A nitrovasodilator is a pharmaceutical agent that causes vasodilation (widening of

blood vessels The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...

) by donation of

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

(NO), and is mostly used for the treatment and prevention of angina pectoris. This group of drugs includes

nitrates Nitrate is a polyatomic ion with the chemical formula . Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insoluble ...

( esters of nitric acid), which are reduced to NO in the body, as well as some other substances.

Examples

Here is a list of examples of the nitrate type (in alphabetical order): # Diethylene glycol dinitrate #

Glyceryl trinitrate Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating ...

(nitroglycerin) # Isosorbide mononitrate and dinitrate #

Itramin tosilate Itramin tosilate (INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation t ...

Nicorandil Nicorandil is a vasodilatory drug used to treat angina. Angina is chest pain that results from episodes of transient myocardial ischemia. This can be caused by diseases such as atherosclerosis, coronary artery disease and aortic stenosis. An ...

(which additionally acts as a potassium channel opener) # Pentaerithrityl tetranitrate # Propatylnitrate # Sinitrodil #Tenitramine #

Trolnitrate Trolnitrate is an organic nitrate with vasodilator activity that is used to prevent or ameliorate attacks of angina pectoris. Trolnitrate dilates the coronary vessels because of its basic action as a smooth muscle depressant, just as do nitrogly ...

Nitrovasodilators which aren't nitrates include molsidomine and its

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

linsidomine, as well as sodium nitroprusside. These substances do not need to be reduced to donate NO.

Medical uses

The nitrates are used for the treatment and prevention of angina and acute myocardial infarction, while molsidomine acts too slowly to be useful for the treatment of acute angina. For quick action in the treatment of angina,

glyceryl trinitrate Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating ...

is used in form of a

sublingual Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. The sublingual glands receive their prima ...

spray (nitro spray) or as soft capsules to be crunched. Nitroprusside is used

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

ly for the treatment of hypertensive crises,

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

, and lowering of blood pressure during surgery.Sodium nitroprusside: .

Contraindications

Nitrovasodilators are contraindicated under circumstances where lowering of blood pressure can be dangerous. This includes, with some variation between the individual substances, severe hypotension (low blood pressure), shock including

cardiogenic shock Cardiogenic shock (CS) is a medical emergency resulting from inadequate blood flow due to the dysfunction of the ventricles of the heart.Textbooks of Internal MedicinHarrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Compan ...

, and anaemia. Whether a specific drug is useful or harmful under heart failure and myocardial infarction depends on its speed of action: Fast acting substances such as glyceryl trinitrate and nitroprusside can be helpful for controlling blood pressure and consequently the amount of blood the heart has to pump, if the application is monitored continuously. Slow acting substances would hold the danger of ischaemia due to an uncontrollably low blood pressure and are therefore contraindicated. Depending on the circumstances, even fast acting substances can be contraindicated – for example, glyceryl trinitrate in patients with obstructive heart failure. These drugs are also contraindicated in patients that have recently taken PDE5 inhibitors such as

sildenafil Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken by ...

(Viagra).

Adverse effects

Most side effects are direct consequences of the vasodilation and the following low blood pressure. They include headache ("nitrate headache") resulting from the widening of blood vessels in the brain,

reflex tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

(fast heart rate), flush, dizziness, nausea and vomiting. These effects usually subside after a few days if the treatment is continued. Occasionally, severe hypotension occurs shortly after beginning of treatment, possibly resulting in intensified angina symptoms or syncope, sometimes with

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

(slow heart rate).

Interactions

A number of drugs add to the low blood pressure caused by nitrovasodilators: for example, other vasodilators, antihypertensive drugs,

tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

s, antipsychotics, general anaesthetics, as well as ethanol. Combination with PDE5 inhibitors, including

(Viagra), is contraindicated because potentially life-threatening hypotension may occur. Nitrates increase the bioavailability of

dihydroergotamine Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy simil ...

(DHE). High DHE levels may result in

coronary spasm Coronary reflex is the change of coronary diameter in response to chemical, neurological or mechanical stimulation of the coronary arteries. The coronary reflexes are stimulated differently from the rest of the vascular system. Causes of coronary c ...

s in patients with coronary disease. This interaction is not described for non-nitrate nitrovasodilators.

Mechanism of action

Nitrovasodilators are

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

s that donate NO by various mechanisms. Nitrates undergo chemical reduction, likely mediated by enzymes. Molsidomine and nitroprusside already contain nitrogen in the right oxidation state (+2) and liberate NO without the aid of enzymes. NO stimulates the soluble form of the enzyme guanylate cyclase in the smooth muscle cells of blood vessels. Guanylate cyclase produces cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP in turn activates cyclic nucleotide-dependent protein kinase G, which phosphorylates various proteins that play a role in decreasing intracellular calcium levels, leading to relaxation of the muscle cells and thus to dilation of blood vessels. The most important effect in angina is the widening of veins, which increases their capacity to hold blood ("venous pooling") and reduces the pressure of the blood returning to the heart (the

preload Preload may refer to: Science and technology * Preload (cardiology), maximum stretch of the heart at the end of diastole * preload (software), code-prefetching software for Linux * Preload (engineering), the internal application of stress to cert ...

). Widening of the large arteries also reduces the pressure against which the heart has to pump, the

afterload Afterload is the pressure that the heart must work against to eject blood during systole (ventricular contraction). Afterload is proportional to the average arterial pressure. As aortic and pulmonary pressures increase, the afterload increases on ...

. Lower preload and afterload result in the heart needing less energy and thus less oxygen. Besides, NO donated by nitrovasodilators can reduce

s, increasing the heart's oxygen supply. PDE5 inhibitors block deactivation of cGMP by the enzyme phosphodiesterase-5. In combination with the increased cGMP production caused by nitrovasodilators, this leads to high concentrations of cGMP, extensive venous pooling, and potentially life-threatening hypotension.

Nitrate tolerance

Nitrates exhibit development of tolerance, or more specifically tachyphylaxis, meaning that repeated application results in a fast decrease of effect, usually within 24 hours. A pause of six to eight hours restores the original effectiveness. This phenomenon was originally thought to be a consequence of depletion of thiol (–SH) groups necessary for the reduction of nitrates. While this theory would fit the fact that molsidomine (which is not reduced) does not exhibit tachyphylaxis, it has meanwhile been refuted. Newer theories include increase of oxidative stress resulting in deactivation of NO to peroxynitrite, and liberation of the vasoconstrictors

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...

and endothelin as the blood vessels' reaction to NO-mediated vasodilation.

Differences in pharmacokinetics

Nitrates mainly differ in speed and duration of their action. Glyceryl trinitrate acts fast and short (10 to 30 minutes), while most other nitrates have a slower onset of action, but are effective for up to six hours. Molsidomine, as has been mentioned, not only acts slowly but also differs from the nitrates in exhibiting no tolerance. Nitroprusside, given intravenously, acts immediately, and after stopping the infusion blood pressure returns to its previous level within ten minutes.

References

{{Nitric oxide signaling Angiology Antianginals Disulfiram-like drugs Vasodilators