Nitrates increase exercise tolerance, improve the ejection fraction, and enhance the hemodynamic profile (decreased ventricular filling pressures and valvular regurgitation, and increased cardiac output). They can be used as adjunctive therapy in patients who remain symptomatic at maximally tolerated doses of angiotensin-con-verting enzyme (ACE) inhibitor, especially if they are still hypertensive or have mitral insufficiency. In addition, nitrates are the specific therapy for concomitant angina. Sublingual or spray nitrates are also useful as a temporary symptomatic or preventive therapy (in predictable situations) for dyspnea.
A major pharmacologic limitation is that their vascular, hemodynamic, and clinical actions are short-lived and rapidly lost on chronic continuous administration.
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The mechanism of tolerance remains unclear. A reasonable hypothesis is that nitrates increase the vascular production of free radicals and bioavailability of superoxide anions, but the connection between oxidative stress and tolerance remains unelucidated.
Management dos and don'ts.
‚ Tachyphylaxis develops more rapidly in response to high doses and/or frequent dosing (every 4 to 6 hours).
‚ Use 10- or 12-hour dosing intervals (eg, morning and evening), or incremental doses (eg, 20,40, 80 mg every 6 hours, followed by an interval). Time the interval to the patient's needs: diurnal, if the complaint is nocturnal dyspnea and orthopnea (although orthopnea is an indication for increased diuresis); nocturnal, to cover the patient during daytime activity.
‚ Use high doses in patients who do not tolerate ACE inhibitors or if there is hemodynamic evidence of a persistent increase in left ventricular filling pressures.
‚ Headache, the most frequent side effect, generally subsides after a few days of treatment (in parallel with the drug's intended effects).
‚ Postural hypotension is more frequent when nitrate and ACE inhibitor (and (3-blocker) are administered at the same time: allow an interval of at least 1 hour between the two.
‚ In postural hypotension or reduced peripheral perfusion, try reducing the diuretic, and possibly withdrawing the nitrate, before reducing or withdrawing the ACE inhibitor.
‚ Patch absorption is variable, which complicates the management of tolerance (give clear instructions as to when to apply and remove the patch).
Drug; nitrate; adjuvant therapy; tachyphylaxis; side effect.