Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Nitrate tolerance Udho Thadani MBBS, MRCP, FRCPC To cite this article: Udho Thadani MBBS, MRCP, FRCPC (1992) Nitrate tolerance, Postgraduate Medicine, 91:5, 307-318, DOI: 10.1080/00325481.1992.11701297 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701297
Published online: 17 May 2016.
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Nitrate tolerance How to prevent it or minimize its effect
Udho Tbadani, MBBS, MRCP, FRCPC
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NITRATE TOLERANCE-Evidence shows that after initial exposure to nitrates, myocardial ischemia during exercise is reduced and pain-free walking distance is increased.8 However, according to the majority of trials, tolerance develops rapidly when long-acting nitrates are given for 1 tion of nitrate exposure. 8 antianginal prophylaxis. 8•9 Long-term exposure to niWith use of transdermal nitrotrates leads to depletion of reglycerin, which provides constant duced sulfhydryl groups; this de- nitroglycerin plasma levels for 24 pletion is, in part, responsible ·hours or longer following applifor the development of tolerance. cation, tolerance to circulatory Other mechanisms, including and antianginal effects develops activation of the neuroendocrine within 24 hours. 3 This effect is system and an increase in plasma not due to inadequate patch size. In a recent multicenter trial monvolume, may also play a role. Many strategies to prevent nitrate itored by the Food and Drug Administration,11 long-term therapy tolerance have been tried, but only a few are clinically useful in with nitroglycerin patches was evaluated in 562 patients. Patches any given situation. delivering up to 105 mg of nitroStable angina pectoris glycerin over 24 hours failed to The majority of patients with sta- produce any objective improvement in exercise duration when ble angina pectoris have reprocompared with effects achieved ducible exertion- or excitementwith placebo patches. Infusion induced angina. Many of these of intravenous nitroglycerin depatients also experience occalivering a high, constant dose also sional episodes of angina at rest. In this group of patients, the aim resulted in development of tolerance within 24 hours. 12 of therapy is to improve quality of life by abolishing or reducing Even with nitrate preparations that do not provide constant daily episodes of angina and by increasing the pain-free walking plasma concentrations, partial tolerance to circulatory and antidistance attainable. continued
Although nitrates are powerful antianginal and anti-Ischemic agents, long-tenn therapy may result in nitrate tolerance. How can this be avoided? Dr Thadani discusses clinically useful strategies to prevent or minimize nitrate tolerance in patients with stable angina pectoris, unstable angina, and congestive heart failure.
Nitrates are inexpensive but potent venous and arterial dilators that are widely used in the treatment of stable angina pectoris, unstable angina, congestive heart failure, and acute myocardial infarction. During long-term nitrate therapy, tolerance develops rapidly, rendering these agents ineffective.1·7 However, with appropriate use of nitrates, tolerance can be avoided or minimized.8•9 Substantial evidence has accumulated to show that prolonged exposure to nitrates causes the venodilatory and arterial blood pressure-lowering effects of these agents to be rapidly attenuated or abolished.?-9 In addition, with continued use, nitrates lose their effectiveness (to a variable degree) in patients with stable angina pectoris, 1-3•7-9 unstable angina, 10 and congestive heart failure. 46•7·9 The rapidity and extent to which nitrate tolerance develops vary according to the nitrate preparation and the dura-
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The rapidity and extent to which nitrate tolerance develops vary according to the nitrate preparation and the duration of nitrate exposure.
b
Figure 1. Plasma concentration (a) and duration of effects (b, c) of isosorbide dinitrate (ISDN) during acute therapy and during sustained therapy (four times daily) in patients with angina pectoris. 0-hour values during sustained therapy represent values 10 hours after preceding (previous night) dose. Plasma drug concentrations were higher during sustained therapy, but peak effects and duration of effects on systolic blood pressure at rest (in standing position), as well as on exercise time to angina, were markedly attenuated.
Adapted, with permission, from Thadani et al.'
c
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Complete tolerance to the antianginal effects of nitrates develops rapidly during long-term therapy with formulations that provide constant plasma concentrations.
anginal effects develops during long-term therapy. 1'8 "When the standard formulation of isosorbide dinitrate (Isordillitradose, Sorbitrate) is given four times a day, the antianginal and circulatory effects of the drug and its active metabolite, isosorbide5-mononitrate, rapidly weaken.'·8 Partial tolerance develops even when isosorbide-5-mononitrate (ISMO) is given every 12 hours. 8 Clinically; this tolerance with long-term use of long-acting oral nitrates is characterized by a reduction in peak effects and in duration of effects as compared with first-dose effects, despite higher plasma concentrations during long-term therapy (figure 1). 1 "When the drug is given four times a day; tolerance develops within 1 week; however, circulatory tolerance has been shown to develop within 24 hours of initiating isosorbide dinitrate therapy. 8 Thus, the current consensus is that complete tolerance to the antianginal effects of nitrates develops rapidly during long-term therapy with formulations that provide constant plasma concentrations (ie, patches, constantrelease oral preparations, intravenous preparations). In contrast, only partial tolerance develops
Figure 2. Mean duration of exercise to angina at different hours during days on which placebo or isosorbide dinitrate (ISDN) was administered. Doses were given at 8 AM, 1 PM, and 6 PM. Clinically significant increase in exercise time was present for only 1 to 2 hours after each ISDN dose.
Adapted, with permission, from Bassan. 14
with intermittent use of oral formulations that produce peaks and valleys in plasma concentrations between doses. AVOIDANCE OF TOLERANCE-
Because nitrate tolerance develops during long-term therapy, it is not possible to provide 24hour antianginal prophylaxis
with any of the available nitrate preparations. Intermittent nitrate therapy with prolonged nitrate-free intervals prevents the development of tolerance or reduces its magnitude. A regimen of isosorbide dinitrate, 20 to 30 mg given either twice daily at 7 AM and
continued
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lntennittent nitrate therapy with prolonged nitrate-free intervals prevents the development of tolerance or reduces its magnitude in patients with stable angina pectoris.
