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Mbutsh USE of MECAMYLAMINE IN 422 FEB. 23, 1957 ADRENOCORTICAL DEFICIENCY STATES MBuTsH cortisone was donated by the Medical Research Council. Since amine leads to little or no drug toleration, a point of this article was written we have learnt that Messrs. Squibb have great practical and theoretical interest. The structural made 9a-fluorohydrocortisone available to hospitals in tablets of 1-mg. and 0.1-mg. strength. formula of mecamylamine (3-methylamineisocamphane hydrochloride) is here shown. REFERENCES The present study describes our experiences with the Bartter, F. C. (1956). Metabolism, 5. 369. Borst, J. 0. G., Ten Holt, S. R., de Vries, L. A., and Molhuysen, J. A. use of mecamylamine in the management of 40 cases (1953). Lancet, 1, 657. Byrnes, W. W., Barnes, L. E., Bowman, B. J., Dulin, W. E., Morley, of hypertension treated for from E. H., and Stafford, R. 0. (1956). Proc. Soc. exp. Biol. (N.Y.), 91, 67. four to eight months. g Cade, Sir S. (1954). Ann. roy. Col. Surg. Engl., 15. 71. HN-CH3 - (1955). British Surgical Progress, edited by E. R. Carling and J. P. Ross. p. 54. Butterworth. Calvert, R. J. (1954). Lancet, 1, 805. Method Cll Card. W. I.. Mitchell, W., Strong, J. A., Taylor, N. R. W., Tompsett, S. L., and Wilson, J. M. G. (1953). Ibid., 1, 663. Mecamylamine was administered by CH2 Fried, J.. and Sabo, E. F. (1954). J. Amer. chem. Soc., 76, 1455. subcutaneous or intravenous injection ' C H3 Galal, E. E. (1955). Brit. J. Pharmacol., 10, 305. Garrod, O., Nabarro, J. D. N., Pawan, G. L. S., and Walker, G. (1955). and by mouth. The blood pressure was \V/ Lancet. 2, 367. measured by the method recommended CH3 Groen, J.. Pelser, H.. Frenkel, M., Kamminga, C. E., and Willebrands, A. F. (1952). J. clin. Invest., 31, 87. by the Committee for the Standardiza- Willebrands, A. F., and Kamminga. C. E. (1951). New Engl. J. tion of Blood Pressure Readings (1939) in order to maintain Med., 244, 471. Hart, F. D. (1956). Ann. roy. Coll. Surg. Engl., 18, 314. uniformity with observations published previously on hexa- Hollander. V. P West, C. D., Whitmore, W. F., jun., Randall, H. T., and methonium, pentolinium (" ansolysen "), and chlorisond- Pearson, 0. H. (1952). Cancer, 5. 1019. Hudson. P. B., Mittelman, A., and Podberezec, M. (1954). New Engl. J. amine (" ecolid ") (Restall and Smirk, 1950; Smirk and Med., 251, 641. Alstad, 1951 ; Smirk, 1953; Smirk and Hamilton, 1956). Liddle. G. W., Richard, J. E., and Tomkins, G. M. (1956). Metabolism. 5. 384. Over a period of from four to eight months (average Louis, L. H., and Conn, J. W. (1956). J. Lab. clin. Med., 47, 20. 4.6) 40 patients (20 males, 20 females) have received a trial Luetscher, J. A., Jun., and Curtis, R. H. (1955). Fed. Proc., 14, 746. Lundy, J. S. (1955). Proc. Mayo Clin., 30, 446. of mecamylamine. Fundal gradings were or had been Maclean. J. P., Li, M. C., Lipsett, M. B., Ray, B., and Pearson, 0. H. grade IV (Keith, Wagener, and Barker, 1939) in five cases, (1955). J. clin. Invest.. 34, 951. Mitchell. W. (1956). Mfg Chem., 27, 168. grade III in nine, and grades II or I in the remainder, most Molhuysen, J. A., Gerbrandy. J., de Vries, L. A., de Jong, J. C., Lenstra, of whom had other severe manifestations such as congestive J. B., Turner, K. P., and Borst, J. G. G. (1950). Lancet, 2, 381. Pearson, 0. H., Mendelsolin, M. L., and West, C. D. (1953). J. clin. cardiac failure. Twenty-five patients had had treatment Endocr., 13. 841. with other ganglion-blocking agents previously. In the Sahatian-Edwards, A., and Holland, J. F. (1954). Cancer, 7, 1242. Simpson. a. A., and Tait, J. F. (1952). Endocrinology, 50, 150. remainder treatment was instituted with mecamylamine. Thorn. G. W., Renold A. E., Morse. W. I., Goldfien, A.. and Reddy, W. J. (1955). Ann. Intern. Med., 43, 979. Van T'Hoff, W. (1956). Quart. J. Med., 25, 571. Wyrnn. V. (1956). Metabolism, 5, 490. Drug Toleration Before comparing the potencies of mecamylamine and other ganglion-blocking drugs it is necessary to consider whether mecamylamine causes drug toleration. At an early USE OF MECAMYLAMINE IN THE stage it became evident that toleration either did not occur or was present to a comparatively minor degree following MANAGEMENT OF HYPERTENSION the repeated administration of mecamylamine. Indeed, if drug toleration does develop it must do so early in the BY course of administration of gradually increasing doses; for F. H. SMIRK, M.D., F.R.C.P. once a fully effective dose has been discovered there is no consistent change in the dose needed to reproduce the same Professor of Medicine, University of Otago Medical fall of blood pressure. In some instances the requisite School, Dunedin, New Zealand dose has increased somewhat after several weeks or months AND of treatment; in other instances, somewhat less frequently, the