Reprinted from the A. M. A. Archives of Internal Medicine May 1956, Vol. 97, pp. 551-561 Copyright 1956, by American Medical Association Mecamylamine, a Vlew, Orally Effective, Hbypotensive Agent Experimental and Clinical Evaluation EDWARD D. FREIS, M.D. and ILSE M. WILSON, M.D., Washington, D. C. I AV ULLAL UN WG 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. Mecamylamine also is well absorbed from the gastrointestinal tract, the L. D.s9 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-. cine, and the Veterans Administration 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, Il, and Sharp & Dohme, Division of Merck & Co., Inc., Philadelphia. * Stone, C. A.; Torchiana, M. L.; O’Neill, G. P., and Beyer, K, H.: Ganglionic Blocking Proper- ties of 3-Methylaminoiso-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 latter drugs in man is approximately 15: 1.7 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 loca] 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. MATERIALS AND 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 investigation used were similar to those published in a previous com- munication. 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. EXPERIMENTAL RESULTS Comparison oF INTRAVENOUS AND Oral Dosaces ' 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 1). These results, in marked contrast to the rela- tively large oral dosages required with other + References 1 and 2. 2 TABLE 1.—Comparative Hypotensive Effects of Single Intravenous and Single Oral Doses of Mecamylamine Intravenous Oral _ A ~ r A—_ — Arterial Pressure, Mm. Hg Arterial Pressure, Mm. Hg AW. A Before After Before After Dose, Dose, Case Me. Supine Erect Supine Erect Mg. Supine Erect Supine Erect 1 20 196/190 180/125 130/90 90/80 10 170/115 160/115 135/90 100/75 2 15 180/110 190/110 130/85 110/70 10 150/92 146/92 120/85 ” 98/70 3 15 190/120 180/130 140/105 120/98 10 190/130 190/130 170/110 150/112 4 20 190/115 190/120 140/95 115/90 10 170/122 168/124 146/102 148/102 é 20 240/160 230/160 180/140 150/120 10 190/140 186/130 160/118 156/110 6 20 200/130 198/185 150/100 130/90 10 205/125 200/135 160/110 150/100 7 20 200/115 190/120 160/98 140/90 10 170/110 160/115 140/90 110/70 8 20 220/115 200/120 160/100 102/75 13 210/120 160/100 145/80 80/60 10 220/120 160/110 160/90 115/80 9 20 230/120 200/120 160/100 100/60 15 210/100 150/100 100/70 80/60 10 200/110 170/110 150/90 90/70 5 200/110 160/110 135/100 120/80 ganglion-blocking agents, provided clear evi- dence that mecamylamine is well absorbed from the human gastrointestinal tract. Following 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 PRESSURE MMHG 2407 200; '60r {20 T bares! beeen end sor [LMECAMYLAMINE 40 20MG LLY. 220 1 80- '4or f 1 00F ' it + MECAMYLAMINE ISMG ORALLY Q i 2 3 2 60 4 HOURS 5 6 7 Fig. 1.—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 were 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. Errect oF MECAMYLAMINE ON SYMPATHETIC VASOCONSTRICTOR REFLEXES Previous studies with the ganglion-block- ing agent hexamethonium demonstrated a marked inhibition or abolition of homeostatic vasoconstrictor reflexes.* 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,‘ the cold pressor test, the skin temperature gra- dient between the digits and the umbilicus in patients exposed in a cold constant-tempera- ture room,® and reflex vasoconstrictor re- Sponses as revealed by digital plethysmog- raphy.” (a) The Valsalva Maneuver.—If a patient blows out forcibly into a closed tube for 10 3 TasLe 2—Vasopressor Responses to the Valsalva Maneuver Before and After the Intravenous Administration of Mecamylamine Control After Mecamylamine AL ~ An. - Arterial Pressure, Mm. Hg Time Arterial Pressure, Mm. Hg Over- After Over- Dose, After shoot,” Drug, After shoot,” Case Me. Basal Valvalsa % Min. Basal Valsalva % 1 20 263/142 288/142 * 20 10 228/123 253/160 15 40 240/150 260/162 9 4 20 261/98 240/125 18 10 160/83 174/95 8 40 162/90 173/98 7 7 20 225/111 253/160 20 2 210/98 232/110 12 30 190/84 2M /88 6 3 15 193/110 290/160 47 10 180/114 225/136 22 40 174/114 218/135 22 2 15 168/90 190/98 il 10 142/82 133/76 0 40 140/80 WH /74 0 5 20 262/160 310/183 18 10 225/145 274/172 4 30 218/150 268/180 29 aD 229/160 270/178 17 120 210/130 232/156 7 * 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. When 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.