Introduction
In 1867, Lauder Brunton described the antianginal properties of nitrites (amyl nitrite) [1]. Nitrates were first used as an antianginal agent in 1879 and since then have been widely used as a short-acting antianginal agent [2]. They come in various formulations: short-acting as intravenous preparations, sublingual tablets and sprays, and long-acting preparations such as transdermal ointments and patches, long and sustained release pills. Short-acting preparations are of use in acute ischaemic events, whereas long-acting nitrates are used in patients with stable angina to reduce cardiovascular mortality, to increase exercise capacity and to provide a better quality of life [2,3].
Mechanism of action
Organic nitrates are an exogenous source of nitric oxide (NO), a potent coronary vasodilator. Glyceryl trinitrate (GTN) and pentaerythritol tetranitrate (PETN) are bio-converted to nitrite by the enzyme mitochondrial aldehyde dehydrogenase (ALDH2) and also by a non-enzymatic mechanism involving the reaction with thiol derivatives, while isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) are activated by the cytochrome P450 enzyme in the endoplasmic reticulum and do not involve mitochondrial ALDH2 [4,5].
Effect on endothelial function
An intact endothelium is a prerequisite for some of the vasoactive agents. Endothelium-derived relaxing factor (EDRF), which is nitric oxide (NO), requires an intact and healthy endothelium to maintain the vascular tone. NO released from the endothelial cells increases the level of cyclic guanosine monophosphate (cGMP) within the cells by activating enzyme guanylate cyclase. This causes vasodilatation and platelet disaggregation [1,2,6].
In coronary artery disease (CAD), when there is a deficiency of EDRF because of endothelial dysfunction and deficient activity of the cGMP/NO pathway, exogenous nitrates, such as GTN, provide a source of NO [7,8]. As nitrate is given systemically, they are not dependent on the intact, functioning endothelium for their vasodilator properties [2]. The action of nitrates is enhanced in vessels which have depleted NO production, as seen in atherosclerotic vessels [8].
Effects on coronary and peripheral circulation
Nitrates are potent venodilators. They also preferentially dilate the coronary arteries and arterioles greater than 100 mcm in diameter [1,9]. They relieve angina symptoms by facilitating flow of blood from epicardial to endocardial vessels and they also augment the flow along the collaterals by selectively relaxing the epicardial vessels, thereby relieving myocardial ischaemia by improving the regional myocardial blood flow [1]. Nitrates, through the preferential dilatation of coronary arteries, also improve the flow across a dynamic stenosis and relieve coronary spasm [1,7]. Nitrates reduce the preload and the workload on the heart by increasing the venous capacitance and peripheral pooling of blood. This in turn reduces the myocardial oxygen demand [1]. Nitrates also reduce the myocardial oxygen requirement by reducing the afterload by a drop in the aortic systolic pressure without a corresponding fall in the peripheral arterial pressure [1,10].
Effect on platelets
Exogenous nitrates are denitrated to NO which activates platelet guanylate cyclase. This in turn increases the level of platelet cGMP and results in the reduced binding of fibrinogen to the glycoprotein IIb/IIIa receptor. This causes platelet disaggregation [11].
Pharmacodynamics & pharmacokinetics
Organic nitrates act by converting to nitric oxide (NO), which is a potent vasodilator. Nitrates are thus a source of exogenous NO, and are clinically significant as they are structurally different from L-arginine and do not need endogenous enzymes to convert to NO [6].
Because of the wide array of drug formulation and various routes of administration, the pharmacodynamics and pharmacokinetics of organic nitrates are complex and each needs to be discussed separately. Organic nitrates are metabolised primarily in the liver and a small percentage of drug is excreted in urine [6].
GTN (nitroglycerine) pharmacokinetics have not been understood or studied well as GTN has a short half-life of only a few minutes and disappears rapidly from blood after intravenous administration. GTN gets converted to longer-acting vasoactive metabolite dinitrates and mononitrates by extrahepatic mechanisms [2,12]. After sublingual administration, the plasma concentration of GTN peaks and declines rapidly. However, it has an extensive (95%) first-pass hepatic metabolism and so the plasma concentration is low after oral administration [13]. Transdermal application as ointment or as a sustained release patch provides a sustained plasma level over the period of application. However, there is a decline in vasodilator effect seen with continuous or repeated administration of GTN through any route, in spite of its having a consistent plasma level [12].
