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Postgrad Med J: first published as 10.1136/pgmj.46.532.94 on 1 February 1970. Downloaded from

Postgraduate Medical Journal (February 1970) 46, 94-96.

CURRENT SURVEY

Anti-anginal

ALBERTO GOLDBARG JAMES PAXINOS M.D. B.S. RUSSELL R. MILLER Pharm.D. University of Chicago Hospitals and Clinics, Chicago, Illinois, U.S.A.

Summary of action of . In normal patients This review of studies on anti-anginal agents and their nitroglycerin increases coronary flow by use in the anginal syndrome shows nitroglycerin to be dilating the but in patients with , unsurpassed in clinical effectiveness. It has a rapid coronary blood flow is not increased (Freidberg, onset of action. Its duration of action is relatively 1967). This has been used by some investigators short but the need for a more prolonged effect has not (Bing et al., 1964, in particular) as a test for coronary been demonstrated. Most anginal attacks subside arterial disease. upon resting and the requirement for relief is im- For the relief of the acute anginal attack, the mediate rather than prolonged. A long-acting anti- standard treatment is the immediate sublingual copyright. anginal agent would have some value if it could prevent administration of nitroglycerin; it has an onset of precipitation of an anginal episode but there is no action of 1-2 min. Other sublingual dosage form convincing evidence to indicate that these drugs have drugs have been introduced that promise relief this capability. In general, clinical experience with equal to nitroglycerin but with a longer duration of long-acting is relatively unsatisfactory. action. However, their onset of action is not as prompt as nitroglycerin. These drugs include ANGINA pectoris is a clinical entity characterized dinitrate (Isordil, Sorbitrate), erythrityl by a constricting pain in the chest, often radiating tetranitrate and

(Cardilate) phosphate http://pmj.bmj.com/ from the precordium to the left shoulder and down (Metamine). The duration of action of these drugs is the left arm. This pain, usually associated with effort, approximately four times that of nitroglycerin but results from failure of the vascular system to provide this should not be construed as a significant advan- an adequate blood supply to the myocardium under tage. The duration of most anginal attacks is a periods of increased demands. Angina can matter of minutes-not hours. Seldom, if ever, does be precipitated by various factors such as physical the pain attributed to the anginal episode last exertion, emotional stress, heavy meals or, in severe longer than 30 minutes (Burge, 1967). The duration cases, merely by assuming routine procedures, such of action of nitroglycerin is approximately 5-30 on September 30, 2021 by guest. Protected as shaving and . min (Russek, 1966) and is of sufficient length to Treatment of the anginal syndrome follows two provide adequate relief from an anginal eposide. basic courses: immediate relief and prevention. The requirements for treatment of an acute anginal Various drugs have been used to relieve acute attack, therefore, are immediate rather than pro- attacks and others have been used prophylactically longed action. Although the newer sublingual to prevent anginal episodes. The pharmacological nitrites1 have been shown effective for the immediate action of these anti-anginal drugs is thought by relief of an anginal attack they are more expensive many to be of the coronary arteries. and have not proven superior to nitroglycerin. In Other investigators believe that these drugs act by addition, none of the newer sublingual nitrites has lessening the work of the or by reducing the an onset of action as short as that of nitroglycerin. oxygen requirements of the myocardium. There is Treatment after onset of an anginal attack, evidence to suggest that the latter is the mechanism 1 Nitrites is a common designation that connotes all Reprint requests to: Dr R. R. Miller, Box 96, University of organic whose pharmacological properties are Chicago Hospitals and Clinics, Chicago, Illinois 60637, U.S.A. similar to those of the inorganic and organic nitrites. Postgrad Med J: first published as 10.1136/pgmj.46.532.94 on 1 February 1970. Downloaded from

