Oral nitrates have been used in the treatment of angina since 1867, when Brunton[1] administered amyl nitrite through inhalation and compared its efficacy with phlebotomy, the standard of care in his time. In 1879, Murrell determined that nitroglycerin had an effect similar to but longer lasting than amyl nitrate.[2]
Pharmacology
Nitrates are effective in the treatment of stable and unstable angina, as well as Prinzmetal's or variant angina pectoris. In patients with acute myocardial infarction, intravenous nitroglycerin is often used to control hypertension and left ventricular failure, and to help reduce infarct size. Nitrates have been shown to reduce filling pressures of the right and left sides of the heart and decrease afterload in patients with congestive heart failure. Nitrates are also effective in the treatment of acute hypertensive episodes.[3,4] They have been shown to reduce preload by venodilatation; to dilate coronary arteries in prestenotic, stenotic and poststenotic segments; to increase collateral coronary artery blood flow; to homogenize flow imbalances, and to exert antiplatelet effects.[3] Although these effects help abate angina and improve exercise tolerance,[3] no studies definitively demonstrate a decrease in mortality with nitrate use.
MECHANISM OF ACTION
Organic nitrates are probably converted into nitric oxide in vascular smooth muscle cells. The nitric oxide may then form Snitrosothiols, which activate guanylate cyclase to produce cyclic guanosine 3,5'-monophosphate (cGMP), which causes venodilation.[5,6] Peripheral pooling of blood and decreased venous return to the heart result, reducing left ventricular end-diastolic pressure (preload).[7,8]
Nitrate effects on the venous system are well documented and occur at routine doses. Afterload may also be reduced because of arteriolar relaxation, resulting in reduced cardiac workload. Detectable decreases in systemic resistance (reflecting arteriolar dilatation) have been measured. These effects become progressively more marked with increasing plasma levels. Left ventricular afterload is reduced as a result of increased arterial conductance and compliance, decreased arterial tone and decreased peripheral vascular resistance caused by nitrates.5 The combined venous and arteriolair effects of the nitrates probably cause decreased myocardial oxygen consumption and demand, and are the effects responsible for reducing ischemia.[7,8]
Pharmacokinetics
Time to onset of action ranges from one minute to more than one hour among the various forms of nitrates (Table 1). Isosorbide mononitrate, the active metabolite of isosorbide dinitrate, is absorbed immediately after oral administration and reaches peak concentrations within one hour. It has a half-life of five hours and is virtually 100 percent bioavailable because it does not undergo significant hepatic first-pass effects.[9] It is excreted in the urine as approximately 98 percent inactive compounds after being metabolized by nitrate reductase in the liver. Consequently, there is no drug accumulation in patients with renal impairment.[8] In one study, accumulation was not a problem in patients with a creatinine clearance as low as 4.3 mL per minute.[9] Even though elimination of isosorbide mononitrate depends on hepatic metabolism, the pharmacokinetics are apparently unchanged even in patients with cirrhosis.[10]
[TABULAR DATA OMITTED]
Preparations, Dosage and Administration
NITROGLYCERIN
Table 2 provides recommended dosage schedules and cost comparisons for nitrate preparations. The patient should be warned that nitroglycerin tablets intended for sublingual or intrabuccal administration should not be chewed or swallowed, especially the extended-release tablets. The patient should be instructed to sit down immediately after administration of translingual spray, or sublingual or intrabuccal tablets. If efficacy appears to be diminished, it should be kept in mind that translingual, sublingual or intrabuccal nitroglycerin may be inadequately absorbed in patients with xerostoma.
Sublingual nitroglycerin is indicated for the treatment or prophylaxis of angina pectoris. The range of dosages is given in Table 2; doses may be given at five-minute intervals, with a maximum of three doses over 15 minutes."
[TABULAR DATA OMITTED]
Intrabuccal nitroglycerin is indicated for the prophylactic management of chronic angina, and the tablets are not to be placed under the tongue or used to treat acute angina. Intrabuccal tablets should be allowed to dissolve undisturbed between the lip and gum above the upper incisors or between the cheek and gum. If the patient inadvertently swallows a tablet, a replacement tablet can be used. The tablets should be used only while the patient is alert, not at bedtime, to reduce the risk of aspiration. After the effectiveness of the initial four to five days of therapy is assessed, the dosage can be titrated upward.[11,12]
Translingual spray is an effective method for both prophylaxis or acute treatment of angina pectoris. It is particularly efficacious in elderly patients with visual or neurologic deficits that impair their ability to handle the small sublingual tablets.[5] The spray form is metered; each canister provides about 200 metered sprays. Without first shaking the canister, a metered spray is directed onto or under the tongue and the mouth is then closed. Patients should be cautioned not to inhale or swallow the spray. It is acceptable to use one to two sprays initially, with additional single sprays at intervals of three to five minutes, up to a maximum of three sprays over 15 minutes. Patients can also use the spray five to 10 minutes before entering situations likely to provoke angina.[11]
The package inserts for sustained-release forms of nitroglycerin designate them as "possibly effective" for the management, prophylaxis or treatment of anginal attacks. The caution is included because of an insufficient number of studies demonstrating the efficacy of sustained-release forms of nitroglycerin over long periods.[13] As with all nitrates at higher doses, sustained-release forms carry risks of hypotension, tachycardia and tolerance. Therefore, physicians should administer the sustained-release forms only on the once-daily and twice-daily schedules recommended in Table 2. In addition, blood pressure should be monitored initially and whenever the dosage is changed.
