Inamrinone

Mechanism of Action

Inamrinone is a phosphodiesterase-III (PDE3) inhibitor. Inodilators such as inamrinone and milrinone increase stroke volume and cardiac output by stimulating myocardial contractility and decreasing afterload from systemic vasodilation (decreased systemic vascular resistance).[8] Inhibition of normal phosphodiesterase-III activity reduces the hydrolysis of cyclic adenosine monophosphate (cAMP), increasing its intracellular concentrations.[9] The mechanisms by which this elevated bioavailability of cyclic adenosine monophosphate increases cardiac output are not yet fully defined. An increased concentration of cyclic adenosine monophosphate may upregulate the cyclic adenosine monophosphate/protein kinase A/calcium pathway in cardiac myocytes.[10] Elevated activity within this pathway acts on specific cellular channels and increases calcium cycling, which induces an influx of calcium to the cardiac myocyte and enhances the heart muscle's action potential.[11][12] This series of events ultimately 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. 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.[13] This systemic vasodilation decreases total peripheral and pulmonary vascular resistance, reducing preload and afterload.[6][14] The subsequent relative ease of blood flow around the vascular network combined with a stronger heartbeat increases stroke volume and cardiac output. These vasodilatory and positive inotropic effects are central to reversing the potentially deadly symptoms of heart failure. However, chronic treatment with PDE3 inhibitors hastens heart failure and should be avoided.[15]

Pharmacokinetics

Inamrinone shows the following pharmacokinetic behavior after 1 to 2 minutes of an intravenous bolus dose in the 0.68 to 1.2 mg/kg range.[16]

Absorption: The onset of action is rapid (within 5 minutes), and the peak effect is observed in 10 minutes. 

Distribution: Inamrionone has minimal plasma protein binding, ranging from 26% to 40%. The volume of distribution is 1.2 L/kg. 

Metabolism: Inamrinone is metabolized by conjugation. Metabolites include N-glycolate, N-acetate, O-glucuronide, and N-glucuronide (pharmacologically inactive).

Elimination: In healthy volunteers, approximately 63% of the orally administered dose was excreted unchanged in urine over 96 hours, while 18% of the administered dose was excreted in feces in 72 hours. Similarly, approximately 10% to 40% of the intravenously administered dose was eliminated in the urine within 24 hours. The terminal half-life was 3.6 hours in normal volunteers and 5.6 hours in patients with congestive heart failure after an intravenous bolus.

Administration

Adult Dosage, Dosage Forms, and Strengths

Inamrinone is available as an injectable solution (5 mg/mL). The following are guidelines for administering 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 μg/kg/min with a 2.5 mg/mL concentration. The infusion rate can be titrated depending on the cardiac response. If the cardiac output has not elevated sufficiently or symptoms of heart failure have not been 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.[17]

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 dosage of inamrinone should not exceed 10 mg/kg.[18] An equivalent volume of normal (0.9%) or half-normal (0.45%) saline should be used to dilute inamrinone for the maintenance infusion. Dextrose-containing diluent should never be used due to the potential for a chemical reaction between the drug and diluent, which may occur over 24 hours. Furosemide should not be administered to the patient in the same intravenous lines used for inamrinone due to the instant chemical reaction between the 2 drugs.

Specific Patient Populations 

Hepatic impairment: No dose adjustment guidance is on the manufacturer label for patients with hepatic impairment. However, hepatotoxicity has been observed rarely in clinical settings after intravenous administration. If an acute hypersensitivity reaction occurs in patients with hepatic impairment, then therapy should be discontinued promptly.

Renal impairment: No dose adjustment guidance is on the manufacturer label for patients with renal impairment. However, in patients with congestive heart failure and compromised renal function, the drug plasma level may be increased, and it may be necessary to monitor the plasma drug level in these patients. 

Pregnancy considerations: Inamrinone is an FDA pregnancy category C medicine.[19] In a few animal studies, oral doses of 16 mg/kg and 50 mg/kg in rabbits were associated with adverse effects of fetal skeletal and gross external malformations. However, in other animal studies, an intravenous dose of 15 mg/kg/d was not associated with malformations. The safety and efficacy of inamrinone have not been adequately studied in pregnant women. Therefore, the use of inamrinone during pregnancy should only be considered after the potential benefit is judged to be greater than the risk to the fetus.

Breastfeeding considerations: Additional medication should be taken while administering inamrinone to breastfeeding women, as it is unknown if the drug is excreted in milk.

Pediatric patients: The safety and efficacy of inamrinone in pediatric patients have not been established. 

