General Monograph, CPhA
Antianginal – Antihypertensive
Pharmacology: Nitroglycerin, in common with other nitrates, produces generalized vasodilation, thereby decreasing venous return and workload on the heart. Both arterial and venous dilation occur, although venous effects predominate. Coronary vasodilation also occurs even in the presence of atherosclerosis. Relaxation of vascular smooth muscle is a result of stimulation of cyclic guanosine monophosphate (GMP) production as well as inhibition of thromboxane synthetase, permitting preferential formation of prostacyclin. Left ventricular end-diastolic pressure and volume are decreased, resulting in reduction of ventricular size and wall tension. Therapeutic doses reduce systolic, diastolic and mean arterial blood pressure; reflex tachycardia may occur, presumably in response to these effects.
Tolerance to the antianginal and hemodynamic effects of nitrates develops and is more likely to occur at higher doses and with formulations which have longer half-lives. It is common in patients being treated with topical, transdermal or continuous i.v. infusions and is not as likely to develop with the use of short-acting preparations.
Efficacy of organic nitrates is restored after a drug-free interval of 10 to 12 hours. The intermittent use of nitrates may be associated with decreased exercise tolerance during the last part of the nitrate-free interval; the clinical relevance of this observation is unknown. There may also be an increase in nocturnal angina attacks during the drug-free period in some patients. Therefore, the possibility of increased frequency or severity of angina during the nitrate-free interval should be considered.
Pharmacokinetics: Nitroglycerin is widely distributed in the body with an apparent volume of distribution of approximately 200 L in adult male subjects (only 1% present in the plasma). Half-life is estimated at 1 to 4 minutes. Nitroglycerin is rapidly metabolized in the liver by hepatic enzymes to dinitrates and mononitrates. The 2 active major metabolites are the hydrolysis products, 1,3- and 1,2-dinitroglycerols. There are also 2 inactive minor metabolites. Nitroglycerin is approximately 60% protein bound while the metabolites 1,2 dinitroglycerol and 1,3 dinitroglycerol are 60 and 30% protein bound, respectively. Extensive first-pass deactivation follows gastrointestinal absorption. Nitroglycerin is excreted by the renal route, primarily as the 2 dinitrometabolites, which have an excretion half-life of approximately 3 to 4 hours.
Indications: Acute symptomatic relief of angina pectoris; prophylactic management in situations likely to provoke angina attacks; long-term prophylactic management of angina pectoris.
I.V.: Congestive heart failure associated with acute MI, control of blood pressure during surgical procedures, especially cardiovascular; treatment of angina unresponsive to oral nitrates or b-blockers.
tag_ContraindicationsContraindications: Nitroglycerin should not be administered to individuals with: a known hypersensitivity to nitroglycerin or a known idiosyncratic reaction to organic nitrates; severe anemia because of potential for reduced hemoglobin level and impaired oxygen delivery; early MI (long-acting forms of nitroglycerin); hypotension or uncorrected hypovolemia, as the use of nitroglycerin in such states could produce severe hypotension or shock; open- or closed-angle glaucoma, although pressure is at most increased only briefly and drainage of aqueous humor is not impeded; head trauma or cerebral hemorrhage (to avoid increased intracranial pressure); constrictive pericarditis and pericardial tamponade.
Warnings: The use of nitroglycerin in acute myocardial infarction or congestive heart failure requires careful clinical and/or hemodynamic monitoring.
Nitrate dependence may occur in patients with chronic use. In industry workers continuously exposed to nitrates, chest pain, acute myocardial infarction and even sudden death have occurred during temporary withdrawal of nitrate exposure. To avoid possible withdrawal effects, the administration of nitroglycerin should be reduced gradually.
Precautions: Nitroglycerin ointment, transdermal or oral tablets are not intended for immediate relief of acute attacks of angina pectoris. Sublingual, metered dose spray, or buccal nitroglycerin preparations should be used for this purpose.
Caution should be exercised in using the drug in patients who are volume depleted or have low systolic blood pressure. Severe hypotension, especially postural, may occur. Nitroglycerin can act as a physiological antagonist to norepinephrine, acetylcholine and histamine. Alcohol may accentuate cerebral ischemic symptoms.
Nitroglycerin should be used with caution in patients with severe liver or renal disease. In patients with gastrointestinal hypermotility or malabsorption syndrome, avoid extended release preparations.
Headaches or symptoms of hypotension, such as weakness or dizziness, particularly when arising suddenly from a recumbent position, may be due to overdosage. If this occurs the dose should be reduced or the frequency of topical application should be reduced.