* After lumbodorsal splanchnicectomy * or cer- tain “sympatholytic” agents t 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* (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 was significantly reduced in only two of the six patients (Table 3). (c) The Skin Temperature Gradient.— 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 3C. 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 followed no consistent pattern (Table +). In three patients there was a sig- nificant elevation of toe temperature ; in four, a partial rise, and in two there was no sig- nificant change. There was a significant rise TasLe 3.—Effect of Intravenous M. ecamylamine on the Responses to the Cold Pressor Test Arterial Pressure, Control A Arterial Pressure After Mecamylamine* AW sr — Peak Peak Response Response Basal, to Ice, Increase,t Basal, to Ice, Increase,t Case Mm, Hg Mm. He % Mm. Hg Mm. He % 1 262/142 300/164 15 239/142 264/266 12 4 194/98 218/112 13 166/95 188/110 14 7 232/100 240/108 5 210/94 218/98 3 3 154/98 188/108 7 174/110 199/120 9 2 198/100 256/138 32 166/93 214/120 23 5 274/156 280/166 3 222/160 225/156 a *The post-treatment tests dosages see Table 1. t See footnote, Table 1. were carried out approximately one-half hour after administration of mecamylamine. For TaBLe 4.—Changes in Skin Temperatures After the Intravenous Administration of Mecamylamine Control A——_— After Mecamylamine An. Blood Pressure, Blood Pressure, Mm. Hg Skin Temp., F* Mm. Hg Skin Temp., F* Dose, + a = an A— Yo — a a —- — Case Mg. Supine Erect R U T F Supine Erect R U T F 10 15 195/115 190/115 68 94 69 72 166/100 140/95 68 92 ik 87 nee 10 190/110 190/110 69 94 69 74 150/95 120/90 70 94 76 88 9 20 230/120 200/115 63 90 vis 66 160/108 110/80 65 87 87 66 12 20 190/135 188/120 68 88 66 70 166/120 150/115 68 82 82 69 13 18 190/125 190/120 70 95 V7 WT 158/108 146/100 70 of % 83 It 28 240/135 230/120 70 91 76 79 170/110 130/120 70 2 % 87 15 16 180/110 180/108 7 86 73 & 130/105 130/100 71 88 79 8&5 16 12 130/90 130/83 67 93 68 74 135/90 100/80 67 o 78 91 17 15 120/735 120/75 71 88 73 8&5 105/72 90/80 7 86 86 95 *R, room temperature; U, umbilicus temperature; T, toe temperature; F, finger temperature. in finger temperature in five cases and an insignificant change in four. (d) 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 * and after hexamethonium.*® 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. mtr BREATH AFTER 20 MG. MECAMYLAMINE mi? BREATH AFTER 50 MG. HEXAME THONIUM Fig. 2—-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 50 mg. of hexamethonium in the same patient. The vasoconstrictor response is completely blocked, the fluctuations in base line being due to respiratory movement. CLINICAL RESULTS Errect oF Continuous Orat ADMINISTRATION on Broop Pressure Thirty-six patients with “fixed” moder- ately severe to severe hypertension were Tasre 5.—Effect of Mecamylamine on Digital Vasoconstrictor Reflexes Control After Mecamylamine Blood Pressure, Blood Pressure, Vasoconstrictor Reflexes, Mm. He Vasocon- Mm. Hg Time After Drug, Min. Dose, strictor r A — Case Mg. Supine Ereet Reflexes Supine Erect 2 10 30 60 10* 20 200/130 170/180 ++++ 180/130 Nottaken +++ +4-++ t+ eeeee 18 10 160/110 160/110 +++ 130/98 100/80 +++ +++ +4++ t++ 19 20 190/120 190/125 +++ 160/110 140/100 +++ +++ ttt nese ee 20 18 190/125 190/120 ++ 150/115 130/100 ++ ++ t+ bea eee 21 20 120/75 120/75 4+4+4+ 95/70 95/70 ++ ++ ++ +++ 22 5 100/65 100/65 +44 90/50 95/50 ++ +++ ++ +++ * Hexamethonium, 50 mg. intravenously, while producing no further reduction of supine blood pressure, completely abclished the vasoconstrictor response in this patient, 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, 8 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. After 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 20% 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. DosacE 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 8a. 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 M ecamylamine in Thirty-Six Hypertensive Patients Optic Control Daily Dura- Age, Fundi, B. P., Dose, tion, Case Yr. Sex Grade Mm. Hg Meg. Mo. 1 57 M II 200/135 3 3 2 41 M TIt 200/130 32.5 3.5 3 42 M Ir 180/120 5 2.5 4 39 M Til 220/130 3 3.5 5 é9 NM II 180/120 32.5. 