PRINCIPIOS DE FARMACOLOGIA

NIACINA

Description: Nitroglycerin, an organic nitrate available in many dosage forms, is a vasodilator proven to be the mainstay of therapy in the management of angina pectoris. Nitroglycerin is also used to control perioperative hypertension, to produce controlled hypotension during surgical procedures, to treat hypertensive emergencies, and to treat congestive heart failure associated with myocardial infarction. Synthesized in 1846, nitroglycerin was found to cause severe headaches when placed on the tongue. The drug was later found to exhibit vasodepressor effects similar to those of the drug amyl nitrite, but with less adverse effects and better dosage control. The use of sublingual nitroglycerin for the relief of acute anginal attacks was established in 1879. Because it is inexpensive, has a rapid onset of action, and has a well-documented efficacy, sublingual nitroglycerin is still considered the drug of choice for the acute relief of angina. Although organic nitrates are still frequently prescribed for the relief of angina, however, they have recently come under scrutiny because of the controversy surrounding claims that nitrate tolerance and attenuation of pharmacodynamic effects have been demonstrated with all forms of these drugs. Nitroglycerin was granted FDA approval in 1938. A topical ointment formulation, known as Anogesic®, is undergoing clinical investigation for the treatment of pain associated with anal fissures. Mechanism of Action: Similar to other nitrites and organic nitrates, nitroglycerin is converted to nitric oxide (NO), a reactive free radical. Nitric oxide, the active intermediate compound common to all agents of this class, activates the enzyme guanylate cyclase, thereby stimulating the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP). This second messenger then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber and the subsequent release, or extrusion, of calcium ions. The contractile state of smooth muscle is normally maintained by a phosphorylated myosin light chain (stimulated by an increase in calcium ions). Thus, the nitrite- or nitrate-induced dephosphorylation of the myosin light chain signals the cell to release calcium, thereby relaxing the smooth muscle cells and producing vasodilation. It is believed that nitrates correct myocardial oxygen imbalances by reducing systemic and pulmonary arterial pressure (afterload) and decreasing cardiac output secondary to peripheral dilation rather than coronary artery dilation. Nitrates therefore relax peripheral venous vessels, causing a pooling of venous blood and decreased venous return to the heart, which decreases preload. Nitrates reduce both arterial impedance and venous filling pressures, resulting in a reduction of the left ventricular systolic wall tension, which decreases afterload. Thus, nitrate-induced vasodilation increases venous capacitance and decreases arteriole resistance, thereby reducing both the preload and afterload, and lowering the cardiac oxygen demand. Total coronary blood flow can be increased by nitrites and nitrates in patients with normal hearts, but in patients with ischemia, nitroglycerin does not increase total coronary blood flow but simply redistributes blood to ischemic areas. This effect is believed to be due to the drug's preferential dilation of the larger conductive vessels of the coronary circulation, which, in the presence of coronary atherosclerosis, redirects the distribution of the coronary blood supply to ischemic areas. Nitrates cause a transient compensatory increase in heart rate and myocardial contractility that normally would increase myocardial oxygen consumption, yet the nitrate-induced decrease in ventricular wall tension results in a net decrease in myocardial oxygen demand and amelioration of the pain of angina pectoris. In addition, nitroglycerin relaxes all other types of smooth muscle including bronchial, biliary, GI, ureteral, and uterine. Nitrites and nitrates are functional antagonists of acetylcholine, norepinephrine, and histamine. In individuals who have minimal reflex tachycardia, syncope can result from the decrease in blood pressure that occurs following higher doses of nitrates and nitrites. Although this is not likely to occur with doses of nitrates that do not cause blood pressure reduction, patients should be sitting or lying down during and immediately after administration of nitroglycerine. The antihypertensive actions of nitroglycerin are secondary to pharmacologic properties that make it an effective antianginal agent but are primarily a result of its peripheral vasodilatory effects. With the exception of greater vascular (venous) specificity and the greater variety of pharmaceutical preparations available, nitroglycerin (NTG) is similar to nitroprusside in many respects. Both agents are capable of producing venous (more so with NTG) and arterial dilation, with beneficial effects on redistribution of myocardial blood flow. Pharmacokinetics: Nitroglycerin can be administered by the oral, lingual (spray), sublingual, intrabuccal, topical, or intravenous routes. Nitroglycerin is well absorbed across the oral mucosa, transdermally, and following systemic oral administration. Irrespective of the route of administration, organic nitrates are virtually completely metabolized by the enzyme glutathione-organic nitrate reductase, so the systemic or presystemic hepatic biotransformation is the key determinant of the bioavailability and duration of action of the various preparations. The onset of action for each nitroglycerin preparation is as follows: IV, immediate; translingual, 2-4 minutes; extended-release capsules and tablets, 20-45 minutes; sublingual, 1-3 minutes; transmucosal (buccal) extended-release tablets, 2-3 minutes; ointment, 20-60 minutes; and transdermal, 40-60 minutes. Duration of action is as follows: IV, several minutes (dose-dependent); translingual, 30-60 minutes; extended-release capsules and tablets, 8-12 hours; sublingual, 30 minutes; transmucosal (buccal) extended-release, 5 hours; ointment, 4-8 hours; and transdermal, 18-24 hours. Nitroglycerin distributes widely throughout the body tissues and is approximately 60% plasma protein-bound. The metabolites of nitroglycerin, 1,3- and 1,2-glyceryl dinitrate, are much less potent than the parent compound and have a half-life of approximately 40 minutes, compared to a parent half-life of 1-3 minutes. The metabolites are excreted by the kidneys.

