Chronic stable angina treatment nitrates: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
(/* ESC Guidelines- Pharmacological therapy to improve symptoms and/or reduce ischaemia in patients with stable angina (DO NOT EDIT) {{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=Guidelines on the ...)
No edit summary
 
(27 intermediate revisions by 5 users not shown)
Line 1: Line 1:
__NOTOC__
{{Chronic stable angina}}
{{Chronic stable angina}}


'''Editor-In-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:mgibson@perfuse.org] Phone:617-632-7753; '''Associate Editor(s)-In-Chief:''' {{CZ}}; [[John Fani Srour, M.D.]]; [[WikiDoc Scholars#WikiDoc Scholars with Distinction|Jinhui Wu, M.D.]]; [[Lakshmi Gopalakrishnan|Lakshmi Gopalakrishnan, M.B.B.S.]]
'''Editor-In-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com]; '''Associate Editor(s)-In-Chief:''' {{CZ}}; [[John Fani Srour, M.D.]]; [[WikiDoc Scholars#WikiDoc Scholars with Distinction|Jinhui Wu, M.D.]]; [[Lakshmi Gopalakrishnan|Lakshmi Gopalakrishnan, M.B.B.S.]]; {{AA}}


==Overview==
==Overview==
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. <ref name="pmid7848896">Thadani U, Lipicky RJ (1994) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7848896 Short and long-acting oral nitrates for stable angina pectoris.] ''Cardiovasc Drugs Ther'' 8 (4):611-23. PMID: [http://pubmed.gov/7848896 7848896]</ref> <ref name="pmid9468470">Parker JD, Parker JO (1998) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9468470 Nitrate therapy for stable angina pectoris.] ''N Engl J Med'' 338 (8):520-31. [http://dx.doi.org/10.1056/NEJM199802193380807 DOI:10.1056/NEJM199802193380807] PMID: [http://pubmed.gov/9468470 9468470]</ref> <ref name="pmid10351980">Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999)[http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=10351980ACC/AHA/ACP-ASIM 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: [http://pubmed.gov/10351980 10351980]</ref> Nitrates at therapeutic doses do not affect coronary vascular resistance, thereby reducing the risk of [[myocardial ischemia]] due to [[Subclavian steal syndrome|coronary steal phenomena]] that is consistent with the use of [[Chronic stable angina treatment dipyridamole|dipyridamole]] and other short acting dihydropyridines.  
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.<ref name="pmid7848896">Thadani U, Lipicky RJ (1994) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7848896 Short and long-acting oral nitrates for stable angina pectoris.] ''Cardiovasc Drugs Ther'' 8 (4):611-23. PMID: [http://pubmed.gov/7848896 7848896]</ref><ref name="pmid9468470">Parker JD, Parker JO (1998) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9468470 Nitrate therapy for stable angina pectoris.] ''N Engl J Med'' 338 (8):520-31. [http://dx.doi.org/10.1056/NEJM199802193380807 DOI:10.1056/NEJM199802193380807] PMID: [http://pubmed.gov/9468470 9468470]</ref><ref name="pmid10351980">Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999)[http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=10351980ACC/AHA/ACP-ASIM 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: [http://pubmed.gov/10351980 10351980]</ref> Nitrates at therapeutic doses do not affect coronary vascular resistance, thereby reducing the risk of [[myocardial ischemia]] due to [[Subclavian steal syndrome|coronary steal phenomena]] that is consistent with the use of [[Chronic stable angina treatment dipyridamole|dipyridamole]] and other short acting dihydropyridines.