Nitroglycerin can cause sudden severe hypotension. Excessive hypotension, especially for prolonged periods of time, must be avoided because of possible deleterious effects on the brain, heart, liver and kidneys from poor perfusion and attendant risk of ischemia, thrombosis, and altered function of these organs. Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension. Patients with normal or low pulmonary capillary wedge pressure are especially sensitive to the hypotensive effects of nitroglycerin. A fall in pulmonary capillary wedge pressure precedes the onset of arterial hypotension and is thus a useful guide to safe titration of the drug.
The smallest dose required for effective relief of the acute anginal attack should be taken. Excessive use may lead to the development of tolerance. Tolerance to nitroglycerin (especially with transdermal, sustained-release and i.v. preparations) and cross tolerance to other nitrates may occur. A minimum interval of 10 to 12 hours per day without the transdermal patch in place is required for continued effectiveness when using this dosage form. With the chronic use of nitrates, there have been reports of anginal attacks being more easily provoked as well as reports of rebound in hemodynamic effects, occurring soon after nitrate withdrawal.
Cardioversion: Remove nitroglycerin patches prior to cardioversion to avoid formation of electrical arc.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals were performed to evaluate the carcinogenic potential of nitroglycerin.
Drug Interactions : Alcohol: Alcohol and nitroglycerin may have additive vasodilatory effects possibly resulting in hypotension. Caution with this combination is advised.
Hypotensive Agents: Patients receiving hypotensive agents and nitroglycerin should be observed for possible additive hypotensive effect.
Heparin: Heparin resistance has been encountered with i.v. nitroglycerin. It is suggested to monitor the APTT when nitroglycerin is added or discontinued in patients receiving heparin. The dose of heparin may need to be adjusted.
Salicylates: Analgesic doses of ASA (>500 mg) may reduce the metabolism of nitroglycerin by decreasing hepatic blood flow. Patients may be more susceptible to headache or hypotension with this combination.
Ergot Alkaloids: The effect of nitroglycerin is antagonized by ergot alkaloids, which may precipitate angina. As well, nitroglycerin can reduce the metabolism of dihydroergotamine.
Pregnancy: Animal reproduction studies have not been conducted with nitroglycerin. It is not known whether nitroglycerin can cause fetal harm when administered to a pregnant woman or whether it can affect reproduction capacity. Nitroglycerin should be given to a pregnant woman only if clearly needed.
Lactation: It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.
Children: Safety and effectiveness in children have not been established.
Adverse Effects: The most frequent adverse reaction to nitroglycerin is headache which occurs in up to 50% of patients at the beginning of therapy and is a result of dilation of cerebral vessels. Headache usually disappears within several days with continued treatment. Acetaminophen may be used to treat nitrate headaches.
Other adverse reactions occurring in less than 1% of patients are: Allergic: itching, wheezing, tracheobronchitis, contact dermatitis with topical dosage forms.
Cardiovascular: hypotension, reflex tachycardia, paradoxical increase of anginal pain, palpitations and bradycardia. Syncope due to nitrate vasodilation, although rare, has been reported.
CNS: headache, weakness, dizziness, apprehension and restlessness.
Dermatologic: exfoliative dermatitis, cutaneous vasodilation, crusty skin lesions, pruritus, rash.
Gastrointestinal: nausea, vomiting, diarrhea and abdominal pain.
Genitourinary: dysuria, urinary frequency, impotence.
Metabolic: methemoglobinemia, especially in the presence of methemoglobin reductase deficiencies or in congenital hemoglobin variants.
Musculoskeletal: arthralgia, muscle twitching.
Ophthalmologic: blurred vision.
Respiratory: bronchitis, pneumonia, upper respiratory infection.
tag_OverdoseOverdose: Symptoms: Symptoms of overdosage are primarily related to vasodilation: cutaneous flushing, headache, nausea, dizziness, hypotension and tachycardia. Methemoglobinemia is also possible with extremely large doses.
Treatment: Most of these effects can be obviated by discontinuing the drug immediately.
Treatment should primarily be symptomatic and supportive. If nitroglycerin has been ingested, empty stomach by using ipecac syrup or gastric lavage. Follow with activated charcoal and a saline cathartic. However, nitrates are usually rapidly absorbed.
Severe hypotension and tachycardia can be treated by elevating the legs and administering i.v. fluids. Since the duration of the hemodynamic effects following nitroglycerin administration is brief, additional corrective measures are usually not required. However, if further therapy is indicated, administration of an i.v. adrenergic agonist (e.g., phenylephrine) should be considered. Oxygen and artificial ventilation may be necessary. If methemoglobinemia occurs, methylene blue should be administered.
Dosage: Prevention of Tolerance: Tolerance can be prevented or attenuated by the use of an intermittent dosage schedule. An appropriate dosing schedule for nitroglycerin should provide for a nitrate-free period of 10 to 12 hours daily. The drug-free time should coincide with the period in which angina pectoris is least likely to occur (usually at night). Patients should be watched carefully for an increase of angina pectoris during the nitrate-free period. Adjustment of other cardiovascular medication may be required.