Indications...Dosage For the treatment of angina: .for the treatment of acute angina pectoris or for acute angina pectoris prophylaxis (i.e. situations likely to provoke an anginal attack): Sublingual dosage: Adults: 1 tablet (0.3 mg, 0.4 mg, or 0.6 mg tablets), dissolved under the tongue or in buccal pouch immediately following indication of anginal attack. During drug administration, the patient should rest, preferably in the sitting position. This may be repeated every 5 minutes as needed. If angina is not relieved after a total of 3 doses given in a 15 minute period, the patient should be taken to a hospital, or a physician contacted. Lingual Spray: Adults: Spray one or two metered doses (400-800 µg) under the tongue. This may be repeated every 5 minutes up to a maximum of 3 doses given in a 15 minute period. If angina is not relieved after a total of 3 doses given in a 15 minute period, the patient should be taken to a hospital, or a physician contacted. .for the treatment of chronic angina pectoris: Oral dosage (extended release capsules): Adults: 2.5-9.0 mg PO every 12 hours as needed. Dosage may be increased to every 8 hours if necessary. Oral dosage (extended release tablets): Adults: 1.3-6.5 mg PO every 12 hours as needed. Dosage may be increased to every 8 hours if necessary. Transmucosal dosage (extended release buccal tablets): Adults: 1 mg inserted under the upper lip and dissolved in place, every 5 hours (during the waking hours), increased in frequency and strength as needed. Topical dosage: Adults: 15-30 mg (2.5-5 cm as squeezed from the tube) applied topically to the skin every 8 hours during waking hours and at bedtime. Frequency of application may be increased to every 6 hours if necessary to alleviate angina attacks. The maximum daily dosage is 75 mg (12.5 cm as squeezed from the tube). The ointment is to applied in a thin layer covering approximately 2-3 inches of skin, but should not be massaged into the skin. Transdermal dosage: Adults: 1 transdermal dosing system applied topically to intact skin, every 24 hours. Initially, the smallest dosing amount should be used, increasing the dosage as necessary. To prevent tolerance to the transdermal system, it is recommended that the patch be left in place for only 12-14 hours, then removed for 10-12 hours prior to placement of the next patch. This allows for a drug-free interval which may prevent nitrate tolerance and/or attenuation of anti-anginal effects. For controlled hypotension induction during anesthesia, congestive heart failure, or IV treatment of acute angina pectoris or acute myocardial infarction, or for treatment of hypertension or hypertensive emergency: Intravenous dosage: Adults: 5 µg/minute as an IV infusion initially, increasing by 5 µg/minute every 3-5 minutes until desired response is achieved, or infusion rate is 20 µg/minute. Dosage may then be further increased by increments of 10 µg/minute, and, if the desired effect is still not achieved, dosage may be increased in increments of 20 µg/minute. The maximum recommended titration is 20 µg/min every 3-5 minutes. Severe hypertensive crisis may require dosages as high as 100 µg/minute. Children: Initially, 0.25-0.5 µg/kg/min by IV infusion; increase by 0.5-1 µg/kg/min every 3-5 minutes. The usual dose is 1-3 µg/kg/min. The usual maximum dose is 5 µg/kg/min; but doses as high as 20 µg/kg/min have been used. Patients with renal impairment: No dosage adjustment needed.

