Nitroglycerin

Introduction

• NTG consists of a glycerol backbone with three hydroxyl groups, each esterified with nitric acid, forming nitrate esters. These nitrate esters are essential to its bioactivation, as enzymatic cleavage of these groups releases nitric oxide (NO), which mediates the desired vasodilatory effect.^1,2

Mechanism of Action

• NTG is converted to nitric oxide (NO) in the body, which activates the enzyme guanylyl cyclase, leading to the conversion of guanosine triphosphate (GTP) to cyclic 3’,5’-guanosine monophosphate (cGMP).^1,3,4
• Elevated cGMP acts as a secondary messenger by activating the protein kinase G (PKG) pathway. cGMP inhibits calcium entry and promotes calcium reuptake into the sarcoplasmic reticulum. Activated PKG induces dephosphorylation of myosin light chains. These effects collectively result in vascular smooth muscle relaxation and the desired vasodilatory response.¹
• At lower therapeutic doses, NTG predominantly causes venodilation, decreasing preload by reducing venous return to the heart. At higher doses, it can induce arterial dilation, which reduces afterload and improves myocardial perfusion.^1,3

Pharmacokinetics/Metabolism

• NTG is primarily eliminated via hepatic metabolism with a mean half-life of 2 to 3 minutes.⁴
• NTG is a pro-drug metabolized by mitochondrial and cytosolic aldehyde dehydrogenase, ALDH-2. ALDH-2 catalyzes the removal of nitrate groups from NG, ultimately releasing nitric oxide (NO).¹

Routes of Administration and Dosage

• NTG sublingual (SL) tablets have an onset of vasodilatory effects within 1 to 3 minutes. Three dosage forms are available (0.3 mg, 0.4 mg, and 0.6 mg) and can be taken every 5 minutes, up to three times, for the acute relief of angina. For prophylactic use, one SL tablet can be taken 10 minutes prior to activities likely to provoke angina attacks.^3,4
• Transdermal NTG administration (ointment) is also commonly used for acute angina attacks in patients who cannot tolerate sublingual tablets. Full absorption takes 5 to 10 minutes. Transdermal patches are typically reserved for angina prophylaxis.^3,4
• NTG continuous IV solution is started at 5 mcg/min and can be increased by 5 mcg/min every 3 to 5 minutes as needed, up to 20 mcg/min.³ From that point, titration of 10-20 mcg/min every 3 to 5 minutes, up to a maximum dose of 500 mcg/min, is advised.
• For obstetric usage, uterine relaxation is noted at doses of 100-200 mcg, administered intravenously.⁶

Clinical Uses

• Common clinical uses of NTG include:
  • Stable Angina: Provides acute relief of anginal attacks and it is commonly used for long-term management as acute prophylaxis before exertion.⁴
  • Acute Coronary Syndrome: Employed for ischemic chest pain relief within the emergency care setting due to the rapid-acting effects of the IV formulation.⁶
  • Congestive Heart Failure: Helps alleviate pulmonary congestion and provides dose-dependent reductions in preload and afterload.^1,5
  • Hypertensive Emergencies: Utilized when rapid lowering of blood pressure is needed in patients with ischemia or pulmonary edema.⁴
  • Vasospastic Angina: This is an off-label use of NTG due to its effectiveness at relieving coronary artery spasm, particularly at night or at rest.⁴
  • Anal Fissures: Topical, low-dose NTG can be applied locally to relieve moderate to severe anal fissure pain.^3,4
• NTG primarily acts as a venodilator, which limits its blood pressure-lowering effect compared to other first-line antihypertensives.
• NTG is used in obstetrics as a fast-acting uterine relaxant. This can be useful for instances of uterine tetany, uterine inversion, or to facilitate the removal of a retained placenta.^7,8

Side Effects

• Flushing: Facial redness and warming of the skin are commonly seen during acute administration due to its vasodilatory effects.³
• Headaches: The onset of headaches is typically observed within the first hour of NTG administration and is indicative of vasodilatory effects caused by the release of NO. Tolerance to headaches often develops over time.¹
• Hypotension: An extended reduction in preload and afterload reduces myocardial oxygen demand but risks the development of symptomatic hypotension. Patients can experience dizziness, lightheadedness, or syncope.³
• Nitrate Toxicity: Excess nitrate intake can lead to visual disturbances, syncope, nausea and vomiting. These symptoms are related to the vasodilatory and hypotensive effects of NTG. Methemoglobinemia is a rare but serious side effect of NTG toxicity- these patients will demonstrate symptoms of hypoxia with cyanosis with normal arterial partial pressure of oxygen.^1,4

Special Considerations

• One of the main benefits of nitroglycerin usage is its rapid onset and short duration of action.
• The development of nitrate tolerance limits NTG use, as prolonged, continuous use (>12 hr) can result in the loss of its hemodynamic effects. Nitrate-free intervals (8-12 hours) are recommended to prevent tolerance.⁴
• NTG is contraindicated with the use of PDE-5 inhibitors (e.g., sildenafil citrate, vardenafil hydroxide, tadalafil) to avoid severe hypotensive effects of nitrates and the precipitation of syncopal episodes.^1,4