Figure 3. Change from 0-hour in time (mean, SEM) to onset of moderate angina after application of nitroglycerin skin patch or placebo patch in patients with stable angina pectoris. Difference between placebotreated patients and group A (1 O-cm2 or 20-cm2 patch) was statistically significant. Difference between group A and group B (40-cm2 patch) was statistically significant. NT, not tested (because of treatmentby-center interaction). Asterisks indicate significant difference from placebo. Adapted, with permission, from DeMots and G/asser. ••
12 noon or three times daily at
7 AM, 12 noon, and 5 PM, did not lead to development of tolerance to the morning dose in one study. 13 Whether the dose given at 12 noon or at 5 PM improved exercise endurance was not studied, however. In another study, 14 isosorbide dinitrate given three times a day increased exercise endurance for only 1 to 2 hours after the second dose and for
only 1 hour after the third dose (figure 2). In contrast, when 20 to 30 mg of isosorbide dinitrate was given twice daily at 8 AM and 2 PM, or 20 mg ofisosorbide-5mononitrate was given twice daily at 7 or 8 AM and 2 or 3 PM, the morning dose increased exercise endurance and prevented development of tolerance8' 15 ; with use of isosorbide-5-mononitrate, the afternoon dose was also effec-
tive and antianginal effects lasted for at least 12 hours during the day.1s When nitroglycerin patches are worn for only 10 to 12 hours during the day and are removed at night, tolerance does not develop.7·9 In a recent multicenter, placebo-controlled study of 206 patients, intermittent 12-hour therapy with nitroglycerin patches increased exercise endurance
continued
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Nitrates reduce myocardial oxygen demand and produce dilation of epicardial coronary arteries and collateral channels in patients with unstable angina.
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How do nitrates work?
Nitrates, by their predominant venodilaror effects, reduce venous return to the heart, with a resultant decrease in ventricular volume and end-diastolic pressure. This leads to a reduction in ventricular wall stress and thus a decrease in myocardial oxygen demand. In addition, nitrates reduce afterload and produce dilation of epicardial coronary arteries, collateral channels, and stenotic sites. Nitrates relax smooth muscles through an endothelium-independent mechanism and can produce vasodilation at the atherosclerotic site, where the endothelium is either denuded or dysfunctional. Nitrates also inhibit platelet aggregation in vitro and reduce platelet deposition and vasoconstriction at the site of experimental endothelial injury. 1 The exact cellular mechanism by which nitrates produce smooth-muscle relaxation is not entirely dear. After entering the cell wall, nitrates are converted to nitric oxide. This process requires the sulfhydryl groups; soluble guanylate cyclase is stimulated by nitrosothiols or the released nitric oxide to produce cyclic guanosine monophosphate. The cyclic nucleotide thus formed causes vasodilation as the calcium content of cells decreases either by inhibition of calcium ion entry or by promotion of calcium exit. Patients with stable angina pectoris invariably have atherosclerotic narrowing of one or more coronary arteries and experience angina when myocardial oxygen demand outstrips a relatively limited oxygen supply during exercise or emotional stress. Nitrate-induced reduction in myo-
VOL 91/NO 51APRIL 1992/POSTGRADUATE MEDICINE • NITRATI! TOLI!RANCE
cardial oxygen demand plays a major role in relieving myocardial ischemia and improving exercise endurance in these patients. In addition, coronary artery dilatory effects increase blood flow to ischemic areas. 2 The underlying lesion in unstable angina is fissuring of an atherosclerotic plaque, which predisposes to platelet deposition and thrombus formation. 3 In some patients, an increase in the severity of coronary narrowing due to plaque progression also plays a role; in others, an increase in myocardial oxygen demand, rather than a reduction in blood flow, may be contributory. Nitrates are effective in treating unstable angina because they reduce myocardial oxygen demand and produce dilation of epicardial coronary arteries and collateral channels. The antiplatelet effects of nitrates may also be somewhat beneficial. In patients with congestive heart failure, nitrate-induced reduction in heart size and ventricular end-diasrolic pressure is important in ameliorating symptoms and signs of heart failure. References 1. lam JY, Chesebro JH, Fuster V. Platdets, vasoconstriction, and nitroglycerin during anerial wall injury: a new antithrombotic role for an old drug. Circulation 1988;78(3):712-6 2. Gage JE, Hess OM, Murakami T, et al. Vasoconstriction of stenotic coronary aneries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73(5):865-76 3. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Hean J 1985;53(4):363-73
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Because of the risk of a rebound increase in angina, intennittent nitrate therapy is not appropriate for patients with unstable angina.
Udho Thadani, MBBS, MRCP, FRCPC Dr Thadani is professor of medicine, director of clinical research, and vice chief of the cardiology section, University of Oklahoma College of Medicine, Oklahoma City. His interests include pathophysiology and treatment of acute and chronic manifestations of ischemic heart disease.
and reduced ST-segment depression during exercise for at least 8 to 12 hours (figure 3). 16 However, smaller patches that deliver less than 15 mg in 24 hours may be ineffective. 16 Thus, tolerance can be avoided by using the following regimens: • Transdermal nitroglycerin during the day only • Oral isosorbide dinitrate, 20 to 30 mg twice daily at 7 AM and 1 PM (but effects of the 1 PM dose have not been studied) • lsosorbide-5-mononitrate, 20
mg twice daily at 7 or 8 AM and
2 or 3
PM
However, these dosing regimens provide antianginal prophylaxis for only 8 to 12 hours during the day. The patient is unprotected at night and in the early morning hours. For patients who experience angina only in the daytime during physical activity, monotherapy with nitrates given intermittently may suffice. However, for those rare patients who experience a rebound increase in angi-
nal attacks at night or for patients with stable angina who have a history of occasional nocturnal or early morning angina, use of another class .of antianginal agent (a long-acting beta blocker or a calcium antagonist) is recommended along with intermittent nitrate therapy. Development of nitrate tolerance is secondary to loss of vascular response, and the probable cellular mechanism is depletion or oxidation of sulfhydryl groups. It has been proposed that administration of sulfhydryl donors {acetylcysteine [Mucomyst] or methionine) may prevent development of tolerance. However, results of studies on preventing tolerance by concomitant use of these agents in patients with stable angina pectoris have been disappointing. 8'9 Furthermore, the added cost and adverse effects of sulfhydryl donors will preclude their clinical use in the future. Theoretically, therapy with angiotensin-converting enzyme inhibitors, which prevent neurohumoral activation induced by nitrates, could prevent nitrate tolerance. However, there are no adequate studies documenting their efficacy in preventing nitrate tolerance in patients with stable angina pectoris. Also, the added
continued
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Use of intravenous nitroglycerin for 24 to 72 hours is recommended in initial management of patients with unstable angina.
cost and potential adverse effects of these agents reduce the likelihood for their routine use.
