Chronic stable angina treatment nitrates

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.; Aysha Anwar, M.B.B.S[3]

## Overview

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In patients with chronic stable angina, nitrates remain the mainstay of therapy. Organic nitrates are therapeutic precursors of endothelium-derived relaxing factor that produce their beneficial effects both, by decreasing myocardial oxygen requirements and by improving myocardial perfusion. The most commonly used nitrates are nitroglycerin, isosorbide dinitrate and isosorbide mononitrate. Short acting nitrates, such as sublingual nitroglycerin, are best suited to treat acute episodes of angina and are effective when used for situational prophylaxis. Long-acting nitrates help to reduce the frequency and severity of angina and may increase exercise tolerance in patients with stable angina.[1][2][3] Nitrates at therapeutic doses do not affect coronary vascular resistance, thereby reducing the risk of myocardial ischemia due to coronary steal phenomena that is consistent with the use of dipyridamole and other short acting dihydropyridines.

## Nitrates

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### Mechanisms of Benefit

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* Nitrates within the vessel wall are metabolized to nitric oxide (NO) which is an endothelium-derived relaxing factor.[4] This stimulates guanylate cyclase to produce cyclic guanosine mono phosphate (cGMP), which is responsible for vasodilation.

* Nitrates induce coronary arterial vasodilation that helps to reduce the degree of coronary artery stenosis produced by an eccentric atherosclerotic plaque.[5]

* Nitrates induce vasodilation even in the collateral vessels, thereby enhancing coronary collateral flow to the ischemic myocardium and subsequently relieving coronary vasospasm.[6]

* Nitrates decrease myocardial oxygen demand by decreasing intra-cardiac volumes consequent to reduced venous return resulting from peripheral venous dilatation (preload reduction) and by reducing arterial pressure resulting from arterial dilation (afterload reduction). These beneficial effects are partly offset by a reflex increase in the heart rate due to the reduced cardiac output, which could be prevented with concomitant beta-blocker use.

* In addition to the above beneficial effects, nitric oxide also inhibits platelet adhesion and aggregation.

### Indications

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* Nitrates are effective in the management of various clinical subsets of stable angina pectoris.

* In patients with exertional angina, nitrates improve exercise tolerance, the time to the onset of angina and ST segment depression during the treadmill exercise test.

* In patients with vasospastic angina, nitrates relax the smooth muscles of epicardial vessels, thereby relieving coronary artery spasm.

* In patients with mixed angina and postprandial angina, nitrates reduce myocardial oxygen demand and promote coronary vasodilation.

* Prophylaxis:

* For situational prophylaxis, short-acting nitrates such as sublingual nitroglycerin may be used several minutes before planned exertion. However, its short duration of action (20 to 30 min) makes it less practical for long-term prevention of ischemia in patients with stable angina.

* For angina prophylaxis, long acting nitrate preparations such as isosorbide dinitrate, mono nitrates, transdermal nitroglycerin patches, and nitroglycerin paste are preferable.

* Nitrates reduce intra-cardiac pressures hence may be effective in patients with left ventricular dysfunction or mitral insufficiency.

* In the presence of increased intraocular pressure, nitrates can be used safely as they do not worsen glaucoma, which was once thought to be a contraindication to their use.

### Contraindications

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* Nitrates are relatively contraindicated in hypertrophic obstructive cardiomyopathy, because in these patients, nitrates can increase LV outflow tract obstruction and severity of mitral regurgitation and can precipitate presyncope or syncope. For the same reason, nitrates should be avoided in patients with aortic valve stenosis.

* A 72-hour interval period is required between the administration of nitrates and sildenafil in order to prevent profound hypotension.[7][8]

* Cardiac tamponade

### Dosage

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* The onset of action of sublingual nitroglycerin tablets or nitroglycerin spray is within 1 to 3 minutes, making these the preferred agents for the acute relief of effort or rest angina.

* The patient needs to be instructed that active nitroglycerin will cause some tingling under the tongue, and that if this does not occur, the efficacy of their nitroglycerine tablets could be expired.

* Oral nitroglycerin is given every 8-12 hours.