Current survey 95 though effective, does have a drawback in that the The most widely used oral anti-anginal , patient experiences the attack before treatment is pentaerythritol tetranitrate, has been the subject of instituted. It has been found that nitroglycerin is numerous studies. They arrive at conflicting con- effective prophylactically by instructing the patient clusions on the drug's efficacy. Cole, Kay & Griffith to take one tablet sublingually 5-10 min prior to an (1957) and Dewar, Horler & Newell (1959) who used anticipated stress period. This procedure is, of the double-blind procedure in evaluating the drug course, limited to those patients who can anticipate did not consider pentaerythritol tetranitrate superior stress periods. When nitroglycerin is used regularly to placebo. Russek (1966), in a double-blind study, throughout the day to prevent attacks, it is usually found pentaerythritol tetranitrate produced a signi- ineffective (Modell, 1966). ficant increase in exercise tolerance when admini- Despite the satisfactory results obtained from stered before meals. On the other hand, Kalmanson these short-acting anti-anginal agents, there remains et al. (1955) in their double-blind study failed to a need for a long-acting drug which could prevent or demonstrate any beneficial effect of this drug on decrease the frequency of the anginal attack. To angina pectoris. fulfil this need, the long acting organic nitrites were Other types of drugs, not of the organic introduced. The oral1 administration of pentaery- family, have been investigated for their anti-anginal thritol tetranitrate (Peritrate, Mycardol, Pentral), properties but have also failed to give satisfactory (Isordil, Sorbitrate, Vascardin), results. In several small scale trials of erythrityl tetranitrate (Cardilate), trolnitrate (Met- (Persantin) it did not give significantly better results amine), hexanitrate (Nitranitol) and nitro- than placebo (Todd, 1967). glycerin (Nitroglyn, Nitrobid, Nitrospan) reportedly Some promise has recently been demonstrated for provided a prolonged effect. These products were propranolol (Inderal), a 3- receptor block- initially received enthusiastically but as they came ing agent, in the prevention of anginal episodes. into greater use they did not measure up to expecta- From their review of studies on propranolol Epstein tions and their value became questionable. & Braunwald (1966) concluded that in doses of 200- Lack of confidence in this class of drugs has been 400 mg propranolol significantly decreases the expressed by various investigators. Nickerson (1965) number of anginal attacks. The use of this drug in copyright. states: 'This lack of confidence is amply justified by the treatment of angina, however, requires careful the results of studies that appear to be adequately patient selection. Rabkin et al. (1966) stress that controlled and allow statistical evaluation of the treatment with propranolol is likely to be effective results. These have almost uniformly shown the long only in patients whose are functionally rela- term prophylactic value of an organic nitrate not to tively sound. Propranolol is hazardous in thepresence differ significantly from that of a placebo.' Nickerson of cardiac failure, overt or impending, and in heart cites Oram & Sowton (1961) and Sandler (1961) to block because of the blockade of the sympathetic support his argument. Although some studies show drive. When used for the how-

proper indications, http://pmj.bmj.com/ favourable results, it should be pointed out that ever, these investigators regard propranolol as a studies which do not use a complete double-blind safe and most effective agent for the prevention of comparison with an appropriate placebo often anginal attacks. can be misleading. Before a definite assessment of the value of P- The importance of adequately controlled double- adrenergic receptor blocking agents in angina blind studies has been stressed by Charlier (1961) pectoris can be established, further investigation of who reviewed studies on trinitrate the efficacy of these agents in angina is necessary.

Metamine). 'As usual, the first studies, conducted) is an important factor in on September 30, 2021 by guest. Protected with neither placebo nor double-blind system, were the success or failure of the anti-anginal drugs. Sub- particularly favorable . . . The clinicians whose lingual administration to relieve the acute anginal observations were satisfactorily controlled by use of episode gives far better results than dosage forms a placebo and the double-blind technique found that are to be swallowed. Sublingual nitroglycerin has that the beneficial subjective effects produced by proven to be the most effective drug in treatment of Metamine were moderate . . . and for Cole et al. the acute anginal syndrome, but use of its oral form they were not superior to those given by the placebo (Nitroglyn, Nitrospan, Nitrobid) is completely with- (1961).' From the results of well-controlled clinical out merit. Modell (1966) states: 'Nitroglycerin is studies of Metamine, the majority of cardiologists very rapidly destroyed in the liver, therefore, any are ofthe opinion that the slight effects it provides are nitroglycerin that gets into the stomach or intestines not sufficient to justify its use. and is absorbed into the portal circulation is in- effective'. Studies have also shown the oral admini- 1 Oral administration refers to dosage forms which are intended to be swallowed and does not include those in- stration of other anti-anginal drugs such as ery- tended for sublingual administration. thrityl tetranitrate (Cardilate), Postgrad Med J: first published as 10.1136/pgmj.46.532.94 on 1 February 1970. Downloaded from