Unstable angina The emphasis of treatment in unstable angina should be rapid institution of therapy with aspirin or heparin or a combination of the two. These agents reduce the incidence of morbidity and mortality but do not immediately relieve chest pain or myocardial ischemia. NTIRATE TOLERANCE-Nitrates play an important role in providing rapid relief of angina and reduce myocardial ischemia in patients with unstable angina. Since these patients are acutely ill and their clinical condition may change rapidly, therapy with intravenous nitroglycerin is recommended. The dose can be adjusted up or down rapidly as the patient's condition warrants. Unfortunately, tolerance to intravenous nitroglycerin develops within 24 to 48 hours. 10 AVOIDANCE OF TOLERANCEPatients with unstable angina are at increased risk for myocardial infarction, and many of them experience recurrent episodes of angina both in the daytime and at night during the first 72 hours of hospitalization. Therapy with
aspirin and heparin reduces the incidence of early morbidity and mortality, and intravenous nitroglycerin infusion relieves angina and myocardial ischemia. Despite the development of tolerance to intravenous nitroglycerin in these patients, intermittent nitrate therapy is not appropriate because of the risk of a rebound increase in angina. Nitrate tolerance for the short term can be overcome by progressively increasing the dose of intravenous nitroglycerin; doses as high as 1,000 J,Lg/min may be required to relieve pain. 10 Use of intravenous nitroglycerin for 24 to 72 hours is recommended in initial management of patients with unstable angina. 10 The dose can be adjusted up as required by the patient's clinical condition, provided he or she experiences no adverse effects (eg, symptomatic hypotension). Once the patient's condition has stabilized, intravenous nitroglycerin therapy can be gradually tapered and intermittent dosing with oral nitrates substituted. (See page 312 for description of regimens.)
Congestive heart failure Continuous nitrate therapy produces rapid tolerance to the drug's circulatory and hemody-
VOL 91/NO 5/APRIL 1992/POSTGRADUATE MEDICINE • NITRATE TOLERANCE
namic effects in patients with congestive heart failure. 4•6 Nitrate-induced reduction in left ventricular end-diastolic pressure is abolished within 24 hours of continuous therapy with intravenous nitroglycerin or transdermal nitroglycerin. 4'6' 17 AVOIDANCE OF TOLERANCEMany patients with congestive heart failure have symptoms throughout the day because of elevated left ventricular enddiastolic pressure and poor pump function. The goal of therapy is to reduce signs and symptoms of heart failure. Although nitrate tolerance can be prevented by intermittent use of intravenous nitroglycerin or transdermal nitroglycerin for only 12 hours during the day,9.17 such therapy cannot be recommended for this group of patients, because beneficial effects of nitrates on hemodynamics are completely lost during the nitrate-free intervals. There is also danger of a rebound increase in left ventricular end-diastolic pressure in the phase following nitrate withdrawal. 17 With oral nitrate formulations, only partial tolerance develops. 18 Beneficial effects on exercise endurance and pulmonary capillary wedge pressure persist during long-term therapy with isosorbide dinitrate, continued
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Oral isosorbide dinitrate, rather than intravenous or transdermal nitroglycerin, plus hydralazine may be useful for patients with chronic heart failure who cannot tolerate angiotensin-converting enzyme inhibitors.
30 to 60 mg given four times a day. 18 Concomitant therapy with hydralazine also reduces mortality but is inferior to therapy with angiotensin-converting enzyme inhibitors. 19 Acetylcysteine may partially reverse hemodynamic tolerance during continuous nitrate therapy. The adverse effects of oral acetylcysteine 7 and recent reports of ineffectiveness20 in reversing tolerance in patients with congestive heart failure raise serious doubts about the usefulness of this agent in these patients.
Summary Continuous therapy with nitrates rapidly produces tolerance along with loss or diminution of circulatory, antianginal, and anti-ischemic effects. Development of tolerance can be avoided by various approaches. In patients with stable angina, intermittent use of nitrates with long nitrate-free intervals, use of transdermal nitroglycerin during the day or oral isosorbide dinitrate or isosorbide-5-mononitrate twice daily in the morning and early afternoon, and intermittent use of nitrates in combination with
another class of antianginal agent are appropriate. In patients with unstable angina, continuous therapy with intravenous nitroglycerin is recommended during the acute phase of angina. Despite development of partial tolerance, oral isosorbide dinitrate, 30 to 60 mg four times a day; plus hydralazine may be useful for patients with congestive heart fuilure who cannot tolerate angiotensin-converting enzyme inhibitors. Concomitant use of sulfhydryl donors or angiotensinconverting enzyme inhibitors, agents that might theoretically
prevent nitrate tolerance, is not recommended. Data on these agents are conflicting, and added costs and adverse effects are likely to preclude their use in the future. FICIW
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Address for correspondence: Udho Thadani, MD, Cardiology Section, University of Oklahoma Health Sciences Center, 920 Stanton L. Young Blvd, SSP-300, Oklahoma City, OK 73104.