Isosorbide dinitrates are converted to active mononitrates in the liver and have a half-life of four to six hours. They are excreted through the kidneys [2]. After intravenous administration, they are metabolised in the liver, but the decline in plasma levels is slower when compared to GTN, the same as seen after sublingual administration. After oral administration, the plasma levels are low because of extensive (70-80%) first-pass hepatic metabolism [13]. Food slows down the absorption [12], while exercise, hepatic or renal failure does not affect the absorption or metabolism of isosorbide dinitrate [12,13]. As with GTN, on sustained therapy the therapeutic effect declines in spite of an increase in plasma concentration [14].
The mononitrates do not undergo any hepatic metabolism and are 100% bioavailable with a half-life of four to six hours. They are extensively used for long-term prophylaxis owing to their higher and sustained plasma concentration and the longer half-life of their metabolites. Isosorbide 2 mononitrate has a half-life of two to four hours, while isosorbide 5 mononitrate has a half-life of around five hours [12,14]. The pharmacokinetics of organic nitrates are not influenced by age, gender, race or coexisting morbidities [13].
Indications
Short-acting nitrates
Sublingual nitrates are the drug of choice for management of angina in acute and emergency settings. They relieve the symptoms of angina by venodilatation of capacitance vessels and preferential dilatation of coronaries, thus reducing the myocardial oxygen demand [1,15]. These effects are so reliable and constant across all conditions and circumstances that pain relief after sublingual administration of nitrates is considered to be virtually diagnostic of cardiac chest pain [15]. Chest discomfort that reduces in intensity or gets completely resolved within 10 minutes of the administration of sublingual nitrates is considered to be due to myocardial ischaemia. However, in cases of pain persisting for more than 10 minutes, other causes of chest pain should be ruled out, both of non-ischaemic cardiac (aortic dissection, aneurysms) and non-cardiac (oesophagitis, costochondritis) origin [16]. In patients with chronic stable angina, prophylactic administration of sublingual nitroglycerin spray improves the exercise tolerance by increasing the exercise duration and also the time to onset of angina [17].
In addition, sublingual nitroglycerin is widely used as a reliable screening test for detection of obstruction in hypertrophic cardiomyopathy (HCM) patients [18], and also in inducing vasovagal reflex during head-up tilt table (HUTT) testing in patients with syncope of uncertain aetiology [19].
GTN sprays are considered better and have a wider acceptance among elderly patients as they act more quickly and the effect lasts longer than tablets. Another advantage is that they do not need ample salivary secretion for complete dissolution and absorption for action [1,20]. Short-acting nitrates can also be used in prophylaxis as part of optimum medical treatment, to reduce the recurrence of angina attacks by increasing the segmental blood flow through the atherosclerotic vessels, to relieve ischaemia and also to relieve symptoms in acute pulmonary oedema, and to reduce the workload on the heart by reducing the preload in patients with left ventricular failure [1].
Long-acting nitrates
Long-acting nitrates as oral tablets or sustained release transdermal patches are used for angina prophylaxis. Owing to tolerance, nitrates are not continuously effective when taken for longer duration. Similarly, sustained or repeated oral administration of isosorbide dinitrate for the prophylaxis of angina does not improve the exercise duration as much with a single use (2 hours vs. 6 to 8 hours), in spite of much higher plasma concentration [21].Eccentric or asymmetric dosing is one way to circumvent this. Isosorbide mononitrate has been shown to provide a prolonged antianginal effect and also improve the exercise duration in patients [13,22]. Mononitrates have a similar action and dosage to isosorbide dinitrate. Tolerance can be minimised by giving a rapid release preparation in an eccentric pattern with a seven-hour interval and a nitrate-free or nitrate-low period in between [13]. An extended release preparation given in higher doses has been shown to have an antianginal effect over prolonged daily use [23].
