Action And Clinical Pharmacology: The principal action of isosorbide dinitrate is that of all nitrates, the relaxation of vascular smooth muscle. The efficacy of nitrates in alleviating pain in angina pectoris is probably due primarily to reduction in myocardial oxygen demand rather than an increase in myocardial oxygen supply. This effect is thought to be brought about predominantly by a peripheral action. Although the venous effects predominate, nitrates produce dilation of both arterial and venous beds. Dilation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (pre-load). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). The decrease in ventricular volume reduces intramyocardial tension and lessens myocardial oxygen demand.
Pharmacodynamics: Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Prolonged administration of nitrate drugs according to traditionally recommended dosage regimens has been shown to produce tolerance. Tolerance results in a loss of efficacy. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. In the large majority of these trials, nitrate effectiveness was indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed.
Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored. Drug-free intervals sufficient to avoid tolerance to isosorbide dinitrate have not been completely defined. In the only regimen of twice-daily Cedocard SR, the 2 doses are given 6 hours apart. The eccentric twice-daily regimen provides antianginal efficacy for up to 14 hours (i.e., 6 hours between doses and 8 hours after second dose).
Pharmacokinetics: Radiotracer studies have shown that isosorbide is almost completely absorbed from the gastrointestinal tract and effectively metabolized in the liver by hepatic enzymes.
After the administration of a single oral dose of 20 mg Cedocard-SR tablets to 10 healthy volunteers mean peak plasma concentrations of 3.2 ng/mL were observed within 2 to 4 hours after dosing.
Plasma concentrations declined to about 1.7 ng/mL at 8 hours after drug administration but trace amounts of it were still detectable 12 hours after dosing.
Equilibrium dialysis experiments suggest that isosorbide is not extensively bound to plasma proteins. According to a recent study, the disposition of isosorbide showed a clear bi-exponential characteristic with half-lives of approximately 1.5 and 4 hours for the alpha and beta phases, respectively. According to this study plasma concentrations after chronic dosing were in general higher than those obtained after the comparable single doses.
Orally administered nitrates are rapidly metabolized in the liver by glutathion reductase. Recent investigations indicate that there is a wide interindividual variation in the pharmacokinetics of isosorbide and that some of the metabolites are also active. Two and 5-isosorbide mononitrate were found to exert a lesser but longer lasting hemodynamic effect than isosorbide dinitrate.
Thus, the active metabolites may contribute to the duration of action of isosorbide. Elimination occurs via the urine and is practically 100% within 24 hours post administration. Intact isosorbide is not found in urine. Twenty to 30% of the dose is excreted as 5-ISMN, 2-ISMN, isosorbide and isoiodide. The remainder is excreted primarily as the ether glucuronide of 5-ISMN and isosorbide.
Indications And Clinical Uses: For the prevention of anginal attacks in patients with chronic stable angina pectoris associated with coronary artery disease.
Not intended for the immediate relief of acute attacks of angina pectoris.
Contra-Indications: Known hypersensitivity to isosorbide dinitrate or to other nitrates or nitrites.
Acute circulatory failure associated with marked hypotension (shock and states of collapse).
Myocardial insufficiency due to obstruction (e.g., in the presence of aortic or mitral stenosis or of constrictive pericarditis).
Increased intracranial pressure.
Increased intraocular pressure.
Manufacturers’ Warnings In Clinical States: The benefits and safety of isosorbide dinitrate in anginal patients with acute myocardial infarction or congestive heart failure have not been established. Because the effects of isosorbide dinitrate are difficult to terminate rapidly, this drug is not recommended in these settings.
Dependence on nitrates may occur with chronic use. To avoid possible withdrawal effects, the administration of isosorbide should not be abruptly discontinued but rather be gradually reduced. In industry workers continuously exposed to nitrates, chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrate exposure.
Precautions: Headaches or symptoms of severe hypotension, such as weakness or dizziness, particularly when rising suddenly from a recumbent position, may occur. Caution should be exercised when using nitrates in patients prone to, or who might be affected by hypotension. Isosorbide dinitrate should therefore be used with caution in patients who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g., below 90 mmHg). Paradoxical bradycardia and increased angina pectoris may accompany nitrate-induced hypotension.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. There is, moreover, physical dependence since chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers. In clinical trials of anginal patients, there are reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal.