* Isosorbide dinitrate (20-80 mg) should not be used more frequently than two times a day.[9]
* Sustained release-isosorbide mononitrate is effective if given twice daily.[10]

* Transdermal nitroglycerin schedule of 12 hours-on and 12 hours-off is most effective in improving exercise performance.[11]

### Adverse Effects

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* Throbbing headache, which tends to decrease with continued use.
* Flushing
* Palpitations

* Paradoxical angina characterized by angina non-responsive to nitroglycerin, postural hypotension and reflex tachycardia may be a result of nitrate overdose.

* The major clinical problem for long term nitrate therapy is nitrate tolerance.

### Nitrate Tolerance

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* Tolerance develops not only to antianginal and hemodynamic effects but also to platelet anti-aggregatory effects.

* The mechanism for development of nitrate tolerance remains unclear. The four important hypothese are:

* Sulfhydryl-Depletion Hypothesis:[12] Decreased availability of sulfhydryl (SH) radicals consequent to continuous long-term nitrate therapy is associated with loss of nitrate efficacy.
* Neurohormonal Hypothesis:[13] An increase in vasoconstrictor response as a consequence of nitrate-induced vasodilation may be responsible for the reduced efficacy of long-term nitrates. Another study postulated the increased production of superoxide anion and vasopressor endothelin being responsible for the loss of nitrate response.[14][15]
* Plasma-Volume-Expansion Hypothesis: Sustained nitrate therapy induces plasma volume expansion[16] that subsequently reverses the effect of nitrates on ventricular preload and contributes to nitrate tolerance. However, studies suggest concomitant use of hydrochlorothiazide or ACEIs did not prevent nitrate induced plasma volume expansion.[17][18]
* Free-Radical Hypothesis: Generation of free radicals by the endothelium with enhanced degradation of nitric oxide has been proposed. The mechanism of nitrate-induced increase in free radical production is unclear, however studies suggest angiotensin II may be an important contributing factor by increasing endothelin production as a response to nitrate therapy.[19][15]

* Prevention of nitrate tolerance:

* The most reliable method for the prevention of nitrate tolerance is to ensure a nitrate free period of approximately 10 hours, usually including sleeping hours, in patients with effort angina.[20]
* Smaller and less frequent dosing.
* Long-term formulations could be avoided unless a prolonged nitrate-free interval is provided.
* Concurrent administration of an SH donor such as SH-containing ACE inhibitors, acetyl or methyl cysteine, and diuretics has been suggested to reduce the development of nitrate tolerance.
* Hydralazine inhibits membrane-bound oxidases thereby reducing free radical production.[21] Hence, concomitant administration of hydralazine has shown to reduce nitrate tolerance.[22]

## 2012 ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina (DO NOT EDIT)[23]

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### Nitrates (DO NOT EDIT)[23]

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Class I

"1. Calcium channel blockers or long-acting nitrates should be prescribed for relief of symptoms when beta blockers are contraindicated or cause unacceptable side effects in patients with SIHD(Level of Evidence: B)"
"2. Calcium channel blockers or long-acting nitrates, in combination with beta blockers, should be prescribed for relief of symptoms when initial treatment with beta blockers is unsuccessful in patients with SIHD. (Level of Evidence: B)"
"3. Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD.(Level of Evidence: B)"

## ESC Guidelines- Pharmacological Therapy to Improve Symptoms and/or Reduce Ischaemia in Patients with Stable Angina (DO NOT EDIT)[24]

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### Nitrates (DO NOT EDIT)[24]

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Class I

"1. Provide short-acting nitroglycerin for acute symptom relief and situational prophylaxis, with appropriate instructions on how to use the treatment. (Level of Evidence: B)"
"2. In case of beta-blocker intolerance or poor efﬁcacy attempt monotherapy with a CCB (Level of Evidence: A), long-acting nitrate (Level of Evidence: C), or nicorandil (Level of Evidence: C)."
Class IIa

"1. If CCB monotherapy or combination therapy (CCB with beta-blocker) is unsuccessful, substitute the CCB with a long-acting nitrate or nicorandil. Be careful to avoid nitrate tolerance. (Level of Evidence: C)"

