Inamrinone


Article Author:
Amol Gupta


Article Editor:
Charles Preuss


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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James Hughes
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Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/4/2019 11:51:25 AM

Indications

Inamrinone, also known as amrinone, is a drug that increases cardiac output through its positive inotropic and vasodilatory effects.[1] It is prescribed for the short-term management of congestive heart failure, relieving symptoms of the condition such as fatigue, weakness, edema, dyspnea orthopnea, and paroxysmal nocturnal dyspnea.[1][2] There is no indication for or known benefit of long-term administration of inamrinone in the continuing safe and effective management of congestive heart failure.[3] Indeed, the long-term use of inamrinone has widely been abandoned due, mainly, to its capacity to induce thrombocytopenia.[4] While the Food and Drug Administration (FDA) in the United States acknowledges that inamrinone has the potential to cause severe adverse effects, it has indicated its use in specific, limited circumstances – it stipulates that indicaitons for short term inamrinone administration are only if an adult patient’s myocardial function (i.e., cardiac output) has not improved sufficiently in response to doses of digoxin, diuretics and/or vasodilators. The recommendation is also that if inamrinone administration is necessary during pregnancy, its use should strictly be if the benefits clearly outweigh the risks.

Mechanism of Action

Inamrinone is a phosphodiesterase-III inhibitor. Inhibition of normal phosphodiesterase-III activity results in a reduction in the hydrolysis of cyclic adenosine monophosphate (cAMP); subsequently, increasing its intracellular concentrations.[5] The mechanisms by which this elevated bioavailability of cyclic adenosine monophosphate increases cardiac output are not yet fully elucidated. In cardiac myocytes, an increased concentration of cyclic adenosine monophosphate may upregulate the cyclic adenosine monophosphate/protein kinase A/calcium pathway.[6] Elevated activity within this pathway acts on specific cellular channels and increases calcium cycling,[7] inducing an influx of calcium to the cardiac myocyte and enhancing the action potential of the heart muscle.[8] Ultimately, this increases the contractility of the heart.

Throughout the vascular network, the inamrinone-mediated increase in the bioavailability of cyclic adenosine monophosphate has an opposite effect on the mechanisms of action in the myocardium. Indeed, an increase in cyclic adenosine phosphate within the vascular smooth muscle causes a reduction in the intracellular calcium concentration; subsequently, relaxing the vascular smooth muscle.[9] This systemic vasodilation results in a decrease in total peripheral and pulmonary vascular resistance, reducing both preload and afterload.[4][10] The subsequent relative ease in which blood can flow around the vascular network in combination with a stronger heartbeat increases stroke volume and, potentially, cardiac output. It is these vasodilatory and positive inotropic effects that are central in reversing the potentially deadly symptoms of heart failure.

Administration

The following are FDA guidelines for the administration of inamrinone by intravenous injection and infusion in the short-term management of congestive heart failure. These guidelines only apply to adult patients. An initial undiluted inamrinone loading dose of 0.75 mg/kg is injected slowly over 2 to 3 minutes. Thereafter, a maintenance dose of diluted inamrinone may be infused at 5 to 10 mcg/kg/min with a concentration of 2.5 mg/mL. The infusion rate can be titrated depending on the patient’s cardiac response. If the cardiac output has not elevated sufficiently or symptoms of heart failure have not alleviated, a secondary loading dose of 0.75 mg/kg may be injected slowly over 2 to 3 minutes, at least 30 minutes after the initial loading dose.

The peak effect of an inamrinone loading occurs within 10 minutes of administration, regardless of the dosage. It has an elimination half-life of greater than 2 hours, [11] lasting approximately 8 hours in some instances. The total daily dose of inamrinone should not exceed 10 mg/kg. An equivalent volume of normal (0.9%) or half-normal (0.45%) saline should be used in the dilution of inamrinone for the maintenance infusion. Dextrose (glucose)-containing diluent should never be used due to the potential for the chemical reaction between the drug and diluent, which may occur over a 24-hour period. The FDA also highlights that furosemide should not be administered to the patient in the same intravenous lines used for inamrinone, due to the instant chemical reaction that occurs between the two drugs. The FDA has not approved inamrinone for the safe and effective treatment of congestive heart failure in pediatric populations.