References
1. Thadani U, Fwtg HL, Darke AC, et al. Oral isosorbide dinitrate in angina pectoris: comparison of duration of action and doseresponse relation during acute and sustained therapy. Am J Cardiol1982;49(2):411-9 2. Parker JO, Fung HL Transdermal nitroglycerin in angina pectoris. Am J Cardiol1984; 54(6):471-6 3. Thadani U, Hamilton SF, Olson E, et al. Transdermal nitroglycerin patches in angina pectoris: dose titration, duration of effect, and rapid tolerance. Ann Intern Med 1986;105(4): 485-92
4. Elkayam U, Kulick D, Mclntosh N, et al. Incidence of early tolerance to hemodynarnic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure. Circulation 1987;76(3):577-84
5. Abrams J. Tolerance to organic nitrates. Circulation 1986;74(6):1181-5 6. Jordan RA, Seth L, Casebolt P, et al. Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure. Ann Intern Med 1986;104(3):295-8 7. Flaherty JT. Nitrate tolerance: a review of the evidence. Drugs 1989;37(4):523-50 8. Thadani U, Whitsett T, Hamilton SF. Nitrate therapy for myocardial ischemic syndrome: current perspectives including tolerance. Curr Probl Cardiol1988;13(11):723-84 9. Elkayam U. Tolerance ro organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 1991; 114(8):667-77 10. Thadani U. Nitrate therapy in unstable angina pectoris. In: Bleifeld W, Harnm CW,
continued
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References: 1. Beaver WT. Aspirin and acetaminophen as constituents of analgesic combinations. Arch Intern Med. 1981 ;141 :293-300.
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LORTAB® 7.5/500 e
Brief Summary Hydrocodone Bitartrate 7.5 mg (Warning: May be habit forming) and Acetaminophen 500 mg Tablets INDICATIONS: For the relief of moderate to moderately severe pain. CONTRAINDICATIONS: Hypersensitivity to acetaminophen or hydrocodone. WARNINGS: Drug Abuse and Dependence: Lortab 7.5/500 tablets are subject to the Federal Controlled Substances Act (Schedule Ill). Psychic dependence, physical dependence and tolerance may develop upon repeated administration of narcotics; therefore, Lortab 7.5/500 tablets should be prescribed and administered with caution. However, psychic dependence is unlikely to develop when Lortab 7.5/500 tablets are used for a short time for the treatment of pain. Respiratory Depression: At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhy1hm, and may produce irregular and periodic breathing. Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute Abdominal Conditions: The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal condi· lions. PRECAUTIONS: Caution: Federal law proh!bits dispensing without prescription. Special Risk Patients: As with any narcotic analgesic agent, Lortab 7.5/500 tablets should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease. prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Information for Patients: Lort3b 7.5/500 tablets, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly. Cough Reflex: Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when Lortab 7.5/500 tablets are used postoperatively and in patients with pulmonary disease. Drug Interactions: Patients receiving other narcotic analgesics, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with Lortab 7.5/500 tablets may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both a!,lents should be reduced. The use of MAO inhibitors or tricyclic antidepressants w1th hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone. The concurrent use of anticholinergics with hydrocodone may produce paraly1ic ileus. Usage In Pregnancy: Teratogenic Effects: Pregnancy Category C. Hydrocodone has been show(! to be teratogenic in hamsters when given in doses 700 times the human dose. There are no adequate and well-controlled studies in pregnant women. Lortab 7.5/500 tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors. hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomit· ing, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Chlorpromazine 0. 7 to 1 mg/kg q6h, and paregoric 2to 4 drops/kg q4h, have been used to treat withdrawal symptoms in infants. The duration of therapy is 4to 28 days, with the dosage decreased as tolerated. Labor and Delivery: As with all narcotics, administration of Lortab 7.51500 tablets to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Nursing Mothers: it is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Lortab 7.5/500 tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatrlc Use: Safety and effectiveness in children have not been established. ADVERSE REACTIONS: The most frequently observed adverse reactions include light· headedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include: Central Nervous System: Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria,_psychic dependence, mood chan!,les. Gastrointestlnal System: The an11emet1c phenoth1azmes are useful m suppress1ng the nausea and vomiting which may occur (see above); however, some phenothiazine derivatives seem to be antianalgesic and to increase the amount of narcotic required to produce pain relief, while other phenothiazines reduce the amount of narcotic required to produce a given level of analgesia. Prolonged administration of Lortab 7.5/500 tablets may produce constipation. Genltourinary System: Ureteral spasm, spasm of vesical sphincters and urinary retention have been reported. Respiratory Depression: Hydrocodone bitartrate may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhy1hm, and may produce irregular and periodic breathing. If significant respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride. Apply other supportive measures when indicated. DOSAGE AND ADMINISTRATION: Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related. The usual adult dosage is one tablet every four to six hours as needed for pain. The total24 hour dose should not exceed 6 tablets. Rev. 4/90
Manufactured for Whitby Pharmaceuticals, Inc. by Central Pharmaceuticals, Inc., Seymour, IN 47274 © 1991 Whitby Pharmaceuticals, Inc., Richmond, VA 23220 All rights reserved. Printed in U.S.A. 0057R891
Braunwald E, eds. Unstable angina. New York: Springer-Verlag, 1990:203-13
11. Steering Committee, '&.msdermal Nitro-
glycerin Cooperatiw Study. Acute and chronic antianginal efficacy of continuous 24-hour application of transdermal nitroglycerin. Am J Cardiol1991;68;1263-73 12. Zimrin D, Reichek N, Bogin liT, et al. Antianginal effects of intravenous nitroglycerin over 24 hours. Circulation 1988;77(6):1376-84 13. Parker JO, Farrell B, Lahey KA, et al. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N EnglJ Med 1987;316(23):1440-4 14. Bassan MM. The daylong pattern of the antianginal effect oflong-term three times daily administered isosorbide dinitrate. J Am Coli Cardiol1990;16(4):936-40 15. Thadani U, IS-5MN Study Group. Isosorbide-5-mononitrate (IS-5MN) in angina pectoris: efficacy of a.m. and p.m. doses, lack of tolerance and zero hour effect during chronic eccentric bid therapy. (Abstr) Circulation 1991; 84(suppl II):II-730 16. DeMots H, Giasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina. JAm Coli Cardiol1989; 13(4):786-95 17. Packer M, Lee WH, Kessler PD, et al. Prevention and reversal of nitrate tolerance in patients with congestive heart f.illure. N Engl J Med 1987;317(13):799-804 18. Leier CV, Huss P, Magorien RD, et al. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart f.illure. Circulation 1983;67(4):817-22 19. Cohn JN, Johnson G, uesche S, et al. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart f.illure. N Engl J Med 1991; 325(5):303-1 0 20. Dupuis J, Lalonde G, Lemieux R, et al. Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with Nacetylcysteine. JAm Coli Cardiol1990;16(4): 923-31
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NITRATE TOLERANCE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Nitrate tolerance Udho Thadani MBBS, MRCP, FRCPC To cite this article: Udho Thadani MBBS, MRCP, FRCPC (1992) Nitrate tolerance, Postgraduate Medicine, 91:5, 307-318, DOI: 10.1080/00325481.1992.11701297 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701297
Published online: 17 May 2016.
