A nitrovasodilator is a pharmaceutical agent that causes

vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...

(widening of

blood vessels Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste an ...

) by donation of

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, 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 den ...

(NO), and is mostly used for the treatment and prevention of

angina pectoris Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of part ...

. 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 insol ...

(

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

s of

nitric acid Nitric acid is an inorganic compound with the formula . It is a highly corrosive mineral acid. The compound is colorless, but samples tend to acquire a yellow cast over time due to decomposition into nitrogen oxide, oxides of nitrogen. Most com ...

), 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 Diethylene glycol dinitrate (DEGDN) is an explosive nitrated alcohol ester with the formula C4H8N2O7. It is commonly used as a plasticizer in propellant or explosive formulations. While chemically similar to numerous other high explosives, pure d ...

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

(nitroglycerin) #

Isosorbide mononitrate Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally ...

and dinitrate #

Itramin tosilate Itramin tosilate ( INN), or itramin tosylate (more commonly), is a vasodilator Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in parti ...

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

(which additionally acts as a

potassium channel opener A potassium channel opener is a type of drug which facilitates ion transmission through potassium channels. Examples Some examples include: * Diazoxide vasodilator used for hypertension, smooth muscle relaxing activity *Minoxidil vasodilator u ...

) # Pentaerithrityl tetranitrate # Propatylnitrate # Sinitrodil #Tenitramine # Trolnitrate Nitrovasodilators which aren't nitrates include

molsidomine Molsidomine (trade names Corvasal, Corvaton and many others) is an orally active, short acting vasodilating drug used to treat angina pectoris. Molsidomine is metabolized in the liver to the active metabolite linsidomine. Linsidomine is an un ...

and its

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

linsidomine, as well as

sodium nitroprusside Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and ...

. 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 A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...

, 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 nitroglycerine), also known as trinitroglycerol (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless or pale yellow, oily, explosive liquid most commonly produced by ...

is used in form of a

sublingual Sublingual (List of abbreviations used in medical prescriptions, abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through Tissue (biology), t ...

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 nutr ...

ly for the treatment of hypertensive crises,

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

, 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 Shock may refer to: Common uses Healthcare * Acute stress reaction, also known as psychological or mental shock ** Shell shock, soldiers' reaction to battle trauma * Circulatory shock, a medical emergency ** Cardiogenic shock, resulting from ...

including

cardiogenic shock Cardiogenic shock is a medical emergency resulting from inadequate blood flow to the body's organs due to the dysfunction of the heart. Signs of inadequate blood flow include low urine production (<30 mL/hour), cool arms and legs, and decreased ...

, and

anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...

. Whether a specific drug is useful or harmful under heart failure and

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

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 Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

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 inhibitor A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating medication, drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vess ...

s such as

sildenafil Sildenafil, sold under the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary hypertension, pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain sym ...

(Viagra).

Adverse effects

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

flush Flush may refer to: Places * Flush, Kansas, a community in the United States Architecture, construction and manufacturing * Flush cut, a type of cut made with a French flush-cut saw or diagonal pliers * Flush deck, in naval architecture * F ...

, 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 called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

(slow heart rate).

Interactions

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

antihypertensive drug Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infa ...

tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

general anaesthetic General anaesthetics (or anesthetics) are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awaren ...

s, as well as

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

. Combination with PDE5 inhibitors, including

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

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

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 simila ...

(DHE). High DHE levels may result in coronary spasms in patients with

coronary disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the a ...

. This interaction is not described for non-nitrate nitrovasodilators.

Mechanism of action

Nitrovasodilators are

prodrug A prodrug is a pharmacologically inactive 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 ...

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 In chemistry, the oxidation state, or oxidation number, is the hypothetical Electrical charge, charge of an atom if all of its Chemical bond, bonds to other atoms are fully Ionic bond, ionic. It describes the degree of oxidation (loss of electrons ...

(+2) and liberate NO without the aid of enzymes. NO stimulates the soluble form of the enzyme

guanylate cyclase Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosi ...

in the smooth muscle cells of blood vessels. Guanylate cyclase produces

cyclic guanosine monophosphate Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in ...

(cGMP) from

guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only di ...

(GTP). cGMP in turn activates cyclic nucleotide-dependent protein kinase G, which

phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

s various proteins that play a role in decreasing intracellular

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

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

vein Veins () are blood vessels in the circulatory system of humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are those of the pulmonary and feta ...

s, which increases their capacity to hold blood ("venous pooling") and reduces the pressure of the blood returning to the heart (the preload). Widening of the large

arteries An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

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 coronary spasms, 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 Tachyphylaxis (Greek ταχύς, ''tachys'', "rapid", and φύλαξις, ''phylaxis'', "protection") is a medical term describing an acute, sudden decrease in response to a drug after its administration (i.e., a rapid and short-term onset of drug ...

, 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 In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

(–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 Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

resulting in deactivation of NO to

peroxynitrite Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate, Preparation Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide: : It is prepared by the rea ...

, and liberation of the

vasoconstrictor Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...

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 ...

and

endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

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