Nitrates

Summary

Nitrates are a class of drugs that include isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin. These drugs work to release nitric oxide in the body, which increases cyclic GMP levels inside cells. This causes smooth muscle relaxation, which leads to vasodilation that preferentially dilates veins over arteries.
This dilation of veins causes a lowering of preload on the heart.

Clinically, nitrates are used to treat heart attacks, as well as other forms of acute coronary syndrome. They are also used in outpatient settings to treat less acute cases of chest pain. Nitrates can also be used to treat pulmonary edema.

Side effects of nitrates include hypotension, as well as reflex tachycardia. Reflex tachycardia can be prevented by giving nitrates together with beta blockers. Nitrates can also cause flushing of the skin of the face. Importantly, nitrates are contraindicated in right ventricular infarction, hypertrophic cardiomyopathy, as well as in patients taking erectile dysfunction drugs. High doses of nitrates can increase methemoglobin levels to cause methemoglobinemia. Headache may also be seen as a side effect of nitrates. Lastly, nitrates cause tolerance, which can present as Monday Disease in patients with industrial exposures to nitrates.

Key Points

• Nitrates
  • Drug Names
    • Nitroglycerin (NTG)
      • Often administered sublingually
    • Isosorbide dinitrate
    • Isosorbide mononitrate
  • Mechanism
    • Vasodilator
      • Increased nitric oxide (NO) → Increased cGMP
        • Causes smooth muscle relaxation
      • Dilate veins >> arteries
        • Preferentially dilate veins, which hold most of the blood volume in the body (60%)
        • Many factors behind this: potency of NO at diff. beds, duration of action, time needed for intracellular conversion from drug form into NO, etc.
      • Decreases Preload
        • Preferential dilation of veins reduces venous return to the heart
  • Clinical Use
    • Treats Angina
      • Sublingual nitrates are first-line for symptomatic relief
      • Via decreased preload (decreased work of heart) and direct vasodilation of coronary arteries
    • Treats acute coronary syndrome (myocardial infarction)
      • Nitrates may be used to treat unstable angina and myocardial infarction
    • Treats pulmonary edema
      • Reducing preload and venous return can reduce pulmonary congestion in heart failure
  • Side Effects
    • Reflex tachycardia
      • Treat with beta-blockers
    • Methemoglobinemia
      • Nitrates are metabolized into nitrites as an intermediate to form nitric oxide (NO)
      • Nitrite can react with hemoglobin to form methemoglobin
    • Hypotension
      • Contraindicated with PDE5 inhibitors (sildenafil)
        • Synergistic effect on cGMP (PDE5 inhibits breakdown) causes severe systemic hypotension/shock
    • Flushing
      • Thought to be caused by vasodilation
    • Headache
      • Thought to be caused by vasodilation
    • Contraindicated in hypertrophic cardiomyopathy
      • Sufficient preload is in hypertrophic cardiomyopathy required to maintain filling that prevents outflow tract obstruction
      • Nitrates reduce preload, leading to outflow obstruction and reduce cardiac output, which can cause life-threatening cardiogenic shock
    • Contraindicated in Right Ventricular Infarction
      • After a right ventricular infarction, the right ventricle usually experiences reduced contractility due to ischemia.
      • This increases the reliance on increased filling (preload) to maintain stroke volume in the setting of a reduced ejection fraction.
      • Nitrates reduce preload, which can result in life-threatening cardiogenic shock
    • Tolerance
      • Responsible for “Monday disease” in industrial exposure
        • Tolerance develops during work week and is lost over weekend → reflex tachycardia, dizziness (hypotension), headache (hypotension) upon reexposure on Monday mornings
      • Requires nitrate-free interval every day in proper dosing schedule
        • Rebound angina is noted in some patients during their nitrate-free interval, so concomitant use of an additional anti-anginal therapy is recommended to prevent this rebound effect