Antianginal Drugs Nitrates and Ranolazine
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Direct answer
Nitrates such as glyceryl trinitrate and isosorbide mononitrate relieve angina by releasing nitric oxide, which dilates veins, lowers preload and reduces myocardial oxygen demand. Their main limitations are nitrate tolerance, which needs a nitrate-free interval, and a strict contraindication with PDE5 inhibitors. Ranolazine, a late sodium current blocker, is an add-on for chronic stable angina that does not lower heart rate or blood pressure.
What you must remember
- Glyceryl trinitrate: drug of choice for acute angina, given sublingually, with relief within minutes and up to three doses at five-minute intervals if pain persists.
- Mechanism: nitric oxide activates guanylyl cyclase, raising cGMP and relaxing smooth muscle, with venodilation dominating at low doses.
- Nitrate tolerance: continuous exposure blunts the response through thiol depletion and oxidative stress, and a nitrate-free interval of about 10 to 12 hours, usually overnight, prevents it.
- PDE5 inhibitor interaction: sildenafil, tadalafil and vardenafil cause profound hypotension with nitrates, so a washout of about 24 hours for sildenafil and 48 hours for tadalafil is needed.
- Ranolazine: inhibits the late sodium current, improves angina without significant change in heart rate or blood pressure, and prolongs the QT interval.
- Ranolazine cautions: contraindicated in liver cirrhosis and with strong CYP3A inhibitors such as ketoconazole and clarithromycin.
- Ivabradine: blocks the funny current in the sinus node, lowers resting heart rate in sinus rhythm and commonly causes transient phosphenes.
A stepwise plan for a patient with stable angina on nitrates
A 62-year-old man on a beta-blocker and isosorbide mononitrate has just been prescribed sildenafil for erectile dysfunction. The steps below show how to keep him safe and add the right agent.
- Check the interaction first: Sildenafil taken with a nitrate can drop blood pressure sharply, so the PDE5 inhibitor must be withheld and washed out before any nitrate is given. Tadalafil needs a longer gap, so this check comes first.
- Protect the nitrate-free interval: A once-daily extended release isosorbide mononitrate tablet taken in the morning leaves the patient nitrate-free overnight, which prevents tolerance.
- Add a heart rate agent: If the beta-blocker is at the maximal tolerated dose and resting heart rate stays at or above about 70 beats per minute in sinus rhythm, ivabradine can be added without a meaningful fall in blood pressure. Warn the patient that phosphenes may occur.
- Add a non-rate agent for persistent symptoms: Ranolazine relieves angina without slowing the heart, so it suits patients in whom heart rate or blood pressure already limits other drugs. Check the QT interval, liver function and interacting drugs such as clarithromycin before starting it.
- Review at follow-up: Ask about headache and postural dizziness, which often ease with continued use, and check that the nitrate-free timing is kept. Refer for revascularisation assessment if symptoms stay limiting on optimal medical therapy.
Where the examiner sets the traps
Most antianginal questions turn on one interaction or one physiological effect.
- Trap: choosing ranolazine to slow a fast heart rate in angina Correct: ranolazine does not change heart rate or blood pressure, so ivabradine or a beta-blocker is the right choice when rate reduction is the goal.
- Trap: treating a PDE5 inhibitor as a harmless add-on in a patient on nitrates Correct: the combination causes severe hypotension, so the drugs must be separated by a washout period.
- Trap: believing nitrate tolerance is overcome by increasing the dose Correct: tolerance follows continuous exposure and is prevented by a nitrate-free interval, not by escalating the dose.
Frequently asked questions
Which nitrate is preferred for relieving an acute attack of angina?
Glyceryl trinitrate given sublingually is the preferred agent for relieving an acute attack of angina, because its onset is within a few minutes. Oral isosorbide mononitrate and isosorbide dinitrate are long-acting preparations used for prevention, not for stopping an attack.
Why does a nitrate-free interval matter with long-acting nitrates?
A nitrate-free interval prevents nitrate tolerance, which develops with continuous exposure through thiol depletion and oxidative stress. Long-acting isosorbide mononitrate is usually scheduled to leave about 10 to 12 hours free of nitrate, often overnight.
Which drugs must never be combined with nitrates?
PDE5 inhibitors such as sildenafil, tadalafil and vardenafil must never be combined with nitrates, because the additive vasodilation causes severe hypotension. A washout of about 24 hours for sildenafil and about 48 hours for tadalafil is required before a nitrate is given.
How does ranolazine work and what are its main cautions?
Ranolazine inhibits the late sodium current in cardiomyocytes, reducing calcium overload and improving myocardial oxygen balance without slowing the heart. Its main cautions are dose-related QT prolongation and interactions with strong CYP3A inhibitors, and ranolazine is contraindicated in liver cirrhosis.
Why is ivabradine not used for rate control in atrial fibrillation?
Ivabradine acts on the funny current of the sinus node, so it slows heart rate only in sinus rhythm. Its visual side effect, phosphenes, is transient and is attributed to blockade of a related current in the retina.