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ANTIARRHYTHMIC DRUGS AFTER MYOCARDIAL INFARCTION
707 of virus in cell culture. So far, all attempts to do this have failed. The reason may be lack of susceptible cells in culture. The site of replication of the virus in vivo is still uncertain, although the liver remains the most obvious and most likely. Thus, Nowoslawski et al.5 have recently described the localisation of Au/SH antigen and particles of 20 nm. (mµ) in hepatic parenchymal cells. Zuckerman et al. 6reported the culture of functional hepatic cells from biopsy samples and these cells may well support virus growth. Failure to infect cells in the past may be due to the presence of antibody as well as virus in icterogenic sera. Another factor preventing virus growth may be the presence of excess virus-coat protein which could block cellular receptors for intact virus. The detection of virus in cells, when no cytopathic change occurred, has until recently posed a serious problem. It is solved as far as serum hepatitis is concerned by an electron-microscopy search for particles with the features of Au/SH antigen or the virus particles described by Dr. Dane and his associates. Moreover, the appearance of the antigen in culture could be detected serologically. The pace of advance in the study of hepatitis remains fast and will, it is to be hoped, be sustained, because of the seriousness of the disease in renaldialysis units, in those given blood-products in treatment, and in drug addicts. Clearly the Au/SH antigen is only part of the story of hepatitis; and Au/SH or serum hepatitis seems distinct from infectious hepatitis. Moreover, the chronic active hepatitis associated with antibodies to smooth muscle and thought to be an autoallergic disease is not associated with Au/SH
antigen.7
P-receptor blockade, however, and an antiarrhythmic compound is needed which may safely be given routinely as a prophylactic measure after an acute infarction. Such a compound must fulfil certain criteria 13. It must reduce the frequency of potentially serious arrhythmias in doses which do not impair cardiovascular function. In particular, it should not appreciably depress myocardial contractility, and other adverse effects must be rare. Finally, a dose schedule should be readily devisable which rapidly achieves and maintains
effective blood-level. Lignocaine is of value in both the treatment and the prophylaxis of ventricular arrhythmias after cardiac infarction,14 optimum blood-levels being between 1-5 and 2-5 jjLg. per m1.15 Although it used to be often given as a single intravenous injection, the effect was shortlived and it required continuous infusion. Scott et al 15 found that intramuscular injections of 200 mg. produced acceptable blood-levels which were maintained for more than two hours. Eddy and Singh 16 gave intravenous phenytoin to 21 patients with post-infarction arrhythmias, and sinus rhythm returned in 6 out of 9 patients with supraventricular arrhythmias and in 10 out of 12 with ventricular arrhythmias. Serious side-effects were rare, but drowsiness was common. Blood-pressure did not fall significantly if the phenytoin was injected slowly in small repeated doses. Its effects on a variety of other types of arrhythmias have been related to its plasmalevel. 17 About 70%of the arrhythmias which responded to phenytoin did so at plasma-levels of between 10 and 18 g. per ml., and in most of these cases a critically effective plasma-level could be demonstrated, which had to be exceeded if the arrhythmia was to be an
suppressed. ANTIARRHYTHMIC DRUGS AFTER
MYOCARDIAL INFARCTION
CARDIAC arrhythmias are a common cause of death within a few hours of myocardial infarction. In 200 patients who had had acute transmural myocardial infarction, Stock et al. found an overall incidence of arrhythmia of 76%excluding sinus tachycardia and of 82-5% including sinus tachycardia. Several different factors may contribute to such arrhythmias, and the roles of local hypoxia, plasma-free-fatty-acids, and catecholamine levels have been discussed.9,10 Although the value of propranolol in the prophylaxis of arrhythmias after acute myocardial infarction is still in dispute,l1 practolol has been shown to be particularly effective in slowing rapid supraventricular arrhythmias in this situation.12 Since this &bgr;-adrenergic-receptor-blocking drug is relatively free of the direct membranedepressant actions of propranolol, it seems likely that P-receptor stimulation is responsible for the arrhythmias in at least some cases. Not all arrhythmias respond to 5. 6.
7. 8. 9. 10. 11. 12.
Nowoslawski, A., Brzosko, W. J., Madalinski, K., Krawczynski, K. Lancet, March 7, 1970, p. 494. Zuckerman, A. J., Tsiquage, K. N., Fulton, F. Br. J. exp. Path. 1967, 48, 20. Wright, R. Lancet, March 7, 1970, p. 521. Stock, E., Goble, A., Sloman, G. Br. med. J. 1967, ii, 719. Lancet, 1969, ii, 1051. Gupta, D. K., Young, R., Jewitt, D. E., Hartog, M., Opie, L. H. ibid. p. 1209. ibid. 1966, ii, 950. Jewitt, D. E., Mercer, C. J., Shillingford, J. P. ibid. 1969, ii, 227.
Procainamide is another compound which has been shown to reduce the incidence of major arrhythmias after myocardial infactions. Koch-Weser et al. 13 studied it in a double-blind trial in 70 patients monitored electrocardiographically after infarction, uncomplicated by shock, heart-block, or severe heart-failure. The drug or placebo was given orally, unless vomiting made intramuscular administration necessary. Procainamide provided highly significant protection against all types of ventricular arrhythmia, the effective plasma concentration being 4-6 jj.g. per ml. Lower plasma-levels gave incomplete protection, and concentrations above 7 ug. per ml. produced hypotension and electrocardiographic changes, suggesting various types of heart-block. In a condition like myocardial infarction, which has a high mortality-rate and in which cardiac function may be precarious, it is particularly important for effective and safe plasma drug levels to be defined and the oral and parenteral doses required to produce these levels determined. Such doses should probably be given on a weight-for-weight basis to increase the accuracy with which a desired blood-level can be achieved. 13. 14. 15. 16. 17.