requisite dose has decreased. In Fig. 1 is shown the E. G. McQUEEN, M.B., M.R.C.P. Senior Medical Research Officer, Department of Medicine, University of Otago Medical School, Dunedin, New Zealand 220- 200 0 1 \ The discovery by Stone et al. (1956) that mecamylamine 180 (" inversine "), a secondary amine, has pharmacological wu160 ac properties in many ways similar to those of the D 0 quaternary ammonium compounds, which are tertiary 1I40 0. amines, is of interest not only in relationship to the 120 properties of the inJectionx substance itself but also because other 00 commenced 0oo Injectiont' injectiont secondary amines as yet untested may prove to be more 0 commenced inection la 100completed satisfactory as ganglion-blocking drugs than any of those 80 completed now available. 60 IV OD I.v(Z) On the basis of both animal (Ford et al., 1955; Stone 40 et al., 1956) and clinical studies (Ford et al., 1955; .- SYSTOLIC Freis, 1955; Freis and Wilson, 1955, 1956; Moyer et al., 20 - DIASTOLIC 1955) it is evident that mecamylamine causes blockade 0 . of both sympathetic and parasympathetic ganglia. It O 20 40 60 0 20 40 60 differs from the methonium compounds, however, in TIME IN MINUTES being readily and completely, or almost completely, FIG. 1.-Effect on blood pressure of identical doses of mecamyl- amine given intravenously. I.V. (1) shows effect of an initial dose absorbed from the alimentary canal. It has also been of 14 mg. of mecamylamine given slowly over the period shown, reported (Freis and Wilson, 1955, 1956) that, contrary in the posture indicated. I.V. (2) shows effect of the same dose to the invariable course of events with the methonium given in the same manner after two weeks of oral therapy, during which time the patient received 14 mg. of mecamylamume twrice compounds, the continued administration of mecamyl- daily. BhmrsH 423 FEB. 23, 1957 MECAMYLAMINE IN HYPERTENSION MEDICAL JOURNAL result of a test in which the initial effective dose was deter- TABLE I mined by intravenous titration. This was repeated after No. of Average Effective Daily Average Effective Daily two weeks of oral therapy, with the production of an Patients Dose Pentolinium (mg.) Dose Mecamylamine(mg.) identical response. 11 460 (oral) 32 (oral) Comparison of the Effective Doses of Mecamylamine, 10 39 (parenteral) 39 Pentolinium, Chlorisondamine, and Hexamethonium The effective dose of mecamylamine may be compared When hypertensive patients receive two or three doses either with the initial doses of quaternary ammonium com- daily there is usually less variation of the blood pressure pounds or with the doses of such compounds which may be throughout the day after mecamylamine than after chlor- required after repeated administration. In a series of 40 isondamine or pentolinium. Indeed, in some patients the patients treated with mecamylamine the least dose to pro- degree of control which can be obtained by mecamylamine duce any significant effect was 3 mg., and 5 mg. is a alone is approximately equal to that which can be obtained suitable initial oral dose. The effective single oral dose by chlorisondamine or pentolinium in combination with reducing the blood pressure in the standing posture to reserpine. Unfortunately, in some patients the develop- about 120 or 130 mm. systolic, with corresponding reduc- ment of side-effects makes it impracticable to administer a tion in the diastolic pressure, was 10 mg. or more in 80% sufficient dose of mecamylamine. Our impression of the of cases. relationship between control over the blood-pressure level The duration of action of mecamylamine is in excess of by mecamylamine as contrasted with pentolinium and chlor- 12 hours. Consequently, when two or more daily doses isondamine is that the best control over blood-pressure are given the effect obtained from one dose is influenced levels can be obtained with mecamylamine in those patients by the residue of the effect from the preceding dose. Hence who are fortunate enough to be able to tolerate it. Un- increase of the night dose will have some effect on the fortunately, mecamylamine in fully adequate doses is more level of the blood pressure next morning, and will influence often associated with prohibitive parasympathetic side- the size of the dose which should be administered then. effects than either pentolinium or chlorisondamine. The A fairly good control over blood-pressure levels can be responses to these drugs are highly individual, some patients obtained usually by two doses a day, the night dose being, for an equivalent degree of control over the blood pressure for preference, approximately 30% higher than the morn- being more comfortable on mecamylamine, and some on ing dose. We have found it an advantage to give a small pentolinium, and some on chlorisondamine.
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