Pharmacodynamics

Exogenous supply of nitric oxide (NO) through nitrate → activation of guanylyl cyclase → ↑ cyclic guanosine monophosphate (cGMP) → activation of protein kinase G
- Increases SERCA activity → ↓ intracellular calcium → ↓ recruitment of contractile units → vasodilation
- Increases myosin light chain phosphatase activity → ↓ phosphorylated myosin → smooth muscle relaxation → vasodilation
  - Peripheral vasodilation
    - Major contributor to angina relief
    - Decreased preload through venous dilation (venous pooling) → reduces myocardial wall tension → improved myocardial perfusion
    - Decreased afterload → reduces contraction effort → ↓ myocardial oxygen demand
    - Greater vasodilatory effect on veins than arteries (except for sodium nitroprusside)
  - Coronary dilation → improved myocardial perfusion
    - In patients with atherosclerotic CAD, arterioles are already dilated to maximize cardiac blood flow (due to flow-limiting stenosis) → difficult to dilate coronary vessels further → limited effect of nitrates
Anginal pain relief: ↓ preload through venous pooling → ↓ heart size → ↓ oxygen demand → ↓ pain

Adverse effects

Circulatory dysregulation: hypotension, reflex sympathetic activity → reflex tachycardia → nitrate syncope
- Beta blockers can be applied to counter this mechanism
Nitrate-induced headache (due to the dilation of the cerebral arteries)
Development of tolerance
- Prevention: intermittent therapy with nitrate-free intervals of at least 8 hours
- Usually the nitrate-free period is timed to occur during the night when the patient is sleeping and cardiac work is the least.
Cyanide toxicity after sodium nitroprusside infusion (see cyanide poisoning)