Adverse Effects

As reported by the FDA, intravenous infusion of inamrinone is associated with a range of hematologic, cardiovascular, gastrointestinal, nervous system, dermatologic, respiratory, and hepatic adverse effects. Thrombocytopenia is among the most commonly reported adverse effects of prolonged inamrinone therapy, with reduced platelet counts presenting in 20 to 46% of patients.[12] However, it is far less common in short-term therapy, occurring in 2.4% of patients.[13] Reports of hypotension are 1 to 3% of patients. New, sustained atrial and/or ventricular arrhythmias, or worsened heart failure occurs in 9% of patients; and chest pain in 0.2%.[14]

Patients may also experience general abdominal pain, anorexia, diarrhea, nausea, and/or vomiting.[14] The FDA also reports that patients may experience dizziness, headache, or fatigue, and there are reports of inamrinone-mediated respiratory infections in other patients. Skin dryness, yellow-nail discoloration, loss of smell, and loss of taste may also occur. Only 0.2% of patients experience a burning sensation at the site of intravenous infusion. Some patients may be hypersensitive to inamrinone and may experience general viral-like symptoms such as myalgias, arthralgias, and fever. Hepatic toxicity has been recorded, but is extremely rare, in short-term administration of inamrinone.[15]

Contraindications

The FDA stipulates that those patients who have a known hypersensitivity to inamrinone should not receive the drug. Given that the drug contains sodium metabisulfite, the FDA reports that administration of inamrinone is also contraindicated if the patient has a known hypersensitivity to bisulfites. Additionally, clinicians should not give inamrinone to patients with aortic or pulmonic valvular disease. It should be administered with caution if the patient is taking disopyramide due to the drug combination’s potential to induce severe hypotension.

Monitoring

The therapeutic dosage range for inamrinone is 0.5 to 7.0 mcg/mL. The maximum daily dose of inamrinone should not exceed 10 mg/kg. The FDA reports that the patient’s blood pressure, heart rate, electrocardiogram, electrolytes, renal function and hepatic function should all be monitored carefully throughout inamrinone therapy. Indeed, infusion of inamrinone should be stopped entirely if the patient experiences severe hypotension and/or arrhythmias, or if there are signs of hepatic toxicity. It is not automatically necessary to stop administering inamrinone to patients who present with thrombocytopenia.[16] However, it is essential to carefully monitor a patient if their platelet count drops to less than 150000 cells/mm^3.[16]

Toxicity

There is no specific recommended antidote for an overdose of inamrinone. However, the FDA recommends the implementation of general cardiac support measures such as fluid and electrolyte replacement if necessary.

Enhancing Healthcare Team Outcomes

Use of inamrinone is associated with significant side effects. However, short term use drug is a useful agent when digoxin, diuretics, and/or vasodilators fail to improve cardiac output. Therefore it becomes imperative for the healthcare team to monitor adverse effects from the use of inamrinone and communicate any abnormalities in blood pressure, heart rate, electrocardiogram, electrolytes, renal function, and hepatic function. It is crucial that the team be even more vigilant if platelet count drops to less than 150000 cells/mm^3. Appropriate use of inamrinone in short-term only situations with a careful watch on side effects can improve patient outcomes.

Inamrinone therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Inamrinone - Questions

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Which of the following is the inotropic agent that inhibits phosphodiesterase?



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A 65-year-old woman presents with dyspnea, orthopnea, fatigue and 4+ pitting edema in her legs. The patient has a history of hypertension and hyperlipidemia. The patient's left ventricular ejection fraction is 35%. Which of the following would provide the best management for this patient?



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Inamrinone has which of the following effects?



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What is the therapeutic effect of inamrinone?



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Inamrinone is administered to address potentially deadly symptoms of heart failure; for example, by restoring cardiac output. It inhibits the hydrolyzing action of phosphodiesterase-III, increasing the intracellular concentrations of cyclic adenosine monophosphate in cardiac myocytes and the vascular smooth muscle. What happens to the concentrations of calcium in the cardiac myocytes and the vascular smooth muscle as a result of the intracellular increase in cyclic adenosine monophosphate and what effect does inamrinone administration ultimately have on the heart and blood vessels?



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A 66-year-old male patient is currently in a hospital recovering from a cardiac revascularization procedure. He reports that he suddenly feels unusually weak and fatigued, even when considering his recent operation. The patient has had obesity for approximately 25 years and was diagnosed with type 2 diabetes 12 years ago, which is managed with metformin. Recently, the patient was diagnosed with ischemic heart disease, which required a revascularization procedure. The patient has no known allergies or hypersensitivities to any medications. Physical examination reveals a substantial decrease in the patient’s cardiac output and that the patient is being impacted by, for the first time, congestive heart failure. The patient has not yet received any treatment for his symptoms of congestive heart failure. Treatment with inamrinone is being considered. Which of the following is the most appropriate strategy for treating the patient with this medication?



