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Pharmacology

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Cardiovascular Pharm

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Nitrates

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Summary

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Key Points

  • Nitrates
    • Drug Names
      • Nitroglycerin (NTG)
      • Isosorbide dinitrate
      • Isosorbide mononitrate
    • Mechanism
      • Vasodilator
        • Increased nitric oxide (NO) → Increased cGMP
          • Requires intracellular conversion into NO (I like to think this is why it affects veins preferentially, b/c veins come after and therefore allow more time for conversion into NO)
          • vascular smooth muscle relaxation
        • Dilate (veins >> arteries)
          • Preferentially dilate veins, which hold most of the blood volume in the body (60%)
            • Reason for this is unclear based on the literature - lot of different things at play: potency of NO at diff. beds, duration of action, etc.
          • Reduce venous return to the heart (decrease preload)
      • Often administered sublingually
    • Indications and Clinical Use
      • Angina pectoris
        • Sublingual nitrates are first-line for symptomatic relief
        • Via decreased preload (decreased work of heart) and direct vasodilation of coronary arteries
      • Hypertension
        • Nitroglycerine is used intravenously for hypertensive emergencies
      • Acute coronary syndrome (myocardial infarction)
      • Pulmonary edema
    • Adverse Effects
      • Severe hypotension with PDE5 inhibitors (sildenafil)
        • Absolutely contraindicated in patients taking PDE inhibitors for erectile dysfunction (sildenafil)
        • Synergistic effect on cGMP (PDE5 inhibits breakdown) causes severe systemic hypotension/shock
      • Contraindicated in “preload-dependent” conditions
        • Hypertrophic cardiomyopathy
          • Preload required due to increased outflow tract obstruction
        • Right ventricular myocardial infarction
          • Preload required to maintain cardiac output
        • Administration in these populations can lead to fatal 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
        • 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
            • This is really important because the fact that myocardial infarction and sudden death occur most commonly in the early morning hours (this is when many patients on anti-anginal therapy are in the midst of their medication-free interval)
          • Long-term exposure to nitrates leads to the development of reactive oxygen species that bind to nitric oxide → decreased NO activity → nitrate tolerance
      • Headache and flushing may be seen
        • Secondary to vasodilation
      • Reflex tachycardia
        • Treat with beta-blockers