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Nitrate tolerance How to prevent it or minimize its effect
Udho Tbadani, MBBS, MRCP, FRCPC
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NITRATE TOLERANCE-Evidence shows that after initial exposure to nitrates, myocardial ischemia during exercise is reduced and pain-free walking distance is increased.8 However, according to the majority of trials, tolerance develops rapidly when long-acting nitrates are given for 1 tion of nitrate exposure. 8 antianginal prophylaxis. 8•9 Long-term exposure to niWith use of transdermal nitrotrates leads to depletion of reglycerin, which provides constant duced sulfhydryl groups; this de- nitroglycerin plasma levels for 24 pletion is, in part, responsible ·hours or longer following applifor the development of tolerance. cation, tolerance to circulatory Other mechanisms, including and antianginal effects develops activation of the neuroendocrine within 24 hours. 3 This effect is system and an increase in plasma not due to inadequate patch size. In a recent multicenter trial monvolume, may also play a role. Many strategies to prevent nitrate itored by the Food and Drug Administration,11 long-term therapy tolerance have been tried, but only a few are clinically useful in with nitroglycerin patches was evaluated in 562 patients. Patches any given situation. delivering up to 105 mg of nitroStable angina pectoris glycerin over 24 hours failed to The majority of patients with sta- produce any objective improvement in exercise duration when ble angina pectoris have reprocompared with effects achieved ducible exertion- or excitementwith placebo patches. Infusion induced angina. Many of these of intravenous nitroglycerin depatients also experience occalivering a high, constant dose also sional episodes of angina at rest. In this group of patients, the aim resulted in development of tolerance within 24 hours. 12 of therapy is to improve quality of life by abolishing or reducing Even with nitrate preparations that do not provide constant daily episodes of angina and by increasing the pain-free walking plasma concentrations, partial tolerance to circulatory and antidistance attainable. continued
Although nitrates are powerful antianginal and anti-Ischemic agents, long-tenn therapy may result in nitrate tolerance. How can this be avoided? Dr Thadani discusses clinically useful strategies to prevent or minimize nitrate tolerance in patients with stable angina pectoris, unstable angina, and congestive heart failure.
Nitrates are inexpensive but potent venous and arterial dilators that are widely used in the treatment of stable angina pectoris, unstable angina, congestive heart failure, and acute myocardial infarction. During long-term nitrate therapy, tolerance develops rapidly, rendering these agents ineffective.1·7 However, with appropriate use of nitrates, tolerance can be avoided or minimized.8•9 Substantial evidence has accumulated to show that prolonged exposure to nitrates causes the venodilatory and arterial blood pressure-lowering effects of these agents to be rapidly attenuated or abolished.?-9 In addition, with continued use, nitrates lose their effectiveness (to a variable degree) in patients with stable angina pectoris, 1-3•7-9 unstable angina, 10 and congestive heart failure. 46•7·9 The rapidity and extent to which nitrate tolerance develops vary according to the nitrate preparation and the dura-
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The rapidity and extent to which nitrate tolerance develops vary according to the nitrate preparation and the duration of nitrate exposure.
b
Figure 1. Plasma concentration (a) and duration of effects (b, c) of isosorbide dinitrate (ISDN) during acute therapy and during sustained therapy (four times daily) in patients with angina pectoris. 0-hour values during sustained therapy represent values 10 hours after preceding (previous night) dose. Plasma drug concentrations were higher during sustained therapy, but peak effects and duration of effects on systolic blood pressure at rest (in standing position), as well as on exercise time to angina, were markedly attenuated.
Adapted, with permission, from Thadani et al.'
c
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Complete tolerance to the antianginal effects of nitrates develops rapidly during long-term therapy with formulations that provide constant plasma concentrations.
anginal effects develops during long-term therapy. 1'8 "When the standard formulation of isosorbide dinitrate (Isordillitradose, Sorbitrate) is given four times a day, the antianginal and circulatory effects of the drug and its active metabolite, isosorbide5-mononitrate, rapidly weaken.'·8 Partial tolerance develops even when isosorbide-5-mononitrate (ISMO) is given every 12 hours. 8 Clinically; this tolerance with long-term use of long-acting oral nitrates is characterized by a reduction in peak effects and in duration of effects as compared with first-dose effects, despite higher plasma concentrations during long-term therapy (figure 1). 1 "When the drug is given four times a day; tolerance develops within 1 week; however, circulatory tolerance has been shown to develop within 24 hours of initiating isosorbide dinitrate therapy. 8 Thus, the current consensus is that complete tolerance to the antianginal effects of nitrates develops rapidly during long-term therapy with formulations that provide constant plasma concentrations (ie, patches, constantrelease oral preparations, intravenous preparations). In contrast, only partial tolerance develops
Figure 2. Mean duration of exercise to angina at different hours during days on which placebo or isosorbide dinitrate (ISDN) was administered. Doses were given at 8 AM, 1 PM, and 6 PM. Clinically significant increase in exercise time was present for only 1 to 2 hours after each ISDN dose.
Adapted, with permission, from Bassan. 14
with intermittent use of oral formulations that produce peaks and valleys in plasma concentrations between doses. AVOIDANCE OF TOLERANCE-
Because nitrate tolerance develops during long-term therapy, it is not possible to provide 24hour antianginal prophylaxis
with any of the available nitrate preparations. Intermittent nitrate therapy with prolonged nitrate-free intervals prevents the development of tolerance or reduces its magnitude. A regimen of isosorbide dinitrate, 20 to 30 mg given either twice daily at 7 AM and
continued
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lntennittent nitrate therapy with prolonged nitrate-free intervals prevents the development of tolerance or reduces its magnitude in patients with stable angina pectoris.