The importance of these observations to the routine, clinical use of oral isosorbide dinitrate has not been fully elucidated.
Caution should be exercised in patients with arterial hypoxemia due to anemia (see Contraindications). Similarly, caution is called for in patients with hypoxemia and a ventilation/perfusion imbalance due to lung disease or ischemic heart failure. Patients with angina pectoris, myocardial infarction or cerebral ischemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia). Under these circumstances, vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, isosorbide dinitrate could reverse this protective vasoconstriction and thus result in increased perfusion to poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.
Tolerance to isosorbide dinitrate with cross tolerance to other nitrates or nitrites may occur (see Pharmacology).
As tolerance to isosorbide dinitrate develops, the effects of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.
Occupational Hazards: As patients may experience faintness and/or dizziness, reaction time when driving or operating machinery may be impaired, especially at the start of treatment.
Pregnancy: No studies in pregnant women have been done. Studies in rabbits given isosorbide dinitrate in oral doses of 35 and 150 times the maximum daily recommended human dose have shown a dose-related increase in embryotoxicity. Isosorbide dinitrate should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether isosorbide dinitrate is excreted in breast milk. Although problems in humans have not been documented, caution should be exercised when isosorbide dinitrate is administered to a nursing mother.
Children: The safety and effectiveness in children have not been established. Therefore its use in children is not recommended.
Drug Interactions: Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquilizers may potentiate the blood pressure lowering effect of isosorbide dinitrate. Dose adjustment may be necessary. Alcohol may enhance sensitivity to the hypotensive effects of nitrates.
Adverse Reactions: The most frequent adverse reaction following administration of isosorbide is vascular headache which may be severe and persistent. This adverse effect occurs most frequently at the beginning of therapy. Headache usually can be controlled by temporary dosage reduction, concomitant administration of commonly used analgesics or by administering the drug during meals. These headaches usually disappear within 1 week of continuous, uninterrupted therapy. It is usually best to advise the patient of their possible occurrence and of their importance in regard to the prevention of angina. Drug and/or exfoliative dermatitis occasionally occur.
Signs of cerebral ischemia associated with postural hypotension such as weakness, transient episodes of dizziness may occasionally develop. Cutaneous vasodilation with flushing may occur. Rarely a marked sensitivity to the hypotensive effects of the drug and severe response (nausea, vomiting, restlessness, perspiration and collapse) can occur and alcohol may enhance this effect. Isosorbide dinitrate can antagonize the effects of histamine or epinephrine, acetylcholine and similar agents.
Symptoms And Treatment Of Overdose: Symptoms: These may include the following: a prompt fall in blood pressure, persistent and throbbing headache, vertigo, palpitation, visual disturbances, flushed and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright position), methemoglobinemia with cyanosis and anoxia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions and possibly death due to circulatory collapse.
Treatment: Prompt removal of the ingested material by gastric lavage is reasonable but not documented to be useful. Keep the patient recumbent in a shock position and comfortably warm. Passive movements of the extremities may aid venous return. Administer oxygen and artificial respiration if necessary.
Dosage And Administration: Cedocard SR tablets are administered orally twice daily, usually in the morning and in the early afternoon. The first and the second dose should be separated by approximately 6 hours, resulting in an interval between the second dose and the next first dose of about 18 hours. The recommended starting dose is 20 mg twice daily. This may be increased to a maximum of 40 mg twice daily depending on patient’s tolerance and responsiveness to Cedocard SR.
While experiencing a reduction in the number of anginal episodes with Cedocard SR therapy, patients apprehensive of particularly stressful situations may still be prone to an attack. In such cases, the therapy should be supplemented with 1 or 2 sublingual isosorbide tablets 5 mg.
Availability And Storage: Each yellow tablet, scored on one side and imprinted “CC-SR” on the other, contains: isosorbide dinitrate 20 mg in sustained release (SR) form. Nonmedicinal ingredients: D&C Yellow No. 10, FD&C Yellow No. 6, lactose, magnesium stearate, polyvinylacetate and talc. Bottles of 100.
CEDOCARD® SR Pharmascience Isosorbide Dinitrate Antianginal Agent