NITRATES+SUMMARY

Nitrates
 * History:** Nitrates and nitrites have been used to relieve anginal pain for over 100 years. Amyl nitrite, a polyol ester of nitrous acid, is a volatile liquid that is administered via inhalation. First utilized for its vasodepressor effects in 1857, amyl nitrite was found to decrease severe angina within 30—60 seconds of inhalation. However, this effect was transient, and the dosage of the drug was difficult to control. It was soon discovered that other organic nitrates (e.g., nitroglycerin) exhibited vasodepressor effects similar to those of amyl nitrite, with less adverse effects.

The first organic nitrate, nitroglycerin, was synthesized in 1846, and by 1879 sublingual use of this drug as an antianginal agent had been clearly established. However, the duration of action of nitroglycerin was short, and the search for a longer-acting nitrate led to the development of isosorbide dinitrate which was approved as antianginal agent in 1986 and is available in several forms, including sublingual, chewable and conventional release oral tablets and capsules, as well as sustained-release oral tablets and capsules. Subsequently, the development and use of sublingual nitroglycerin for the relief of acute anginal attacks was established. Because it is inexpensive, has a rapid onset of action, and efficacy is well documented, sublingual nitroglycerin is still considered the drug of choice for the acute relief of angina. However, although organic nitrates are still frequently prescribed for angina, they have come under scrutiny because of the controversy surrounding claims of nitrate tolerance demonstrated with all forms of these drugs.

Today, because amyl nitrite is expensive, inconvenient, and often causes headaches, tachycardia, and orthostatic hypotension, it is rarely used for the relief of angina. Amyl nitrite inhalants are sometimes used illicitly to enhance sexual pleasure and produce euphoria, and abuse of the drug has been associated with severe toxicity. Street names for amyl nitrite inhalants include "Amy" and "poppers". Amyl nitrite also comprises a component in the treatment of cyanide toxicity.

Clinical research into the use of these products for acute and chronic congestive heart failure has been actively pursued during the past 20 years. Intravenous nitroglycerin for cardiogenic shock and oral nitrates for chronic heart failure are well-established therapies. An oral nitrate in combination with hydralazine has been shown to improve survival.[209] However, due to the common side effects of headache, dizziness, gastrointestinal distress, and central nervous system effects as well as the multiple doses per day regimen, oral nitrates in combination with hydralazine is second-line to ACE inhibitors. (ACE-inhibitors have also been shown to improve survival in chronic congestive heart failure.) Today, oral or topical nitrates remain the agent of first choice for stable angina.


 * Mechanism of Action:** The treatment of angina necessitates restoratation of the balance between myocardial oxygen supply and demand. This can be accomplished by either increasing blood flow and, consequently, myocardial oxygen supply, and/or by reducing the heart's "workload", decreasing oxygen demand. It is believed that nitrates correct myocardial oxygen imbalances by reducing demand. Demand is reduced secondary to a reduction in systemic and pulmonary arterial pressure (afterload) and a decrease in cardiac output secondary to peripheral dilation rather than coronary artery dilation. Nitrites, ultimately relax peripheral venous vessels, causing a pooling of venous blood, decreased venous return to the heart, thereby decreasing preload.

Nitrites reduce both arterial impedence and venous filling pressures, resulting in a reduction of the left ventricular systolic wall tension, thereby decreasing afterload. Thus, nitrite-induced vasodilatation increases venous capacitance, and decreases arteriole resistance. Both the preload and afterload are reduced and cardiac oxygen demand is reduced. Total coronary blood flow may be increased by nitrites and nitrates in patients with normal hearts, but, in patients with ischemia, the drug does not increase total coronary blood flow, but simply redistributes the blood to the ischemic areas. This effect is thought to be due to the drug's preferential dilatation of the larger conductive vessels of the coronary circulation, which, in the presence of coronary atherosclerosis, redirects the distribution of the coronary blood supply to the ischemic areas.

The nitrates relax the smooth muscle of the vascular walls to produce dilation. Vasodilation is a result of two cellular mechanisms including increased cyclic GMP and decreased thromboxane A2. Dilation occurs in peripheral veins, peripheral arteries, and coronary arteries. The venodilation decreases blood return to the heart which reduces ventricular filling pressures. Myocardial work and oxygen demand are decreased, relieving anginal pain. Patients with severe congestive heart failure will particularly benefit from intravenous nitroglycerin when there is primarily pulmonary congestion and a high preload.

Nitrites cause a transient reflex compensatory increase in heart rate and myocardial contractility which would normally increase myocardial oxygen consumption, yet the nitrite-induced decrease in ventricular wall tension results in a net decrease in myocardial oxygen demand and amelioration of the pain of angina pectoris. Additionally, amyl nitrite relaxes all other types of smooth muscle including bronchial, biliary, GI, ureteral, and uterine. Nitrites and nitrates are functional antagonists of acetylcholine, norepinephrine, and histamine.

Continuous use of nitrates (oral, transdermal, intravenous) results in tolerance to beneficial effects. Tolerance can develop within 24 to 48 hours. The mechanism is postulated as a depletion of sulfhydryl groups within the receptor and decreased cyclic GMP production. To prevent tolerance, a nitrate-free period of 8 to 12 hours is recommended. For example, transdermal nitroglycerin should be placed in the morning and removed at bedtime. For patients with primarily nocturnal angina, the on/off schedule can be reversed.


 * Distinguishing Features:** The nitrates may be classified into short or long-acting agents. Short-acting nitroglycerin products include sublingual tablets, translingual spray, and intravenous injection. The lingual products act within 1—3 minutes and last for 10—30 minutes. These are particularly useful for treatment of acute chest pain and for prevention of exercised-induced angina.

Long-acting nitrates take effect in 5—30 minutes and last 2—8 hours depending on the preparation. Transmucosal (buccal) tablets, topical ointment, transdermal patch, and sustained-release capsules are formulations of nitroglycerin that are available. The transdermal patches are preferred for patient convenience. There are a variety of transdermal delivery systems, but no evidence that one is more advantageous than another. Long-acting oral nitrates include isosorbide dinitrate (ISDN), isosorbide mononitrate, and pentaerythritol tetranitrate. ISDN is extensively used and less expensive. There is no comparative clinical evidence that any nitrate product is more effective than another. ISDN (like any nitrate) requires a nitrate free interval to prevent tolerance and is optimally dosed at 7AM, 12 PM, and 5PM.

For congestive heart failure (CHF), the use of nitrates in combination with hydralazine is very effective. Nitrates reduce preload and hydralazine reduces afterload, providing complementary actions to increase cardiac output. The Veterans Administration Cooperative Study showed that patients with moderate CHF treated with hydralazine (300 mg/day) and isosorbide dinitrate (160 mg/day) had decreased symptoms, improved exercise tolerance, and decreased mortality.[1069] However, patient acceptance of this regimen is low due to a high incidence of side effects and multiple daily doses. This regimen in CHF has been replaced by the use of ACE-inhibitors like enalapril which benefit mortality with fewer side effects and less frequent dosing.


 * Adverse Effects:** Side effects are similar for all nitrate products. Headache, dizziness, and hypotension are common. Tolerance usually develops to the headache within the first weeks. Acetaminophen is beneficial for headaches. Because of the hypotension, all patients using short-acting sublingual tablets or translingual spray should be counseled to sit down before and during use. Prolonged intravenous nitroglycerin can produce methemoglobinemia. Hypotension in patients given nitroglycerin is best treated by stopping or decreasing the rate of the nitroglycerin infusion and administering fluids.