A nitrovasodilator is a pharmaceutical agent that causes

vasodilation Vasodilation 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. The process is the opposite of vasoconstrictio ...

(widening of blood vessels) by donation of nitric oxide (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 obstru ...

. This group of drugs includes nitrates (

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

s of

nitric acid Nitric acid is the inorganic compound with the formula . It is a highly corrosive mineral acid. The compound is colorless, but older samples tend to be yellow cast due to decomposition into oxides of nitrogen. Most commercially available nitri ...

), 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 nitration, nitrated Alcohol (chemistry), alcohol ester with the formula C4H8N2O7. While chemically similar to numerous other high explosives, pure diethylene glycol dinitrate is difficult to ig ...

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 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 #

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 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, long acting vasodilating drug used to treat angina pectoris. Molsidomine is metabolized in the liver to the active metabolite linsidomine. Linsidomine is an unsta ...

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 Linsidomine (3-morpholinosydnonimine or SIN-1) is a vasodilator. It is a metabolite of the antianginal drug molsidomine and acts by releasing NO from the endothelial cells nonenzymatically. It also hyperpolarizes the cell membrane through influen ...

, 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 d ...

. 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 to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may t ...

, 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 spray (nitro spray) or as soft capsules to be crunched.

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 ...

is used intravenously for the treatment of

hypertensive crises Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 120—sometimes termed malignant or accelerated hypertension) is referred to as a hypertensive crisis, as blood pressure at this level confers a high risk ...

, heart failure, 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 Collective noun *Shock, a historic commercial term for a group of 60, see English numerals#Special names * Stook, or shock of grain, stacked sheaves Healthcare * Shock (circulatory), circulatory medical emergen ...

including cardiogenic shock, and

anaemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

. 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 blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

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 American and British English spelling differences#ae and oe, or ischaemia is a restriction in blood supply to any tissue (biology), tissue, Skeletal muscle, muscle group, or Organ (biology), organ of the body, causing a shortage of oxyg ...

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 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 vessels supplyi ...

s such as sildenafil (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 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 * Fl ...

, 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 (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 and myocardial infarction. Evidence suggests th ...

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 ...

antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...

general anaesthetic General anaesthetics (or anesthetics, see spelling differences) 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 com ...

s, as well as

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

. Combination with PDE5 inhibitors, including sildenafil (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%. Ho ...

of dihydroergotamine (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 Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

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

Mechanism of action

Nitrovasodilators are prodrugs 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 charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...

(+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 guanos ...

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 r ...

(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 d ...

(GTP). cGMP in turn activates cyclic nucleotide-dependent

protein kinase G cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle ...

, which

phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

s various proteins that play a role in decreasing intracellular

calcium Calcium is a chemical element with the 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 t ...

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 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 the pulmonary and umbilical veins, both of which carry oxygenat ...

s, 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 An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

also reduces the pressure against which the heart has to pump, the afterload. 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 Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme () from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to p ...

. 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 to ...

, 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 gro ...

(–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 react ...

, 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 vess ...

s angiotensin II 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