Antianginal Drugs

After bioactivation, nitric oxide diffuses into vascular smooth muscle cells and activates an enzyme called soluble guanylyl cyclase, which raises intracellular levels of cyclic guanosine monophosphate. Cyclic guanosine monophosphate activates protein kinase G, which ultimately reduces the muscle's ability to maintain contraction. The result is vascular smooth muscle relaxation, which translates into vasodilation.

This pathway is identical to how endothelial cells normally signal blood vessels to relax. In patients with atherosclerosis, the diseased vessel lining often cannot produce enough nitric oxide on its own. Organic nitrates effectively supply this signal from the outside.

Nitrates do not affect every blood vessel equally, and which vessels respond depends on the dose. At low to standard doses, the large capacitance veins are the most sensitive target. Venodilation pools blood in the peripheral venous system, which reduces the volume of blood returning to the heart and lowers ventricular filling pressure. This is preload reduction, and it is the dominant effect of nitrates at typical doses.

At higher doses, arterial smooth muscle becomes affected as well, producing afterload reduction in addition to the venous effect. Coronary arteries, by contrast, are sensitive to nitrates at virtually any dose. This is why sublingual nitroglycerin works so reliably and so quickly in vasospastic angina, discussed in Module 1: it directly dilates the spastic epicardial coronary artery, independent of whatever else is happening with venous tone.

Continuous nitrate exposure reduces the activity of the enzyme responsible for converting the prodrug into active nitric oxide. With less nitric oxide generated per dose, the vasodilatory response weakens even though the patient is taking the same amount of drug. Patients and clinicians sometimes mistake this attenuated response for worsening of the underlying coronary disease rather than recognizing it as a predictable pharmacologic phenomenon.

Because the nitrate-free interval typically falls overnight, and overnight and early morning hours are already the period of highest circadian risk for angina, patients on long-acting nitrate therapy should also be maintained on a heart-rate-reducing agent that provides continuous protection independent of nitrate coverage.

In each of these three conditions, the heart's ability to generate adequate output is already compromised in a way that depends on maintaining ventricular filling. Removing preload, the one parameter nitrates reliably reduce, removes the compensation the heart is relying on. The same logic explains why alcohol, which independently produces vasodilation and blunts the baroreceptor reflex, potentiates nitrate-induced hypotension and is generally avoided around the time of nitrate dosing.