• Organic nitrates are polyol esters of nitric acid (HNO3). They are potent vasodilators. They have been used as mainstay treatment of angina for more than 100 years.
• The first organic nitrate ‘nitroglycerine’s medical usefulness was discovered by William Murrell, a physician in 1879.
• Some commonly used organic nitrates in clinical practice are:
– Nitroglycerine (NTG or GTN)
– Isosorbide 5- mononitrate (ISMN)
– Isosorbide dinitrate (ISDN)
– Pentaerythritol tetranitrate (PETN).
Mechanism of action of Organic Nitrates
Figure 2- Mechanism of action of organic nitrates (Source- Lippincott’s Illustrated reviews)
• Organic nitrates serve as exogeneous source of nitric oxide (NO) so termed as NO donors. Organic nitrates after administration undergoes intracellular conversion (reduction) to organic nitrites which are then converted to nitric oxide (NO).
• NO produced activates guanylate cyclase and increases the cell’s cyclic guanosine monophosphate (cGMP). Elevated cGMP leads to dephosphorylation of myosin light chain which relaxes vascular smooth muscle.
• Nitrates cause vasodilation of both arteries and veins. The dilation of large veins reduces preload and work of heart. They also dilate coronary vasculature providing increased blood supply to heart.
Pharmacological Actions of Organic Nitrates
Cardiovascular Actions
Figure 1- Antianginal hemodynamic effects of acutely administered NTG (Source- Daiber et al, 2015)
• They relax systemic venous and arteriolar bed and reduce preload (end diastolic left ventricular pressure) and after load (resistance to left ventricular ejection).
• In normal person, transient decrease in coronary resistance and increase in total coronary flow occurs. In patients with angina, they dilate large coronary arteries without affecting arterioles, dilate collateral vessels and cause redistribution of coronary blood flow.
• They reduce oxygen consumption of heart during exercise and increase duration of exercise in patients with angina.
• Nitrates also cause vasodilation of other vessels which are responsible for its side effects. Like dilation of skin vascular bed cause flushing, meningeal vessels dilation cause throbbing headache and dilation of kidney vessels cause reduction in blood flow.
Action on other smooth muscles
• Nitrates relax the smooth muscles of gall bladder, biliary duct, GI tract, bronchi, ureter and uterus.
Pharmacokinetics of Organic Nitrates
• When administered through oral route, they undergo first-pass hepatic metabolism. So, the preferred route is sublingual or transdermal route (patches or ointment) to avoid hepatic first-pass effect, for rapid absorption and predictable effects. They are also available in spray or tablet form.
• Nitrates differ in onset of action of rate of elimination.
• Sublingual nitroglycerine (NTG) shows peak plasma concentration within 4 minutes and has half-life of 1-3 minutes. The normal sublingual dose is 0.3 to 0.6 mg at the onset of angina pain. Dose can be repeated every 5 minutes for 15-30 minutes up to maximum of 3 doses. Transdermal nitroglycerine disk has slow onset of action and peak effect occurs at 1-2 hours. NTG ointment form also has similar prolonged duration of action and is useful in nocturnal angina.
• Sublingual isosorbide dinitrate shows peak plasma concentration within 6 minutes and have half-life of 45 minutes. It is also available as oral extended-release tablet.
• Isosorbide mononitrate doesn’t undergo first pass metabolism, so it is administered orally. It is available both as plain tablet and sustained release form. Both forms have longer duration of action than isosorbide dinitrate.
Therapeutic Uses of Organic Nitrates
• In all varieties of angina pectoris including stable angina, unstable angina.
• In long term management of chronic heart failure due to ischemic heart disease.
• For treating onset of pain of acute myocardial infarction (except in those with right ventricular involvement).
• NTG is useful in acute LVF (Left ventricular failure) and paroxysmal nocturnal dyspnea due to LVF.
• In acute anal fissure. NTG ointment or isosorbide dinitrate ointment are applied locally to relieve spasm and pain and for healing fissure.
• In achalasia cardia (motility disorder of esophagus).
Adverse Effects
• The most common adverse effect is headache which is due to dilation of meningeal blood vessels. It usually decreases gradually on repeated administration and can be controlled by aspirin.
• Other common adverse effects are facial flushing, postural hypotension, tachycardia, palpitations, nausea, vomiting, giddiness and weakness. Rashes may occur occasionally.
• Sudden withdrawal during long term therapy leads to precipitation of severe angina.
• Repeated administration of nitrates can develop nitrate tolerance. The exact mechanism behind this is not well understood till date. It mostly occurs with long acting nitrates like sustained release preparation and transdermal form due to exposure of patient to nitrates all 24 hours of the day. It is rare with sublingual administration due to intermittent exposure. The blood vessels become desensitized to nitrate gradually and their therapeutic efficacy vanishes gradually.
It can be overcome by providing daily ‘nitrate-free interval’ which can be done by omitting nighttime dose of long acting preparations. In case of severe angina, during ‘nitrate-free interval’ another anti-anginal drug should be given.
In patients with nocturnal angina, nitrate-free interval should be maintained during day time or waking hours.
Drug Interaction
• Concurrent administration with antihypertensive drugs (especially vasodilators), and with alcohol can cause marked hypotension.
• Phosphodiesterase type 5 inhibitors like sildenafil (Viagra), tadalafil (Cialis) and similar agents used in erectile dysfunction potentiate action of organic nitrates so should not be administered together.
Contraindication
• Nitrates should not be used in patients with hypertrophic cardiomyopathy.
• They should be avoided in patients with history of migraine.
References
- https://www.verywellhealth.com/nitrates-for-treating-angina-1745818
- https://www.ncbi.nlm.nih.gov/books/NBK547928/
- Munzel T, Steven S, Daiber A. Organic nitrates: Update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascular Pharmacology. 2014; 63(3): 105-113.
- Nossaman VE, Nossaman BD, lKadowitz PJ. Nitrates and Nitrites in the Treatment of Ischemic Cardiac Disease. Cardiol Rev. 2010; 18(4): 190–197.
- Miller MR, Wadsworth RM. Understanding organic nitrates – a vein hope? Br J Pharmacol. 2009; 157(4): 565–567.
- Daiber A, Munzel T. Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress. Antioxid Redox Signal. 2015; 23(11): 899–942.
- Shaughnessy MO. Arterial hypertension, angina pectoris, myocardial infarction and heart failure. Clinical Pharmacology (Eleventh Edition). 2012; 393-427.
- Lippincott Illustrated Reviews Pharmacology, 6th edition.
- Pharmacology and pharmacotherapeutics. 24th edition.
- Goodman and Gillman Manual of Pharmacology and Therapeutics.