Erythrityl Tetranitrate
Indications: Angina pectoris
DESCRIPTION:
Cardilate (erythrityl tetranitrate) is an antianginal drug that belongs to the organic nitrate class of pharmaceutical agents. Erythrityl tetranitrate is soluble in alcohol, ether and glycerol, but insoluble in water. It has the empirical formula C4H6N4O12, molecular weight of 302.12 and melting point of 61Β°C.
Erythrityl tetranitrate is known chemically as (R *S *)-1,2,3,4-butanetetrol tetranitrate.
In the pure state, erythrityl tetranitrate will explode upon percussion, but properly diluted with lactose, as in Cardilate tablets, it is nonexplosive. Since it is a low melting solid, erythrityl tetranitrate does not evaporate from the Cardilate tablets.
Cardilate Oral/Sublingual Tablets contain 10 mg erythrityl tetranitrate and the inactive ingredients lactose, magnesium stearate and potato starch, with disintegration characteristics that permit sublingual or oral (swallowed) administration.
CLINICAL PHARMACOLOGY:
Cardilate exerts its effects by relaxation of vascular smooth muscle.1 The action is maximal on the post-capillary vessels, including the large veins. Venodilation results in peripheral blood pooling, which decreases venous return to the heart, central venous pressure and pulmonary capillary wedge pressure (preload reduction).2 Pulmonary arteriolar dilatation causes a reduction in pulmonary vascular resistance.2 A decrease in systemic arterial pressure (afterload reduction) can also occur, but is usually less pronounced. Augmentation of cardiac output generally occurs in those patients with increased filling pressures and high resting systemic vascular resistance.2
Mechanism of Action: The inadequate myocardial oxygenation that precipitates angina can be corrected by: (1) increasing the supply of oxygen to ischemic myocardium through direct dilatation of the large coronary conductance vessels or (2) decreasing the myocardial oxygen demand secondary to a reduction of cardiac work (preload and afterload reduction).3 The beneficial effect of Cardilate probably involves both mechanisms.
Pharmacokinetics and Metabolism: Cardilate is readily absorbed from the sublingual, buccal and gastrointestinal mucosae. The peak effect from a swallowed dose is diminished but of longer duration when compared to the sublingual route.4 The biotransformation of Cardilate is thought to occur by reductive hydrolysis catalyzed by the hepatic enzyme glutathione-organic nitrate reductase.3 Differences in response among various nitrates may relate to both intrinsic potency at cardiovascular sites, as well as factors related to pharmacokinetics and biotransformation.5
Time to onset of effect is approximately 5 minutes for the sublingual route and 15 to 30 minutes for swallowed tablets, with peak effect in 15 minutes and 60 minutes, respectively. Duration of action will vary, but vasodilatory effects have been demonstrated for up to 3 hours after sublingual administration4,6 and for 6 hours after the oral (swallowed) route.4
INDICATIONS AND USAGE:
Cardilate (erythrityl tetranitrate) is intended for the prophylaxis and long-term treatment of patients with frequent or recurrent anginal pain and reduced exercise tolerance associated with angina pectoris, rather than for the treatment of the acute attack of angina pectoris, since its onset is somewhat slower than that of nitroglycerin.
CONTRAINDICATIONS:
Cardilate should not be administered to individuals with a known hypersensitivity or idiosyncratic reaction to organic nitrates.
WARNINGS:
The use of nitrates in acute myocardial infarction or congestive heart failure should be undertaken only under close clinical observation and/or in conjunction with hemodynamic monitoring.
PRECAUTIONS:
General: Cardilate should be used with caution in patients with severe liver or renal disease. Development of tolerance and cross-tolerance to the effects of erythrityl tetranitrate and other organic nitrates may occur. However, recent studies in patients with chronic heart failure1 indicate that nitrates produce sustained beneficial hemodynamic effects.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed.
Pregnancy, Teratogenic Effects, Pregnancy Category C: Animal reproduction studies have not been conducted with Cardilate. It is also not known whether Cardilate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cardilate should be given to a pregnant woman only if clearly needed.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cardilate is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children have not been established.
ADVERSE REACTIONS:
The most frequent adverse reaction in patients treated with Cardilate is headache. Lowering the dose and the use of analgesics will help control headaches, which usually diminish or disappear as therapy is continued. Other adverse reactions occurring are the following: cutaneous vasodilatation with flushing, and transient episodes of dizziness and weakness, plus other signs of cerebral ischemia associated with postural hypotension. Occasional individuals exhibit marked sensitivity to the hypotensive effects of organic nitrates, and severe responses (e.g., nausea, vomiting, weakness, restlessness, pallor, perspiration and collapse) can occur even with the usual therapeutic dose. Alcohol may enhance this effect. Drug rash and/or exfoliative dermatitis may occasionally occur.
OVERDOSAGE:
Accidental overdosage of Cardilate may result in severe hypotension and reflex tachycardia, which can be treated by laying the patient down and elevating the legs. If further treatment is required, the administration of intravenous fluids or other means of treating hypotension should be considered.
DOSAGE AND ADMINISTRATION:
The Cardilate Oral/Sublingual Tablet can be placed under the tongue or swallowed. Sublingual therapy may be initiated with a dose of 5 to 10 mg prior to each anticipated physical or emotional stress, and at bedtime for patients subject to nocturnal attacks of angina. The dose may be increased as needed.
If the patient is to swallow the tablet, therapy may be initiated with 10 mg before each meal, as well as mid-morning and mid-afternoon if needed, and at bedtime for patients subject to nocturnal attacks. The dose may be increased or decreased as needed.
Dosage titration up to 100 mg daily has been well tolerated, but temporary headache is more apt to occur with increasing doses. When headache occurs, the dose should be reduced for a few days. If headache is troublesome during adjustment of dosage, it may be effectively relieved with an analgesic.
REFERENCES:
1. Chatterjee K, Parmley WW: Vasodilator therapy for chronic heart failure. Ann Rev Pharmacol Toxicol . 1980;20:475-512.
2. Goldberg S, Mann T, Grossman W: Nitrate therapy of heart failure in valvular heart disease. Am J Med . 1978;65:161-166.
3. Needleman P, Johnson EM: Vasodilators and the treatment of angina, in Gilman AG, Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics, ed 6. New York, Macmillan Publishing Co Inc, 1980, pp 819-833.
4. Hannemann RE, Erb RJ, Stoltman WP, et al: Digital plethysmography for assessing erythrityl tetranitrate bioavailability. Clin Pharmacol Ther . 1981;29:35-39.
5. Wastila WB, Namm DH, Maxwell RA: Comparison of the vascular effects of several organic nitrates in anesthetized rats and dogs after intravenous and intraportal administration, in Second International Symposium on Vascular Neuroeffector Mechanisms, Odense, 1975 . Basel, Karger. 1976, pp 216-225.
6. Haffty GB, Nakamura Y, Spodick DH, et al: Bioavailability of organic nitrates: A comparison of methods for evaluating plethysmographic responses. J Clin Pharmacol . 1982;22:117-124.