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==Overview==
==Overview==
In patients with chronic stable angina, nitrates remain the mainstay of therapy. 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 while 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>
In patients with chronic stable angina, nitrates remain the mainstay of therapy. Nitrates are '''endothelium independent vasodilators''' 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 while 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 observed with [[Chronic stable angina treatment dipyridamole|dipyridamole]] and other short acting dihydropyridines.


==Mechanisms of benefit==
==Mechanisms of benefit==
*[[Nitroglycerin]] and other nitrates are '''endothelium independent vasodilators''' that produce their beneficial effects both by decreasing myocardial oxygen requirements and by improving myocardial perfusion.  
*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]].


*It has been postulated that nitrates, after entering the vessel wall, are converted to nitric oxide (NO), which stimulates guanylate cyclase to produce cyclic guanosine mono phosphate (cGMP), the substance that is responsible for vasodilation.
*Nitrates cause dilation of epicardial vessels that help 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 dilate large coronary arteries and collateral vessels, thereby increasing collateral blood flow to the ischemic myocardium and relieve coronary [[vasospasm]]
*Nitrates induce vasodilation even in the collateral vessels, thereby increasing the collateral blood 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 also decrease the degree of coronary artery stenosis produced by an eccentric atherosclerotic plaque.  


*Nitrates also decrease myocardial oxygen requirements by decreasing intra cardiac volumes consequent to reduced venous return resulting from peripheral venous dilatation and by reducing arterial pressure. These beneficial effects may be offset partly by a reflex increase in [[heart rate]], which can be prevented by simultaneous [[beta adrenergic blockade]].
*Nitrates '''decrease myocardial oxygen demand''' by decreasing intra-cardiac volumes consequent to reduced venous return ([[preload]]) resulting from peripheral venous dilatation and by reducing arterial pressure ([[afterload]]). These beneficial effects may be partly offset by a [[tachycardia|reflex increase in the heart rate]] due to the reduced [[cardiac output]], which can be prevented by concomitant [[beta-blocker]] use.
 
*In addition to the above beneficial effects, [[nitric oxide]] also '''inbitis platelet adhesion and aggregation'''.  


==Indications==
==Indications==

Revision as of 17:31, 19 August 2011

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Phone:617-632-7753; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [3]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview

In patients with chronic stable angina, nitrates remain the mainstay of therapy. Nitrates are endothelium independent vasodilators 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 while 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 observed with dipyridamole and other short acting dihydropyridines.

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 cause dilation of epicardial vessels that help to reduce the degree of coronary artery stenosis produced by an eccentric atherosclerotic plaque.[5]
  • Nitrates induce vasodilation even in the collateral vessels, thereby increasing the collateral blood 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 (preload) resulting from peripheral venous dilatation and by reducing arterial pressure (afterload). These beneficial effects may be partly offset by a reflex increase in the heart rate due to the reduced cardiac output, which can be prevented by concomitant beta-blocker use.
  • In addition to the above beneficial effects, nitric oxide also inbitis platelet adhesion and aggregation.

Indications

  • Nitrates are effective for the management of various clinical subsets of stable angina pectoris.
  • In patients with vasospastic angina, nitrates relax the smooth muscles of the epicardial coronary arteries and thereby relieve coronary artery spasm.
  • Prophylaxis with Nitrates:
  • Nitroglycerin is also very useful for prophylaxis when 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.

Contra-indications

  • Nitrates do not worsen glaucoma, once thought to be a contraindication to their use, and they can be used safely in the presence of increased intraocular pressure.
  • 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.

Dosage

A variety of nitrate preparations are currently available.

  • 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 should 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 may be expired.
  • Isosorbide dinitrate should not be used more frequently than three times a day, or a transdermal patch more often than every 12 hours.

Adverse effects

  • Throbbing headache, which tends to decrease with continued use.
  • Postural dizziness and weakness occur in some patients, frank syncope due to hypotension is relatively uncommon.

Nitrate Tolerance:

  • Tolerance develops not only to antianginal and hemodynamic effects but also to platelet antiaggregatory effects.
  • The mechanism for development of nitrate tolerance remains unclear.
  • The decreased availability of sulfhydryl (SH) radicals, activation of the renin-angiotensin-aldosterone system, an increase in intravascular volume due to an altered transvascular Starling gradient, and generation of free radicals with enhanced degradation of nitric oxide have been proposed.
  • The 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.
  • Concomitant administration of hydralazine has also been reported to reduce nitrate tolerance.
  • However, 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.

Supportive trial data

ACC/AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT) [3][7]

“

Class I

1. Calcium channel blocker (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as initial therapy when beta blockers are contraindicated. (Level of Evidence: B)

2. Calcium channel blocker (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates in combination with beta blockers when initial treatment with beta blockers is not successful. (Level of Evidence: B)

3. Calcium channel blocker (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as a substitute for beta blockers if initial treatment with beta blockers leads to unacceptable side effects. (Level of Evidence: C)

4. Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina. (Level of Evidence: C)

”

ESC Guidelines- Pharmacological therapy to improve symptoms and/or reduce ischaemia in patients with stable angina (DO NOT EDIT)[8]

“

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)

”

Vote on and Suggest Revisions to the Current Guidelines

Sources

  • Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology [8]
  • The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina [3]
  • TheACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina [7]
  • The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina [9]

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. ↑ 3.0 3.1 3.2 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. ↑ 7.0 7.1 Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) 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: 12515758
  8. ↑ 8.0 8.1 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.
  9. ↑ Fraker TD, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J et al. (2007)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.[1] PMID: 17998462


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