Amrinone, also known as inamrinone, and sold as Inocor, is a

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...

phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca²⁺ calmodulin kinase pathways.

Actions

Increases cardiac contractility, vasodilator. Acts by inhibiting the breakdown of both cAMP and cGMP by the phosphodiesterase ( PDE3) enzyme. There is a long-standing controversy regarding whether the drug actually increases cardiac contractility in diseased myocardium (and therefore whether it is of any clinical use). The issue has been reviewed extensively by Dr Peter Wilmshurst, one of the first cardiologists and researchers to question the drug's efficacy.

PDE-III inhibition and cardiac function

PDE III is present in cardiac muscle, vascular smooth muscle and platelets. PDE III degrades the phosphodiester bond in cAMP to break it down. When PDE III is inhibited, cAMP cannot be inactivated. An increase in cAMP with the administration of amrinone in

vascular smooth muscle Vascular smooth muscle is the type of smooth muscle that makes up most of the walls of blood vessels. Structure Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood v ...

produces vasodilation by facilitating calcium uptake by the sarcoplasmic reticulum (a special type of smooth ER) and decreasing the calcium available for contraction. In myocytes, the increase of cAMP concentration increases in turn the activity of PKA; this

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

improves the Ca²⁺ inward current through the L-type Ca²⁺ channels, which leads to calcium-induced calcium release from the sarcoplasmic reticulum, giving rise to a calcium spark that triggers the contraction; this results in an inotropic effect. Furthermore, PKA phosphorylates and deactivates the phospholambans that inhibit SERCA, which is an enzymatic pump that, to terminate the contraction, removes the Ca²⁺ from the cytoplasm, stores it back in the sarcoplasmic reticulum and promotes the subsequent arterial relaxation as well, producing a lusitropic effect. Both inotropic and lusitropic effects justify the use of amrinone to treat

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. Amrinone decreases the pulmonary capillary wedge pressure while increasing cardiac output, as it functions as an arterial vasodilator and increases venous capacitance while decreasing venous return. There is a net decrease in myocardial wall tension, and O₂ consumption when using amrinone. Amrinone also has beneficial effects during

diastole Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are refilling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventricul ...

in the left ventricle, including relaxation, compliance and filling in patients with congestive heart failure.

Indications

Short-term management of severe CHF (not used long term because of increased mortality, probably due to heart failure).

Effects in congestive heart failure

Congestive heart failure (CHF) is characterized by a reduction in ventricular performance and abnormalities in peripheral circulation and organs. A reduced release of endothelium derived relaxing factor (EDRF) causes a decrease in the stimulation of guanylate cyclase, and

cyclic GMP Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in res ...

(cGMP) levels fall in vascular smooth muscle. This impairs relaxation in the vasculature and is a part of the vicious cycle of CHF. Patients with CHF have a down-regulation of their β-1 adrenergic receptors which alters their ability to activate intracellular adenylate cyclase, which catalyzes cAMP formation. cAMP is the second messenger that controls the level of calcium available to allow the heart to contract. An IV administration of amrinone has been shown to increase

cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: tha ...

(CO) and

stroke volume In cardiovascular physiology, stroke volume (SV) is the volume of blood pumped from the ventricle (heart), ventricle per beat. Stroke volume is calculated using measurements of ventricle volumes from an Echocardiography, echocardiogram and subtra ...

(SV), while concurrently reducing the filling pressure of the left ventricle and decreasing the resistance in the peripheral vasculature. This does not lead to an increase in heart rate or blood pressure. The improvement in performance of the ventricles is likely to result from a direct stimulation of the depressed myocardium as well as a decrease in peripheral vascular resistance.

Contraindications

Patients with aortic stenosis, hypertrophic cardiomyopathy, or history of hypersensitivity to the drug.

Precautions

May increase myocardial ischemia. Blood pressure, pulse, and ECG should be constantly monitored. Amrinone should only be diluted with normal saline or 1/2 normal saline; no dextrose solutions should be used.

Furosemide Furosemide, sold under the brand name Lasix among others, is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease. Furosemide may also be used for the treatment of high blood pressure. It can ...

, a

loop diuretic Loop diuretics are pharmacological agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle. They are often used for the treatment of hypertension and e ...

, should not be administered into an IV line delivering amrinone.

Side effects

Thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

is the most prominent and dose-related side effect, but it is transient and asymptomatic.

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, hepatotoxicity,

arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

s and fever are other adverse effects.

Amrinone discovery and progression

Early studies in patients with heart failure showed that amrinone produced short-term hemodynamic improvement, but had limited long-term clinical benefit. Some serious side effects of long term administration included sustained

ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple ...

resulting in circulatory collapse, worsening myocardial ischemia, acute myocardial infarction, and worsening congestive heart failure. Amrinone has good absorption from the gastrointestinal tract and has led to gastrointestinal upset when taken orally. The oral form of the drug is no longer in use. Currently, only acute intravenous administration takes place. The effects of amrinone vary widely with species and experimental condition; therefore, its inotropic effects are variable. A loss in sensitivity to phosphodiesterase 3 inhibitors, including amrinone, has been observed in end stage heart failure in humans; other treatment options may be more useful for improvement in these stages.

Naming

Amrinone is the INN, while inamrinone is the United States Adopted Name, which was adopted in 2000 in an attempt to avoid confusion with

amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxys ...

Synthesis

References

{{Cardiac stimulants excluding cardiac glycosides Cardiac stimulants Inotropic agents 4-Pyridyl compounds Vasodilators PDE3 inhibitors 2-Pyridones Aromatic amines