What Is Milrinone?

The chemical name of Milinone is: 2-methyl-6-oxy-1,6-dihydro-3,4'bispyridine-5carbonitrile, molecular formula: C12H9N3O, molecular weight: 211.22, off-white or light yellow crystalline powder ; Odorless. Almost insoluble in water or ethanol, slightly soluble in dilute hydrochloric acid. It is clinically used for chronic congestive heart failure and refractory heart failure.

The chemical name of Milinone is: 2-methyl-6-oxy-1,6-dihydro-3,4'bispyridine-5carbonitrile, molecular formula: C12H9N3O, molecular weight: 211.22, off-white or light yellow crystalline powder ; Odorless. Almost insoluble in water or ethanol, slightly soluble in dilute hydrochloric acid. It is clinically used for chronic congestive heart failure and refractory heart failure.

Chinese name

Milinone

Foreign name

Milrinone

CAS number

78415-72-2

Molecular formula

C12H9N3O

Molecular weight

211.22

Density

1.28 g / cm3

Introduction to Milinone compounds

Basic information of Milinone

Chinese name:

Chinese alias: 2-methyl-6-oxy-1,6-dihydro- [3,4'bispyridine] -5-carbonitrile; carbonitrile; carbonitrile; ketone;

English name: milrinone

English alias: 1,6-Dihydro-2-methyl-6-oxo- (3,4'-bipyridine) -5-carbonitrile; Corotrope; Primacor; 6-methyl-2-oxo-5-pyridin-4-yl- 1H-pyridine-3-carbonitrile; Corotrop; 2-methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile; Milrinona; Milrinonum; Milrinone; Milrila;

CAS number: 78415-72-2

EINECS number: 278-903-6

RTECS number: DW1762000

Molecular formula: C ₁₂ H ₉ N ₃ O

Structural formula:

Molecular weight: 211.21900

Exact mass: 211.007500

PSA: 69.54000

LogP: 1.61698

Physicochemical properties of Milinone

Appearance and properties: off-white solid

Density: 1.28 g / cm ³

Melting point:> 3000C

Boiling point: 448.7ºC at 760 mmHg

Flash point: 225.2ºC

Stability: Stable. Incompatible with strong oxidizing agents.

Storage conditions: 2-8ºC

Milinone Safety Information

Packing level: III

Hazard category: 6.1 (b)

Customs Code: 2933399090

Dangerous Goods Transport Code: UN 2811 6.1 / PG 3

WGK Germany: 3

Danger category code: R23 / 24/25

Safety instructions: S36 / 37 / 39-S45

RTECS number: DW1762000

Dangerous goods mark: T ^[1]

Milinone Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 1

3.Number of hydrogen bond acceptors: 3

4.Number of rotatable chemical bonds: 1

5.Number of tautomers: 7

6. Topological molecular polar surface area 65.8

7.Number of heavy atoms: 16

8.Surface charge: 0

9.Complexity: 419

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Milinone synthesis method

Method 1: 4-methylpyridine was dissolved in anhydrous ether, protected by nitrogen, and an ether solution of phenyllithium was added dropwise at room temperature under stirring, and the reaction was continued after the addition. Stop nitrogen flow, cool to 0 ° C, add ethyl acetate dropwise, and react below 10 ° C. Acidify with concentrated hydrochloric acid to Ph = 1 2, separate the aqueous layer, alkalinize with saturated sodium carbonate to Ph = 9, precipitate an oil, extract several times with chloroform, dry, evaporate chloroform, fractionate under reduced pressure, collect 130-132 The fraction at / 1.47kPa is 1- (4-pyridyl) acetone.

1- (4-pyridyl) acetone, acetonitrile and N, N-dimethylformamide dimethyl acetal are refluxed together. The solvent was distilled off under reduced pressure, and the residue was dissolved in an appropriate amount of chloroform. The extract was heated and refluxed with an alumina column (Soxhlet extractor). The extract was concentrated and recrystallized with carbon tetrachloride-cyclohexane (4: 1). To obtain 1- (4-pyridyl) -2- (dimethylamino) vinylmethyl ketone.

1- (4-pyridyl) -2- (dimethylamino) vinyl methyl ketone, cyanoacetamide, sodium methoxide, and dimethylformamide are heated under reflux, the solvent is distilled off under reduced pressure, and the residue is warmly dissolved by adding acetonitrile , Cool to 10 ° C; precipitate solid, filter, dissolve in appropriate amount of water, decolorize activated carbon, acidify with 6mol / L hydrochloric acid to Ph = 6.5 ~ 7, precipitate solid, and recrystallize with dimethylformamide to obtain light yellow granular crystal, It is milrinone with a melting point> 300 ° C.

Method 2: using 4-pyridylacetone as a raw material, condensing with triethyl orthoformate, and then reacting with 2-cyanoacetamide to obtain milrinone.