Contraindications Nitroglycerin IV injection should not be used in patients with increased intracranial pressure (e.g., head trauma) or intracranial bleeding because the drug's vasodilatory effect on the meningeal blood vessels could increase cerebrospinal fluid pressure. The drug should also be used cautiously in patients with glaucoma due to the risk of drug-induced increased intraocular pressure. Nitroglycerin is contraindicated in patients with severe anemia because the drug causes oxidation of hemoglobin to methemoglobin, which could exacerbate anemia. Intravenous nitroglycerin should not be used in patients with constrictive pericarditis, or pericardial effusion or tamponade because the drug reduces venous return, decreases preload, and decreases cardiac output, which can be worsened in patients with these conditions. Nitroglycerin should be used cautiously in patients who have had a recent myocardial infarction because drug-induced hypotension and/or tachycardia can worsen ischemia. Nitroglycerin should not be given to patients with uncorrrected hypovolemia due to the risk of inducing profound hypotension. Patients with normal or low pulmonary capillary wedge pressures may be unusually sensitive to the hypotensive effects of nitroglycerin. Nitroglycerin should be used with caution in patients with hypotension or orthostatic hypotension because the drug can worsen hypotension, cause a paradoxical bradycardia, and exacerbate angina. Nitrate-induced hypotension has resulted in fatalities. In a controlled setting, such as during surgery, IV nitroglycerin can be used to produce hypotension. Nitrate therapy can worsen angina due to hypertrophic cardiomyopathy. Nitroglycerin should be used cautiously in patients with hepatic disease because metabolism of the drug can be impaired, resulting in an increased risk of methemoglobinemia. Nitroglycerin is relatively contraindicated in patients with hyperthyroidism. Nitroglycerin is classified as pregnancy risk category C. Although no adequate human studies have examined the effects of this drug on the fetus, animal reproduction studies have shown adverse fetal effects. Therefore, in making the decision to administer this drug during pregnancy, the potential risks to the fetus must be weighed against the potential benefits to the mother. Extended-release nitroglycerin products should be avoided in patients with GI disease such as hypermotility or malabsorption syndromes. This dosage form may not dissolve and may be excreted intact in these conditions. The safety and effectiveness of nitroglycerin in children have not been established.

 