3 6 43 M Tit 240/135 25 2.5 7 39 M Til 200/130 25 2.5 8 39 M Til 200/135 20 3.5 9 45 M II 190/120 25 3 10 61 M II 198/125 40 3.5 1 47 M II 220/133 27.5 4 12 38 M II 185/130 30 3.5 13 59 M Iv 220/140 55 4 14 62 M HI 200/115 32.5 3 16 43 M TIT 200/135 10 3.5 16 37 M si 190/135 27.5 3 17 45 M Tr 210/120 27.5 2.6 18 65 M IIt 200/140 25 2.5 19 5A M II 210/115 8 1 20 62 M IV 220/130 40 1.6 21 29 M Iv 200/150 32.5 2 22 49 ¥F II 230/130 40 3 23 53 M I 200/120 50 3.5 24 45 ¥F IV 230/130 15 3.5 25 31 F TIE 250/140 25 3.5 26 58 M Iv 230/130 50 2 27 55 M II 230/120 35 2 28 40 F Ir 220/120 30 4 29 48 M IV 210/120 10 3.5 30 39 F Ir 260/150 40 3 31 59 M It 220/140 22 3.5 32 45 M IIl 220/150 90 2 33 59 M IIl 235/135 47.5 i 34 53 M IV 230/130 15 1 35 55 F Ht 230/120 80 3 36 58 M IV 240/130 40 1 Mean 217/129 29 2.8 Post-Treatment Blood Pressure, Per Cent Decrease Mm. Hg Supine Erect o AN “ A mY A — Supine Erect Systolic Diastolic Systolic Diastolic 160/105 150/102 20 22 25 24 150/110 130/100 24 15 35 23 168/110 154/100 6 8 14 16 145/110 125/103 34 15 43 19 140/95 120/90 22 20 33 25 172/116 162/106 28 14 36 21 180/108 170/100 10 7 15 23 170/120 140/115 15 il 30 15 160/105 150/100 16 13 21 17 150/100 120/90 24 20 39 26 180/115 176/110 18 15 22 19 170/120 160/115 8 q 4 19 200/115 170/110 9 18 " 93 21 180/110 170/105 10 4 15 9 170/120 150/110 15 11 25 19 140/102 135/100 26 23 28 26 170/112 170/115 19 6 19 4 150/110 150/10 25 2) 26 21 150/98 135/90 28 15 35 22 205/105 197/105 6 19 10 19 180/115 176/110 10 23 lb 27 170/160 160/100 . 26 23 30 23 168/110 160/108 16 8 20 10 370/105 160/100 26 19 31 23 155/100 150/93 38 28 40 30 180/110 160/105 21 35 30 19 175/110 168/105 2t 8 27 13 158/108 150/110 28 10 31 8 155/100 150/95 26 WW 28 20 160/105 155/100 38 30 40 83 190/115 180/110 4 7 18 21 182/112 170/108 17 25 23 28 200/110 210/112 14 19 11 17 170/110 130/93 26 15 43 27 165/98 120/80 28 18 47 33 130/100 130/93 37 23 45 27 167/108 153/101 21 16 27 20 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. When 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 SG Fig. 3.—Roentgenograms of the chest taken essential in determining the need and extent of such modifications.® Oruer Cuinicat Errects (a) Optic Fundi—-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 IIT 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 JI and six reverted to Grade I. 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 48 hours, until a hypotensive effect is obtained. At this point the three doses dur- ing the day are individually raised or lowered. 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 Status—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, 1.8 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- ze BEFORE TREATMENT AFTER 2 MONTHS OF TREATMENT Fig. 4.—Cuttings taken from electrocardiograms of a 45-year-old man with essential hyper- tension. After two months of treatment with mecamylamine the pattern of left ventricular. hyper- trophy disappeared. . grams of 28 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. fc) Renal Function 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, 11 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, In 22 cases the excretion of phenolsul- fonphthalein (PSP) dye was measured in a sample collected 15 minutes after the dye was injected. A change of 5% excretion or more was considered significant. Ten pa- tients showed a mean decrease of 11% of dye excretion following treatment ; seven ex- hibited no change, while in five patients there was a mean increase of 12% of dye excreted. The blood urea nitrogen level was meas- ured in 28 cases before and after therapy. Nine exhibited elevations of blood urea nitro- gen concentration before treatment, the levels varying between 26 and 51 mg. per 100 cc. In five of these patients the BUN decreased to the normal range after therapy, and in one it changed toward but not to normal. In two cases there was no significant change, 8 urinary stream. In two cases there was in- ability to empty the bladder completely, characterized by repeated small frequent voidings. This cleared later in both patients. Dryness of the mouth due to inhibition of salivary gland secretion occurred in 7 of the patients early in treatment and in 11, or 30%, of the cases at some time later in the course of treatment. In general, the side-effects did not tend to disappear over the relatively short period of this study. “TOLERANCE” The extent of “tolerance” was estimated by comparing the dosage requirement early and Jate in treatment. Over the period of therapy with mecamylamine, varying from one to four months, there was no increase in Tasie 7.