==Mechanisms of benefit==
==Nitrates==
*Nitrates within the vessel wall are metabolized to [[nitric oxide]] (NO) which is an '''endothelium-derived relaxing factor'''.<ref name="pmid7504210">Moncada S, Higgs A (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7504210 The L-arginine-nitric oxide pathway.] ''N Engl J Med'' 329 (27):2002-12. [http://dx.doi.org/10.1056/NEJM199312303292706 DOI:10.1056/NEJM199312303292706] PMID: [http://pubmed.gov/7504210 7504210]</ref> This stimulates guanylate cyclase to produce cyclic guanosine mono phosphate (cGMP), which is responsible for [[vasodilation]].
===Mechanisms of Benefit===
*Nitrates within the vessel wall are metabolized to [[nitric oxide]] (NO) which is an endothelium-derived relaxing factor.<ref name="pmid7504210">Moncada S, Higgs A (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7504210 The L-arginine-nitric oxide pathway.] ''N Engl J Med'' 329 (27):2002-12. [http://dx.doi.org/10.1056/NEJM199312303292706 DOI:10.1056/NEJM199312303292706] PMID: [http://pubmed.gov/7504210 7504210]</ref> 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.<ref name="pmid6794931">Brown BG, Bolson E, Petersen RB, Pierce CD, Dodge HT (1981) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6794931 The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response.] ''Circulation'' 64 (6):1089-97. PMID: [http://pubmed.gov/6794931 6794931]</ref>  
*Nitrates induce coronary arterial vasodilation that helps to reduce the degree of coronary artery stenosis produced by an eccentric atherosclerotic plaque.<ref name="pmid6794931">Brown BG, Bolson E, Petersen RB, Pierce CD, Dodge HT (1981) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6794931 The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response.] ''Circulation'' 64 (6):1089-97. PMID: [http://pubmed.gov/6794931 6794931]</ref>  


*Nitrates induce vasodilation even in the collateral vessels, thereby '''enhancing coronary collateral flow''' to the ischemic myocardium and subsequently relieving [[coronary vasospasm]].<ref name="pmid4204133">Goldstein RE, Stinson EB, Scherer JL, Seningen RP, Grehl TM, Epstein SE (1974) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=4204133 Intraoperative coronary collateral function in patients with coronary occlusive disease. Nitroglycerin responsiveness and angiographic correlations.] ''Circulation'' 49 (2):298-308. PMID: [http://pubmed.gov/4204133 4204133]</ref>
*Nitrates induce vasodilation even in the collateral vessels, thereby enhancing coronary collateral flow to the ischemic myocardium and subsequently relieving [[coronary vasospasm]].<ref name="pmid4204133">Goldstein RE, Stinson EB, Scherer JL, Seningen RP, Grehl TM, Epstein SE (1974) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=4204133 Intraoperative coronary collateral function in patients with coronary occlusive disease. Nitroglycerin responsiveness and angiographic correlations.] ''Circulation'' 49 (2):298-308. PMID: [http://pubmed.gov/4204133 4204133]</ref>


*Nitrates '''decrease myocardial oxygen demand''' by decreasing intra-cardiac volumes consequent to reduced venous return resulting from peripheral venous dilatation ([[preload|preload reduction]]) and by reducing arterial pressure resulting from arterial dilation ([[afterload|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.
*Nitrates decrease myocardial oxygen demand by decreasing intra-cardiac volumes consequent to reduced venous return resulting from peripheral venous dilatation ([[preload|preload reduction]]) and by reducing arterial pressure resulting from arterial dilation ([[afterload|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'''.  
*In addition to the above beneficial effects, [[nitric oxide]] also inhibits platelet adhesion and aggregation.  


==Indications==
===Indications===
*Nitrates are effective in the management of various clinical subsets of stable angina pectoris.  
*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 [[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 [[Chronic stable angina clinical subset- vasospastic angina|vasospastic angina]], nitrates relax the smooth muscles of epicardial vessels, thereby relieving coronary artery spasm.  
:*In patients with [[Chronic stable angina clinical subset- vasospastic angina|vasospastic angina]], nitrates relax the smooth muscles of epicardial vessels, thereby relieving coronary artery spasm.  
Line 27: Line 29:


*Prophylaxis:
*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 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.
:*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]].
*Nitrates reduce intra-cardiac pressures hence may be effective in patients with left ventricular dysfunction or [[mitral insufficiency]].
Line 35: Line 37:
*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.
*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.


