General (including evidence of efficacy)
This group includes the short-acting oral nitrates (e.g., isosorbide dinitrate), longer-acting oral nitrates (e.g., isosorbide mononitrate) and the nonoral preparations (e.g., nitroglycerin ointment or patch, sublingual nitroglycerin).
Differences between drugs within the class
While most nitrate preparations have been studied to some degree in heart failure, more data have been accrued for isosorbide dinitrate. The discussion will focus on isosorbide dinitrate.
Isosorbide dinitrate (ISDN) is generally started at 10 mg every 6 to 8 hours with gradual incrementation to 20 to 40 mg every 6 to 8 hours. Side effects will limit the dose in some. The effects are relatively short lived, generally 4 to 6 hours and thus require frequent dosing, similar to the dosing schedule of hydralazine. Longer nitrate activity can be rendered with isosorbide mononitrate (15 to 90 mg every 12 hours) or high-dose nitroglycerin ointment.
Pharmacodynamic tolerance can occur with more frequent dosing (>4 times a day), and can be averted with a QID or TID dosing schedule (instead of every 6 or 8 hours); this allows the blood level of ISDN to fall toward baseline (in the night time) on a daily basis.
At doses of ≥ 20 mg, ISDN evokes a fall in ventricular diastolic filling pressure with less effect on systemic arterioles. Along with diuretics, nitrates are the principal means of reducing ventricular preload, diastolic filling pressure, pulmonary capillary wedge pressure, and right atrial pressure. Nitrates have a favorable effect on coronary blood flow, myocardial perfusion, and myocardial energetics.
Indications and contraindications
In the setting of heart failure, ISDN is generally administered with hydralazine. Thereby providing the patient with a balanced preload-afterload reduction plan. Nitrates alone may have a role in managing the patient whose heart failure is closely linked to high grade occlusive coronary artery disease and angina pectoris not amenable to intervention (e.g., angioplasty-stent deployment, coronary bypass surgery).
Some patients are extremely intolerant of nitrates and cannot be started on any preparation, even at the lowest dose.
Headache and flushing are common side effects and may require dose reduction. Nausea and vomiting can occur, but generally accompany a severe headache. Hypotension is uncommon, but may occur during the early course of nitrate therapy. Most of the side effects decrease in severity with dose reduction and if mild, with repeated dosing (pharmacodynamic tolerance develops for side effects after several doses).
Preload reduction to a certain extent is also achieved during the administration diuretics, ACE inhibitors, ARBs, and during the extended treatment with beta-adrenergic blockers.
What's the Evidence?
Munzel, T, Daiber, A, Gori, T. ” Nitrate therapy: new aspects concerning molecular action and tolerance”. Circulation. vol. 123. 2011. pp. 2132-44. (A good review addressing some of the molecular mechanisms of nitrate therapy.)
Leier, CV, Huss, P, Magorien, RD, Unverferth, DV. ” Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure”. Circulation. vol. 67. 1983. pp. 817-22. (A placebo-controlled study showing that nitrates may have a beneficial effect on hemodynamics (resting and exercise) and symptoms in chronic systolic heart failure. There are no large, randomized, placebo-controlled trials addressing this therapy.)
Elkayam, U, Karralp, IS, Wani, OR. ” The role of organic nitrates in the treatment of heart failure”. Prog Cardiovasc Dis. vol. 41. 1964. pp. 255-64. (A nice overview of the role and limitations of nitrate therapy in chronic systolic heart failure.)
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