Nitrosol Aerosol Spray

Indications

• Angina pectoris
• Heart failure
• Hypertensive emergencies
• Myocardial infarction

Dosage

Children: Dosing in children is not well established; refer to

Adults: For acute angina, 0.3 to 0.6 mg sublingually. For transdermal patches, doses vary based on the specific product; consult guidelines for individualized dosing.

Mechanism of action

Nitroglycerin is converted by mitochondrial aldehyde dehydrogenase in vascular smooth muscle cells to nitric oxide (NO). NO activates guanylate cyclase, leading to the conversion of guanosine triphosphate (GTP) to cyclic guanosine 3',5'-monophosphate (cGMP). cGMP induces relaxation of vascular smooth muscle, which results in vasodilation and increased blood flow, particularly to the heart. This mechanism reduces myocardial oxygen requirements and alleviates angina symptoms.

Pharmacodynamics

Nitroglycerin causes relaxation of vascular smooth muscles, leading to both arteriolar and venous dilation. This results in increased myocardial blood flow, reduced cardiac preload and afterload, and lowered myocardial wall stress. Additionally, it alleviates coronary artery spasms and decreases systemic vascular resistance and blood pressure. Tolerance may develop with prolonged use, reducing efficacy due to desensitization of smooth muscle and potential inhibition of mitochondrial aldehyde dehydrogenase.

Pharmacokinetics

Nitroglycerin is rapidly absorbed and undergoes significant first-pass metabolism when administered orally. It has a half-life of about 1-4 minutes when given intravenously. The onset of action varies depending on the route of administration, with sublingual forms acting within minutes and transdermal patches providing sustained release. The drug is metabolized primarily in the liver and excreted in urine as metabolites.

Contra-indications

• Hypersensitivity to nitroglycerin or any of its components
• Severe anemia
• Increased intracranial pressure
• Hypotension
• Cardiomyopathy with obstructive lesions
• Severe aortic stenosis

Adverse effects

• Headache
• Dizziness
• Hypotension
• Tachycardia
• Nausea
• Flushing
• Methemoglobinemia

Interactions

• Concurrent use with phosphodiesterase type 5 inhibitors (e.g., sildenafil, tadalafil) may lead to severe hypotension
• Antihypertensives may enhance the hypotensive effect of nitroglycerin
• Alcohol may increase the risk of hypotension
• Other vasodilators may have additive effects

Precautions

• Use with caution in patients with renal or hepatic impairment
• Monitor blood pressure regularly
• Consider potential for tolerance with prolonged use
• Should not be abruptly discontinued after long-term use

Pregnancy

Nitroglycerin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data available.

Breast-feeding

Nitroglycerin is excreted in breast milk, caution is advised when administering to nursing mothers.

Storage

Store in a tightly closed container at room temperature, away from moisture and heat.

Formulations

• Sublingual tablets
• Transdermal patches
• Oral extended-release capsules
• Intravenous infusion
• Topical ointment

Indications

• Angina pectoris
• Heart failure
• Myocardial infarction prophylaxis
• Hypertensive emergencies
• Acute pulmonary edema

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated, as doses may vary significantly.

Mechanism of action

Nitroglycerin is converted to nitric oxide (NO) in the body, which activates guanylate cyclase. This enzyme increases levels of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells, leading to relaxation and vasodilation. The resultant decrease in preload and afterload reduces the workload of the heart, alleviating symptoms of angina.

Pharmacodynamics

The primary pharmacological effect of trinitrate is the relaxation of vascular smooth muscle, which leads to vasodilation. This effect is particularly pronounced in the venous system, reducing venous return to the heart (preload) and thereby decreasing myocardial oxygen consumption. Additionally, trinitrate has a mild effect on coronary arteries, enhancing blood flow to ischemic areas of the myocardium.

Pharmacokinetics

Trinitrate is rapidly absorbed following sublingual administration, with onset of action typically within 1-3 minutes. It undergoes extensive first-pass metabolism when given orally, resulting in lower bioavailability. The half-life of nitroglycerin is approximately 1-4 minutes, necessitating multiple doses for sustained effect. The drug is primarily metabolized in the liver and excreted via the kidneys.