==Contra-indications/Caution==
===Contraindications===
*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]].
*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 [[hypotension|profound hypotension]].<ref name="pmid12058245">Simonsen U (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12058245 Interactions between drugs for erectile dysfunction and drugs for cardiovascular disease.] ''Int J Impot Res'' 14 (3):178-88. [http://dx.doi.org/10.1038/sj.ijir.3900846 DOI:10.1038/sj.ijir.3900846] PMID: [http://pubmed.gov/12058245 12058245]</ref> <ref name="pmid11851538">Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11851538 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: [http://pubmed.gov/11851538 11851538]</ref>  
*A 72-hour interval period is required between the administration of nitrates and [[sildenafil]] in order to prevent [[hypotension|profound hypotension]].<ref name="pmid12058245">Simonsen U (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12058245 Interactions between drugs for erectile dysfunction and drugs for cardiovascular disease.] ''Int J Impot Res'' 14 (3):178-88. [http://dx.doi.org/10.1038/sj.ijir.3900846 DOI:10.1038/sj.ijir.3900846] PMID: [http://pubmed.gov/12058245 12058245]</ref><ref name="pmid11851538">Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11851538 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: [http://pubmed.gov/11851538 11851538]</ref>  


*[[Cardiac tamponade]]
*[[Cardiac tamponade]]


==Dosage==
===Dosage===
*The onset of action of [[nitroglycerin|sublingual nitroglycerin]] tablets or [[nitroglycerin|nitroglycerin spray]] is within 1 to 3 minutes, making these the preferred agents for the acute relief of effort or rest angina.  
*The onset of action of [[nitroglycerin|sublingual nitroglycerin]] tablets or [[nitroglycerin|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.  
:*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.  
*[[nitroglycerin|Oral nitroglycerin]] is given every 8-12 hours.
*[[nitroglycerin|Oral nitroglycerin]] is given every 8-12 hours.


*[[Isosorbide dinitrate]] (20-80mg) should not be used more frequently than two times a day.<ref name="pmid3574424">Parker JO, Farrell B, Lahey KA, Moe G (1987) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=3574424 Effect of intervals between doses on the development of tolerance to isosorbide dinitrate.] ''N Engl J Med'' 316 (23):1440-4. [http://dx.doi.org/10.1056/NEJM198706043162303 DOI:10.1056/NEJM198706043162303] PMID: [http://pubmed.gov/3574424 3574424]</ref>
*[[Isosorbide dinitrate]] (20-80 mg) should not be used more frequently than two times a day.<ref name="pmid3574424">Parker JO, Farrell B, Lahey KA, Moe G (1987) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=3574424 Effect of intervals between doses on the development of tolerance to isosorbide dinitrate.] ''N Engl J Med'' 316 (23):1440-4. [http://dx.doi.org/10.1056/NEJM198706043162303 DOI:10.1056/NEJM198706043162303] PMID: [http://pubmed.gov/3574424 3574424]</ref>
*Sustained release-[[isosorbide mononitrate]] is effective if given twice daily.<ref name="pmid8256699">Chrysant SG, Glasser SP, Bittar N, Shahidi FE, Danisa K, Ibrahim R et al. (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8256699 Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris.] ''Am J Cardiol'' 72 (17):1249-56. PMID: [http://pubmed.gov/8256699 8256699]</ref>
*Sustained release-[[isosorbide mononitrate]] is effective if given twice daily.<ref name="pmid8256699">Chrysant SG, Glasser SP, Bittar N, Shahidi FE, Danisa K, Ibrahim R et al. (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8256699 Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris.] ''Am J Cardiol'' 72 (17):1249-56. PMID: [http://pubmed.gov/8256699 8256699]</ref>


*[[nitroglycerin|Transdermal nitroglycerin]] schedule of '''12 hours-on and 12 hours-off''' is most effective in improving exercise performance.<ref name="pmid7867175">Parker JO, Amies MH, Hawkinson RW, Heilman JM, Hougham AJ, Vollmer MC et al. (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7867175 Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group.] ''Circulation'' 91 (5):1368-74. PMID: [http://pubmed.gov/7867175 7867175]</ref>
*[[nitroglycerin|Transdermal nitroglycerin]] schedule of 12 hours-on and 12 hours-off is most effective in improving exercise performance.<ref name="pmid7867175">Parker JO, Amies MH, Hawkinson RW, Heilman JM, Hougham AJ, Vollmer MC et al. (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7867175 Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group.] ''Circulation'' 91 (5):1368-74. PMID: [http://pubmed.gov/7867175 7867175]</ref>


==Adverse effects==
===Adverse Effects===
*[[Headache|Throbbing headache]], which tends to decrease with continued use.  
*[[Headache|Throbbing headache]], which tends to decrease with continued use.  
*[[Flushing]]
*[[Flushing]]
*[[Palpitations]]
*[[Palpitations]]


*Paradoxical angina characterized by angina non-responsive to [[nitroglycerin]], postural [[hypotension]] and reflex [[tachycardia]] may be a result of '''nitrate overdose'''.
*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'''.
*The major clinical problem for long term nitrate therapy is nitrate tolerance.