ISOSORBIDE DINITRATE
Isosorbide dinitrate is used for the acute relief of angina pectoris and for prophylaxis. It can be used in conjunction with cardiac glycosides and diuretics, or with hydralazine (Apresoline) for the treatment of refractory congestive heart failure, although this use is not currently approved by the U.S. Food and Drug Administration.
Isosorbide dinitrate taken four times daily may lead to tolerance. However, a regimen of 30 mg at 7 a.m. and at noon, or 30 mg at 7 a.m., at noon and at 5 p.m. did not lead to tolerance.[13] The sustained-release form, 80 mg taken at 8 a.m. and 2 p.m., did not to appear to lead to tolerance; however, if the doses were taken at 8 a.m. and 8 p.m., tolerance did result. Recommended dosing regimens are given in Table 2. The recommendations provided in the table do not necessarily coincide with those in the Physicians' Desk Reference (PDR). The PDR deals little with the benefits of eccentric dosing, which is well documented elsewhere in the literature.
ISOSORBIDE MONONITRATE
Isosorbide 5-mononitrate (Imdur, Ismo, Monoket) is the major active metabolite of isosorbide dinitrate. As previously noted, once-daily dosing is recommended for sustained-release forms of this drug, since partial tolerance has been shown to occur with dosing at 12-hour intervals. When twice-daily dosing of non-sustained-release forms is used, the timing must be eccentric (i.e., 8 a.m. and 2 p.m.).[14,15] Studies have demonstrated that tolerance develops with four daily doses.[11]
Isosorbide mononitrate is not indicated for stopping acute anginal attacks but offers the following advantages in prophylaxis: (1) it is completely bioavailable after oral administration; (2) it has a longer elimination half-life than isosorbide dinitrate, and (3) chronic therapy with a regimen of 20 mg twice daily has not resulted in the clinical rebound phenomenon.
Tolerance
Tolerance is difficult to strictly differentiate from progression of the underlying disease,[16] but its often rapid development is well documented in the literature.[17-21] Tolerance may occur as a result of the consumption of sulfhydryl-containing agents such as glutathione during the bioconversion of nitrates to nitric oxide and then into S-nitrosothiols.[4] Some studies have shown that the sulfhydryl-containing drugs such as N-acetylcysteine potentiate the coronary and peripheral vasodilator effects of nitrates by restoring the sulfhydryl pool,[4,22] but this possibility is still being debated.[16,23]
Other researchers have speculated that tolerance is the result of reflex stimulation of catecholamines and renin in response to nitrate-induced vasodilation, leading to vasoconstriction and at least a partial attenuation of the vasodilatory effects of nitrates. [18,24] Nitrate use may also lead to an expansion of plasma volume or an increase in body weight, which is likely to attenuate the increase in venous capacitance that is initially observed with nitroglycerin.(18,24)
Whatever the cause, tolerance can be circumvented with the provision of a daily nitrate-free interval.[16-20] Strategies for avoiding tolerance with oral therapy include once-daily dosing or intermittent intake of high doses.1[6] Once-daily ingestion of up to 120 mg of isosorbide dinitrate in the sustained-release form does not result in tolerance.[25] Tolerance can also be avoided by using isosorbide mononitrate in the sustained-release form, 120 or 240 mg once daily.[26]
Intermittent intake of low doses is yet another strategy for avoiding tolerance. A dosing regimen of 30 mg of non-sustained-release isosorbide dinitrate, taken twice daily at 7 a.m. and noon, or three times daily at 7 a.m., noon and 5 p.m., also helps prevent tolerance.[27]
An important consideration in choosing among the aforementioned methods of avoiding tolerance is the duration of the maximal effects obtained. A single dose of 15 to 30 mg of non-sustained-release isosorbide dinitrate exerted anti-ischemic effects for eight hours but had maximum effects for only two to three hours. A 120-mg capsule of isosorbide dinitrate was shown to exert anti-ischemic effects for up to 12 hours; its six-hour effects were identical to its effects at two hours. The non-sustained-release form of isosorbide dinitrate at a dosage level of 40 mg had considerably less anti-ischemic effect at six hours than it did at one hour.[16]
If tolerance occurs despite eccentric dosing, the use of conjunctive therapy with beta blockers and other agents has been advocated. Beta blockers have been shown to contribute to a decrease in the incidence of sudden death due to myocardial ischemia and infarction.[11]
Adverse Effects