Figure 3. Change from 0-hour in time (mean, SEM) to onset of moderate angina after application of nitroglycerin skin patch or placebo patch in patients with stable angina pectoris. Difference between placebotreated patients and group A (1 O-cm2 or 20-cm2 patch) was statistically significant. Difference between group A and group B (40-cm2 patch) was statistically significant. NT, not tested (because of treatmentby-center interaction). Asterisks indicate significant difference from placebo. Adapted, with permission, from DeMots and G/asser. ••
12 noon or three times daily at
7 AM, 12 noon, and 5 PM, did not lead to development of tolerance to the morning dose in one study. 13 Whether the dose given at 12 noon or at 5 PM improved exercise endurance was not studied, however. In another study, 14 isosorbide dinitrate given three times a day increased exercise endurance for only 1 to 2 hours after the second dose and for
only 1 hour after the third dose (figure 2). In contrast, when 20 to 30 mg of isosorbide dinitrate was given twice daily at 8 AM and 2 PM, or 20 mg ofisosorbide-5mononitrate was given twice daily at 7 or 8 AM and 2 or 3 PM, the morning dose increased exercise endurance and prevented development of tolerance8' 15 ; with use of isosorbide-5-mononitrate, the afternoon dose was also effec-
tive and antianginal effects lasted for at least 12 hours during the day.1s When nitroglycerin patches are worn for only 10 to 12 hours during the day and are removed at night, tolerance does not develop.7·9 In a recent multicenter, placebo-controlled study of 206 patients, intermittent 12-hour therapy with nitroglycerin patches increased exercise endurance
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Nitrates reduce myocardial oxygen demand and produce dilation of epicardial coronary arteries and collateral channels in patients with unstable angina.
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How do nitrates work?
Nitrates, by their predominant venodilaror effects, reduce venous return to the heart, with a resultant decrease in ventricular volume and end-diastolic pressure. This leads to a reduction in ventricular wall stress and thus a decrease in myocardial oxygen demand. In addition, nitrates reduce afterload and produce dilation of epicardial coronary arteries, collateral channels, and stenotic sites. Nitrates relax smooth muscles through an endothelium-independent mechanism and can produce vasodilation at the atherosclerotic site, where the endothelium is either denuded or dysfunctional. Nitrates also inhibit platelet aggregation in vitro and reduce platelet deposition and vasoconstriction at the site of experimental endothelial injury. 1 The exact cellular mechanism by which nitrates produce smooth-muscle relaxation is not entirely dear. After entering the cell wall, nitrates are converted to nitric oxide. This process requires the sulfhydryl groups; soluble guanylate cyclase is stimulated by nitrosothiols or the released nitric oxide to produce cyclic guanosine monophosphate. The cyclic nucleotide thus formed causes vasodilation as the calcium content of cells decreases either by inhibition of calcium ion entry or by promotion of calcium exit. Patients with stable angina pectoris invariably have atherosclerotic narrowing of one or more coronary arteries and experience angina when myocardial oxygen demand outstrips a relatively limited oxygen supply during exercise or emotional stress. Nitrate-induced reduction in myo-
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cardial oxygen demand plays a major role in relieving myocardial ischemia and improving exercise endurance in these patients. In addition, coronary artery dilatory effects increase blood flow to ischemic areas. 2 The underlying lesion in unstable angina is fissuring of an atherosclerotic plaque, which predisposes to platelet deposition and thrombus formation. 3 In some patients, an increase in the severity of coronary narrowing due to plaque progression also plays a role; in others, an increase in myocardial oxygen demand, rather than a reduction in blood flow, may be contributory. Nitrates are effective in treating unstable angina because they reduce myocardial oxygen demand and produce dilation of epicardial coronary arteries and collateral channels. The antiplatelet effects of nitrates may also be somewhat beneficial. In patients with congestive heart failure, nitrate-induced reduction in heart size and ventricular end-diasrolic pressure is important in ameliorating symptoms and signs of heart failure. References 1. lam JY, Chesebro JH, Fuster V. Platdets, vasoconstriction, and nitroglycerin during anerial wall injury: a new antithrombotic role for an old drug. Circulation 1988;78(3):712-6 2. Gage JE, Hess OM, Murakami T, et al. Vasoconstriction of stenotic coronary aneries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73(5):865-76 3. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Hean J 1985;53(4):363-73
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Because of the risk of a rebound increase in angina, intennittent nitrate therapy is not appropriate for patients with unstable angina.
Udho Thadani, MBBS, MRCP, FRCPC Dr Thadani is professor of medicine, director of clinical research, and vice chief of the cardiology section, University of Oklahoma College of Medicine, Oklahoma City. His interests include pathophysiology and treatment of acute and chronic manifestations of ischemic heart disease.
and reduced ST-segment depression during exercise for at least 8 to 12 hours (figure 3). 16 However, smaller patches that deliver less than 15 mg in 24 hours may be ineffective. 16 Thus, tolerance can be avoided by using the following regimens: • Transdermal nitroglycerin during the day only • Oral isosorbide dinitrate, 20 to 30 mg twice daily at 7 AM and 1 PM (but effects of the 1 PM dose have not been studied) • lsosorbide-5-mononitrate, 20
mg twice daily at 7 or 8 AM and
2 or 3
PM
However, these dosing regimens provide antianginal prophylaxis for only 8 to 12 hours during the day. The patient is unprotected at night and in the early morning hours. For patients who experience angina only in the daytime during physical activity, monotherapy with nitrates given intermittently may suffice. However, for those rare patients who experience a rebound increase in angi-
nal attacks at night or for patients with stable angina who have a history of occasional nocturnal or early morning angina, use of another class .of antianginal agent (a long-acting beta blocker or a calcium antagonist) is recommended along with intermittent nitrate therapy. Development of nitrate tolerance is secondary to loss of vascular response, and the probable cellular mechanism is depletion or oxidation of sulfhydryl groups. It has been proposed that administration of sulfhydryl donors {acetylcysteine [Mucomyst] or methionine) may prevent development of tolerance. However, results of studies on preventing tolerance by concomitant use of these agents in patients with stable angina pectoris have been disappointing. 8'9 Furthermore, the added cost and adverse effects of sulfhydryl donors will preclude their clinical use in the future. Theoretically, therapy with angiotensin-converting enzyme inhibitors, which prevent neurohumoral activation induced by nitrates, could prevent nitrate tolerance. However, there are no adequate studies documenting their efficacy in preventing nitrate tolerance in patients with stable angina pectoris. Also, the added
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Use of intravenous nitroglycerin for 24 to 72 hours is recommended in initial management of patients with unstable angina.
cost and potential adverse effects of these agents reduce the likelihood for their routine use.