Older patients: The safety and efficacy have not been adequately studied in older patients. However, based on previous clinical trials, inamrinone may be used in older patients with congestive heart failure to improve hemodynamics.[20]

Adverse Effects

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 in 20% to 46% of patients.[21] However, it is far less common in short-term treatment, occurring in 2.4% of patients.[22] New, sustained atrial or ventricular arrhythmias or worsened heart failure occurs in 9% of patients and chest pain in 0.2%.[23] Inodilators such as inamrinone worsen myocardial ischemia from oxygen supply-demand mismatch.[8] Patients may also experience general abdominal pain, anorexia, diarrhea, nausea, and vomiting.[23] Patients may experience dizziness, headache, or fatigue; additionally, there are reports of inamrinone-associated respiratory infections. 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 intravenous infusion site.

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 it is infrequent in the short-term administration of inamrinone.[24] Excessive vasodilation and hypotension can be significant limitations of type-3-phosphodiesterase inhibitors, particularly when administered at high doses and when therapy is initiated with a bolus dose.[5] Severe ventricular arrhythmias and sudden cardiac death are the leading causes of mortality, the mechanism of which could be explained by the intracellular calcium overload due to cAMP in myocardial cells and disproportionate increase of cardiac contractility, heart rate, and metabolism.[10]

Drug-Drug Interactions

Avoiding the concomitant use of inamrinone with other phosphodiesterase 3 (PDE3) inhibitors, like milrinone and cilostazol, is recommended due to the potential synergistic effects on cardiac function. Combining these drugs elevates the risk of adverse cardiac events. Inamrinone should be administered with caution if the patient is taking disopyramide due to this drug combination’s potential to induce severe hypotension.[17]

Contraindications

Patients who have a known hypersensitivity to inamrinone should not receive the drug. Administering inamrinone is contraindicated in patients with known hypersensitivity to excipient sodium metabisulfite, which can cause contact dermatitis.[25]

Warning and Precautions

Clinicians should not prescribe inamrinone to patients with aortic or pulmonic valvular disease.[26]

Monitoring

The therapeutic dosage range for inamrinone is 0.5 to 7.0 μg/mL. The maximum daily dose of inamrinone should not exceed 10 mg/kg. It is recommended that the patient’s blood pressure, heart rate, electrocardiogram, electrolytes, renal function, and hepatic function be monitored carefully throughout inamrinone therapy.[17]

Infusion of inamrinone should stop entirely if the patient experiences severe hypotension and arrhythmias or if there are signs of hepatic toxicity. It is not automatically necessary to stop administering inamrinone to patients who present with thrombocytopenia. However, it is essential to carefully monitor patients if their platelet count drops to less than 150,000 cells/mm³.[27]

Patients requiring inotropic support should have continuous telemetry monitoring, as patients risk developing arrhythmias.[28] In selected patients with heart failure and worsening clinical features, invasive hemodynamic monitoring can be helpful.[4]

Toxicity

There is no specific recommended antidote for an overdose of inamrinone. Supportive measures include providing cardiac support and fluid and electrolyte replacement if necessary. It is essential to consult a medical toxicologist in an accidental overdose of inamrinone.[29]

Enhancing Healthcare Team Outcomes

The use of inamrinone is associated with significant side effects. However, inamrinone is valuable for short-term treatment when digoxin, diuretics, and vasodilators fail to improve cardiac output. Therefore, the healthcare team must monitor the adverse effects of inamrinone and communicate any abnormalities in blood pressure, heart rate, electrocardiogram, electrolytes, renal function, and hepatic function. Clinicians must be even more vigilant if platelet count drops to less than 150,000 cells/mm³. Nursing staff should ensure short-term use of inamrinone with a careful watch on side effects to improve patient outcomes. Pharmacists should perform medication reconciliation and notify the prescriber if drug interactions are present. Critical care and cardiology consultations are required for refractory heart failure or cardiogenic shock. A systematic review and meta-analysis found that including critical care pharmacists in the interprofessional ICU team decreases mortality and ICU stay.[30]

In addition, due to the intricacy of heart failure management and coordination of other health and social services required, advanced heart failure care is optimal if delivered by interprofessional teams that include cardiologists, nurses, and pharmacists specializing in heart failure, social workers, primary care clinicians, and additional specialists.[31][32] Consequently, inamrinone therapy requires an interprofessional team approach, including cardiologists, clinicians, specialty-trained nurses, and pharmacists collaborating to achieve optimal patient outcomes.