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INTRODUCTION

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Phosphodiesterase inhibitors (PDEI) are a broad category of drugs that act to prevent the hydrolysis of cyclic 3,5 adenosine monophosphate (cAMP) and 3,5 guanosine monophosphate (cGMP) by phosphodiesterases. Phosphodiesterases (PDEs) are a heterogeneous group of at least 11 isoenzymes, with over 50 isoforms, present in a wide variety of tissues, and their actions are important in regulating intracellular levels of cAMP and cGMP, both important components of intracellular second messenger systems. Inhibition of phosphodiesterases will lead to an increase in intracellular cyclic nucleotides and amplify their actions in various organ beds. The main clinical interest of anesthesiologists resides with the direct effects of PDEIs in cardiac and vascular tissue mediated by the PDEI type III (3) isoenzyme. Other PDEIs have clinical applications in treating primary pulmonary hypertension, persistent pulmonary hypertension of the newborn, and erectile dysfunction (PDEI type 5); this will be discussed briefly at the conclusion of this chapter. PDEI, primarily type 4, may also prove to be of benefit in treating inflammatory (eg, reactive airway disease) and some neoplastic disease states (where cAMP levels have found to be reduced).

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Hydrolysis of cAMP is caused by the action of PDE, yielding a monophosphate and a free hydroxyl moiety. Clinically, relevant drugs that inhibit PDE and thus improve contractility are the biguanides, amrinone and milrinone, and the imidazoline-derived enoximone (which is not available in the United States). For all intents, milrinone has supplanted amrinone in clinical practice in the United States.

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Figure 165-1 illustrates the mechanism of myocardial contraction at the myocyte and how PDEI type 3 promotes contractility. Inhibiting the action of PDE will lead to amplification of the adrenergic-initiated generation of cAMP from the G protein-linked adenylyl cyclase, and thus increase intracellular Ca2+ and the force of contraction. Activation of protein kinase A (PKA) by cAMP will not only cause release of Ca2+ through L-type calcium channels, but also through its ability to phosphorylate regulatory proteins involved with contraction, phospholamban, and calmodulin. These, in turn, will promote the release of Ca2+ from the sarcoplasmic reticulum, independent of L-type calcium channel Ca2+ release, and this is felt to be a more important feature of PDEI action than via catecholamine-mediated stimulation of L-type channels.

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Figure 165-1

Schematic drawing of myocyte showing mechanism of action for contraction and the effects of PDEI type 3 inhibitors like milrinone. Adrenergic receptor activation by norepinephrine and epinephrine will lead to generation of cAMP via G protein (GP)-linked adenylyl cyclase, which will in turn activate PKA and lead to both stimulation of the L-type Ca2+ channel (Ca2+ influx) and phosphorylation of contractile proteins to enhance contractility. Milrinone will prevent the breakdown of cAMP by PDE and thus amplify cAMP-mediated inotropic activity.

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PDEI type 3 also exert their action on vascular smooth muscle. Activation of beta-2 adrenergic receptors ...

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