Milrinone

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

PDE3 3A, 3B 1 for 3A 2 for 3B Transmembrane domains/ membrane targeting PKB, PKA cAMP > cGMP Milrinone... 

The PDE3 inhibitor, cilostazol, has been used as an antithrombotic agent and is currently being used in patients being treated for intermittent claudication. Cilostazol is also used for the prevention of restenosis after treatments such as angioplasty. Another PDE3 selective inhibitor, milrinone, has been used in the treatment of congestive heart failure. Milrinone also has been shown to increase the conductance of the CFTR transporter in vitro. 

CJH4N2O 107-91-5) see Alloputinol Amrinone Ethionamide Milrinone Nevirapine Olprinone hydrochloride Protionamide cyanoacetic acid... 

C7H )N2 1122-58-3) see Paclitaxel Zafiilukast 4-dimethylamino-3-(4-pyridyl)-3-bulen-2-one (CHH14N2O 7 504 61-7) see Milrinone 2-dimethylaminosulfunylphenothiazine... 

Milrinone 50 pg/kg over 10 minute bolus then 0.375-0.75 pg/kg/minute 5-15 minutes Arrhythmia, headache Increased CO, decreased SVR... 

Limited experience with dobutamine and milrinone co administration... 

Add nitroprusside or nesiritide if Cl <2.2 L/min/m2 and clinical end point not achieved despite therapeutic dobutamine +/- milrinone... 

Abciximab, aminophylline, amiodarone, amrinone, aspirin, carbamazepine, chlorpromazine, danazol, diltiazem, eptifi-batide, heparin, histamine2-receptor antagonists, low molecular weight heparins, methyldopa, milrinone, procainamide, quinidine, quinine, NSAIDs, thiazide diuretics, ticlopidine, tirofiban, and valproic acid... 

Milrinone 0.375-0.75 mcg/kg per minute BP, HR, urinary output and function, ECG, changes in ischemic symptoms (e.g., chest pain), electrolytes... 

Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of thrombocytopenia seen with inamrinone. 

Dosing recommendations for milrinone include a loading dose of 50 mcg/kg, followed by an infusion beginning at 0.5 mcg/kg per minute (range 0.23 mcg/kg per minute for patients with renal failure up to 0.75 mcg/kg per minute). A loading dose is not necessary if immediate hemodynamic effects are not required or if patients have low systolic blood pressures (less than 90 mm Hg). Decreases in blood pressure during an infusion may necessitate dose reductions as well. 

FIGURE 8-2. General treatment algorithm for acute decompensated heart failure (ADHF) based on clinical presentation. IV vasodilators that may be used include nitroglycerin, nesiritide, or nitroprusside. Metolazone or spironolactone may be added if the patient fails to respond to loop diuretics and a second diuretic is required. IV inotropes that may be used include dobutamine or milrinone. (D/C, discontinue HF, heart failure SBP, systolic blood pressure.) (Reprinted and adapted from J Cardiac Fail, Vol 12, pages el-el 22, copyright 2006, with permission from Elsevier.)... 

Milrinone is a bipyridine derivative that inhibits phosphodiesterase 111 and produces positive inotropic and arterial and venous vasodilating effects hence, milrinone has been referred to as an inodilator. It has supplanted use of amrinone, which has a higher rate of thrombocytopenia. 

During IV administration, milrinone increases stroke volume (and cardiac output) with little change in heart rate. It also decreases PAOP by venodilation and thus is particularly useful in patients with a low cardiac index and an elevated LV filling pressure. However, this decrease in preload can be hazardous for patients without excessive filling pressure, leading to a decrease in cardiac index. 

Milrinone should be used cautiously as a single agent in severely hypotensive HF patients because it will not increase, and may even decrease, arterial blood pressure. 

The usual loading dose of milrinone is 50 mcg/kg over 10 minutes. If rapid hemodynamic changes are unnecessary, the loading dose should be eliminated because of the risk of hypotension. Most patients are simply started on the maintenance continuous infusion of 0.25 mcg/kg/min (up to 0.75 mcg/kg/min). 

Dopamine should generally be avoided in decompensated HF, but its pharmacologic actions may be preferable to dobutamine or milrinone in patients with marked systemic hypotension or cardiogenic shock in the face of elevated ventricular filling pressures, where dopamine in doses greater than 5 mcg/kg/min may be necessary to raise central aortic pressure. 

Sodium nitroprusside is a mixed arterial-venous vasodilator that acts directly on vascular smooth muscle to increase cardiac index and decrease venous pressure. Despite its lack of direct inotropic activity, nitroprusside exerts hemodynamic effects that are qualitatively similar to those of dobutamine and milrinone. However, nitroprusside generally decreases PAOP, SVR, and blood pressure more than those agents do. 

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