Method 3: The reaction of pyridylacetone and 2,2-dicyanovinyl ethyl ether can produce milrinone. ^[2]

Milinone uses

1. Cardiotonic drugs, which have the effect of enhancing myocardial contractility and directly dilating blood vessels.

2. New non-glycosides and non-catecholamines cardiotonic drugs, phosphodiesterase inhibitors, are similar drugs of amrinone, and its mechanism of action is the same as that of amrinon, which is well tolerated. It has the effect of dilating vascular smooth muscle, can reduce the heart load, and can also improve the kidney and muscle blood supply. No serious adverse reactions. It is suitable for acute and chronic refractory congestive heart failure caused by various reasons that are ineffective or ineffective in the treatment of digitalis, diuretics, and vasodilators. ^[2]

Milli Pesticide Standard

Main active ingredients of milrinone

Calculated, including C12H9N3O shall not be less than 98.5%.

Milinone traits

Off-white or light yellow crystalline powder; odorless.

Almost insoluble in water or ethanol, slightly soluble in dilute hydrochloric acid.

Milinone identification

(1) Take about 20mg. Add 1ml / L hydroxylamine hydrochloride propylene glycol solution 2ml and 1ml / L potassium hydroxide propylene glycol solution 2ml, boil on the water bath for 2 minutes, add 1 drop of 5% ferric chloride test solution, it should be red To fuchsia.

(2) Take about 20mg, add 2ml of pyridine to dissolve, and add 8ml of silver nitrate solution, then white precipitation will occur.

(3) Take about 20mg, dissolve it with 0.2ml of lactic acid, dilute with water to a solution containing 6g per 1ml, and measure it by spectrophotometry (Chinese Pharmacopoeia 1995 Edition, Appendix II IVA). It has maximum absorption at 266nm and 325nm wavelengths. .

(4) Infrared first absorption Mandarin should be consistent with the reference spectrum.

Milinone inspection

Clarity and color of the sodium hydroxide solution was taken as 1 g, and the sodium hydroxide test solution was dissolved in 10 m.

The solution should be clarified (Appendix IX B of the Second Part of the Chinese Pharmacopoeia 1995 Edition), and if it is colored, it should not be deeper than the yellow 6 standard of the same volume.

Relevant substances were added with methanol to make a solution containing 5mg per 1ml as the test solution. A precise amount was taken and diluted with methanol to make a solution containing 0.075mg per 1ml as a control solution. According to the thin-layer chromatography (Chinese Pharmacopoeia 1995 edition, Appendix B) test, 20 l of each of the two solutions was measured and spotted on the same silica gel GF254 thin-layer plate. Chloroform-methanol-aqueous ammonia (9: 2: 0.2) was used as The developing agent was unfolded and air-dried. The solution was examined under an ultraviolet (254nm) lamp. The test solution showed impurity spots, not more than one impurity spot, and a lighter color than the control main spot.

Take 1g of chloride , add 50ml of water, shake and filter thoroughly, take 25ml of filtrate, check according to law (Chinese Pharmacopoeia 1995 edition, Appendix A), if turbidity occurs, compare with a control solution made of 7ml of standard sodium chloride solution. Thicker (0.014%).

Loss on drying Take 1g and dry at 105 ° C to constant weight. Loss of weight must not exceed 1.0% (Chinese Pharmacopoeia 1995 Edition Appendix II L).

Take 1g of burning residue and inspect it according to law. The remaining residue should not exceed 0.1% (Chinese Pharmacopoeia 1995 Edition Appendix N).

The residues left under the item of burning residue of heavy metals shall be inspected according to law (the second method of Appendix H of the Chinese Pharmacopoeia 1995 Edition) containing no more than 20 parts per million of heavy metals.

Determination of milrinone

Add about 0.16g. Weigh accurately. Add 30ml of glacial acetic acid, heat and dissolve below 60 , let cool, add 1 drop of crystal violet indicator solution, titrate with perchloric acid solution (0.1mol / L) until the solution becomes blue, The titration results are obtained by correcting the blank test. Each 1ml of perchloric acid solution (0.1mol / L) is equivalent to 21.12mg of C12H9N3O. ^[3]

Physiological action of mili pesticide

This product is a phosphodiesterase inhibitor, a similar drug of Amrinon, with the same mechanism of action as Amrinon. Both oral and intravenous injection are effective, with both positive inotropic effect and vasodilator effect. But its effect is 10 to 30 times stronger than ammonia. Well tolerated. The positive inotropic effect of this product is mainly through the inhibition of phosphodiesterase, which increases the concentration of cyclic adenosine monophosphate (CAMP) in cardiac muscle cells, increases intracellular calcium, strengthens myocardial contractility and increases cardiac output. And it has nothing to do with the adrenaline & szlig; 1 receptor or the cardiomyocyte Na +, K + -ATPase, its vasodilation effect may be directly on the small arteries or caused by it, which can reduce the anterior and posterior load of the heart, reduce the left ventricular filling pressure, Improved left ventricular function and increased cardiac index, but had no significant effect on mean arterial pressure and heart rate. The cardiovascular effect of Milinone is related to the dose. At low doses, it mainly shows positive muscle strength. When the dose increases, it gradually reaches the steady state maximum positive muscle strength effect. Its vasodilator effect can also vary with the dose. Increase and gradually strengthen. This product is safer for patients with conduction blocks. This product has serious adverse reactions when taken orally and should not be used for a long time. ^[4]

