Postgrad Med J (1992) 68, 857 - 866 i The Fellowship of Postgraduate Medicine, 1992 Postgrad Med J: first published as 10.1136/pgmj.68.805.857 on 1 November 1992. Downloaded from Review Arficle An update on nitrate tolerance: can it be avoided? S.R.J. Maxwell and M.J. Kendall Department ofMedicine, Queen Elizabeth Hospital, Edgbaston, Birmingham BJ5 2TH, UK Introduction Organic nitrates have been recognized by physic- The widespread use of nitrates in the munition ians as potent vasodilators and effective therapy for factories became a recognized source of industrial angina pectoris for over 100 years."2 Despite the exposure amongst those who manufactured nitro- advent of beta-blockers and calcium channel glycerin. Elbright5 reported that, although the antagonists in the 1960s the organic nitrates remain headaches associated with the production ofnitro- important antianginal agents and are well-estab- glycerin rapidly subsided during continued expo- lished as the drugs of choice in acute angina. sure, this 'immunity' was quickly lost outside the Recently interest in nitrate therapy has increased as working environment. Swartz6 went on to show a result of the widespread use of intravenous that the reappearance of symptoms ('Monday nitrates in coronary care, and in the management head') could be prevented by applying nitrates to Protected by copyright. of acute heart failure and because of this, their the skin or clothing over the weekend. Animal inclusion in the ISIS-4 study. studies have similarly confirmed the development The excellent response to acute nitrate adminis- of tolerance in all species tested, both in vivo and in tration led to a search for a method ofgiving nitrate isolated vascular preparations. Furthermore, treat- therapy prophylactically. Unfortunately initial ment with one nitrate compound can induce a state attempts were disappointing because, in many of 'cross-tolerance' to other nitrates.7 instances, chronic dosing with either oral or trans- The pharmacodynamic effects of organic nitra- cutaneous preparations was associated with the tes occur in all areas ofthe cardiovascular sytem. It development of tolerance and results in significant is therefore necessary, when discussing nitrate attentuation of the antianginal effect. This loss of tolerance, to specifiy which haemodynamic res- effect threatened to prevent the successful long- ponse is being assessed. For example, higher doses term use ofan apparently effective and safe form of ofnitrates are required to dilate the arterial circula- therapy for patients with angina. This review will tion than the venous capacitance vessels.8 The therefore focus on the evidence for tolerance, the former effect is responsible for the hypotensive http://pmj.bmj.com/ possible mechanisms which cause it and the thera- action and the headache associated with therapy, peutic attempts that have been made to circumvent while the latter effect is mainly responsible for it. venous pooling and preload reduction that under- lies much ofthe beneficial action in angina pectoris. Historical perspective It is now well-established that there is rapid tolerance to the hypotensive action of nitrates Even in the earliest reports of amyl nitrate use in making these drugs ineffective antihypertensive angina pectoris there was evidence that progres- agents.9 However, because functional studies ofthe on September 23, 2021 by guest. sively larger doses were required to achieve a venous circulation are technically difficult it is not satisfactory therapeutic response.' The first report easy to make direct assessments of tolerance to the of haemodynamic tolerance was made by Stewart venous actions of nitrates. Only indirect measure- who noted that persistent use ofnitroglycerin (NG) ments such as pulmonary capillary wedge pressures led to attenuation of the side effects of headache and exercise time to angina are available. In and flushing.3 This early clinical observation led to addition, since the antianginal effect is not only a the first major review ofthe subject in 1905 in which reflection of the venodilatation but may also Stewart advocated the use of the 'nitrate free' depend to some extent on arterial and coronary interval as a means of avoiding tolerance.4 vasodilatation,'° it is not surprising that no clear consensus has emerged from the studies addressing Correspondence: S.R.J. Maxwell the issue of nitrate tolerance in stable angina Accepted: 27 May 1992 pectoris. 