dye characterized by repeated small frequent was injected. A change of 5% excretion or voidings. This cleared later in both patients. more was considered significant. Ten pa- Dryness of the mouth due to inhibition of tier&s showed a mean decrease of 11% of salivary gland secretion occurred in 7 of the dye excretion following treatment ; seven ex- patients early in treatment and in 11, or 30%, hibited no change, while in five patients there of the cases at some time later in the course was a mean increase of 12% of dye excreted. of treatment. In general, the side-effects did The blood urea nitrogen level was meas- not tend to disappear over the relatively ured in 28 cases before and after therapy. short period of this study. Nine exhibited elevations of blood urea nitro- gen concentration before treatment, the levels "TOLERANCE" varying between 26 and 51 mg. per 100 cc. The extent of "tolerance" was estimated In five of these patients the BUN decreased by comparing the dosage requirement early to the normal range after therapy, and in one and late in treatment. Over the period of it changed toward but not to normal. In therapy with mecamylamine, varying from two cases there was no significant change, one to four months, there was no increase in TABLE 7.-Change.s in Degree of Albuminuria After Mecamylamine in Twenty-Eight Cases Degree of Alb,unnm$a ._ Degree of Albuminuria After Treatment PaGtits. r 8 \ Treatment _ ++++ +++ ++ + TC. Neg. +++I- 2 . . . . 1 . . 1 . . +-H- 1 . . . . . . 1 . . ,. ++ 4 1 . . 1 1 . . 1 + I . . . . . . 4 2 1 Tr. 8 . . 1 1 1 2 3 Neg. 6 . . . . . . . . 2 4 while in one, who had the highest level before treatment, there was an increase from 51 to 76 mg. per 100 cc. SIDE-EFFEnS The commonest side-effect encountered was constipation, which occurred in 32, or SSY,, of the patients (Table 8) ~ In all except three of these the constipation could be con- trolled by giving neostigmine, 15 to 45 mg: orally, before breakfast and/or laxatives such as cascara sagrada or magnesium hydroxide. Impaired visual accommodation and postural faintness each occurred in 10, or 27's, of the cases. Impotence was complained of in 10 patients; it was partial in 4 and complete in 6. Difficulty in emptying the urinary bladder and dry mouth were common, each occurring at some time during treatment in nearly 30%. The urinary difficulty usually was mild, consisting only of diminution of the TABLE K-Incidence of Side-Eflects Occurring in Thirty-Six Hypertensive Patients Under Contimous Treatment with Oral Mecamylamine Early fn Treatment After 1 to 4 MO. ------- Side-Effect Patients Cent EL% Zt Constipation .......... 32 88 a hfild.. ................ 11 .... ." Moderate. ........... 15 ...... Severe ................ 6 ...... Constipation cou- trolled with laxa- tives and/or neo- stigmine.. . . . . . . . . . . . Impaired vlsuel accommodation.. . . . Dry mouth . . . . . . . . . . . . Impotence.. . . . . . . . . . Incomplete.. . . . . . . . . . Complete.. . . . . . . . . . . Postursl faintness..... Postural syncope.. . . . . DifEculty In emptying urinsr~ bladder.. . . Mild.....-. ............ Moderate ............ Severe ................ . . . . 29 II 10 27 8 !22 I 19 11 so . . . . 10 27 . . .- 4 . . . . . . 6 . . 10 27 9 25 1 8 4 11 I 19 11 so 5 .- 7 . . 1 . . 4 . . 1 . . 0 . . 9 dosage in 19, or 53% ; in 10 of these the dosage requirement actually lessened (Table 9). In 12, or 33%, an increase of 5 to 20 mg. in the total daily dosage was required. In TXSLE 9.-Extent of "Tolerance" to Oral Mecamgl- amine: Change in Daily Dosage Requirement After One to Four Months of Treatment Change in Daily NO. Dosage Requirement Patients More than j mg. decrease.. ........... 10 28 So essential change.. ................. 9 25 Between 5 and 20 mg. increase.. ..... 12 33 Vore than 20 mg. increase.. .......... 5 14 Total. ............................. 36 loo five patients the dosage increase was greater than 20 mg. per day. During the period of this study, therefore, in the majority of cases the development of tolerance was slight or nonexistent. TREATMEST FAILURE AND COMPLICATIONS Three patients died either while under treatment or shortly thereafter. TWO of these had malignant hypertension with uremia. Both exhibited significant but not excessive reduction of blood pressure and a decreased urinary output. The blood urea nitrogen rose in one case and decreased slightly in the other. Autopsy revealed advanced malig- nant nephrosclerosis in both instances. The third patient was a 55-year-old man with long-standing hypertensive heart dis- ease. The blood pressure had been reduced from 230/120 to approximately 170/110 mm. Hg, with apparent improvement in cardiac decompensation. After six weeks of treatment, while at home, he suddenly was seized with severe substernal pain and died two hours later. The clinical impression was myocardial infarction; autopsy was not ob- tained. Treatment was discontinued in four pa- tients because of abdominal distention and vomiting, either with obstipation