==Nitrate Tolerance==
===Nitrate Tolerance===
*Tolerance develops not only to antianginal and hemodynamic effects but also to platelet anti-aggregatory effects.
*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:
*The mechanism for development of nitrate tolerance remains unclear. The four important hypothese are:
:*'''Sulfhydryl-Depletion Hypothesis: <ref name="pmid4631470">Needleman P, Johnson EM (1973) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=4631470 Mechanism of tolerance development to organic nitrates.] ''J Pharmacol Exp Ther'' 184 (3):709-15. PMID: [http://pubmed.gov/4631470 4631470]</ref>''' Decreased availability of sulfhydryl (SH) radicals consequent to continuous long-term nitrate therapy is associated with loss of nitrate efficacy.  
:*Sulfhydryl-Depletion Hypothesis:<ref name="pmid4631470">Needleman P, Johnson EM (1973) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=4631470 Mechanism of tolerance development to organic nitrates.] ''J Pharmacol Exp Ther'' 184 (3):709-15. PMID: [http://pubmed.gov/4631470 4631470]</ref> Decreased availability of sulfhydryl (SH) radicals consequent to continuous long-term nitrate therapy is associated with loss of nitrate efficacy.  
:*'''Neurohormonal Hypothesis: <ref name="pmid1835676">Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO (1991) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1835676 Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.] ''Circulation'' 84 (6):2336-45. PMID: [http://pubmed.gov/1835676 1835676]</ref>''' 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.<ref name="pmid7814613">Münzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7814613 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. [http://dx.doi.org/10.1172/JCI117637 DOI:10.1172/JCI117637] PMID: [http://pubmed.gov/7814613 7814613]</ref> <ref name="pmid7539147">Münzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7539147 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: [http://pubmed.gov/7539147 7539147]</ref>
:*Neurohormonal Hypothesis:<ref name="pmid1835676">Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO (1991) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1835676 Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.] ''Circulation'' 84 (6):2336-45. PMID: [http://pubmed.gov/1835676 1835676]</ref> 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.<ref name="pmid7814613">Münzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7814613 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. [http://dx.doi.org/10.1172/JCI117637 DOI:10.1172/JCI117637] PMID: [http://pubmed.gov/7814613 7814613]</ref><ref name="pmid7539147">Münzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7539147 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: [http://pubmed.gov/7539147 7539147]</ref>
:*'''Plasma-Volume-Expansion Hypothesis:''' Sustained nitrate therapy induces plasma volume expansion <ref name="pmid1976661">Dupuis J, Lalonde G, Lemieux R, Rouleau JL (1990) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1976661 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: [http://pubmed.gov/1976661 1976661]</ref> 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.<ref name="pmid1512341">Parker JD, Farrell B, Fenton T, Parker JO (1992) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1512341 Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin.] ''J Am Coll Cardiol'' 20 (3):616-22. PMID: [http://pubmed.gov/1512341 1512341]</ref> <ref name="pmid8473654">Parker JD, Parker JO (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8473654 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: [http://pubmed.gov/8473654 8473654]</ref>
:*Plasma-Volume-Expansion Hypothesis: Sustained nitrate therapy induces plasma volume expansion<ref name="pmid1976661">Dupuis J, Lalonde G, Lemieux R, Rouleau JL (1990) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1976661 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: [http://pubmed.gov/1976661 1976661]</ref> 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.<ref name="pmid1512341">Parker JD, Farrell B, Fenton T, Parker JO (1992) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1512341 Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin.] ''J Am Coll Cardiol'' 20 (3):616-22. PMID: [http://pubmed.gov/1512341 1512341]</ref><ref name="pmid8473654">Parker JD, Parker JO (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8473654 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: [http://pubmed.gov/8473654 8473654]</ref>
:*'''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.<ref name="pmid8621776">Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK et al. (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8621776 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. [http://dx.doi.org/10.1172/JCI118623 DOI:10.1172/JCI118623] PMID: [http://pubmed.gov/8621776 8621776]</ref> <ref name="pmid7539147">Münzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7539147 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: [http://pubmed.gov/7539147 7539147]</ref>  
:*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.<ref name="pmid8621776">Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK et al. (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8621776 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. [http://dx.doi.org/10.1172/JCI118623 DOI:10.1172/JCI118623] PMID: [http://pubmed.gov/8621776 8621776]</ref><ref name="pmid7539147">Münzel T, Giaid A, Kurz S, Stewart DJ, Harrison DG (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7539147 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: [http://pubmed.gov/7539147 7539147]</ref>  


