Antianginal Drug

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Antianginal Drug Br. J. clin. Pharmac. (1981), 11 LETTERS TO THE EDITORS 307 References D'ARGENIO, D.Z. & SCHUMITZKY, A. (1979a). A program LOPATA, M. & LOURENCO, R.V. (1980). Evaluation of package for simulation and parameter estimation in respiratory control. Clinics in Chest Medicine, 1, 33-45. pharmacokinetic systems. Computer Prog. Biomed., 9, ROBSON, R.H. & PRESCOTT, L.F. (1977). A rapid gas-liquid 115-134. chromatographic estimation of doxapram in plasma. J. D'ARGENIO, D.Z. & SCHUMITZKY, A. (1979b). A users Chromat. Biomed. appl., 143,527-529. guide to the ADAPTprograms. Laboratory for Applied ROBSON, R.H. & PRESCOTT, L.F. (1978). A pharmacoki- Pharmacokinetics, University of Southern California netic study of doxapram in patients and normal volun- School of Medicine, Los Angeles, California 90033. teers. Br. J. clin. Pharmac., 7, 81-87. POSSIBLE MECHANISMS OF ACTION OF OXYFEDRINE AS AN ANTIANGINAL DRUG In a recent paper published in the Journal, Whitting- We would like to draw attention to another property ton & Raftery (1980) compared the efficacy of the of oxyfedrine which would certainly be valuable in aminoketone oxyfedrine with that of isosorbide dini- the therapy of angina and might indeed be a major trate in patients with angina pectoris. They concluded explanation for the Northwich Park results. This is a that 'oxyfedrine is a safe and well tolerated drug peripheral venodilator action, rather like that of which improves the electrocardiographic responses nitroglycerin. In dog isolated saphenous veins oxy- to exercise . and is to be preferred to isosorbide fedrine is just as active as nitroglycerin (the veno- dinitrate'. In the introduction to their paper they dilator par excellence) at relaxing noradrenaline-in- ascribe the beneficial effects of this partial agonist at duced contractions of the circularly arranged smooth ,31-adrenoceptors to an improved myocardial per- muscle (Figure 1). We have previously demonstrated- formance and to an increased coronary blood flow (Mackenzie & Parratt, 1977) that nitroglycerin is 'without a disproportionate increase in oxygen re- highly selective at relaxing isolated venous smooth quirements'. We would agree that, at least in experi- muscle. We would therefore suggest that the reduc- mental animals, these are precisely the acute effects tion in LVEDP, observed when oxyfedrine is admin- one obtains with this compound. There are increases istered to experimental animals with myocardial in myocardial contractility (through stimulation of ischaemia, is due to a combination of myocardial ,8-adrenoceptors) sometimes, for example in acute stimulation and a peripheral venodilator action- myocardial ischaemia, without a significant increase both incidentally properties possessed by nitro- in oxygen consumption (Parratt & Ledingham, 1972). glycerin (Parratt, 1979). This would adequately ex- The explanation for this result is that the decrease in plain the reported beneficial effects observed by myocardial oxygen requirements resulting from the Whittington & Raftery (1980). However, it would we reduced left ventricular end-diastolic pressure think be a major contribution to the clinical pharma- (LVEDP), volume and heart size (and hence myo- cology of this fascinating compound if studies were cardial wall tension) is more pronounced than the performed in which left ventricular end-diastolic increase in oxygen requirements resulting from the pressure and volume were measured, preferably to- enhanced contractility. There is also a marked in- gether with myocardial lactate extraction/production crease in myocardial blood flow in acutely ischaemic data, during angina induced by electrical pacing or by regions of the left ventricular wall; indeed, in a series exercise (e.g. Parker, 1972). Another intriguing ques- of studies in anaesthetized greyhounds subjected to tion which requires answering is whether, following acute coronary artery ligation, oxyfedrine proved to prolonged administration of oxyfedrine to anginal be the most active substance examined at increasing