Untoward responses that occur with the use of nitrates are secondary to effects on the cardiovascular system, the most common of which is headache. Headaches usually subside after a few days of therapy; dosage reduction may be necessary in some cases to abate headaches. Dizziness, weakness and syncope can also occur. These effects are exacerbated by alcohol and usually occur with the patient standing immobile. However, even if severe, these effects can usually be reversed if the patient physically repositions himself or herself or uses other procedures that facilitate venous return.[11]
Aspirin may interact with nitrates by increasing serum nitrate concentration. Use of nitrates with calcium channel blockers may cause marked symptomatic orthostatic hypotension and may, therefore, necessitate dosing adjustments. Dihydroergotamine (D.H.E. 45) may cause functional antagonism with nitrates through its ability to increase mean standing blood pressure. Conflicting data exist on the ability of nitrates to decrease the pharmacologic effects of heparin.[11]
Potential adverse reactions classified by systems are shown in Table 3.[28]
Final Comment
The treatment of acute angina is relatively straightforward-sublingual or translingual
TABLE 3
Adverse Reactions of Oral Nitrates
System Reactions Gastrointestinal Local burning or tingling sensation in the
oral cavity with sublingual nitroglycerin;
nausea; vomiting; diarrhea; dyspepsia;
involuntary passing of urine and feces;
abdominal pain; tenesmus; tooth disorder Central nervous system Headache, which may be severe and
persistent (up to 50%); apprehension;
restlessness; nightmares; dyscoordination;
hypoesthesia; hypokinesia Cardiovascular Tachycardia; retrosternal discomfort;
palpitations; hypotension (possibly with
paradoxical bradycardia and increased
angina pectoris); syncope; collapse;
crescendo angina; rebound hypertension;
arrhythmias; atrial fibrillation;
premature ventricular contractions; postural
hypotension Dermatologic Drug rash or exfoliative dermatitis; cutaneous
vasodilation with flushing; crusty skin
lesions; pruritis; rash Genitourinary Dysuria; impotence; urinary frequency Musculoskeletal Arthralgia Respiratory Bronchitis; tracheobronchitis; wheezing;
pneumonia; upper respiratory tract infection Hematologic Chnically significant methemoglobinemia at
conventional doses (rare). Formation of
methemoglobin is dose-related. Treatment is
high-flow oxygen and intravenous
methylene blue. Miscellaneous Muscle twitching; pallor; perspiration; cold
sweats; hemolytic anemia; asthenia; blurred
vision; diplopia; edema; malaise; neck
stiffness; rigors; increased appetite
Adapted from Drug facts and comparisons. St. Louis, Mo.: Lippincott, 1994:143c. 143d.
administration of nitrate preparations, with repeated doses. Failure to respond to three doses usually requires a trip to the emergency department. Confusion seems to arise over prophylaxis, because of the variety of nitrate forms available. Whether the physician's choice is sustained-release nitroglycerin, one of the two forms of isosorbide dinitrate or non-sustained-release isosorbide mononitrate, simplicity and efficacy are usually obtained with twice-daily eccentric dosing (i.e., 8 a.m. and 2 p.m.).
These regimens may be further simplified a patient responds to once-daily sustained-release isosorbide mononitrate. However, evidence is insufficient to support the contention that isosorbide mononitrate offers any therapeutic advantage over the other types of nitrates. In addition, a considerable difference in cost exists between nitroglycerin and isosorbide dinitrate versus isosorbide mononitrate. The difference in cost is relatively small among sustained-release nitroglycerin and both forms of isosorbide dinitrate. Eccentric twice-daily dosing of isosorbide dinitrate is not usually a difficult regimen for most patients.
The authors thank Robert S. Frederick, M.D., for his valuable review of the manuscript, and two anonymous reviewers, for their comments.
The Authors
JEFFREY W BOMBER, D.O., PH.D. is a family practice resident at the Toledo (Ohio) Hospital Family Practice Residency Program. He graduated from the University of Osteopathic Medicine and Health Sciences of Des Moines, lowa, and earned a Ph.D. from the Florida Institute of Technology, Melbourne.
PAMELA L. DE TULLIO, PHARM.D. is currently manager of patient care services in the Department of Pharmacy at St. Joseph Mercy Hospital, Ann Arbor, Mich. She was formerly clinical pharmacist at the Toledo Hospital Family Practice Residency Program and adjunct associate professor at the University of Toledo (Ohio) College of Pharmacy. She graduated from the University of California, San Francisco.
