Patients should be instructed to remain seated when taking rapid-acting nitrate products as a safety precaution to avoid syncope from vasodilation. Tolerance to the headaches could develop after a few weeks of continuing the medication. Prophylactic analgesics can be helpful until headache toler- ance develops. Methemoglobinemia is a rare adverse effect, usually seen only with large doses. Nitrates are relatively contraindicated in hypertrophic obstructive cardiomyopathy because of the potential to increase the outflow tract obstruc- tion and mitral regurgitant flow. They should be avoided in patients with severe aortic valvular stenosis. Coadministra- tion of the phosphodiesterase inhibitors sildenafil, tadala- fil, or vardenafil with long-acting nitrates should be strictly avoided within 24 hours of nitrate administration because of the risk of profound hypotension (eg, 25 mm Hg drop in systolic BP). Patients should be advised not to take phosphodiesterase inhibitors within 24 hours of long- acting nitrates, and nitrates should not be taken for 24 hours after use of sildenafil or 48 hours after tadalafil; a suitable time interval after vardenafil has not been deter- mined. Patients should be made aware of the possibility of intensification of their angina if nitrates are discontinued abruptly. This effect could be reduced by concomitant administration of other antianginals or by tapering of the long-acting nitrate dosage. 4.4.3.1.4. Ranolazine. Ranolazine inhibits the late inward sodium current, indirectly reducing the sodium-dependent calcium current during ischemic conditions and leading to improvement in ventricular diastolic tension and oxygen consumption. Minimal changes in mean heart rate (,2 beats per minute) and systolic BP (,3 mm Hg) occur in controlled studies. 