or with small frequent liquid stools diagnosed as a low-grade paralytic ileus. These symptoms cleared promptly on discontinuation of ther- apy. In one case it was possible to resume treatment in reduced dosaFe without recur- rence. In another patient two later attempts at therapy were followed again by symptoms of ileus. Treatment was discontinued in another uremic patient with malignant hypertension because of severe postural hypotension with syncope, decreased urinary output, and in- creasing uremia. This patient improved when veratrum was substituted for mecamylamine, although the blood pressure level rose. Treat- ment was discontinued in a 57-year-old-man because of severe postural hypotension with increased angina and in a 59-year-old man because of difficulty in emptying the urinary bladder and severe dryness of the mouth not relieved by oral pilocarpine nitrate. One patient developed acute appendicitis after one month of therapy. He was operated upon, and recovery was uneventful. Another patient with congestive heart failure and massive ascites failed to respond to mecamyl- amine, even in large doses, until paracentesis was performed. After removal of the ascitic fluid the blood pressure fell from 220/120 mm. Hg to nearly normotensive levels on a total daily dose of 20 mg. of mecamylamine. He has remained clear of congestive heart failure and ascites over a three-month period. It is suggested that the tight ascites produced sufficient abdominal compression to overcome the vasodilator effects of the mecamylamine in the splanchnic area. ADDITIOX OF OTHER HYWTENSNE AGENTS In assessing the effect of the addition of other agents the blood pressures were deter- mined three to five times per day either in the hospital or at home. The average of the blood pressure values for the week immedi- ately preceding and immediateIy following the change in medication were averaged and compared. (5) Add,ition of Hydralazine.-The hypo- tensive effect of hydralazine when added to mecamylamine was tested in 13 patients. The daily dosage of hydralazine varied between 75 and 200 mg. per day, the average dose being 100 mg. per day. In three of these cases an additional hypotensive effect was observed. The reduction was not preat. varv- 10 ing between 10% and 14% below the values obtained with mecamylamine alone. In the remaining 10 patients no additional hypo- tensive effects were observed following hy- dralazine. Two patients developed mild head- aches ; one, mild palpitation, and one, severe palpitation. These side-effects were transient. It is possible that the addition of hydralazine might have produced additional hypotensive effects in a greater number of patients if it had been given in larger doses. Such in- creases in dosage were not attempted, how- ever, because of the possibility of developing collagen vascular syndromes.10 (b) Addition of Reserpine.-Reserpine was added to the regimen of 11 patients in dosages of 0.25 to 1.0 mg. (mean, 0.5 mg.) per day. In 5 of the 11 cases additional reductions of blood pressure occurred, vary- ing between 9% and 25% below the values obtained with mecamylamine alone. Among these five patients, one experienced nasal stufiness while the remaider had no side- effects attributable to reserpine. COMPARISOS OF MECAMYLAMISE AND PENTOLINIUM TARTRATE In 19 patients who had been under treat- ment with pentolinium tartrate for six months or longer the drug was discontinued and mecamylamine was substituted. The daily dosages of pentolinium tartrate had varied between 60 and 1150 mg. (average, 580 mg.). This had resulted in reductions of "mean" ( systolic + diastolic 2 ) blood pressure av- eraging 16% in the supine and 20% in the erect position. The daily dosages of mecamylamine in the same group of patients varied between 3 and 90 mg. (average, 35 mg.). In general, the patients who required the higher dosages of pentolinium tartrate also needed the largest daiiy requirement of mecamylamine. The reductions of mean blood pressure averaged 21% in the supine and 25% in the erect position. When asked which medication they pre- ferred, 14 favored mecamylamine. The chief reason given was that the blood pressure reduction was more uniform from morning to night and from day to day with mecamyl- amine (all of these patients recorded their blood pressure levels at home). However, five patients preferred pentolinium tartrate, since they obtained a more uniform reduction with the latter drug and also experienced fewer or less severe side-effects. CONMENT Clinically, mecamylamine behaved as a typical ganglion-blocking agent. Experimen- tally, the inhibition of sympathetic vasocon- strictor reflexes was less than had been ob- served previously with l~examethonium.s The reason for this discrepancy is not evident at present. The dosages of mecamylamine were smaller than those given in the hexametho- nium studies. However, the doses of the two agents were approximately equipotent so far as hypotensive effects were concerned. It is possible that if the