858 S.R.J. MAXWELL & M.J. KENDALL Postgrad Med J: first published as 10.1136/pgmj.68.805.857 on 1 November 1992. Downloaded from Modern evidence mittent non-compliance and variability in the timing of the exercise tests in relation to nitrate Oral nitrates doses.9"7 From the 1960s onwards oral nitrate preparations Transdermal nitrates became widely available for the prophylaxis of angina pectoris. A number ofearly reports suggest- The development ofthe transdermal NG patch has ed that the aims of 24 hour antianginal cover (as made a great impact on the treatment of stable assessed by exercise tolerance testing) had been angina pectoris. This method ofnitrate delivery has realized by 3-4 times daily dosing regimens with proved convenient for patients and is known to isosorbide dinitrate (ISDN), 1"12 isosorbide-5- rapidly produce steady-state plasma levels lasting mononitrate (IS-5-MN)'3"4 and oral NG.'5"6 How- throughout the 24 hour dosing period.25 However, ever, these encouraging studies were followed by this method of continuous administration has increasingly widespread reports of partial or com- initiated a reappraisal of the role of nitrates in plete tolerance to the anti-ischaemic effects of both angina and reopened the tolerance debate. Many oral ISDN and IS-5-MN, its principal metabolite investigations of continuous patch therapy have in the body. demonstrated that rapid development of tolerance These studies employed non-sustained release occurs following an initial beneficial response.26 3' preparations of ISDN at a dose of 15-120 mg The improvement in exercise tolerance following 6 hourly and assessed antianginal efficacy using patch application is seemingly lost within 12 hours treadmill walking time (TWT) to angina. In of the first patch application.32 However, tolerance general, the first dose of ISDN reduced blood to the antianginal effects of the NG patch is by no pressure and prolonged TWT but sustained, regu- means a universal finding with many apparently lar treatment led to partial or complete attenuation well-conducted studies coming to the opposite of these responses. 17-19 However, the development conclusion.33 36 Protected by copyright. oftolerance was less marked ifthe last two doses of To address the problem of tolerance to the NG the day were omitted.'8 In another study, ISDN patch the Food and Drugs Administration multi- 100 mg given continuously as a transdermal oint- centre trial was set up in 1985 after the granting of ment20 prolonged TWT for 8 hours after the first conditional status to these preparations in the application but there were no effects demonstrable USA.37 The study was randomized, double blind at 24 hours. After a week of sustained therapy no and placebo-controlled in design and involved a benefit could be seen at any time during the 24 hour total of 562 patients with baseline TWT of 3-7 dosing period. This loss of response occurred after minutes (Bruce protocol). After initial patch appli- sustained treatment despite substantially higher cations of 15 mg/day, significant benefits were blood levels of ISDN and its metabolite IS-5-MN. noted at 4 hours but the effect had been lost at 24 This suggested that the tolerance phenomenon was hours indicating the rapid onset of tolerance. truly a pharmacodynamic rather than pharmaco- Although TWT improved by a mean of90 seconds kinetic effect. Furthermore, this 'continuous' at the end of the active therapy phase, this did not method of administration produced complete differ significantly from the control group who http://pmj.bmj.com/ tolerance compared with only partial attenuation benefited from a non-specific training effect from resulting from four times daily oral ingestion ofthe the regular exercise tests. The trial design allowed same drug.'7 This may reflect the difference for cohorts ofpatients to have weekly increments in between even and uneven plasma nitrate levels and dosage but even up to 150 mg/day no return of may partly explain some of the inconsistent results antianginal efficacy could be achieved. This clear found with respect to tolerance development in the demonstration ofrapid and complete tolerance was literature (see below). The studies of the anti- significant in that it involved much greater numbers anginal effects of IS-5-MN have led to similarly of patients than previous reports. on September 23, 2021 by guest. confusing results. While sustained antianginal There is inconsistency between the results of efficacy has been shown with 20 mg 8 hourly'3"14'2' studies of the efficacy of the NG patch that cannot others have shown tolerance development at 50 mg be explained by uneven plasma levels. A number of 8 hourly.2223 other factors may have been important (Table I). That the findings from the many studies of oral Marked variations exist in the number of patients, nitrate therapy are so divergent is interesting and the duration ofthe study, the daily dose ofNG and requires explanation. Since both the onset of the method of exercise testing.38'39 However, the tolerance following nitrate exposure and the loss of factor likely to have been of greatest importance tolerance following withdrawal are very rapid, even was the use of concomitant antianginal therapy. very short periods of low nitrate levels may allow Some studies recruited patients with stable angina some recovery of nitrate responsiveness.24 Thus who completed the study period using their usual explanations include irregularity of dosing, inter- antianginal medication as well as the nitrate patch, NITRATE TOLERANCE UPDATE 859 Postgrad Med J: first published as 10.1136/pgmj.68.805.857 on 1 November 1992.