## References

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1. ↑ Thadani U, Lipicky RJ (1994) Short and long-acting oral nitrates for stable angina pectoris. Cardiovasc Drugs Ther 8 (4):611-23. PMID: 7848896
2. ↑ Parker JD, Parker JO (1998) Nitrate therapy for stable angina pectoris. N Engl J Med 338 (8):520-31. DOI:10.1056/NEJM199802193380807 PMID: 9468470
3. ↑ Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999)guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina).Circulation 99 (21):2829-48. PMID: 10351980
4. ↑ Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329 (27):2002-12. DOI:10.1056/NEJM199312303292706 PMID: 7504210
5. ↑ Brown BG, Bolson E, Petersen RB, Pierce CD, Dodge HT (1981) The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation 64 (6):1089-97. PMID: 6794931
6. ↑ Goldstein RE, Stinson EB, Scherer JL, Seningen RP, Grehl TM, Epstein SE (1974) Intraoperative coronary collateral function in patients with coronary occlusive disease. Nitroglycerin responsiveness and angiographic correlations. Circulation 49 (2):298-308. PMID: 4204133
7. ↑ Simonsen U (2002) Interactions between drugs for erectile dysfunction and drugs for cardiovascular disease. Int J Impot Res 14 (3):178-88. DOI:10.1038/sj.ijir.3900846 PMID: 12058245
8. ↑ Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA (2002) Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA 287 (6):719-25. PMID: 11851538
9. ↑ Parker JO, Farrell B, Lahey KA, Moe G (1987) Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 316 (23):1440-4. DOI:10.1056/NEJM198706043162303 PMID: 3574424
10. ↑ Chrysant SG, Glasser SP, Bittar N, Shahidi FE, Danisa K, Ibrahim R et al. (1993) Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris. Am J Cardiol 72 (17):1249-56. PMID: 8256699
11. ↑ Parker JO, Amies MH, Hawkinson RW, Heilman JM, Hougham AJ, Vollmer MC et al. (1995) Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group. Circulation 91 (5):1368-74. PMID: 7867175
12. ↑ Needleman P, Johnson EM (1973) Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther 184 (3):709-15. PMID: 4631470
13. ↑ Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO (1991) Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation 84 (6):2336-45. PMID: 1835676
14. ↑ Münzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG (1995) Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 95 (1):187-94. DOI:10.1172/JCI117637 PMID: 7814613
15. ↑ 15.0 15.1 Münzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG (1995) Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance. Proc Natl Acad Sci U S A 92 (11):5244-8. PMID: 7539147
16. ↑ Dupuis J, Lalonde G, Lemieux R, Rouleau JL (1990) Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine. J Am Coll Cardiol 16 (4):923-31. PMID: 1976661
17. ↑ Parker JD, Farrell B, Fenton T, Parker JO (1992) Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin. J Am Coll Cardiol 20 (3):616-22. PMID: 1512341
18. ↑ Parker JD, Parker JO (1993) Effect of therapy with an angiotensin-converting enzyme inhibitor on hemodynamic and counterregulatory responses during continuous therapy with nitroglycerin. J Am Coll Cardiol 21 (6):1445-53. PMID: 8473654
19. ↑ Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK et al. (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97 (8):1916-23. DOI:10.1172/JCI118623 PMID: 8621776
20. ↑ Parker JO, Fung HL, Ruggirello D, Stone JA (1983) Tolerance to isosorbide dinitrate: rate of development and reversal. Circulation 68 (5):1074-80. PMID: 6616789
21. ↑ Münzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA et al. (1996) Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest 98 (6):1465-70. DOI:10.1172/JCI118935 PMID: 8823313
22. ↑ Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE et al. (1986) Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 314 (24):1547-52. DOI:10.1056/NEJM198606123142404 PMID: 3520315
23. ↑ 23.0 23.1 Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP; et al. (2012). "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons". Circulation. 126 (25): 3097–137. doi:10.1161/CIR.0b013e3182776f83. PMID 23166210.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
24. ↑ 24.0 24.1 Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F; et al. (2006). "Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology". Eur Heart J. 27 (11): 1341–81. doi:10.1093/eurheartj/ehl001. PMID 16735367.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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