Buccal: Initial dose is 1 mg every 5 hours during waking hours, adjusted to control symptoms. Tablets should be placed between the lip and gum, above the incisors, and should not be swallowed.
I.V.: Not for direct i.v. injection. Nitroglycerin must be diluted in dextrose 5% injection USP or sodium chloride 0.9% injection USP, prior to infusion. Nitroglycerin should not be mixed with other drugs.
Caution: Several preparations of nitroglycerin for injection are available which differ in concentration and/or volume/vial. When switching from one product to another, attention must be paid to the dilution, dosage and administration instructions.
Because of alterations to the amount of nitroglycerin delivered to the patient caused by variations in administration sets, pumps, and the great variations in responsiveness of individual patients to nitroglycerin, there is no fixed optimum dose of nitroglycerin. Each patient must be titrated to the desired level of hemodynamic function.
Initial dosage should be 5 to 10 g/min delivered through an infusion pump capable of exact and constant delivery of the drug. Subsequent titration must be adjusted to the clinical situation, with dose increments becoming more cautious as partial response is seen. Initial titration should be in 5 g/min increments with increases every 3 to 5 minutes until some response is noted. If no response is seen at 20 g/min, increments of 10 to 20 g/min can be used. Once a partial blood pressure response is observed, the dose increase should be reduced and the interval between increments should be lengthened. Some patients with normal or low left ventricular filling pressure or pulmonary capillary wedge pressure (e.g., angina patients without other complications) may respond fully to doses as small as 5 g/min. These patients require especially careful titration and monitoring.
Ointment: May be applied every 4 to 8 hours if necessary. May be wiped off at bedtime to provide a nitrate-free interval. The usual dose is 2.5 to 5 cm as squeezed from the tube. The optimal dose is determined by starting with an application of 1.25 cm and increasing the dose by 1.25 cm increments until side effects (usually headache) occur or satisfactory response is obtained. Some patients may require as much as 10 to 12.5 cm and/or application every 4 hours.
Any nonhairy skin area may be used; some patients psychologically prefer the chest.
The dose and frequency of application should be adjusted to meet the individual patient’s needs.
Methods of Application: Apply ointment using specially designed dose-determining applicator. The ointment is spread over at least 2 x 3 inch (50 x 75 mm) area in a thin uniform layer using the applicator. The dose-determining applicator serves the dual purpose of measuring the amount of ointment and preventing absorption of the ointment through the fingers while it is being applied. The dose/area ratio should be kept constant.
Oral Sustained-release Tablets: Recommended initial dosage is 1 tablet (2.6 mg) 3 times daily, before breakfast, late afternoon before a meal and before retiring. Dosage may be increased progressively up to 2 tablets 3 times a day.
Spray: For an acute attack of angina pectoris or for prophylaxis before planned exercise: 1 or 2 metered doses (0.4 or 0.8 mg) of nitroglycerin administered onto or under the tongue, without inhaling. The mouth must be closed immediately after each dose. May be repeated twice at 5- to 10-minute intervals.
Sublingual: Usual adult dosage range: 0.3 to 0.6 mg. One tablet should be dissolved under the tongue or in the buccal pouch immediately upon indication of an acute anginal attack. This dose may be repeated every 5 minutes until relief is obtained. If pain persists after a total of 3 tablets over a 15-minute period, the physician should be contacted. For prophylactic use, 1 sublingual tablet can be taken 5 to 10 minutes before engaging in activities which may precipitate an anginal event.
Storage: Store at room temperature, below 30°C. To prevent loss of potency, the tablets should be dispensed and kept in tight amber glass containers. The container should be closed tightly immediately after each use. No more than 100 tablets should be packaged in a container.
Repeated opening of the container may shorten the period of potency of sublingual tablets. Replacement of tablet stock is recommended 6 months after opening the bottle. Specific manufacturers may have different recommendations. The stabilized sublingual tablets are designed to provide potency for longer periods, but must still receive proper storage. Whether the tablet stings or tingles when placed under the tongue is not an indication of potency and should not be used to assess whether the tablets will work or not.
Transdermal: Patient instructions provided with the product should be consulted for each individual product. Generally a patch is applied to a hairless, clean area of skin that is not subject to excessive movement (i.e., trunk). Do not apply to areas with cuts, burns or abrasions or use on distal parts of extremities (i.e., forearms). Each successive application should be placed on a different site. Patch is applied once daily (usually in the morning) and left on for 12 to 14 hours, then removed. The starting dose is usually 0.2 mg/hour (10 cm. Maximum dose is 0.8 mg/hour (40 cm. x
NITROGLYCERINGeneral Monograph, CPhAGlyceryl TrinitrateAntianginal – Antihypertensive