Inotrope – Vasodilator
Action And Clinical Pharmacology: Amrinone is a positive inotropic agent with vasodilatory activity, different in structure and mode of action from either digitalis glycosides or catecholamines. Its mechanism of action has not been fully elucidated. Experimental evidence indicates that it is not a beta-adrenergic agonist. It inhibits myocardial cyclic adenosine monophosphate phosphodiesterase (c-AMPase) activity and increases cellular levels of c-AMP. Unlike digoxin, it does not inhibit sodium-potassium adenosine tri-phosphatase activity.
Vasodilatory effect of amrinone is the result of direct relaxant effect on vascular smooth muscle. The drug reduces both the afterload and preload.
Following an i.v. loading dose (1 to 2 minutes) of 0.68 to 1.2 mg/kg to normal volunteers, amrinone had a volume of distribution of 1.2 L/kg. Following a distributive phase half-life of about 4.6 minutes in plasma, amrinone had a mean apparent first-order terminal elimination half-life of about 3.6 hours.
In patients with congestive heart failure receiving infusions of amrinone the mean apparent first-order terminal elimination half-life was 5.8 hours. Following loading doses of 1.5 to 3.5 mg/kg, steady-state plasma levels of about 2.4 µg/mL were maintained during infusion of 5 to 10 µg/kg/min. Amrinone has been shown in one study to be 10 to 22% bound to human plasma protein by ultrafiltration in vitro, and in another study 36 to 49% bound by either ultrafiltration or equilibrium dialysis.
The drug is excreted in man as both unchanged amrinone and several metabolites (N-glycolyl, N-acetate, 0-glucuronide and N-glucuronide), primarily via the urine. Oral amrinone is 92% bioavailable relative to i.v. amrinone. Approximately 63% of an oral dose was excreted in the urine over a 72-hour period. In the first 8 hours, 51% appeared as amrinone in the urine, with 5% as the N-acetate, 8% as the N-glycolate, and less than 5% for each glucuronide. Approximately 18% of the dose was excreted in the feces in 72 to 96 hours.
In a 24-hour nonradioactive i.v. study, 10 to 40% of the dose was excreted in the urine as unchanged amrinone. The N-acetyl metabolite represented less than 2% of the dose.
In patients with depressed myocardial function, amrinone produces a prompt increase in cardiac output due to its inotropic and vasodilator actions.
Following a single i.v. bolus dose of amrinone of 0.75 to 3 mg/kg in patients with congestive heart failure, dose related increases in cardiac output occur (a maximum of about 28% increase at 0.75 mg/kg to about 61% increase at 3 mg/kg). The peak effect occurs within 10 minutes at all doses. The duration of effect depends upon dose, lasting about 1/2 hour at 0.75 mg/kg and approximately 2 hours at 3 mg/kg.
Over the same range of doses, pulmonary capillary wedge pressure and total peripheral resistance show dose related decreases (mean maximum decreases of 29% in pulmonary capillary wedge pressure and 29% in systemic vascular resistance). At doses up to 3.0 mg/kg, dose related decreases in diastolic pressure (up to 13%) have been observed. Mean arterial pressure decreases (9.7%) at the dose of 3.0 mg/kg.
The changes in hemodynamic parameters are maintained during continuous i.v. infusion and for several hours following the infusion with no evidence of tachyphylaxis.
Amrinone is effective even in fully digitalized patients. Its inotropic effects are independent of those of digitalis. In heart failure patients, it produces positive inotropic effects without increasing myocardial oxygen demand or causing clinically significant increases in heart rate.
Most patients have been studied hemodynamically for periods up to 24 hours. Some patients have been maintained on infusions of amrinone for longer periods and demonstrated consistent hemodynamic and clinical effects. The duration of therapy should depend on patient responsiveness.
Indications And Clinical Uses: For the short-term management of severe congestive heart failure. Because of limited experience and potential for serious adverse effects (see Adverse Effects), amrinone should only be used in patients who can be closely monitored and have not responded adequately to digitalis, diuretics, and/or vasodilators. It has been used concomitantly with other agents including digitalis, diuretics, and vasodilators.
Contra-Indications: In patients with hypersensitivity to amrinone or sensitivity to bisulfites.
Manufacturers’ Warnings In Clinical States: Allergic Reactions: Amrinone contains sodium metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Reduction of Blood Platelet Counts: Administration of amrinone resulted in platelet count reductions to below 100 000/mmin 2.4% of patients. Blood platelet counts should be determined before and during amrinone therapy. Clinically significant lowering of platelet counts warrants consideration of reduction or discontinuation of amrinone therapy. Amrinone therapy should be discontinued if platelet count is £50 000/mm
Platelet reduction appears to be dose-related. This reduction may be due to a decrease in platelet survival time which is postulated to be due to direct amrinone binding. Bone marrow examinations were normal in several patients who developed thrombocytopenia while receiving amrinone. There is no evidence relating platelet reduction to immune response or to a platelet activating factor.