Address correspondence to Jeffrey W. Bomber, D.O., Ph.D., Family Practice Residency Program, Toledo Hospital, 2051 W. Central Ave., Toledo, OH 43606. forms only on the once-daily and twice-daily schedules recommended in Table 2. In addition, blood pressure should be monitored initially and whenever the dosage is changed.
REFERENCES
[1.] Brunton TL. Use of nitrate of amyl in angina pectoris. Lancet 1867;II:97-8. [2.] Needleman P, Johnson EM. Vasodilators and the treatment of angina. In: Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. 6th ed. New York: Macmillan, 1980:819-33. [3.] Flaherty JT. Nitrate tolerance. A review of the evidence. Drugs 1989;37:523-50. [4.] Horowitz JD. Thiol-containing agents in the management of unstable angina pectoris and acute myocardial infarction. Am J Med 1991;91(Suppl 3C):113-7. [5.] Abrams J. The role of nitrates in coronary heart disease. Arch Intern Med 1995;155:357-64. [6.] Harrison DG, Bates JN. The nitrovasodilators. New ideas about old drugs. Circulation 1993;87(5):1461-7. [7.] Fung HL, Chung SJ, Bauer JA, Chong S, Kowaluk EA. Biochemical mechanism of organic nitrate action. Am J Cardiol 1992;70:4B-10B. [8.] Fung HL. Clinical pharmacology of organic nitrates. Am J Cardiol 1993;72:9C-1,5C. [9.] Abshagen UW. Pharmacokinetics of isosorbide mononitrate. Am J Cardiol 1992;70:6LG-6G. [10.] Akpan W, Endele R, Neugebauer G, Steudel H. Pharmacokinetics of IS-5MN after oral and intravenous administration in patients with hepatic failure. In: Cohn JN, Rittinghausen R, eds. Mononitrates. New York: Springer-Verlag, 1985:53-66. [11.] Murad F. Drugs used for the treatment of angina: organic nitrates, calcium channel blockers, and - adrenergic antagonists. In: Goodman LS, Gilman A, et al., eds. The pharmacologic basis of therapeutics. 8th ed. New York: Pergamon, 1990:764-83. [12.] Vasodilating agents. In: Kastrup EK, et al, eds. Drug facts and comparisons. St. Louis: Lippincott, 1987:626-9. [13.] Thadani U. Role of nitrates in angina pectoris. Am J Cardiol 1992;70:43B-53B. [14.] Thadani U, de Vane PJ. Isosorbide-5-mononitrate LS-5MN) in angina pectoris: efficacy of AM and PM doses, lack of tolerance and zero hour effect during eccentric BID therapy [Abstract]. Circulation 1991; 84(Suppl II):11-730. [15.] Thadani U, de Vane PJ. Efficacy of isosorbide mononitrate in angina pectoris. Am J Cardiol 1992;70:67G-71G. [16.] Silber S. Nitrates: why and how should they be used today? Current status of the clinical usefulness of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate. Eur J Clin Pharmacol 1990;38(Suppl 1):S35-S51. [17.] Parker JO, Parker JD. Neurohormonal activation during nitrate therapy: a possible mechanism for tolerance.: AM J Cardiol 1992;70:93B-7B. [18.] Elkayam U, Mehra A, Shotan A, Osprzega E. Possible mechanisms of nitrate tolerance. Am J Cardiol 1992-70:49G-54G. [19.] Amsterdam EA. Rationale for intermittent nitrate therapy. Am J Cardiol 1992;70:55G-W. [20.] Maxwell SR, Kendall M). An update on nitrate tolerance: can it be avoided? Postgrad Med J 1992;68: 857-66. [21.] Thadani U, Maranda CR, Amsterdam E, Spaccavento L, Friedman RG, Chemoff R, et al. Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate. Ann Intern Med 1994,120:353-9. [22.] Horowitz JD, Antman EM, Lorell BH, Barry WH, Smith TW. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation 1983;68:1247-53. [23.] Parker JO, Farrell B, Lahey KA, Rose BF. Nitrate tolerance: the lack of effect of N-acetylcysteine. Circulation 1987;76:572-6. [24.] Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance: in patients with congestive heart failure. N ENSI Med 1987;317:799-804. [25.] Silber S, Vogler AC, Krause KH, Vogel M, Theisen K. Induction and circumvention of nitrate tolerance applying different dosage intervals. Am J Med 1987;83:860-70. [26.] Chrysant SG, Glasser SP, Bittar N, Shahidi FE, Danisa K, lbrahim R, et al. Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris. Am J Cardiol 1993;72:1249-56. [27.] Parker JO, Farrell B, Lahey KA, Moe G. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987,316:1440-4. [28.] Antianginal agents. In: Kastrup EK, et al., eds. Drug facts and comparisons. St. Louis: Lippincott, 1994:626-39.
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