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).
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.
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.
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.
PDEI type 3 also exert their action on vascular smooth muscle. Activation of beta-2 adrenergic receptors will also produce a rise in intracellular cAMP via G protein complex-mediated adenylyl cyclase activity and subsequent activation of PKA. However, in contradistinction to cardiac cells, activation of PKA in smooth muscle will result in a reduction in intracellular Ca2+ by activating calcium channel pumps to sequester calcium out of the cell, thus promoting relaxation and vasodilation. PDEI type 3 has affinity for arterial and venous smooth muscles, in addition to cardiac muscle; PDEI type 5 drugs such as sildenafil are active on corpus cavernosum-specific PDE type 5 isozymes, leading also to vascular relaxation and penile erection.
Together, PDEI type 3 drugs promote enhanced cardiac performance by both increasing cardiac inotropy while at the same time reducing afterload by reducing vascular resistance. As such, they are termed “inodilators” in view of their dual mechanism of actions. These make them ideal candidates in treating patients with congestive heart failure, either in the acute or chronic setting. In the acute setting, however, monotherapy with PDEI type 3 drugs may often lead to excessive vasodilation and hypotension without corresponding increases in cardiac output. In acute heart failure, such as that which occurs after cardiac surgery, the primary mechanism for failure may be due to lack of sufficient cAMP generation. Intracellular cAMP levels are too low to receive inhibition. In these instances, dual therapy with both an adrenergic-stimulating agent to generate more cAMP and PDEI drugs that prevent their subsequent breakdown will shift the Frank–Starling relationship to the left for improved cardiac performance. Thus, at normal therapeutic dosing levels, there is greater vascular relaxation and afterload reduction than improvements in inotropy.
In the chronic setting, the pathophysiology of congestive heart failure (CHF) is a bit different. Failure in this instance generates further adrenergic stimulation, which begets myocardial adrenergic desensitization and further adrenergic output, leading to worsening failure and increases in vascular resistance and afterload (hence, the paradoxical benefits of moderate beta-1 blockade in CHF). In these instances, treatment with PDEI type 3 agents will reduce afterload and improve cardiac performance by enhancing myocyte calcium cycling and promoting vascular smooth muscle relaxation, and thus decreasing vascular resistance. This will lead to improvements in left ventricular performance and an increase in the ejection fraction (EF). Decreases in vascular resistance may lead to compensatory increases in heart rate and may limit their usefulness. In addition, long-term treatment with these agents has been associated with decreased survival, and hence, has fallen out of favor as a chronic treatment modality. They remain useful, however, for treating acute episodes of decompensated CHF, in combination with other agents such as diuretics, ACE inhibitors, and beta blockers, as well as digoxin.
In the acute setting of either the operating room or the ICU, milrinone is given as a bolus followed by continuous infusion. Steady-state levels are achieved in 6-12 hours, and the terminal elimination half-life is approximately 2.5 hours. Milrinone is primarily excreted by the kidney, and thus needs to be adjusted in patients with renal impairment. In studies of patients undergoing cardiac surgery, milrinone will reliably reduce systemic vascular resistance, pulmonary capillary wedge pressure, and central venous pressure, all by 15%-40%, which will reduce myocardial wall stress and oxygen consumption, and lead to increases in EF of approximately 30%. The most common side effect may be ventricular arrhythmias, occurring up to 10 or more percent (which, given the setting of heart failure, is quite common).
As mentioned earlier, the type 5 isoform of PDE is found in the corpus cavernosum of the penis and in vascular smooth muscle. This enzyme is responsible for breaking down cGMP that forms in response to increased nitric oxide generated by the endothelium. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation. PDEI type 5 specific agents may have a role in reducing pulmonary vascular resistance as well, in patients with primary pulmonary hypertension and in persistence pulmonary hypertension of the newborn. For patients using PDEI type 5 drugs for erectile dysfunction, concomitant reduction in systemic vascular resistance may result and lead to hypotension, angina, and headaches, especially when taken in combination with other vasodilating medications.