Unstable angina The emphasis of treatment in unstable angina should be rapid institution of therapy with aspirin or heparin or a combination of the two. These agents reduce the incidence of morbidity and mortality but do not immediately relieve chest pain or myocardial ischemia. NTIRATE TOLERANCE-Nitrates play an important role in providing rapid relief of angina and reduce myocardial ischemia in patients with unstable angina. Since these patients are acutely ill and their clinical condition may change rapidly, therapy with intravenous nitroglycerin is recommended. The dose can be adjusted up or down rapidly as the patient's condition warrants. Unfortunately, tolerance to intravenous nitroglycerin develops within 24 to 48 hours. 10 AVOIDANCE OF TOLERANCEPatients with unstable angina are at increased risk for myocardial infarction, and many of them experience recurrent episodes of angina both in the daytime and at night during the first 72 hours of hospitalization. Therapy with
aspirin and heparin reduces the incidence of early morbidity and mortality, and intravenous nitroglycerin infusion relieves angina and myocardial ischemia. Despite the development of tolerance to intravenous nitroglycerin in these patients, intermittent nitrate therapy is not appropriate because of the risk of a rebound increase in angina. Nitrate tolerance for the short term can be overcome by progressively increasing the dose of intravenous nitroglycerin; doses as high as 1,000 J,Lg/min may be required to relieve pain. 10 Use of intravenous nitroglycerin for 24 to 72 hours is recommended in initial management of patients with unstable angina. 10 The dose can be adjusted up as required by the patient's clinical condition, provided he or she experiences no adverse effects (eg, symptomatic hypotension). Once the patient's condition has stabilized, intravenous nitroglycerin therapy can be gradually tapered and intermittent dosing with oral nitrates substituted. (See page 312 for description of regimens.)
Congestive heart failure Continuous nitrate therapy produces rapid tolerance to the drug's circulatory and hemody-
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namic effects in patients with congestive heart failure. 4•6 Nitrate-induced reduction in left ventricular end-diastolic pressure is abolished within 24 hours of continuous therapy with intravenous nitroglycerin or transdermal nitroglycerin. 4'6' 17 AVOIDANCE OF TOLERANCEMany patients with congestive heart failure have symptoms throughout the day because of elevated left ventricular enddiastolic pressure and poor pump function. The goal of therapy is to reduce signs and symptoms of heart failure. Although nitrate tolerance can be prevented by intermittent use of intravenous nitroglycerin or transdermal nitroglycerin for only 12 hours during the day,9.17 such therapy cannot be recommended for this group of patients, because beneficial effects of nitrates on hemodynamics are completely lost during the nitrate-free intervals. There is also danger of a rebound increase in left ventricular end-diastolic pressure in the phase following nitrate withdrawal. 17 With oral nitrate formulations, only partial tolerance develops. 18 Beneficial effects on exercise endurance and pulmonary capillary wedge pressure persist during long-term therapy with isosorbide dinitrate, continued
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Oral isosorbide dinitrate, rather than intravenous or transdermal nitroglycerin, plus hydralazine may be useful for patients with chronic heart failure who cannot tolerate angiotensin-converting enzyme inhibitors.
30 to 60 mg given four times a day. 18 Concomitant therapy with hydralazine also reduces mortality but is inferior to therapy with angiotensin-converting enzyme inhibitors. 19 Acetylcysteine may partially reverse hemodynamic tolerance during continuous nitrate therapy. The adverse effects of oral acetylcysteine 7 and recent reports of ineffectiveness20 in reversing tolerance in patients with congestive heart failure raise serious doubts about the usefulness of this agent in these patients.
Summary Continuous therapy with nitrates rapidly produces tolerance along with loss or diminution of circulatory, antianginal, and anti-ischemic effects. Development of tolerance can be avoided by various approaches. In patients with stable angina, intermittent use of nitrates with long nitrate-free intervals, use of transdermal nitroglycerin during the day or oral isosorbide dinitrate or isosorbide-5-mononitrate twice daily in the morning and early afternoon, and intermittent use of nitrates in combination with
another class of antianginal agent are appropriate. In patients with unstable angina, continuous therapy with intravenous nitroglycerin is recommended during the acute phase of angina. Despite development of partial tolerance, oral isosorbide dinitrate, 30 to 60 mg four times a day; plus hydralazine may be useful for patients with congestive heart fuilure who cannot tolerate angiotensin-converting enzyme inhibitors. Concomitant use of sulfhydryl donors or angiotensinconverting enzyme inhibitors, agents that might theoretically
prevent nitrate tolerance, is not recommended. Data on these agents are conflicting, and added costs and adverse effects are likely to preclude their use in the future. FICIW
-®
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Address for correspondence: Udho Thadani, MD, Cardiology Section, University of Oklahoma Health Sciences Center, 920 Stanton L. Young Blvd, SSP-300, Oklahoma City, OK 73104.
