Amrinone

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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. In myocytes, the increase of cAMP concentration increases in turn the activity of PKA; this kinase 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. 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 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. This does not lead to an increase in heart rate or blood pressure.

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, a loop diuretic, 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, diarrhea, hepatotoxicity, arrhythmias 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. 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.

Synthesis

See also: Milrinone and Pelrinone.

References

References

1. (August 1999). "Effects of single administration of a phosphodiesterase III inhibitor during cardiopulmonary bypass: comparison of milrinone and amrinone". Japanese Circulation Journal.
2. (August 2004). "Diminished inotropic response to amrinone in ventricular myocytes from myopathic hamsters is linked to depression of high-gain Ca2+-induced Ca2+ release". The Journal of Pharmacology and Experimental Therapeutics.
3. "The HealthWatch Award 2003: Dr Peter Wilmshurst - "Obstacles to honesty in medical research"".
4. (1990). "Pharmacokinetics and pharmacodynamics of phosphodiesterase-III inhibitors.". Journal of Cardiothoracic Anesthesia.
5. (January 1989). "Effects of phosphodiesterase inhibition on skeletal muscle vasculature". The American Journal of Cardiology.
6. (December 1984). "Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure". Circulation.
7. (July 1981). "Hemodynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure". The American Journal of Cardiology.
8. (July 1980). "Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease". Circulation.
9. (February 1986). "Relative contribution of inotropic and vasodilator effects to amrinone-induced hemodynamic improvement in congestive heart failure". The American Journal of Cardiology.
10. (July 1986). "Withdrawal of long-term amrinone therapy in patients with congestive heart failure: a placebo controlled trial". European Heart Journal.
11. (November 1979). "Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one]". Circulation Research.
12. (March 2000). "Amrinone Becomes Inamrinone". [[United States Pharmacopeia]].
13. "3-Cyano-5-(pyridinyl)-2(1H)-pyridinones".
14. "3-Amino-5-(pyridinyl)-2(1H)-pyridinones".
15. "5-(Pyridinyl)-2(1H)-pyridinones".
16. "Process for preparing 5-cyano(3,4'-bipyridin)-6(1H)-one".