Koch-Weser, J., Klein, S. W., Foo-Canto, L. L., Kastor, J. A., De Sanctis, R. W. New Engl. J. Med. 1969, 281, 1254. Lawrie, D. M., Higgins, M. R., Goodman, M. J., Oliver, M. F., Julian, D. G., Donald, K. W. Lancet, 1968, ii, 523. Scott, D. B., Jepson, P. J., Vellani, C. W., Julian, D. G. ibid. p. 1209. Eddy, J. D., Singh, S. P. Br. med. J. 1969, iv, 270. Bigger, T. J., Schmidt, D. H., Kutt, H. Circulation, 1968, 38, 363.
antigen.7
P-receptor blockade, however, and an antiarrhythmic compound is needed which may safely be given routinely as a prophylactic measure after an acute infarction. Such a compound must fulfil certain criteria 13. It must reduce the frequency of potentially serious arrhythmias in doses which do not impair cardiovascular function. In particular, it should not appreciably depress myocardial contractility, and other adverse effects must be rare. Finally, a dose schedule should be readily devisable which rapidly achieves and maintains
effective blood-level. Lignocaine is of value in both the treatment and the prophylaxis of ventricular arrhythmias after cardiac infarction,14 optimum blood-levels being between 1-5 and 2-5 jjLg. per m1.15 Although it used to be often given as a single intravenous injection, the effect was shortlived and it required continuous infusion. Scott et al 15 found that intramuscular injections of 200 mg. produced acceptable blood-levels which were maintained for more than two hours. Eddy and Singh 16 gave intravenous phenytoin to 21 patients with post-infarction arrhythmias, and sinus rhythm returned in 6 out of 9 patients with supraventricular arrhythmias and in 10 out of 12 with ventricular arrhythmias. Serious side-effects were rare, but drowsiness was common. Blood-pressure did not fall significantly if the phenytoin was injected slowly in small repeated doses. Its effects on a variety of other types of arrhythmias have been related to its plasmalevel. 17 About 70%of the arrhythmias which responded to phenytoin did so at plasma-levels of between 10 and 18 g. per ml., and in most of these cases a critically effective plasma-level could be demonstrated, which had to be exceeded if the arrhythmia was to be an
suppressed. ANTIARRHYTHMIC DRUGS AFTER
MYOCARDIAL INFARCTION
CARDIAC arrhythmias are a common cause of death within a few hours of myocardial infarction. In 200 patients who had had acute transmural myocardial infarction, Stock et al. found an overall incidence of arrhythmia of 76%excluding sinus tachycardia and of 82-5% including sinus tachycardia. Several different factors may contribute to such arrhythmias, and the roles of local hypoxia, plasma-free-fatty-acids, and catecholamine levels have been discussed.9,10 Although the value of propranolol in the prophylaxis of arrhythmias after acute myocardial infarction is still in dispute,l1 practolol has been shown to be particularly effective in slowing rapid supraventricular arrhythmias in this situation.12 Since this &bgr;-adrenergic-receptor-blocking drug is relatively free of the direct membranedepressant actions of propranolol, it seems likely that P-receptor stimulation is responsible for the arrhythmias in at least some cases. Not all arrhythmias respond to 5. 6.
7. 8. 9. 10. 11. 12.
Nowoslawski, A., Brzosko, W. J., Madalinski, K., Krawczynski, K. Lancet, March 7, 1970, p. 494. Zuckerman, A. J., Tsiquage, K. N., Fulton, F. Br. J. exp. Path. 1967, 48, 20. Wright, R. Lancet, March 7, 1970, p. 521. Stock, E., Goble, A., Sloman, G. Br. med. J. 1967, ii, 719. Lancet, 1969, ii, 1051. Gupta, D. K., Young, R., Jewitt, D. E., Hartog, M., Opie, L. H. ibid. p. 1209. ibid. 1966, ii, 950. Jewitt, D. E., Mercer, C. J., Shillingford, J. P. ibid. 1969, ii, 227.
Procainamide is another compound which has been shown to reduce the incidence of major arrhythmias after myocardial infactions. Koch-Weser et al. 13 studied it in a double-blind trial in 70 patients monitored electrocardiographically after infarction, uncomplicated by shock, heart-block, or severe heart-failure. The drug or placebo was given orally, unless vomiting made intramuscular administration necessary. Procainamide provided highly significant protection against all types of ventricular arrhythmia, the effective plasma concentration being 4-6 jj.g. per ml. Lower plasma-levels gave incomplete protection, and concentrations above 7 ug. per ml. produced hypotension and electrocardiographic changes, suggesting various types of heart-block. In a condition like myocardial infarction, which has a high mortality-rate and in which cardiac function may be precarious, it is particularly important for effective and safe plasma drug levels to be defined and the oral and parenteral doses required to produce these levels determined. Such doses should probably be given on a weight-for-weight basis to increase the accuracy with which a desired blood-level can be achieved. 13. 14. 15. 16. 17.
Koch-Weser, J., Klein, S. W., Foo-Canto, L. L., Kastor, J. A., De Sanctis, R. W. New Engl. J. Med. 1969, 281, 1254. Lawrie, D. M., Higgins, M. R., Goodman, M. J., Oliver, M. F., Julian, D. G., Donald, K. W. Lancet, 1968, ii, 523. Scott, D. B., Jepson, P. J., Vellani, C. W., Julian, D. G. ibid. p. 1209. Eddy, J. D., Singh, S. P. Br. med. J. 1969, iv, 270. Bigger, T. J., Schmidt, D. H., Kutt, H. Circulation, 1968, 38, 363.