*Prevention of nitrate tolerance:
*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.<ref name="pmid6616789">Parker JO, Fung HL, Ruggirello D, Stone JA (1983) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6616789 Tolerance to isosorbide dinitrate: rate of development and reversal.] ''Circulation'' 68 (5):1074-80. PMID: [http://pubmed.gov/6616789 6616789]</ref>  
:*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.<ref name="pmid6616789">Parker JO, Fung HL, Ruggirello D, Stone JA (1983) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=6616789 Tolerance to isosorbide dinitrate: rate of development and reversal.] ''Circulation'' 68 (5):1074-80. PMID: [http://pubmed.gov/6616789 6616789]</ref>  
:*Smaller and less frequent dosing.
:*Smaller and less frequent dosing.
:*Long-term formulations could be avoided unless a prolonged nitrate-free interval is provided.  
:*Long-term formulations could be avoided unless a prolonged nitrate-free interval is provided.  
Line 77: Line 79:
:*[[Hydralazine]] inhibits membrane-bound oxidases thereby reducing free radical production.<ref name="pmid8823313">Münzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA et al. (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8823313 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. [http://dx.doi.org/10.1172/JCI118935 DOI:10.1172/JCI118935] PMID: [http://pubmed.gov/8823313 8823313]</ref> Hence, concomitant administration of hydralazine has shown to reduce nitrate tolerance.<ref name="pmid3520315">Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE et al. (1986) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=3520315 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. [http://dx.doi.org/10.1056/NEJM198606123142404 DOI:10.1056/NEJM198606123142404] PMID: [http://pubmed.gov/3520315 3520315]</ref>
:*[[Hydralazine]] inhibits membrane-bound oxidases thereby reducing free radical production.<ref name="pmid8823313">Münzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA et al. (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8823313 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. [http://dx.doi.org/10.1172/JCI118935 DOI:10.1172/JCI118935] PMID: [http://pubmed.gov/8823313 8823313]</ref> Hence, concomitant administration of hydralazine has shown to reduce nitrate tolerance.<ref name="pmid3520315">Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE et al. (1986) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=3520315 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. [http://dx.doi.org/10.1056/NEJM198606123142404 DOI:10.1056/NEJM198606123142404] PMID: [http://pubmed.gov/3520315 3520315]</ref>


==ACC/AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT) <ref name="pmid10351980">Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999)[http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=10351980ACC/AHA/ACP-ASIM 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: [http://pubmed.gov/10351980 10351980]</ref><ref name="pmid12515758">Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12515758 ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina).] ''Circulation'' 107 (1):149-58. PMID: [http://pubmed.gov/12515758 12515758]</ref>==
==2012 ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina (DO NOT EDIT)<ref name="pmid23166210">{{cite journal| author=Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP et al.| title=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. | journal=Circulation | year= 2012 | volume= 126 | issue= 25 | pages= 3097-137 | pmid=23166210 | doi=10.1161/CIR.0b013e3182776f83 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23166210  }} </ref>==
 
===Nitrates (DO NOT EDIT)<ref name="pmid23166210">{{cite journal| author=Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP et al.| title=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. | journal=Circulation | year= 2012 | volume= 126 | issue= 25 | pages= 3097-137 | pmid=23166210 | doi=10.1161/CIR.0b013e3182776f83 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23166210  }} </ref>===