96 Current survey (Nitranitol), triethanolamine trinitrate (Metamine) References and isosorbide dinitrate (Isordil, Sorbitrate) to be BING, R.J., BENNISH, A., BLUEMCHEN, G., COHEN, A., inferior to their corresponding sublingual forms in GALLAGHER, J.P. & ZALESKI, E.J. (1964) The determina- relief of anginal pain (Riseman, Altman & Koretsky, tion of coronary flow equivalent with coincidence counting the technic. Circulation, 29, 833. 1958; Russek, 1966). It would suffice to say BURKE, G. (1967) The treatment ofangina pectoris. Geriatrics, sustained or controlled release form of these drugs is 22, 168. even less reliable than their oral counterparts. CHARLIER, R. (1961) Coronary vasodilators. International Tolerance develops readily to the nitrites. This Series of Monographs of Pure and Applied Biology, Modern property has been observed among factory workers Trends in Physiological Sciences Division, Vol. 10. Perga- exposed to nitrites. They frequently suffer from mon Press, New York. severe and weakness COLE, S.L., KAY, H. & GRIFFITH, G.C. (1957) Assay of headaches, dizziness, postural anti-anginal agents. 1. A curve analysis with multiple during the first few days of employment. Tolerance control periods. Circulation, 15, 405. then develops and these symptoms disappear. DEWAR, H.A., HORLER, A.R. & NEWELL, D.J. (1959) A Tolerance can be minimized by using the lowest of penta-, a khellin effective dose and intermittent administration to derivative (Recordel), and iproniazid in angina of effort. prevent continuous exposure to the drug. However, British Heart Journal, 21, 315. of the of a EPSTEIN, S.E. & BRAUNWALD, E. (1966) Beta adrenergic in the case long-acting nitrites, something receptor blocking drugs. Mechanisms of action and therapeutic paradox is presented because of toler- clinical applications. New England Journal of Medicine, ance. The purpose of the prophylactic administration 275, 1106. of the long-acting nitrites is to provide continuous FRIEDBERG, C.K. (1967) Angina pectoris. Geriatrics, 22, 144. protection from an anginal attack. If their effective- KALMANSON, G.M., DRENICK, E.J., BINDER, M.J. & ROSOVE, ness diminishes with constant use then their true L. (1955) Pentaeyrthritol tetranitrate in the treatment of angina pectoris; clinical evaluation. Archives of Internal value when administered in this manner would 819. to be limited. Medicine, 95, appear very MODELL, W. (Ed.) (1966) The choice of drugs for diseases of Untoward side-effects to the therapeutic use of the heart. Drugs of Choice, 1966-67, Pp. 365-415. Mosby, nitrites are almost all secondary to their action on St Louis. the cardio-vascular system. Headache is a common NICKERSON, M. (1965) The nitrites. The Pharmacological copyright. side-effect which usually disappears upon adjust- Basis of Therapeutics. (Ed. by S. Goodman and A. Gilman). ment of the dose, continued use and development 3rd edn, pp. 736-753. Macmillan, New York. of tolerance. A effect be associated ORAM, S. & SOWTON, E. (1961) Failure of hypotensive may and pentaerythritol tetranitrate to prevent attacks of with the use of nitroglycerin and certain other anti- angina pectoris. British Medical Journal, 2, 1745. anginal agents. This property can be of serious con- RABKIN, R., STABLES, D.P., LEVIN, N.W. and MOSES, M. sequence with patients who have suffered a recent (1966) The prophylactic value of propranolol in angina myocardial infarct. The use of nitroglycerin could pectoris. American Journal of Cardiology, 18, 370. the state induced the RISEMAN, J.E.F., ALTMAN, G.E. & KORETSKY, S. (1958) aggravate hypotensive by http://pmj.bmj.com/ infarct and . Other side- Nitroglycerin and other nitrites in the treatment of precipitate possible angina pectoris. Comparison of six preparations and four effects are dizziness and increased intraocular routes of administration. Circulation, 17, 22. pressure. The oral anti-anginal agents may, in RUSSEK, H.I. (1966) The therapeutic role of coronary addition, cause and gastro-intestinal dis- vasodilators; glyceryl trinitrate, isosorbide dinitrate, and turbances. pentaerythritol tetranitrate. American Journal of Medical Science, 252, 9. SANDLER, G. (1961) Clinical evaluation of propatylnitrate Acknowledgments in angina pectoris. British Medical Journal, 2, 1741. Dr Miller's contribution to this paper was undertaken TODD, R.G. (Ed.) (1967) Extra pharmacopaeia Martindale, on September 30, 2021 by guest. Protected while he was a recipient of a training grant from the Nation- 25th edn, np. 630 and 1967. The Pharmaceutical Press, al Library of Medicine, United States Public Health Service. London.