patients had been studied for longer intervals than from 30 to 60 min- utes after mecamylamine a more complete inhibition of sympathetic vasoconstrictor re- flexes would have been observed. Still, the reflexes remained active in three patients who were restudied during continuous oral ad- ministration of the drug. Finally, there is the possibility that mecamylamine in man has peripheral or central vasodilator effects in addition to its ganglion-blocking action. However, this supposition gains no support from the animal data Q or from our own clinical observations. Because of its potency, relatively long duration of action, and complete absorb- ability, the daily dose requirement of me- camylamine was far less than that of other ganglion-blocking drugs. It was hoped that the complete oral absorption of mecamyI- amine would obviate some of the difficulties entailed in the use of ganglionic blocking agents clinically. In the majority of the pa- 5 Stone, C. A.; Torchiana, M. L. ; O'Neill, G. P., and Beyer, K. H.: Ganglionic Blocking Properties of 3-Methylaminoiso-Camphane Hydrochloride (Me- camylamine), a Secondary Amine, read before the American Society for Pharmacology and Experi- mental Therapy, Iowa City, Sept. 7,195. 11 tients the blood pressure response was more uniform from day to day than with pen- tolinium tartrate, but this was not always the case. In addition, such side-effects as constipation were just as prominent with the small completely absorbed doses of mec- amylamine as with the relatively large poorly absorbed doses of other ganglion-blocking agents. StXINARY AND CONCLUSIONS Mecamylamine seems to be completely absorbed from the intestinal tract of man. The hypotensive effect began after 1 hour, reached the lowest values at 2 hours and disappeared in 6 to 12 hours. In equipotent hypotensive doses mecamyl- amine did not produce as marked an inhibi- tion of sympathetic vasoconstrictor reflexes as had been observed previously with hex- amethonium. In 36 patients xvith severe hypertension treatment with mecamylamine in an average dose of 29 mg. per day was followed by a mean reduction in blood pressure of 21% systolic and 16% diastolic in the supine posi- tion and 27% systolic and 20% diastolic in the erect position. Continuous treatment for one to four months frequently resulted in improvement . in the optic fundi and occasionally in the electrocardiographic patterns. A decrease in blood urea nitrogen levels also was noted in most patients exhibiting slight elevations but not in those with marked nitrogen retention. The side-effects were typical of those ex- perienced with other ganglion-blocking agents. In the majority of patients the develop- ment of "tolerance" was slight or nonex- istent. The addition of small doses of hydralazine appeared to produce a slight additional hypo- tensive effect in 3 of 13 patients. Reserpine seemed to produce an additional hypotensive effect in 5 of 11 patients. Mecamylamine appears to offer a slight advantage over other ganglion-blocking agents in that the effective dose is much smaller, and with careful dosage regulation the blood pressure usually fluctuates less than with other Hocking agents. REFERENCES 1. Freis, E. D.; Finnerty, F. A., Jr.; Schnaper, H. W., and Johnson, R. L.: The Treatment of Hypertension with Hexamethonium, Circulation 5 : 20, 1952. 2. Freis, E. D.; Partenope, E. A.; Lilienfield, L. S., and Rose, J. C: A Clinical Appraisal of Pentapyrrolidinium (11 & B 2050) in Hypertensive Patients, Circulation 9:X), 193-1. 3. Finnerty, F. A., Jr., and Freis, E. D.: Ex- perimental and Clinical Evaluation in Man of Hexa- methonium (C6), a Xew Ganglionic Blocking Agent, Circulation 2:828,1950. 4. \%-ilkins, R. W., and Culbertson, J. W.: The Effects of Surgical Sympathectomy upon Certain Vasopressor Responses in Hypertensive Patients, Tr. A. Am. Physicians 110:195, 1947. 5. Freis, E. D.; Stanton, J. R.; Litter, J.; Cul- bertson, J. W.; Halperin, 91. H.; Moister, F. C., and Wilkins, R. W. : The Hemodynamic Effects of Hypotensive Drugs in Man: II. Dihydroergo- cornine, J. Clin. Invest. 28:1387, 1949. 6. Uprus, V.; Gaylor, J. B., and Carmichael, E. A.: Vasodilitation and Vasoconstriction in Re- sponse to Warming and Cooling of the Body: Criticism of Methods, Clin. SC. 2:301, 1936. 7. Bolton, B.; Carmichael, E. A., and Stiirup, G. : Vasoconstriction Followicg Deep Inspiration, J. Physiol. 86:83, 1936. 8. Keith, N. >I.; Wagener, H. P., and Barker, N. W.: Some Different Types of Essential Hyper- tension: Their Course and Progress, Am. J. M. SC. 197:332,1939. 9. Freis, E. D. : The Discrepancy Between Home and Office Recordings of Blood Pressure in Pa- tients Tinder Treatment with Pentapyrrolidinium : Importance of Home Recordings in Adjusting Dos- ages, hf. Ann. District of Columbia 28:363, 1954. 10. Dustan, H. P.; Taylor, R. D.; Corcoran, A. C., and Page, I. H. : Rheumatic and Febrile Syn- drome During Prolonged Hydralazine Treatment, J. A. hi. A. 154:23, 1954. Pribitrd and Published in the United States of Anreriro