Interactions Two separate studies have shown that concomitant administration of IV nitroglycerin can compromise the therapeutic efficacy of alteplase, TPA. In one study, reperfusion occurred in 91% of patients receiving alteplase without nitroglycerin while only 44% of patients receiving alteplase with nitroglycerin were reperfused, however this was an uncontrolled study. In another controlled study, patients who did not receive concomitant IV nitroglycerin reperfused faster, more often, and had fewer reocclusions. Although the mechanism of this drug interaction is uncertain, it is possible that nitroglycerin enhances the hepatic clearance of alteplase since alteplase plasma concentrations were lower in patients receiving concomitant nitroglycerin. Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antihypertensive agents or other peripheral vasodilators including diuretics; antidepressants; phenothiazines; some antiarrhythmics, such as quinidine or procainamide; benzodiazepines; or opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with any of these drugs. Although it has not been demonstrated clinically, the combination of ethanol and nitroglycerin could theoretically produce additive vasodilation, possibly leading to cardiovascular collapse. Unless the physician is aware of the patient's ethanol use, this cardiovascular collapse may be incorrectly attributed to coronary insufficiency or occlusion. Patients receiving nitroglycerin should be advised to use ethanol with caution. Clinicians should note that many intravenous preparations of nitroglycerin contain ethanol. Ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. This represents a pharmacodynamic interaction. In addition, nitroglycerin can increase the bioavailability of dihydroergotamine by decreasing its first-pass hepatic metabolism. This drug combination should be avoided, if possible, but if it is absolutely necessary, patients should be closely monitored for increased ergot alkaloid effects or decreased antianginal effects. Some reports suggest IV nitroglycerin can decrease the anticoagulant effects of heparin, however, other reports have not documented an interaction. Until this drug-drug interaction is studied further, clinicians should be alert to a possible reduction in heparin effectiveness if IV nitroglycerin is coadministered. Administration of sympathomimetics, including epinephrine, phenylephrine, or ephedrine, can result in antagonism of the antianginal effects of nitroglycerin. In addition, nitroglycerin may block the alpha-adrenergic effects of epinephrine, possibly precipitating tachycardia and severe hypotension. Nitrites and nitrates are functional antagonists of acetylcholine, norepinephrine, and histamine. Thus, nitroglycerin can reduce the effects of these agents (i.e., acetylcholine, norepinephrine, and histamine) if administered concomitantly. Limited data suggest that patients receiving aspirin, ASA in high doses can exhibit an exaggerated response to sublingual nitroglycerin. Although hypotension and tachycardia were more significant during concomitant therapy, no special precautions appear necessary. Hawthorn, Crataegus laevigata may lower peripheral vascular resistance and exhibit additive hypotensive effects with nitrates. Nitrates amplify the vasodilatory effects of sildenafil if coadministered and result in severe hypotension. Sildenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is considered contraindicated. Although there is no data available, there is the possibility that other nitric oxide donor compounds, such as nitroglycerin, may have an additive effect with inhaled nitric oxide on the risk of developing methemoglobinemia.

Adverse Reactions A persistent, throbbing headache commonly occurs with nitroglycerin therapy. Although nitrate-induced headaches usually diminish quickly, aspirin or other analgesic agents may be given to alleviate the pain. Transient cutaneous vasodilation and flushing of the head and neck region can occur with nitroglycerin therapy. Hypersensitivity to nitroglycerin also can occur, resulting in pallor, diaphoresis, tachycardia, and palpitations or, possibly, cardiovascular collapse. Reflex sinus tachycardia that occurs following nitrate administration can precipitate hypotension; in this case, patients should be placed in the Trendelenburg position to increase venous return and facilitate recovery. Patients should be sitting or lying down during and immediately after therapy. Orthostatic hypotension can occur following administration of nitroglycerin, accompanied by dizziness, weakness, and occasionally syncope. Gastrointestinal disturbances, such as nausea/vomiting, also have been reported and may be alleviated by a decrease in dosage. Xerostomia (dry mouth), rash, and sublingual burning have been reported during administration of nitroglycerin. Methemoglobinemia is a rare adverse reaction with nitroglycerin products. Symptoms of methemoglobinemia include cyanosis (blue discoloration of the lips and mucous membranes), nausea/vomiting, coma, and shock. These symptoms are usually associated with high doses/overdoses of nitrate products and the IV formulation, but can be seen at normal therapeutic doses. Tolerance to nitroglycerin can develop when large or sustained dosages are given. This can be avoided by using the lowest possible dose and using an intermittent-dosing regime.

Nitroglycerin Anogesic®, Deponit®, Minitran®, Nitrek®, Nitro-Bid®, Nitrodisc®, Nitro-Dur®, Nitrogard®, Nitroglyn®, Nitrol®, Nitrolingual®, Nitrostat®, Nitro-Time®, Transderm-Nitro®, Tridil®, Nitroglycerin by Geneva | Nitro ParT | NitrobonT | Nitrocot TDT | NitroglycT SR | Nitrol® Appli-Kit® | Nitrong® | Nitroquick® | SustachronT | SustachronT ER | Transdermal-NTG®