{| class="wikitable"
{| class="wikitable"
Line 83: Line 87:
| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' [[Chronic stable angina calcium channel blocker therapy|Calcium channel blocker]] (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as initial therapy when [[Chronic stable angina beta blocker therapy|beta blockers]] are contraindicated. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])'' <nowiki>"</nowiki>
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''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''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' [[Chronic stable angina calcium channel blocker therapy|Calcium channel blocker]] (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates in combination with [[Chronic stable angina beta blocker therapy|beta blockers]] when initial treatment with [[Chronic stable angina beta blocker therapy|beta blockers]] is not successful. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])'' <nowiki>"</nowiki>
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''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. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''3.''' [[Chronic stable angina calcium channel blocker therapy|Calcium channel blocker]] (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as a substitute for [[Chronic stable angina beta blocker therapy|beta blockers]] if initial treatment with [[Chronic stable angina beta blocker therapy|beta blockers]] leads to unacceptable side effects. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C]])'' <nowiki>"</nowiki>
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''3.''' Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD.''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''4.''' Sublingual [[nitroglycerin]] or nitroglycerin spray for the immediate relief of [[Chronic stable angina definition|angina]]. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C]])'' <nowiki>"</nowiki>
|}
|}


==ESC Guidelines- Pharmacological therapy to improve symptoms and/or reduce ischaemia in patients with stable angina (DO NOT EDIT) <ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=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. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367}}</ref>==
==ESC Guidelines- Pharmacological Therapy to Improve Symptoms and/or Reduce Ischaemia in Patients with Stable Angina (DO NOT EDIT)<ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=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. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367}}</ref>==
 
===Nitrates (DO NOT EDIT)<ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=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. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367}}</ref>===


{| class="wikitable"
{| class="wikitable"
Line 98: Line 102:
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
|-
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Provide short-acting nitroglycerin for acute symptom relief and situational prophylaxis, with appropriate instructions on how to use the treatment. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])'' <nowiki>"</nowiki>
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Provide short-acting nitroglycerin for acute symptom relief and situational prophylaxis, with appropriate instructions on how to use the treatment. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' In case of [[Chronic stable angina beta blocker therapy|beta-blocker]] intolerance or poor efficacy attempt monotherapy with a [[Chronic stable angina calcium channel blocker therapy|CCB]] ''([[European society of cardiology#Level of Evidence|Level of Evidence: A]])'', long-acting nitrate ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])'', or [[nicorandil]] ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''.'' <nowiki>"</nowiki>
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' In case of [[Chronic stable angina beta blocker therapy|beta-blocker]] intolerance or poor efficacy attempt monotherapy with a [[Chronic stable angina calcium channel blocker therapy|CCB]] ''([[European society of cardiology#Level of Evidence|Level of Evidence: A]])'', long-acting nitrate ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])'', or [[nicorandil]] ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''.<nowiki>"</nowiki>
|}
|}


Line 107: Line 111:
| colspan="1" style="text-align:center; background:LemonChiffon"| [[European society of cardiology#Classes of Recommendations|Class IIa]]
| colspan="1" style="text-align:center; background:LemonChiffon"| [[European society of cardiology#Classes of Recommendations|Class IIa]]
|-
|-
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' If [[Chronic stable angina calcium channel blocker therapy|CCB]] monotherapy or combination therapy ([[Chronic stable angina calcium channel blocker therapy|CCB]] with [[Chronic stable angina beta blocker therapy|beta-blocker]]) is unsuccessful, substitute the [[Chronic stable angina calcium channel blocker therapy|CCB]] with a long-acting nitrate or [[nicorandil]]. Be careful to avoid nitrate tolerance. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])'' <nowiki>"</nowiki>
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' If [[Chronic stable angina calcium channel blocker therapy|CCB]] monotherapy or combination therapy ([[Chronic stable angina calcium channel blocker therapy|CCB]] with [[Chronic stable angina beta blocker therapy|beta-blocker]]) is unsuccessful, substitute the [[Chronic stable angina calcium channel blocker therapy|CCB]] with a long-acting nitrate or [[nicorandil]]. Be careful to avoid nitrate tolerance. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
|}
|}
==Vote on and Suggest Revisions to the Current Guidelines==
*[[The Living Guidelines: Chronic Stable Angina Pectoris | The Chronic Stable Angina Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines]]
==Guidelines Resources==
*[http://circ.ahajournals.org/content/99/21/2829.full.pdf The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina]<ref name="pmid10351980">Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=10351980 ACC/AHA/ACP-ASIM 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. [http://circ.ahajournals.org/content/99/21/2829.full.pdf] PMID: [http://pubmed.gov/10351980 10351980]</ref>
*[http://content.onlinejacc.org/cgi/reprint/41/1/159.pdf The ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina]<ref name="pmid12515758">Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12515758 ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina).] ''Circulation'' 107 (1):149-58.[http://content.onlinejacc.org/cgi/reprint/41/1/159.pdf] PMID: [http://pubmed.gov/12515758 12515758]</ref>
*[http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-angina-FT.pdf Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology]<ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=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. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= |url=url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367 [http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-angina-FT.pdf]}} </ref>
*[http://content.onlinejacc.org/cgi/reprint/50/23/2264.pdf The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina]<ref name="pmid17998462">Fraker TD, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J et al. (2007)[http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17998462 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina.] ''Circulation'' 116 (23):2762-72.[http://content.onlinejacc.org/cgi/reprint/50/23/2264.pdf] PMID: [http://pubmed.gov/17998462 17998462]</ref>


