Nitrates (FETT)

GLYCERYL TRINITRATE

ISOSORBIDE

MONONITRATE

Nitrates are a class of medications that increase the release of nitric oxide (NO) in vascular smooth muscle cells, leading to smooth muscle relaxation and subsequent vasodilation. Veins are affected more than arteries, and most therapeutic effects of nitrates result from venous pooling and subsequently decreased preload.

• Organic nitrates (nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate) require activation by mitochondrial aldehyde reductase, therefore, the onset of action is not immediate.

• Sodium nitroprusside is activated non-enzymatically; therefore the onset of action is immediate

• Oral nitrates undergo extensive first-pass metabolism in the liver.

• 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

      • 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

• 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)

• Flushing

• Gastroesophageal reflux (due to the relaxation of the lower esophageal sphincter)

• Development of tolerance

  • Prevention: intermittent therapy with nitrate-free intervals of at least 8 hours

• Cyanide toxicity after sodium nitroprusside infusion (see cyanide poisoning)

• Methemoglobinemia

• Industrial workers who are exposed to nitrates during the work week develop a tolerance over the course of the week.

• No exposure during weekends leads to loss of tolerance.

• Reexposure on Monday causes dizziness, tachycardia, and headache.

• Angina pectoris

  • Short-acting nitrates such as sublingual nitroglycerin, isosorbide dinitrate, or nitroglycerin spray for treatment of acute attacks

  • Long-acting nitrates such as isosorbide mononitrate can be taken regularly (2–3 times daily) for anginal prophylaxis: unlike some other nitrates, isosorbide mononitrate does not undergo first-pass metabolism by the liver and thus has ∼100% bioavailability.

• Hypertensive crisis: short-term reduction of blood pressure

• Acute coronary syndrome

• Hypertensive pulmonary edema

• Chronic heart failure

• Hypotension

  • Risk of life-threatening hypotension if taken within 24 hours of a PDE-5 inhibitor (e.g., patients with angina pectoris)

• Stenosis of the left ventricular ejection tract (e.g., aortic stenosis, hypertrophic cardiomyopathy)

• Myocardial infarction with right ventricular failure

• Increased intracranial pressure