USMLE

Nitrates

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Cardiovascular Pharm
  1. Adenosine
  2. Magnesium
  3. Nitroprusside
  4. Nitrates
  5. Ivabradine
  6. Digoxin/Digitalis
  7. Class IA Antiarrhythmics
  8. Class IB Antiarrhythmics
  9. Class IC Antiarrhythmics
  10. Class II Antiarrhythmics
  11. Class III Antiarrhythmics - Amiodarone
  12. Class III Antiarrythmics - Sotalol
  13. Class III Antiarrhythmics - Ibutilide, Dofetilide
  14. Class IV Antiarrhythmics - Verapamil, Diltiazem
  15. HMG-CoA Reductase Inhibitors (Statins)
  16. Ezetimibe
  17. Fibrates
  18. PCSK9 Inhibitors (Alirocumab, Evolocumab)
  19. Fish Oil and Omega-3s
  20. Milrinone
  21. Aliskiren
  22. Hydralazine
  23. Ranolazine
  24. Sacubitril

Summary

Nitrates are a class of drugs that include nitroglycerin, isosorbide dinitrate and isosorbide mononitrate. Nitrates work by inducing vasodilation, by way of increasing nitric oxide and cGMP levels, which in turn cause the relaxation of smooth muscle. Importantly, Nitrates preferentially dilate veins over arteries. Clinically, Nitrates are used to treat hypertension and angina. However, tolerance to nitrates can develop, so patients should follow a rigid dosing schedule with nitrate-free intervals. Other possible adverse effects include reflex tachycardia, headaches, and flushing. Finally, nitrates are absolutely contraindicated in patients taking PDE5 inhibitors or in patients with “preload dependent” conditions, as use in these patients can lead to fatal hypotension and shock.

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