Millipore agrochemical kinetics

It takes effect after oral administration for 30 minutes, the peak time is 1 to 3 hours, and the effect should be maintained for 4 to 8 hours. The bioavailability of patients with heart failure is 76%. Plasma half-life is 1 hour, while in patients with heart failure it is prolonged for more than 2 hours. Nearly 80% to 85% of Milinone is excreted through the kidney in its original form, so when renal function is impaired, the half-life is prolonged, and the dosage should be appropriately reduced. ^[5]

Milinone indications

It is suitable for acute and chronic refractory congestive heart failure caused by various reasons that are ineffective or ineffective in the treatment of digitalis, diuretics, and vasodilators. ^[4]

Usage and dosage of milrinone

Intravenous injection: load 25 75ug / ug, slow intravenous injection for 5 ~ 10 minutes, and then maintain it by 0.25 1.0ug / every minute. The maximum daily dose does not exceed 1.13 mg / .

Oral: 2.5-7.5mg once a day, 4 times a day.

Milinone adverse reactions

Rare than ammonia farmers. A few have headaches, ventricular arrhythmias, weakness, and decreased platelet counts. There may be hypotension and tachycardia when overdose. Long-term oral administration is no longer used due to its large side effects, which can cause long-term mortality. ^[4]

Contraindications to milrinone

Hypotension, tachycardia, myocardial infarction should be used with caution; renal insufficiency should be reduced. ^[4]

Notes for Milinone

Monitor heart rate, heart rate, blood pressure, and adjust the dose if necessary.

Should not be used in patients with severe stenosis and obstructive hypertrophic cardiomyopathy. Use with caution in patients with acute ischemic heart disease.

When combined with strong diuretics, the left ventricular filling pressure can be excessively reduced, and it is easy to cause water and electrolyte imbalance.

For patients with atrial flutter and atrial fibrillation, the ventricular rate increases due to increased atrioventricular conduction, so digitalis preparations should be used to control ventricular rate.

use with caution in patients with impaired liver and kidney function.

It has not been used for myocardial infarction, pregnant women and nursing women, children, so it should be cautious.

Medication for pregnant women and lactating women

Not clear yet.

Medication for elderly patients

Not clear yet.

Milinone 's medication for children

Not clear yet. ^[4]

Milrinone drug interactions

Rhenium can cause hypotension when used in combination with propidium.

Combined with commonly used cardiotonic, diuretic, vasodilator drugs, no adverse interactions have been seen.

Rhenium and nitrates have an additive effect.

This product has a positive muscle strength effect of digitalis, so it is not necessary to stop digitalis during application. ^[4]

Milinone compatibility taboo

This product is diluted with normal saline or 5% glucose solution and cannot be diluted with dextran-containing solution.

Rhenium mixed with furosemide immediately precipitated.

Milinone Milidone Poisoning

Milrinone (methyramidone, cyanurinone, and milrinone) is a homologue of amrinone, which has both positive inotropic effect and vasodilator effect, but its effect is stronger, which is 20 to that of amrinone A 30-fold increase in cardiac index is superior to amrinone, with no significant effect on arterial pressure and heart rhythm. This product is effective after oral administration for 0.5h, and the maximum effect is achieved in 1-3h. The effect is maintained for 4-6h, the half-life is 4-6h, and 80% is excreted from the urine.

Oral 2.5 to 7.5 mg each time, 2 to 3 / d, a total of 30 mg per day. Each intravenous infusion is 1.25 to 2.5 mg, 0.25 to 0.75 g / (kg · min), and the maximum amount is 56 mg.

Clinical manifestations of milrinone

Poisoning manifestations: headache, chest pain, insomnia, diarrhea, hypotension, tremor, muscle weakness, thrombocytopenia, hypokalemia, arrhythmia, and hyperthyroidism.

Milinone treatment

The main points for the treatment of milizone poisoning are:

Related content with Amrinone:

1. Stop the medicine immediately.

2. Potassium can be added when the potassium is low, orally at 3 / d, 1-2g / times in mild cases; potassium chloride is added to 500ml of 5% glucose in the IV.

3. If atrial fibrillation occurs, rapid digitalis can be used; if ventricular premature contractions, ventricular tachycardia and ventricular fibrillation occur, intravenous lidocaine can be used.

4. Hepatic protection drugs can be used for patients with severe liver function changes. Ganlixin 150mg plus 5% glucose 250ml intravenous drip and oral bifendate. ^[6]

Milinone storage

Shading, airtight storage ^[4]