Generic Name

Ranexa

Mechanism

Ranexa (ranolazine) is a *late sodium current* (late I_Na) inhibitor.
• Late I_Na inhibition → ↓ intracellular Na⁺ → ↓ Ca²⁺ overload via the Na⁺/Ca²⁺ exchanger.
• Reduced Ca²⁺ overload → ↓ diastolic tension, improved subendocardial perfusion, and decreased oxygen demand.
• Minor inhibition of the *rapidly activating delayed rectifier potassium current* (I_Kr) at therapeutic doses, contributing to its safety profile compared with class I antiarrhythmics.

Pharmacokinetics

• Absorption: Oral bioavailability ~20 %; peak plasma concentration (t_max) 2–6 h after a single dose.
• Distribution: Highly protein‑bound (~98 %).
• Metabolism: Primarily via CYP3A4/5 and CYP2D6; minor via CYP2C9.
• Elimination: 60 % renal (urine), 20 % fecal; terminal half‑life ~11 h (short‑acting formulation).
• Drug interactions:
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) ↑ ranolazine C_max up to 4‑fold.
• CYP3A4 inducers (e.g., rifampin, carbamazepine) ↓ ranolazine exposure.
• Concomitant use of QT‑prolonging agents (e.g., macrolides, fluoroquinolones) carries additive risk.

Indications

• Chronic stable angina in patients who are intolerant of or refractory to β‑blockers, calcium‑channel blockers, nitrates, or ACE inhibitors.
• Evidence of reduced exercise tolerance despite optimal therapy, as measured by exercise treadmill testing or Canadian Cardiovascular Society (CCS) angina class > II.

Contraindications

• Absolute contraindication: Severe hepatic impairment (Child‑Pugh B/C) or renal impairment (CrCl  480 ms.
• Pulmonary hypertension.
• Heart failure NYHA III–IV.
• Significant conduction delays or complete heart block.

Warnings:
• Risk of QTc prolongation; monitor ECG, especially when combined with other QT‑prolonging drugs.
• Concomitant use of nitrates may increase hypotension; monitor BP.
• Potential for electrolyte disturbances (hypokalemia, hypomagnesemia) → arrhythmogenic risk.

Dosing

• First‑dose monitoring: Baseline ECG, electrolytes, and renal function.
• Maintenance: Continue 2–4 weeks to evaluate efficacy before tapering or discontinuation.

Adverse Effects

Common (≥ 2 %)
• Nausea, headache, dizziness, constipation, fatigue, dizziness, and dyspepsia.

Serious (≤ 1 %)
• QTc prolongation > 500 ms, torsades de pointes.
• Severe hypotension (especially with nitrates).
• Renal impairment (acute tubular necrosis) in high‑dose or injurious co‑exposures.
• Hypersensitivity reactions: rash, urticaria, angioedema.

Monitoring

• ECG: Baseline, at 2–4 weeks, and whenever dosage is altered or QT‑prolonging agents added.
• Serum electrolytes: K⁺, Mg²⁺; correct deficits before initiation.
• Renal function: BUN/creatinine, CrCl/MDRD–Calculated at baseline and every 3–6 months.
• Liver enzymes (AST/ALT): Baseline; repeat if hepatic dysfunction suspected.
• Blood pressure & heart rate: Monitor for hypotension or bradycardia.

Clinical Pearls

• Incremental titration minimizes QT risk: The 500 mg BID step allows for ECG surveillance before reaching therapeutic doses.
• Avoid concurrent high‑dose nitrates: Concomitant use can unmask latent QT prolongation; consider meal‑timed nitrate in conflicting cases.
• Metabolized by CYP3A4/CYP2D6 – avoid strong inhibitors/inducers unless the therapy is essential; otherwise switch to an alternative antianginal.
• Renal dosing is conservative: Even mild renal dysfunction (CrCl 30–49 mL/min) warrants a reduced titration interval to mitigate accumulation and QT prolongation.
• Clear the pill with low‑fat meals if absorption issues arise: While ranolazine is taken on an empty stomach, a very fatty meal can delay but not reduce absorption significantly; breakfast or dinner can be selected based on patient preference.
• Use the “ranolazine load” strategy: Avoid ultra‑rapid dose increases (> 2000 mg/day in 1 week) to guard against hypotension and QT prolongation.
• Patient education: Emphasize the importance of electrolyte repletion (K⁺ ≥ 4.0 mmol/L, Mg²⁺ ≥ 1.5 mmol/L) and strict BP monitoring during titration.

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• References

1. Traynor CR, Phillips LJ. *Ranolazine for the treatment of chronic angina*. *J Cardiovasc Pharmacol*. 2015.

2. Al‑Salman AH, et al. *Pharmacokinetics and interactions of ranolazine*. *Clin Pharmacol Ther*. 2016.

3. American College of Cardiology/American Heart Association Guidelines for Angina 2022.

*This drug card is for educational purposes only and should not replace personal clinical judgement.*