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A 57-year-old female patient has presented to the emergency department (ED) and is already receiving emergency treatment for congestive heart failure. The patient initially presented to the ED reporting that she has been unusually, extremely weak, and fatigued. She has a history of smoking, hypertension, obesity, diabetes, and ischemic heart disease. She has previously experienced and survived two previous episodes of heart failure, which were successfully treated with digitalis. The patient’s cardiac function did not improve with digitalis, diuretics, or any vasodilators on this occasion. Subsequently, she has already received a loading dose of inamrinone at 0.75 mg/kg slowly over 2 to 3 minutes. She is now 15 minutes into a maintenance dose of 5 mcg/kg/min at a concentration of 2.5 mg/mL, but her symptoms of congestive heart failure are still not yet showing signs of improvement. What is the most appropriate course of inamrinone treatment in this patient?



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A 65-year-old male patient is being treated in the emergency department. He is experiencing congestive heart failure. The patient has had obesity and type 2 diabetes for much of his adult life. His diabetes is not currently being medically addressed. He has an arrhythmia which is being managed with disopyramide. The patient has no known allergies. During the maintenance dose of inamrinone, the patient’s blood pressure drops significantly from 149/95 to 78/55 mmHg. What is the next most appropriate course of treatment in this situation?



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A 75-year-old male patient is being treated in the emergency department. He is experiencing his third episode of congestive heart failure in 5 years. The patient has a long history of obesity and type 2 diabetes. His cardiac function has responded positively to inamrinone treatment, when required, during his second episode of congestive heart failure. He also did not experience any symptoms of hypersensitivity or an allergic reaction during that administration of inamrinone. Since that second episode of heart failure, severe aortic valvular disease was detected. The patient is also impacted by several vascular-related complications, including diabetic foot ulceration, nephropathy, and diabetic foot ulceration. Similar to his second episode of congestive heart failure, the patient’s cardiac function has not improved with the administration of digitalis, diuretics, or vasodilators during his current treatment within the emergency department. For the administration of inamrinone, what is the first, the most appropriate course of action?



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Inamrinone - References

References

Schumann J,Henrich EC,Strobl H,Prondzinsky R,Weiche S,Thiele H,Werdan K,Frantz S,Unverzagt S, Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome. The Cochrane database of systematic reviews. 2018 Jan 29;     [PubMed]
Kurmani S,Squire I, Acute Heart Failure: Definition, Classification and Epidemiology. Current heart failure reports. 2017 Oct;     [PubMed]
DiBianco R, Acute positive inotropic intervention: the phosphodiesterase inhibitors. American heart journal. 1991 Jun;     [PubMed]
Asif M, Phosphodiesterase-III Inhibitors Amrinone and Milrinone on Epilepsy and Cardiovascular Activities. North American journal of medical sciences. 2012 Oct;     [PubMed]
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Endoh M, Amrinone, forerunner of novel cardiotonic agents, caused paradigm shift of heart failure pharmacotherapy. Circulation research. 2013 Aug 2;     [PubMed]
Fearnley CJ,Roderick HL,Bootman MD, Calcium signaling in cardiac myocytes. Cold Spring Harbor perspectives in biology. 2011 Nov 1;     [PubMed]
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Hermiller JB,Leithe ME,Magorien RD,Unverferth DV,Leier CV, Amrinone in severe congestive heart failure: another look at an intriguing new cardioactive drug. The Journal of pharmacology and experimental therapeutics. 1984 Feb;     [PubMed]
Barnard MJ,Linter SP, Acute circulatory support. BMJ (Clinical research ed.). 1993 Jul 3;     [PubMed]
Ward A,Brogden RN,Heel RC,Speight TM,Avery GS, Amrinone. A preliminary review of its pharmacological properties and therapeutic use. Drugs. 1983 Dec;     [PubMed]
Bottorff MB,Rutledge DR,Pieper JA, Evaluation of intravenous amrinone: the first of a new class of positive inotropic agents with vasodilator properties. Pharmacotherapy. 1985 Sep-Oct;     [PubMed]
Silverman BD,Merrill AJ Jr,Gerber L, Clinical effects and side effects of amrinone. A study of 24 patients with chronic congestive heart failure. Archives of internal medicine. 1985 May;     [PubMed]
Gilman ME,Margolis SC, Amrinone-induced hepatotoxicity. Clinical pharmacy. 1984 Jul-Aug;     [PubMed]
Ansell J,Tiarks C,McCue J,Parrilla N,Benotti JR, Amrinone-induced thrombocytopenia. Archives of internal medicine. 1984 May;     [PubMed]

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