Continuing Education Activity

Inamrinone is a medication used in the short-term management and treatment of congestive heart failure. It is a phosphodiesterase-III inhibitor, which increases cardiac inotropy. This activity outlines the indications, action, and contraindications for this drug as a valuable agent in the management of acute congestive heart failure. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients with CHF and related conditions.

Objectives:

• Identify the most common adverse events associated with inamrinone therapy.
• Explain the importance of monitoring for patients given inamrinone.
• Identify the indications for the use of inamrinone.
• Outline the importance of improving collaboration and communication amongst the interprofessional team to improve outcomes for patients affected with acute congestive heart failure exacerbation resistant to commonly used medications.

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 indications 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 (PD3) 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, inducing an influx of calcium to the cardiac myocyte and enhancing the action potential of the heart muscle.[7][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. After that, 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, lasting approximately 8 hours in some instances. The total daily dose of inamrinone should not exceed 10 mg/kg.[11] 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 24 hours. 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 includes administration of inamrinone as a contraindication 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 recommends that the patient’s blood pressure, heart rate, electrocardiogram, electrolytes, renal function, and hepatic function should all be monitored carefully throughout inamrinone therapy. Infusion of inamrinone should stop 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 150,000 cells/mm3.[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

The use of inamrinone is associated with significant side effects. However, for 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. The team must be even more vigilant if platelet count drops to less than 150,000 cells/mm3. 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 outcomes. [Level V]