Acute M.I.: Amrinone injection is not recommended in the acute phase of myocardial infarction as insufficient data are available to support its use for this indication.
Hepatic: Hepatotoxicity has been observed in man in 0.2% of patients following i.v. administration. There have been rare reports of increases in hepatic enzymes, bilirubin elevation and jaundice.
It is advisable to perform liver function tests before and during therapy. If alterations in liver enzymes occur together with clinical symptoms suggesting an idiosyncratic hypersensitivity reaction, therapy should be promptly discontinued.
Exceptionally, excessive hypotension has been reported when amrinone was used concurrently with disopyramide.
Concurrent administration with disopyramide should be undertaken with caution until additional clinical experience is available.
Precautions: Amrinone should not be used in severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in conditions like hypertrophic subaortic stenosis.
During i.v. therapy, blood pressure and heart rate should be monitored and the rate of infusion decreased in patients showing hypotension. At the same time, dosage of concomitant medications (e.g., vasodilators) should be readjusted as required. In addition, pulmonary capillary wedge pressure and cardiac index should be obtained to demonstrate patient responsiveness whenever possible.
Fluid and electrolyte changes and serum creatinine should be carefully monitored during amrinone therapy.
Patients who have been extensively dehydrated by vigorous diuretic therapy may have insufficient cardiac filling pressure to respond adequately to amrinone, in which case correction or adjustment of fluids/electrolytes and diuretic dosage is essential to obtain satisfactory response with amrinone. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmia. Therefore hypokalemia should be corrected by potassium supplementation in advance of or during use. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic.
In patients with atrial fibrillation or flutter, digitalis should be administered concomitantly to control the possible enhanced atrioventricular conduction induced by amrinone. In such cases, and in those with multifocal or runs of premature ventricular contractions, careful dose titration and close electrocardiographic monitoring is advisable, during i.v. therapy. As supraventricular and ventricular arrhythmias have been observed in the high-risk population treated, and as the potential for arrhythmia, present in heart failure itself, may be increased by many drugs or combination of drugs, patients receiving amrinone should be closely monitored during infusion.
Plasma levels of amrinone may rise higher than expected during the infusion period in some congestive heart failure patients in whom associated compromised renal and hepatic perfusion is present. In these cases especially careful monitoring of hemodynamic response and/or plasma levels is necessary.
Pregnancy: There are no adequate studies in pregnant women. Amrinone should not be used during pregnancy unless the potential benefit to the patient justifies the potential risk to the fetus.
Lactation: Caution should be exercised when amrinone is administered to a nursing woman, since it is not known whether it is excreted in human milk.
Children: Safety and effectiveness in children have not been established. Amrinone should only be used when the potential benefits outweigh the potential risks.
Drug Interactions: No specific drug interaction study has been done in humans with injectable amrinone.
Amrinone has been used concurrently with the following drugs: digitalis glycosides, quinidine, propranolol, metoprolol, prazosin, hydralazine, captopril, isosorbide dinitrate, nitroglycerin, lidocaine, furosemide, ethacrynic acid, hydrochlorothiazide, chorthalidone, spironolactone, potassium supplements, insulin, heparin, warfarin sodium and diazepam. No serious adverse effects due to the interaction between these drugs and amrinone were reported. However, careful dosage readjustments of concurrent medication may be required.
Disopyramide (see Warnings).
Chemical Interactions : A chemical interaction occurs slowly over a 24 hour period when the i.v. solution of amrinone is mixed directly with dextrose (glucose)-containing solutions. Therefore, amrinone injection should not be diluted with solutions that contain dextrose (glucose) prior to injection.
A chemical interaction occurs immediately, which is evidenced by the formation of a precipitate when furosemide is injected into an i.v. line of an infusion of amrinone. Therefore, furosemide should not be administered in i.v. lines containing amrinone.
Adverse Reactions: Thrombocytopenia: Administration of amrinone resulted in platelet count reductions to below 100 000/mmin 2.4% of the patients (see Warnings).
Gastrointestinal Effects: nausea (1.7%), vomiting (0.9%), abdominal pain (0.4%), anorexia (0.4%) and diarrhea.
Cardiovascular Effects: Ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, or ventricular ectopy have been reported in patients receiving amrinone. Supraventricular arrhythmia including tachycardia, flutter and bradycardia have also been described, as well as hypotension.