—Changes in Degree of Albuminuria After Mecamylamine in Twenty-Eight Cases Degree of Albuminuria " Degree of Albuminuria After Treatment A Before Treatment 44+ ++ ++ + Tr. Neg. Patients, — No. +t+++ 0 +++ ee 1 m CO ay mm If bO Tr. 1 ++ + Neg. 1 1 1 . . | te et tore res os eo mths e while in one, who had the highest level before treatment, there was an increase from 51 to 76 mg. per 100 cc. Swe-EFFECTS The commonest side-effect encountered was constipation, which occurred in 32, or 889%, 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%, 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 Taste 8.—Incidence of Side-Effects Occurring in Thirty-Six Hypertensive. Patients Under Continuous Treatment with Oral Mecamylamine Early in Treatment After 1 to 4 Mo, No. of Per No. of Per Side-Effect Patients Cent Patients Cent Constipation.......... 32 83 3 8 p. 6) (A lL a 7 os Moderate............ 15 ee o or Severe.........c.ee00. 6 oe o « Constipation con- trolled with laxa- tives and/or neo- stigmine............. 28 7 Impaired visual accommodation..... 10 27 8 22 Dry mouth..,.......... 7 19 11 30 Impotence............- . 10 27 Incomplete........... . «- 4 .- Complete............ - - 6 . Postural faintness..... 10 27 9 25 Postural syncope...... 1 3 4 i Difficulty in emptying urinary biadder.... 7 19 11 30 Mild....0....- cesses 5 - q - Moderate 1 . 4 . Severe..........0..006 1 o o 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 Tase 9.—Extent of “Tolerance” to Oral Mecamyl- amine: Change in Daily Dosage Requirement After One to Four Months of Treatment Change in Daily No. Per Cent Dosage Requirement Patients of Total More than 5 mg. decrease............. 10 28 No essential change...............00-5 9 25 Between 5 and 20 mg. increase....... 12 33 More than 20 mg. increase............ 5 4 0) :) 36 100 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. TREATMENT FatLureE anp 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 reatment, 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 dosage 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. AppiTIon oF OTHER HyPporensivE 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 immediately following the change in medication were averaged and compared, (a) Addition 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 great, vary- 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.?° . (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 stuffiness while the remaider had no side- effects attributable to reserpine, CoMPARISON OF MECAMYLAMINE 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 systolic -+ diastolic 2 “mean” ( ) 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 daily 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 10 reduction was more uniform from morning to night and from day to day with mecamy!}- 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. COMMENT 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 hexamethonium.? 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§ 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 mecamyl- amine would obviate some of the difficulties entailed in the use of ganglionic blocking agents clinically. In the majority of the pa- § 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, 1955. 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. SUMMARY 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 with 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. 11 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 blocking 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 (M & B 2050) in Hypertensive Patients, Circulation 9:540, 1954. 3. Finnerty, F. A., Jr., and Freis, E. D.: Ex- perimental and Clinical Evaluation in Man of Hexa- methonium (C6), a New Ganglionic Blocking Agent, Circulation 2:828, 1950. 4, Wilkins, 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, M. 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 Sttrup, G.: Vasoconstriction Fotlowirg Deep Inspiration, J. Physiol. 86:83, 1936. 8. Keith, N. M.; 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 Under Treatment with Pentapyrrolidinium: Importance of Home Recordings in Adjusting Dos- ages, M. 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. M. A. 154:23, 1954. Printed and Published in the United States of America