patients, it loses its agonist properties whilst retaining blood flow through the ischaemic region (Marshall & its antagonist properties at f3-adrenoceptor sites. In Parratt, 1974). Since, however, similar increases were a relevant animal study, although admittedly with not observed with other myocardial stimulants much larger doses than those used by the Northwich (glucagon, isoprenaline) there must clearly be some Park group, one of us (Parratt, 1974) found that other contributory mechanism (apart, that is, from isoprenaline dose-responses curves were shifted to enhanced myocardial contractility) for the reduction the right following oral treatment with oxyfedrine for in left ventricular filling pressure observed experi- 3-4 weeks (evidence of f8-adrenoceptor blockade) yet mentally. there was no reduction in resting cardiac output, left 0 LETTERS TO THE EDITORS Br. J. clin. Pharmac. (1981), 11 100- ventricular dP/dt max. or systolic ejection time and no alteration in the haemodynamic responses to oxyfedrine itself. This would suggest that prolonged 80- oral treatment with oxyfedrine does result in some degree of f-adrenoceptor blockade. The myocardial stimulation which results when the drug is admin- istered is however retained, as presumably is the 0 60- peripheral venodilator action. It would be of interest x to determine whether these are indeed the effects of co prolonged oral oxyfedrine administration to patients * 40- with angina. J.R. PARRATI & J.E. MACKENZIE Department ofPhysiology and Pharmacology, Royal 20- College, University ofStrathclyde, Glasgow G0 IXW Received September 19, 1980 0 0.01 0.1 1 10 100 Drug concentration (ltM) Figure 1 Comparison of the relaxant effects of oxyfedrine (0) and nitroglycerin (-) in dog isolated sphenous veins References MACKENZIE, J.E. & PARRATT, J.R. (1977). Comparative pranolol. Br. J. Pharmac., 51, 513. effects of glyceryl trinitrate on venous and arterial PARRA1T, J.R. (1979). Nitroglycerin-the first hundred smooth muscle in vitro; relevance to antianginal activity. years: new facts about an old drug. J. Pharm. Pharmac., Br. J. Pharmac., 60, 155-160. 31,801-809. MARSHALL, R.J. & PARRATT, J.R. (1974). Drug-induced PARRAlT, J.R. & LEDINGHAM, I. McA. (1972). Experi- changes in blood flow in the acutely ischaemic canine mental infarction in the dog: changes in blood flow and myocardium; relationship to subendocardial driving in oxygen extraction induced by oxyfedrine in areas of pressure. Clin. exp. Pharmac. Physiol., 1, 9-112. developing myocardial ischaemia. In Action ofoxyfed- PARKER, J.Q. (1972). Hemodynamic and metabolic rine, eds Gerlach, E. & Moser, K., pp. 201-207. Schat- changes during myocerdial ischaemia. Arch. int. Med., tauer Verlag: Stuttgart. 129,790-798. WHI1TINGTON, J. & RAFTERY, E.B. (1980). A controlled PARRATT, J.R. (1974). The haemodynamic effects of pro- comparison of oxyfedrine, isosorbide dinitrate and longed oral administration of oxyfedrine, a partial placebo in the treatment of patients suffering attacks of agonist at ,-adrenoceptors: comparison with pro- angina pectoris. Br. J. clin. Pharmac., 10, 211-216. THE EFFECT OF BETAHISTINE METHANESULPHONATE UPON CEREBRAL BLOOD FLOW Betahistine is an analogue of histamine and is used to Matthew, Hartmann & Rivera (1974) report that in treat episodes of dizziness in patients with Meniere's ten patients with a diagnosis of cerebrovascular disease. The first studies involving the use of beta- ischaemic disease based on the history ofabrupt onset histine in man were carried out in 1943 by Horton of focal neurological deficits and/or episodic but pro- who was investigating histamine headache (Horton & gressive and severe neurological deficit due to diffuse von Leden, 1962). cerebral arteriosclerosis, mean regional cerebral Our interest in this drug was aroused when we blood flow increased by 20% + 4.75% (mean + s.d.). found isolated reports that betahistine hydrochloride In healthy male volunteers cerebral blood flow, as increases cerebral blood flow. For example, Meyer, measured by a rheoencephalographic method, was.
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