Harvey's Garden

Nitrates

2 min read

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
  • 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)

Contraindications

  • PDE-5 Inhibitors (e.g., sildenafil, tadalafil): ABSOLUTE CONTRAINDICATION. Both drug classes increase cGMP, leading to synergistic and potentially fatal hypotension. A nitrate should not be administered within 24 hours of sildenafil or 48 hours of tadalafil.
  • Right-Sided MI (RV Infarction): These patients are highly preload-dependent. Nitrates can cause a catastrophic drop in cardiac output and severe hypotension.
  • Hypertrophic Obstructive Cardiomyopathy (HOCM): Decreased preload can worsen the dynamic LV outflow tract obstruction.
  • Severe Aortic Stenosis: Preload reduction can lead to syncope and hypotension.

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