References
1. Thadani U, Fwtg HL, Darke AC, et al. Oral isosorbide dinitrate in angina pectoris: comparison of duration of action and doseresponse relation during acute and sustained therapy. Am J Cardiol1982;49(2):411-9 2. Parker JO, Fung HL Transdermal nitroglycerin in angina pectoris. Am J Cardiol1984; 54(6):471-6 3. Thadani U, Hamilton SF, Olson E, et al. Transdermal nitroglycerin patches in angina pectoris: dose titration, duration of effect, and rapid tolerance. Ann Intern Med 1986;105(4): 485-92
4. Elkayam U, Kulick D, Mclntosh N, et al. Incidence of early tolerance to hemodynarnic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure. Circulation 1987;76(3):577-84
5. Abrams J. Tolerance to organic nitrates. Circulation 1986;74(6):1181-5 6. Jordan RA, Seth L, Casebolt P, et al. Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure. Ann Intern Med 1986;104(3):295-8 7. Flaherty JT. Nitrate tolerance: a review of the evidence. Drugs 1989;37(4):523-50 8. Thadani U, Whitsett T, Hamilton SF. Nitrate therapy for myocardial ischemic syndrome: current perspectives including tolerance. Curr Probl Cardiol1988;13(11):723-84 9. Elkayam U. Tolerance ro organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 1991; 114(8):667-77 10. Thadani U. Nitrate therapy in unstable angina pectoris. In: Bleifeld W, Harnm CW,
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References: 1. Beaver WT. Aspirin and acetaminophen as constituents of analgesic combinations. Arch Intern Med. 1981 ;141 :293-300.
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LORTAB® 7.5/500 e
Brief Summary Hydrocodone Bitartrate 7.5 mg (Warning: May be habit forming) and Acetaminophen 500 mg Tablets INDICATIONS: For the relief of moderate to moderately severe pain. CONTRAINDICATIONS: Hypersensitivity to acetaminophen or hydrocodone. WARNINGS: Drug Abuse and Dependence: Lortab 7.5/500 tablets are subject to the Federal Controlled Substances Act (Schedule Ill). Psychic dependence, physical dependence and tolerance may develop upon repeated administration of narcotics; therefore, Lortab 7.5/500 tablets should be prescribed and administered with caution. However, psychic dependence is unlikely to develop when Lortab 7.5/500 tablets are used for a short time for the treatment of pain. Respiratory Depression: At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhy1hm, and may produce irregular and periodic breathing. Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute Abdominal Conditions: The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal condi· lions. PRECAUTIONS: Caution: Federal law proh!bits dispensing without prescription. Special Risk Patients: As with any narcotic analgesic agent, Lortab 7.5/500 tablets should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease. prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Information for Patients: Lort3b 7.5/500 tablets, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly. Cough Reflex: Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when Lortab 7.5/500 tablets are used postoperatively and in patients with pulmonary disease. Drug Interactions: Patients receiving other narcotic analgesics, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with Lortab 7.5/500 tablets may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both a!,lents should be reduced. The use of MAO inhibitors or tricyclic antidepressants w1th hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone. The concurrent use of anticholinergics with hydrocodone may produce paraly1ic ileus. Usage In Pregnancy: Teratogenic Effects: Pregnancy Category C. Hydrocodone has been show(! to be teratogenic in hamsters when given in doses 700 times the human dose. There are no adequate and well-controlled studies in pregnant women. Lortab 7.5/500 tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors. hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomit· ing, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Chlorpromazine 0. 7 to 1 mg/kg q6h, and paregoric 2to 4 drops/kg q4h, have been used to treat withdrawal symptoms in infants. The duration of therapy is 4to 28 days, with the dosage decreased as tolerated. Labor and Delivery: As with all narcotics, administration of Lortab 7.51500 tablets to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Nursing Mothers: it is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Lortab 7.5/500 tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatrlc Use: Safety and effectiveness in children have not been established. ADVERSE REACTIONS: The most frequently observed adverse reactions include light· headedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include: Central Nervous System: Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria,_psychic dependence, mood chan!,les. Gastrointestlnal System: The an11emet1c phenoth1azmes are useful m suppress1ng the nausea and vomiting which may occur (see above); however, some phenothiazine derivatives seem to be antianalgesic and to increase the amount of narcotic required to produce pain relief, while other phenothiazines reduce the amount of narcotic required to produce a given level of analgesia. Prolonged administration of Lortab 7.5/500 tablets may produce constipation. Genltourinary System: Ureteral spasm, spasm of vesical sphincters and urinary retention have been reported. Respiratory Depression: Hydrocodone bitartrate may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhy1hm, and may produce irregular and periodic breathing. If significant respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride. Apply other supportive measures when indicated. DOSAGE AND ADMINISTRATION: Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related. The usual adult dosage is one tablet every four to six hours as needed for pain. The total24 hour dose should not exceed 6 tablets. Rev. 4/90
Manufactured for Whitby Pharmaceuticals, Inc. by Central Pharmaceuticals, Inc., Seymour, IN 47274 © 1991 Whitby Pharmaceuticals, Inc., Richmond, VA 23220 All rights reserved. Printed in U.S.A. 0057R891
Braunwald E, eds. Unstable angina. New York: Springer-Verlag, 1990:203-13
11. Steering Committee, '&.msdermal Nitro-
glycerin Cooperatiw Study. Acute and chronic antianginal efficacy of continuous 24-hour application of transdermal nitroglycerin. Am J Cardiol1991;68;1263-73 12. Zimrin D, Reichek N, Bogin liT, et al. Antianginal effects of intravenous nitroglycerin over 24 hours. Circulation 1988;77(6):1376-84 13. Parker JO, Farrell B, Lahey KA, et al. Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N EnglJ Med 1987;316(23):1440-4 14. Bassan MM. The daylong pattern of the antianginal effect oflong-term three times daily administered isosorbide dinitrate. J Am Coli Cardiol1990;16(4):936-40 15. Thadani U, IS-5MN Study Group. Isosorbide-5-mononitrate (IS-5MN) in angina pectoris: efficacy of a.m. and p.m. doses, lack of tolerance and zero hour effect during chronic eccentric bid therapy. (Abstr) Circulation 1991; 84(suppl II):II-730 16. DeMots H, Giasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina. JAm Coli Cardiol1989; 13(4):786-95 17. Packer M, Lee WH, Kessler PD, et al. Prevention and reversal of nitrate tolerance in patients with congestive heart f.illure. N Engl J Med 1987;317(13):799-804 18. Leier CV, Huss P, Magorien RD, et al. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart f.illure. Circulation 1983;67(4):817-22 19. Cohn JN, Johnson G, uesche S, et al. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart f.illure. N Engl J Med 1991; 325(5):303-1 0 20. Dupuis J, Lalonde G, Lemieux R, et al. Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with Nacetylcysteine. JAm Coli Cardiol1990;16(4): 923-31
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