Amrinone

# Overview
Amrinone (INN) or inamrinone (USAN, changed in 2000 to prevent confusion with amiodarone), trade name Inocor, is a pyridine 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.

# Uses
It is used in the treatment of congestive heart failure.
It has been studied for use before coronary artery bypass surgery.

# 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 produces vasodilation by facilitating calcium uptake by the sarcoplasmic reticulum (a special type of smooth ER) and decreasing the calcium available for contraction.   Since amrinone inhibits PDE III, it also inhibits the L type Ca2+ current in myocytes as well as facilitating an increase in Ca2+ uptake by the sarcoplasmic reticulum (SR).  This may contribute to its positive inotropic effect on cardiac myocytes. Amrinone decreases the pulmonary capillary wedge pressure while increasing cardiac output because 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 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).

# How Inamrinone is used to correct 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 (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 -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 (CO) and stroke volume (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.  This 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 EG should be constantly monitored. Amrinone should only be diluted with normal saline or 1/2 normal saline; no dextrose solutions should be used. Furosemide should not be administered into an IV line delivering Amrinone.

# Side effects
Thrombocytopenia is the most prominent and dose-related side effect, but it is transient and asymptomatic. Nausea, diarrhoea, hepatotoxicity, arrhythmias and fever are other adverse effects.

# Routes
IV bolus and infusion as described earlier.

# Pediatric dosage
Safety in children has not been established.

# 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 resulting in circulatory collapse, worsening myocardial ischemia, acute myocardial infarction, and worsening congestive heart failure. Amrinone has good absorption from the gastrointestinal tract  and may lead to some 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 inotropic effects are variable.  A loss in sensitivity to PDE III inhibitors has been observed in end stage heart failure in humans and thus other treatment options may be necessary to improvement in these stages.