Amrinone

Amrinone

Clinical data
Trade names	Inocor
Other names	inamrinone (USAN US)
AHFS/Drugs.com	International Drug Names
Routes of administration	Intravenous
ATC code	C01CE01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	n/a
Protein binding	10 to 49%
Metabolism	Hepatic
Elimination half-life	5 to 8 hours
Excretion	Renal (63%) and fecal (18%)
Identifiers
IUPAC name 5-amino-3,4'-bipyridin-6(1H)-one
CAS Number	60719-84-8^Y
PubChem CID	3698
IUPHAR/BPS	7202
DrugBank	DB01427^Y
ChemSpider	3570^Y
UNII	JUT23379TN
KEGG	D00231^Y
ChEBI	CHEBI:2686
ChEMBL	ChEMBL12856^Y
CompTox Dashboard (EPA)	DTXSID9022603
ECHA InfoCard	100.056.700
Chemical and physical data
Formula	C10H9N3O
Molar mass	187.202 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C2C(/N)=C\C(\c1ccncc1)=C/N2
InChI InChI=1S/C10H9N3O/c11-9-5-8(6-13-10(9)14)7-1-3-12-4-2-7/h1-6H,11H2,(H,13,14)^Y Key:RNLQIBCLLYYYFJ-UHFFFAOYSA-N^Y
(verify)

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor.^[1] It is a drug that may improve the prognosis in patients with congestive heart failure.^[2] Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR).^[3] 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.^[3]

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.^[4]

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.^[5][6] 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.^[5][7] 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.^[5] 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.^[5]

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.^[6] 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.^[6] 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.^[5] 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.^[2][8][9] This does not lead to an increase in heart rate or blood pressure.^[2][8][9] 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.^[10]

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.^[7] 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.^[7][11] Amrinone has good absorption from the gastrointestinal tract ^[12] and has led to gastrointestinal upset when taken orally. The oral form of the drug is no longer in use.^[11] Currently, only acute intravenous administration takes place.^[11] The effects of amrinone vary widely with species and experimental condition; therefore, its inotropic effects are variable.^[3] 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.^[3]

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.^[13]

Synthesis

Amrinone synthesis:^{[14][15][16][17]}

See also: Milrinone and Pelrinone.

References

1. Hamada Y, Kawachi K, Yamamoto T, Nakata T, Kashu Y, Sato M, Watanabe Y (August 1999). "Effects of single administration of a phosphodiesterase III inhibitor during cardiopulmonary bypass: comparison of milrinone and amrinone". Japanese Circulation Journal. 63 (8): 605–609. doi:10.1253/jcj.63.605. PMID 10478810.
2. Klein NA, Siskind SJ, Frishman WH, Sonnenblick EH, LeJemtel TH (July 1981). "Hemodynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure". The American Journal of Cardiology. 48 (1): 170–175. doi:10.1016/0002-9149(81)90587-7. PMID 7246440.
3. Xiong W, Ferrier GR, Howlett SE (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. 310 (2): 761–773. doi:10.1124/jpet.103.064873. PMID 15064331. S2CID 6036283.
4. Wilmshurst P. "The HealthWatch Award 2003: Dr Peter Wilmshurst - "Obstacles to honesty in medical research"". Archived from the original on 2015-04-25.
5. Levy JH, Ramsay J, Bailey JM (1990). "Pharmacokinetics and pharmacodynamics of phosphodiesterase-III inhibitors". Journal of Cardiothoracic Anesthesia. 4 (6): 7–11. doi:10.1016/0888-6296(90)90226-6.
6. LeJemtel TH, Scortichini D, Levitt B, Sonnenblick EH (January 1989). "Effects of phosphodiesterase inhibition on skeletal muscle vasculature". The American Journal of Cardiology. 63 (2): 27A–30A. doi:10.1016/0002-9149(89)90389-5. PMID 2909994.
7. Packer M, Medina N, Yushak M (December 1984). "Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure". Circulation. 70 (6): 1038–1047. doi:10.1161/01.cir.70.6.1038. PMID 6388899. S2CID 6325011.
8. Benotti JR, Grossman W, Braunwald E, Carabello BA (July 1980). "Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease". Circulation. 62 (1): 28–34. doi:10.1161/01.cir.62.1.28. PMID 7379283.
9. Konstam MA, Cohen SR, Weiland DS, Martin TT, Das D, Isner JM, Salem DN (February 1986). "Relative contribution of inotropic and vasodilator effects to amrinone-induced hemodynamic improvement in congestive heart failure". The American Journal of Cardiology. 57 (4): 242–248. doi:10.1016/0002-9149(86)90899-4. PMID 3004184.
10. LeJemtel TH, Keung E, Ribner HS, Davis R, Wexler J, Blaufox JD, Sonnenblick EH (January 1980). "Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure". The American Journal of Cardiology. 45 (1): 123–129. doi:10.1016/0002-9149(80)90229-5. PMID 7350759.
11. Rettig G, Sen S, Fröhlig G, Schieffer H, Bette L (July 1986). "Withdrawal of long-term amrinone therapy in patients with congestive heart failure: a placebo controlled trial". European Heart Journal. 7 (7): 628–631. doi:10.1093/oxfordjournals.eurheartj.a062114. PMID 3530768.
12. Alousi AA, Farah AE, Lesher GY, Opalka CJ (November 1979). "Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one]". Circulation Research. 45 (5): 666–677. doi:10.1161/01.RES.45.5.666. PMID 39684.
13. "Amrinone Becomes Inamrinone". USP Quality Review. 73. United States Pharmacopeia. March 2000. Archived from the original on 2008-10-03.
14. US Patent 4004012, Lesher GY, Opalka CJ, "3-Cyano-5-(pyridinyl)-2(1H)-pyridinones", issued 18 January 1977, assigned to STWB Inc. 
15. US Patent 4072746, Lesher GY, Opalka CJ, "3-Amino-5-(pyridinyl)-2(1H)-pyridinones", issued 7 February 1978, assigned to Aventis Pharmaceuticals Inc. 
16. US 4107315, Lesher GY, Opalka CJ, "5-(Pyridinyl)-2(1H)-pyridinones", issued 15 August 1978, assigned to Aventis Pharmaceuticals Inc. 
17. GB 2070008, Gelotte KO, Parady ED, "Process for preparing 5-cyano(3,4'-bipyridin)-6(1H)-one", published 3 September 1981, issued 18 April 1984, assigned to Sterling Drum Inc.