What is the role of Ranexa (ranolazine) and Imdur (isosorbide mononitrate) in treating chronic angina?

Role of Ranolazine and Isosorbide Mononitrate in Treating Chronic Angina

Ranolazine and isosorbide mononitrate serve complementary roles in chronic angina management, with ranolazine being most effective as add-on therapy when standard treatments are inadequate, while isosorbide mononitrate works as a traditional nitrate that reduces cardiac preload and workload. 1, 2

Mechanism of Action

Ranolazine (Ranexa)

• Unique mechanism: Inhibits late sodium current in cardiac myocytes
• Prevents intracellular calcium overload during ischemia
• Reduces left ventricular wall tension without affecting heart rate or blood pressure
• May improve glucose metabolism under ischemic conditions 1

Isosorbide Mononitrate (Imdur)

• Traditional nitrate that causes vasodilation
• Reduces preload and afterload
• Decreases myocardial oxygen demand
• Improves coronary blood flow to ischemic areas

Clinical Efficacy

Ranolazine

• FDA-approved for chronic angina treatment
• Extended-release formulation (500-1000 mg twice daily)
• Provides modest but significant improvements in:
  • Exercise duration
  • Reduced angina frequency
  • Decreased nitroglycerin consumption 3, 4
• Particularly useful when beta-blockers or calcium channel blockers cause bradycardia or hypotension 1
• Does not improve cardiovascular outcomes or mortality 1

Special Populations for Ranolazine

• Patients with diabetes: May provide additional benefit due to glycemic improvements 1
• Patients with left ventricular hypertrophy: May be more effective due to effects on sodium current and calcium homeostasis 1
• Patients with microvascular angina: Mixed evidence, with larger trials not showing superiority over placebo 1

Dosing and Administration

Ranolazine

• Starting dose: 500 mg twice daily
• Maximum dose: 1000 mg twice daily
• Take with or without food
• Swallow tablets whole (do not crush, break, or chew) 2

Dose Modifications for Ranolazine

• Limit to 500 mg twice daily with moderate CYP3A inhibitors (diltiazem, verapamil)
• Contraindicated with strong CYP3A inhibitors or inducers
• Use caution with P-gp inhibitors 2

Safety Considerations

Ranolazine

• QT interval prolongation (dose-related)
• Common side effects: constipation, nausea, dizziness, headache, asthenia 3, 4
• Contraindications:
  • Liver cirrhosis
  • Strong CYP3A inhibitors/inducers
  • Pre-existing significant QT prolongation 2
• Drug interactions: digoxin (increased concentration), moderate CYP3A inhibitors 1, 5

Treatment Algorithm

1. First-line therapy:

   • Beta-blockers and/or calcium channel blockers

2. When to add ranolazine:

   • When symptoms persist despite first-line therapy
   • When patients cannot tolerate beta-blockers or calcium channel blockers due to bradycardia or hypotension
   • Consider earlier in patients with diabetes or left ventricular hypertrophy 1, 5

3. When to use isosorbide mononitrate:

   • Can be used as first-line or add-on therapy
   • Particularly useful for preload reduction
   • Requires nitrate-free interval to prevent tolerance

4. Combination therapy:

   • Ranolazine can be safely combined with beta-blockers, calcium channel blockers, and nitrates 2
   • Provides complementary mechanisms of action

Monitoring

• ECG monitoring for QT prolongation with ranolazine
• Renal function tests, especially in at-risk patients
• Symptom assessment for efficacy and side effect management 5

Key Pitfalls to Avoid

1. Ranolazine contraindications: Never use with strong CYP3A inhibitors or in patients with liver cirrhosis 2

2. QT interval monitoring: Be cautious in patients with other QT-prolonging medications or conditions 5

3. Realistic expectations: Ranolazine provides modest symptomatic improvement but does not reduce cardiovascular events or mortality 1, 3

4. Nitrate tolerance: Ensure proper nitrate-free intervals when using isosorbide mononitrate

5. Dose adjustment: Reduce ranolazine dose to 500 mg twice daily when used with moderate CYP3A inhibitors like diltiazem or verapamil 2