Transdermal patches were designed to release GTN for the time period during which they are applied and to provide round-the-clock pain relief, but this may lead to early development of tolerance, so intermittent application rather than continuous application of a patch may be more useful in the relief of angina symptoms [22].
Pentaerythritol tetranitrate (PETN) on continuous administration has shown a preserved vasodilatory effect and lack of endothelial dysfunction [15]. It also increased the response to sublingual GTN in patients with CAD [24].
Adverse effects
Rarely, nitrates, if given unmonitored, may cause hypotension and giddiness, which is the most serious complication. Headache caused by the vasodilatation of cerebral veins is the commonest side effect; headache is more common with GTN, both sublingual and transdermal preparations [25]. Headache is dose-dependent and has been reported to be more severe with sublingual tablets; GTN spray has rarely caused taste disturbance [2].
Nitrate use is to be avoided in patients allergic to organic nitrates, using phosphodiesterase-5 inhibitors such as sildenafil and similar agents, as it may cause severe hypotension and even acute myocardial infarction. Nitrates should be administered with care in patients with severe aortic stenosis and hypertrophic cardiomyopathy, as they can worsen the obstruction and, in severe cases, trigger angina attacks and syncope [2].
Nitrate tolerance
Acute therapy with short-acting nitrates is considered to be the gold standard in the treatment of angina. However, long-term treatment with nitrates has not been as rewarding owing to nitrate tolerance [15].
Nitrate tolerance is a complex and multifactorial phenomenon, involving an initial intravascular volume expansion and neurohormonal counter-regulation characterised by unopposed vasoconstriction mediated by angiotensin II, catecholamines and oxidative stress, collectively called pseudo-tolerance [5,15]. This is followed by a late more specific intrinsic vascular phenomenon (vascular tolerance), for which a number of hypotheses have been proposed. These include intracellular sulphydryl depletion, increased superoxide production, increased free radicals leading to oxidative stress and endothelial dysfunction, impaired nitrate activation and, more recently, reactive oxygen species (ROS) formation and inhibition of mitochondrial aldehyde dehydrogenase (ALDH2) [2,5,26].
Chronic use of NTG induces cross-tolerance by desensitising the response to other NO donors, both exogenous and endothelial-derived [15,26].
In order to overcome tolerance, the most commonly practised approach has been to have a nitrate-free or low nitrate period of 12 to 14 hours during the night. This strategy did help in improving the symptomatic response of patients and it also avoids tolerance, but it was fraught with the danger of paradoxically increasing the incidence of an ischaemic event during the nitrate-free period at night [15].
Conclusion
Organic nitrates have been the cornerstone of acute management of angina and are widely used now based on guidelines. What needs to be highlighted is the use of nitrates in long-term settings. Though there are conflicting reports from various studies, non-randomised studies have suggested an increase in the incidence of acute coronary syndrome with long-term nitrates [27]. The Global Registry of Acute Coronary Events (GRACE) has shown that long-term nitrate therapy has resulted in fewer ST-elevation myocardial infarctions and a reduction in the severity of acute coronary syndrome [28].The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial revealed that the primary outcome of death and myocardial infarction in patients with stable ischaemic heart disease (SIHD) was similar in patients on optimum medical therapy (OMT) when compared with percutaneous intervention and OMT [29]. Similarly, the intermittent use of nitrates for prophylaxis before exertion or during emotional stress should be highlighted. Self-administration of nitrates should be encouraged prior to exercise as it would increase the exercise time as well as the self-confidence of the patient.
Optimum utilisation of nitrate therapy would require a greater interaction and understanding between the clinician and the patient, to assess the severity of the symptoms, the preferences and convenience of each patient and then tailor the treatment plan to ensure a better quality of life and optimum adherence to treatment. Patient education is paramount. However, it would be prudent to tailor the dosage and regimen of the nitrates for each patient after taking into account patient compliance, adverse effect profile and drug interactions.
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