Contra-indications

• Severe hypotension
• Severe anemia
• Increased intracranial pressure
• Concurrent use with phosphodiesterase-5 inhibitors
• Hypersensitivity to nitrates or any component of the formulation

Adverse effects

• Headache
• Dizziness
• Flushing
• Hypotension
• Tachycardia
• Nausea
• Vomiting
• Skin rash
• Syncope

Interactions

• Concurrent use with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) can lead to severe hypotension
• Caution with antihypertensive agents as additive hypotensive effects may occur
• Alcohol may enhance hypotensive effects
• Other vasodilators may increase the risk of hypotension

Precautions

• Use with caution in patients with cardiovascular disease
• Use with caution in patients with hepatic or renal impairment
• Monitor blood pressure regularly during therapy
• Avoid abrupt withdrawal after long-term use to prevent rebound angina

Pregnancy

Trinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data on human use.

Breast-feeding

Trinitrate is excreted in breast milk, caution is advised when administering to breastfeeding mothers.

Storage

Store at room temperature, away from light and moisture. Keep the medication tightly closed and out of reach of children.

Formulations

• Sublingual tablets
• Transdermal patches
• Oral extended-release capsules
• Intravenous infusion
• Topical ointment

Mechanism of action

Nitroglycerin is converted by mitochondrial aldehyde dehydrogenase in smooth muscle cells to nitric oxide (NO), a potent vasodilator. NO activates the enzyme guanylate cyclase, which converts guanosine triphosphate (GTP) to cyclic guanosine 3',5'-monophosphate (cGMP) in vascular smooth muscle and other tissues. cGMP is an endogenous vasodilator of vascular smooth muscle: it causes protein kinase-dependent phosphorylation and activates downstream cascades that promote relaxation and increased blood flow in veins, arteries and cardiac tissue. An _in vitro_ study using mouse aorta suggests that nitric oxide, an active metabolite of nitroglycerin, targets the natriuretic peptide receptors. The drugs used to treat angina alleviate symptoms by increasing blood flow to the ischemic myocardium and/or by reducing myocardial oxygen requirements. ... /Nitrates/ reduce myocardial oxygen requirements through their effects on the systemic circulation. Their major systemic action is a reduction in venous tone, which leads to pooling of blood in peripheral veins, decreased venous return, and reduced ventricular volume and myocardial tension (preload). /Org nitrates/ Although it predominately affects vascular smooth muscle /nitroglycerin/, the bronchioles, gastrointestinal tract (including biliary system), ureters, and uterus are affected. Free radicals of nitric oxide may activate guanylate cyclase, resulting in increased synthesis of cyclic GMP. Nitric oxide may combine with sulfhydryl groups in the endothelium and produce S-nitrosothiols, which stimulate guanylate cyclase production. N-acetyl-cycteine may enhance this process by providing a source of sulfhydryl groups. Cyclic GMP appears to reduce stored calcium and interfere with calcium-activated smooth muscle contractions. Organic nitrates... lead to the formation of the reactive free radical nitric oxide, which can activate guanylyl cyclase and increase the synthesis of cyclic GMP in smooth muscle and other tissues... A cyclic GMP-dependent protein kinase catalyzes the phosphorylation of various proteins in smooth muscle. Eventually, the light chain of myosin is dephosphorylated. Phosphorylation of the myosin chain regulates the maintenance of the contractile state in smooth muscle. Nitrates also may alter the prostaglandin system by inhibiting thromboxane synthetase and permitting preferential formation of prostacyclin over thromboxane A2. Both of these two short-acting vasoactive substances are formed from prostaglandin precursors. Prostacyclin is a potent vasodilator which causes smooth muscle relaxation through phosphorylation of the myosin light chain kinase. This reduces its ability to to be activated by calciun and calmodulin.

Pharmacodynamics

Nitroglycerin causes the relaxation of vascular smooth muscles, causing arteriolar and venous dilatation. It increases blood flow to the myocardium and reduces cardiac preload and afterload, decreasing myocardial wall stress and ameliorating anginal symptoms. Nitroglycerin also reduces coronary artery spasm, decreasing systemic vascular resistance as well as systolic and diastolic blood pressure. Like other organic nitrates, repeated and prolonged administration of nitroglycerin can lead to the development of tolerance or desensitization of vascular smooth muscle to further nitroglycerin-induced vasorelaxation. This loss of efficacy may be associated with the inhibition of mitochondrial aldehyde dehydrogenase, which is an important enzyme involved in the bioactivation of nitroglycerin. Nitroglycerin tolerance may be accompanied by pro-oxidant effects, endothelial dysfunction, and increased sensitivity to vasoconstrictors.