==References==
==References==
Line 127: Line 119:
{{WikiDoc Sources}}
{{WikiDoc Sources}}


[[Category:Disease]]
[[Category:Ischemic heart diseases]]
[[Category:Ischemic heart diseases]]
[[Category:Disease]]
[[Category:Cardiology]]
[[Category:Cardiology]]
[[Category:Emergency medicine]]
[[Category:Emergency medicine]]
[[Category:Intensive care medicine]]
[[Category:Up-To-Date]]
[[Category:Up-To-Date]]
[[Category:Up-To-Date cardiology]]
[[Category:Up-To-Date cardiology]]

Latest revision as of 18:38, 31 October 2016

Chronic stable angina Microchapters

Acute Coronary Syndrome Main Page

Home

Patient Information

Overview

Historical Perspective

Classification

Classic
Chronic Stable Angina
Atypical
Walk through Angina
Mixed Angina
Nocturnal Angina
Postprandial Angina
Cardiac Syndrome X
Vasospastic Angina

Differentiating Chronic Stable Angina from Acute Coronary Syndromes

Pathophysiology

Epidemiology and Demographics

Risk Stratification

Pretest Probability of CAD in a Patient with Angina

Prognosis

Diagnosis

History and Symptoms

Physical Examination

Test Selection Guideline for the Individual Basis

Laboratory Findings

Electrocardiogram

Exercise ECG

Chest X Ray

Myocardial Perfusion Scintigraphy with Pharmacologic Stress

Myocardial Perfusion Scintigraphy with Thallium

Echocardiography

Exercise Echocardiography

Computed coronary tomography angiography(CCTA)

Positron Emission Tomography

Ambulatory ST Segment Monitoring

Electron Beam Tomography

Cardiac Magnetic Resonance Imaging

Coronary Angiography

Treatment

Medical Therapy

Revascularization

PCI
CABG
Hybrid Coronary Revascularization

Alternative Therapies for Refractory Angina

Transmyocardial Revascularization (TMR)
Spinal Cord Stimulation (SCS)
Enhanced External Counter Pulsation (EECP)
ACC/AHA Guidelines for Alternative Therapies in patients with Refractory Angina

Discharge Care

Patient Follow-Up
Rehabilitation

Secondary Prevention

Guidelines for Asymptomatic Patients

Noninvasive Testing in Asymptomatic Patients
Risk Stratification by Coronary Angiography
Pharmacotherapy to Prevent MI and Death in Asymptomatic Patients

Landmark Trials

Case Studies

Case #1

Chronic stable angina treatment nitrates On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Chronic stable angina treatment nitrates

CDC onChronic stable angina treatment nitrates

Chronic stable angina treatment nitrates in the news

Blogs on Chronic stable angina treatment nitrates

to Hospitals Treating Chronic stable angina treatment nitrates

Risk calculators and risk factors for Chronic stable angina treatment nitrates

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

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

Mechanisms of Benefit

  • 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

  • Nitrates are effective in the management of various clinical subsets of stable angina pectoris.
  • In patients with vasospastic angina, nitrates relax the smooth muscles of epicardial vessels, thereby relieving coronary artery spasm.
  • 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

Dosage

  • 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.

Adverse Effects

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

Nitrate Tolerance

  • 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]

Nitrates (DO NOT EDIT)[23]

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]

Nitrates (DO NOT EDIT)[24]

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

  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.
  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.

Template:WikiDoc Sources

Retrieved from "https://www.wikidoc.org/index.php?title=Chronic_stable_angina_treatment_nitrates&oldid=1265571"