| Nitrovasodilator | |
|---|---|
| Drug class | |
 | |
| Class identifiers | |
| Use | Angina pectoris,vasodilation |
| ATC code | C01DA |
| Biological target | Guanylate cyclase |
| Legal status | |
| In Wikidata | |
Anitrovasodilator is a pharmaceutical agent that causesvasodilation (widening ofblood vessels) by donation ofnitric oxide (NO),[1] and is mostly used for the treatment and prevention ofangina pectoris.
This group of drugs includesnitrates (esters ofnitric acid), which arereduced to NO in the body, as well as some other substances.
Here is a list of examples of the nitrate type (in alphabetical order):[2]
Nitrovasodilators which aren't nitrates includemolsidomine and itsactive metabolitelinsidomine, as well assodium nitroprusside. These substances do not need to be reduced to donate NO.[2][3]
The nitrates are used for the treatment and prevention of angina andacute myocardial infarction, while molsidomine acts too slowly to be useful for the treatment of acute angina.[2] For quick action in the treatment of angina,glyceryl trinitrate is used in form of asublingual spray (nitro spray) or assoft capsules to be crunched.[4]
Nitroprusside is usedintravenously for the treatment ofhypertensive crises,heart failure, and lowering of blood pressure during surgery.[5][6]
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 includingcardiogenic shock, andanaemia. Whether a specific drug is useful or harmful under heart failure andmyocardial 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 ofischaemia 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.[2][4]
These drugs are also contraindicated in patients that have recently takenPDE5 inhibitors such assildenafil (Viagra).[4]
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, dizziness, nausea and vomiting. These effects usually subside after a few days if the treatment is continued.[2]
Occasionally, severe hypotension occurs shortly after beginning of treatment, possibly resulting in intensified angina symptoms orsyncope, sometimes withbradycardia (slow heart rate).[4]
A number of drugs add to the low blood pressure caused by nitrovasodilators: for example, other vasodilators,antihypertensive drugs,tricyclic antidepressants,antipsychotics,general anaesthetics, as well asethanol. Combination with PDE5 inhibitors, includingsildenafil (Viagra), is contraindicated because potentially life-threatening hypotension may occur.[2][4]
Nitrates increase thebioavailability ofdihydroergotamine (DHE). High DHE levels may result incoronary spasms in patients withcoronary disease.[4] This interaction is not described for non-nitrate nitrovasodilators.
Nitrovasodilators areprodrugs that donateNO by various mechanisms. Nitrates undergo chemical reduction, likely mediated by enzymes. Molsidomine and nitroprusside already contain nitrogen in the rightoxidation state (+2) and liberate NO without the aid of enzymes.[3]
NO stimulates the soluble form of the enzymeguanylate cyclase in the smooth muscle cells of blood vessels. Guanylate cyclase producescyclic guanosine monophosphate (cGMP) fromguanosine triphosphate (GTP). cGMP in turn activates cyclic nucleotide-dependentprotein kinase G, whichphosphorylates various proteins that play a role in decreasing intracellularcalcium levels, leading to relaxation of the muscle cells and thus to dilation of blood vessels.[3][7]
The most important effect in angina is the widening ofveins, which increases their capacity to hold blood ("venous pooling") and reduces the pressure of the blood returning to the heart (thepreload). Widening of the largearteries also reduces the pressure against which the heart has to pump, theafterload. Lower preload and afterload result in the heart needing less energy and thus less oxygen. Besides, NO donated by nitrovasodilators can reducecoronary spasms, increasing the heart's oxygen supply.[2]
PDE5 inhibitors block deactivation of cGMP by the enzymephosphodiesterase-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.[8][9]
Nitrates exhibit development of tolerance, or more specificallytachyphylaxis, 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 ofthiol (–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 ofoxidative stress resulting in deactivation of NO toperoxynitrite, and liberation of thevasoconstrictorsangiotensin II andendothelin as the blood vessels' reaction to NO-mediated vasodilation.[2]
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.[2] Nitroprusside, given intravenously, acts immediately, and after stopping the infusion blood pressure returns to its previous level within ten minutes.[6]
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