Phosphodiesterase III

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. 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

A recent report from the U. K. deals with 1,4-bis(oxodihydropyridazin-yl)benzenes and congeners which are also potent phosphodiesterase inhibitors and inodilators [159], This investigation, together with computer-aided modelling studies on various phosphodiesterase III inhibitors [160], may well stimulate the rational design of additional pyridazine-derived inodilators. 

Mectianism of Action A phosphodiesterase III inhibitor that inhibits platelet aggregation. Dilates vascular beds with greatest dilation in femoral beds. Therapeutic Effect Improves walking distance in patients with intermittent claudication. Pharmacokinetics Moderately absorbed from the GI tract. Protein binding 95%-98%. Extensively metabolized in the liver. Excreted primarily in the urine and, to a lesser extent, in the feces. Not removed by hemodialysis. Half-life 11-13 hr. Therapeutic effect is usually noted in 2-4 wk but may take as long as 12 wk. 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

Figure 8.4 Schematic representation of the effect of B-adrenoceptor agonists and phosphodiesterase III inhibitors.

Phosphodiesterases are a group of enzymes that, among other actions, hydrolyse cAMP. Phosphodiesterase inhibitors are selective for phosphodiesterase III (PDE-III) isoenzyme present in the heart. They prevent the degradation of cAMP, thereby increasing its intracellular concentration (Figure 8.4). This leads to an increase in the intracellular concentration of Ca2+ and an increased contractility and heart rate. PDE-III inhibitors have no adrenoceptor agonistic activity and therefore can be used in combination with other sympathomimetic drugs. They also increase cAMP levels in vascular smooth muscle, but this results in lower intracellular Ca2+ concentrations and thus vasodilatation. 

Phosphodiesterase III inhibitors are very useful in combination with a pi-adrenoceptor agonist in the treatment of acute left ventricular dysfunction. The pi agonist increases the intracellular cAMP by activation of adenylyl cyclase, while the phosphodiesterase III inhibitor prevents degradation of cAMP. The combined effects are additive and may be synergistic in the failing myocardium. 

Amsallem E, Kasparian C, Haddour G, et al. Phosphodiesterase III inhibitors for heart failure. Cochrane Database Syst Rev. 2005 CD002230. 

Muller et al. determined the structure of />-toluoyl-protected tetrazole nucleoside 50 <2005CEJ6246>. The structures of optically active stereoisomers of antifungal agent 51 were solved <2001CPB1110>. Two polymorphic forms of the drug cilostazol 52 (inhibitor of phosphodiesterase III) have been characterized <2002AXCo525>. 

As previously mentioned, for SMC proliferation after coronary angioplasty, cell activation and cell-to-cell interaction of platelets and leukocytes mediated by adhesion molecules are considered to be important. Coronary stenting produces the release of an adhesion molecule, P-selectin, from d-granule of activated platelets. P-selectin-mediated platelet-leukocyte interaction has a crucial role in the development of stent restenosis. Cilostazol is an antiplatelet, antithrombotic, phosphodiesterase III inhibitor that by inhibiting P-selectin release has inhibitory effects on SMC migration. In addition, cilostazol may directly act to inhibit intimal hyperplasia. 

Kohda N, Tani T Nakayama S, et al. Effect of cilostazol, a phosphodiesterase III inhibitor, on experimental thrombosis in the porcine carotid artery. Thromb Res 1999 96 261-268. 

Nomura, Y., Horimoto, H., Mieno, S., Nakahara, K., Okawa, H., Yoshida, M., and Shinjiro, S. 2003. Repetitive preischemic infusion of phosphodiesterase III inhibitor olprinone elicits cardioprotective effects in the failing heart after myocardial infarction. Mol. Cell. Biochem. 248 179-184. 

Sanada, S., Kitakaze, M., Papst, P.J. Asanuma, H., Node, K., Takashima, S., Asakura, M., Ogita, H., Liao, Y., Sakata, Y., Ogai, A., Fukushima, T., Yamada, J., Shinozaki, Y., Kuzuya, T., Mori, H., Terada, N., and Hori, M. 2001. Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors. The role of protein kinase A and p35 mitogen-activated protein kinase. Circulation 104 705-710. 

Milrinone is a bipyridine derivative that inhibits phosphodiesterase III 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. 

The phosphodiesterase III inhibitors have no known direct dysrhythmogenic effects. However, the authors speculated that raised concentrations of cAMP may have contributed to the ventricular tachycardia, mainly because ventricular dysrhythmias have been mentioned with other agents of the same family in patients with heart failure. Whether some populations are particularly vulnerable is unknown. 

Mizushige K, Ueda T, Yukiiri K, Suzuki H. Olprinone a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. Cardiovasc Drug Rev 2002 20(3) 163-74. 

Cyclic adenosine monophosphate (cAMP) activates PKA, which in turn phosphor-ylates Cx43 in rat cardiomyocytes.33 Increases in the cAMP concentration increase electrical conductance between paired cardiomyocytes31,34,35 and increase cell permeability - assessed as dye transfer - in non-cardiomyocytes.36 38 Apart from increased cell-cell conductance and permeability, cAMP also increases the extent of gap junction formation.36 38 Increased cAMP concentration results from its enhanced production following stimulation of adenyl cyclase or from inhibition of phosphodiesterase III secondary to an increased concentration of cyclic guanosine monophosphate (cGMP).39-41... 

Erhardt, P. W., Chou, Y-L. (1991). A topographical model for the cAMP phosphodiesterase III active site. Life Sciences, 49, 553-568. 

Aryl-l,3,4-thiadiazin-2-ones are phosphodiesterase III/IV inhibitors <1999WO9947505>. l,3,4-Thiadiazin-2-ones <1998WO9810765> are nonsteroidal contraception agents for females <1998WO9810765>. Some 1,3,4-thiadiazin-... 

Figure 44 Activity-activity relationship of a series of phosphodiesterase III inhibitors. The in vitro inhibitory effects on membrane-bound cAMP-specific phosphodiesterase are plotted against the in vivo positive inotropic responses to these drugs in the anesthetized dog (reproduced from Figure 3 of ref. [795] with permission from the American Heart Association, Dallas, TX, USA).

Anagrelide should not be used with other phosphodiesterase III inhibitors (e.g. milrinone) because of the potential for increased inotropic effects. Inhibitors of CYP1A2 (e.g. fluvoxamine) are predicted to increase anagrelide levels. Some caution might be required with concurrent aspirin and other platelet inhibitors. Whether anagrelide inhibits theophylline metabolism to a clinically relevant extent is not known. No pharmacokinetic interaction occurs with digoxin or warfarin. 

Anagrelide is a cyclic AMP phosphodiesterase III inhibitor, and consequently has positive inotropic effects. The manufacturer recommends against its concurrent use with other phosphodiesterase III inhibitors, because of the potential increased inotropic effects, and they specifically mention amrlnone, cllostazol, enoximone, milrinone, and olprinone. ... 

Isaacs, K. R., Joseph, E. C., and Betton, G. R. (1989). Coronary vascular lesions in dogs treated with phosphodiesterase III inhibitors. Toxicol Pathol 17, 153-63. 

W. H. Moos, C. C. Humblet, 1. Sircar, C. Rithner, R. E. Weishaar, J. A. Bristol, and A. T. McPhail, /. Med. Chem., 30,1963 (1987). Cardiotonic Agents. 8. Selective Inhibitors of Adenosine 3, 5 -Cyclic Phosphate Phosphodiesterase III. Elaboration of a Five-Point Model for Positive inotropic Activity. 

Phosphodiesterase-III Inhibitors Cilostazol Pletal Oral Launched... 

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