Hepatotoxicity: liver enzymes elevation (0.2%) (see Warnings).
Other: Additional adverse reactions observed in i.v. amrinone clinical studies include fever (0.9%), chest pain (0.2%), and burning at site of injection (0.2%). Rarely headache, chills, hematuria, pneumothorax, yellowing of the nails, burning and cutaneous necrosis at the injection site, anemia and leukocytosis have also been reported.
Hypersensitivity: There have been reports of several apparent hypersensitivity reactions in patients treated with oral amrinone for about two weeks. The oral formulation is not marketed. Signs and symptoms were variable but included pericarditis, pleuritis, interstitial pneumonitis and ascites (1 case), myositis with interstitial shadowing on chest x-ray and elevated sedimentation rate (1 case) and vasculitis with nodular pulmonary densities, hypoxemia, and jaundice (1 case). The first patient died, not necessarily of the possible reaction, while the last two resolved with discontinuation of therapy. None of the cases were rechallenged so that attribution to amrinone is not certain, but possible hypersensitivity reactions should be considered in any patient maintained for a prolonged period on amrinone.
Renal Function Tests: Abnormalities of renal function tests and isolated cases of renal failure have been reported. The contribution of the underlying heart failure to these abnormalities is not clear.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Because of its vasodilatory and inotropic effect, amrinone injection in excessive doses may produce hypotension and/or arrhythmia. If hypotension or arrhythmia does occur, amrinone administration should be reduced or stopped. No antidote is known, but general measures for circulatory support should be taken.
It is suggested dialysis be considered when clinically necessary.
A death has been reported with a massive accidental overdose of amrinone (840 mg over 3 hours by initial bolus and infusion), although causal relation is uncertain. Diligence should be exercised during product preparation and administration.
Dosage And Administration: Adequate facilities and personnel must be available for monitoring the cardiac and circulatory response.
Monitoring central venous pressure (CVP) may be valuable in the assessment of hypotension and fluid balance management. Prior correction or adjustment of fluid/electrolytes may be necessary to obtain satisfactory response.
Inspect ampuls visually and do not use if evidence of particulate matter or discoloration.
Protect amrinone ampuls from prolonged exposure to light. Ampul packaging is light resistant for protection during storage in original containers. Store at room temperature.
Administer i.v. as supplied or dilute in normal (0.9%), or half normal saline solution to a concentration of 1 to 3 mg/mL. Use diluted solutions within 24 hours.
A chemical interaction occurs slowly when the i.v. solution of amrinone is mixed directly with glucose (dextrose) solutions. Solutions of amrinone must not be diluted with glucose solutions prior to injection. However, amrinone may be injected into running glucose infusions through a Y-connector or directly into the tubing.
A chemical interaction occurs immediately, which is evidenced by the formation of a precipitate when furosemide is injected into an i.v. line of an amrinone infusion. Therefore, furosemide should not be administered in i.v. lines containing amrinone.
Initiate therapy with a 0.75 mg/kg loading dose given slowly over 2 to 3 minutes. Continue therapy with maintenance infusion of 5 to 10 µg/kg/minute. Based on clinical response, an additional loading dose of 0.75 mg/kg may be given 30 minutes after the initiation of therapy. Maintain infusion at approximately 5 to 10 µg/kg/minute such that the total daily dose (including loading doses) does not exceed 10 mg/kg. In a limited number of patients a dosage regimen up to 18 mg/kg/day was used. However be cautioned about the possibility of increased incidence of adverse reactions with a dosage higher than 10 mg/kg/day. The rate of administration should be adjusted according to the patient’s response. Reduce or titrate the infusion downward based on clinical responsiveness or occurrence of untoward effects. In most patients amrinone was administered up to 24 hours. Its administration is not recommended for a period over 24 hours unless the potential benefit clearly exceeds the risk of longer therapy.
Table I is provided as an example of applicable dosages and flow-rates when using a specific dilution (2.5 mg amrinone/mL) of the original (5 mg/mL) ampuls.
SuppliedSupplied: Each mL of clear, yellow solution contains: amrinone 5 mg as amrinone lactate. Nonmedicinal ingredients: sodium metabisulfite and water for injection. pH adjusted to 3.2 to 4.0 with lactic acid or sodium hydroxide. The total concentration of lactic acid can vary between 5.0 mg/mL and 7.5 mg/mL. Gluten-, lactose- and tartrazine-free. Ampuls of 20 mL, boxes of 5.
Protect from prolonged exposure to light. Ampul packaging is light resistant for protection during storage in original containers. Store at room temperature.
INOCOR® Sanofi Amrinone Lactate Inotrope – Vasodilator
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