Pentaerythrityl Tetranitrate: Long-acting Nitrate

Pentaerythrityl tetranitrate (PETN, trade name Pentalong) is an organic nitrate from the class of long-acting nitrates, used in the therapy of coronary artery disease. PETN differs from other organic nitrates such as glyceryl trinitrate and isosorbide mononitrate through a longer duration of action and lower tolerance development. In Germany, PETN has been available for decades and has a well-established role in long-term therapy of stable angina pectoris. Despite newer therapeutic options such as beta blockers, calcium antagonists, and ranolazine, PETN remains a proven alternative or add-on therapy in patients with persistent anginal symptoms.

PETN has demonstrated good clinical data in the Pentalong study (PENTACOR) for reducing anginal attacks and improving exercise tolerance. The substance is primarily administered orally as tablets and is usually taken once to three times daily. Important in long-term therapy is adherence to the nitrate-free interval to avoid tolerance development, which frequently occurs with short-acting nitrates. In this regard, PETN is considered more favorable than short-acting nitrates.

Mechanism of Action

PETN, like all organic nitrates, works through endothelial and cellular release of nitric oxide (NO). NO activates soluble guanylate cyclase in the vascular smooth muscle cell, leading to an increase in cyclic GMP (cGMP) and activation of protein kinase G. This results in inhibition of intracellular calcium influx and relaxation of vascular smooth muscle. The vasodilatory effect primarily affects venous capacitance vessels and thereby reduces preload on the heart, which lowers myocardial oxygen consumption.

At higher doses, PETN also acts on coronary arteries and reduces spasms or dilates collateral vessels, thereby improving myocardial oxygen supply. The combination of preload reduction and improved coronary perfusion explains the antianginal effect. PETN also has positive effects on endothelial dysfunction, which with chronic use may contribute to improved vascular function.

Pharmacokinetically, PETN is rapidly absorbed after oral administration but undergoes pronounced first pass metabolism in the liver. PETN itself has a plasma half-life of approximately 3 to 4 hours, but is metabolized to pharmacologically active metabolites such as pentaerythritol mononitrate and pentaerythritol dinitrate. These active metabolites have considerably longer half-lives of 8 to 14 hours and contribute to the prolonged duration of action. Elimination occurs predominantly via the renal route.

Indications

• Stable angina pectoris as long-term therapy for attack prophylaxis
• Vasospastic angina (Prinzmetal angina), in specific indications with coronary spasms
• Left ventricular insufficiency with increased preload in specific constellations, especially with concurrent symptomatic angina
• Adjunctive therapy in stable coronary artery disease in combination with beta blockers, calcium antagonists, or ranolazine

PETN is not suitable for acute termination of an anginal attack; glyceryl trinitrate sublingually is used as an acute preparation for this purpose. In patients with high-frequency attacks, PETN is used as a basic prophylactic component.

Dosage and Administration

Stable angina pectoris Adults: 50 mg one to three times daily orally. Begin with a low dose (50 mg once daily), gradually increase according to effect and tolerability. Maximum dose 240 mg per day.

Distribution throughout the day: ideally to prevent tolerance development with adequate nitrate-free interval, for example in the morning and midday, so that an 8 to 10 hour nitrate-free interval exists at night.

Administration: take with water, whole tablet, preferably fasting or before meals for better absorption. Do not divide or crush tablets as this may affect bioavailability.

At therapy initiation: start with low dose, slow increase over several days to reduce headache and hypotension.

Renal insufficiency: exercise caution with severe impairment and consider dose reduction if needed. Hepatic insufficiency: exercise caution with severe impairment due to enhanced effect.

Important: gradual dose reduction when discontinuing therapy, as abrupt cessation can trigger rebound angina.

Side Effects

Very common (especially at initiation): headache, often pronounced in the first few days and usually resolving after 1 to 2 weeks.

Common: dizziness, weakness, flushing, tachycardia, hypotension, orthostatic symptoms, nausea, vomiting.

Occasional: tendency to collapse, paradoxical bradycardia with syncope, allergic skin reactions, rash.

Rare to very rare: methemoglobinemia (especially with overdose), severe allergic reactions including anaphylaxis, worsening of narrow angle glaucoma, exfoliative dermatitis.

Tolerance development: with continuously high levels, reduction in effectiveness, making the nitrate-free interval important. PETN is considered less susceptible to tolerance than short-acting nitrates.

Drug Interactions

• Phosphodiesterase 5 inhibitors (sildenafil, tadalafil, vardenafil): contraindicated combination, as massive hypotension with shock is possible. Minimum interval 24 hours (sildenafil, vardenafil) or 48 hours (tadalafil).
• Riociguat: contraindicated due to severe hypotension.
• Antihypertensive agents: additive hypotension, use with caution in combination, dose adjustment.
• Diuretics: enhanced hypotensive effect with volume depletion.
• Tricyclic antidepressants, antipsychotics: enhanced orthostatic hypotension.
• Alcohol: enhanced vasodilation and hypotension.
• Acetylsalicylic acid and other NSAIDs: theoretical reduction of antianginal effect, clinical relevance unclear.

Special Notes

Pregnancy: generally not recommended due to limited data. In cases of compelling indication, strict benefit-risk assessment. Breastfeeding: transfer into breast milk unclear, exercise caution.

Children: not approved for children due to insufficient data.

Contraindications: known hypersensitivity to nitrates, severe hypotension, shock, acute circulatory failure, hypertrophic obstructive cardiomyopathy, severe anemia, elevated intracranial pressure, concurrent use of PDE 5 inhibitors or riociguat, narrow angle glaucoma.

Before therapy: detailed cardiovascular history, blood pressure, EKG, exercise stress test if appropriate, check concomitant medications.

During therapy: regular clinical follow-up, attack frequency, blood pressure, tolerability. With worsening symptoms, cardiac reevaluation.

Lifestyle: address coronary artery disease risk factors (smoking, hypertension, lipids, diabetes, exercise). Adherence is important, avoid abrupt discontinuation.

Fitness to drive: do not drive or operate heavy machinery at therapy initiation and after dose adjustments due to dizziness and hypotension. Generally possible with stable treatment.

You might also be interested in

• Glyceryl trinitrate, short-acting nitrate as spray or capsule for acute treatment
• Isosorbide mononitrate, long-acting nitrate as alternative
• Molsidomin, NO donor with similar effect
• Ranolazine, antianginal agent with different mechanism of action
• Metoprolol, beta blocker for stable angina

Frequently Asked Questions

Sources

• Gelbe Liste, Pentaerythrityl Tetranitrate Active Ingredient Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• German Society for Cardiology (DGK), Guidelines for Stable Angina Pectoris
• AWMF National Care Guideline Chronic Coronary Artery Disease