Phosphodiesterase Type III Inhibitors

Introduction and Physicochemical Properties

• Milrinone and amrinone are bipyridines, a subclass of pyridones.¹
• Dipyridamole is a tertiary amine member of the piperidine family.²
• Cilostazol is a quinolone derivative.³
• Milrinone is available as an intravenous and inhaled formulation; amrinone is available only as an intravenous formulation; cilostazol is an oral tablet; and dipyridamole is available in both oral and intravenous formulations.
• PDE3 inhibitors are chemically distinct from catecholamines.

Mechanism of Action

• Inhibition of PDE3 results in decreased degradation of cAMP into its inactive form, AMP.⁴
• Milrinone blocks PDE3 in vascular smooth muscle and cardiac myocytes, leading to vasodilation, increased inotropy, and increased lusitropy (Figure 1).
• Cilostazol inhibits PDE3 in platelets, vascular smooth muscle, and adipose tissue, resulting in platelet inhibition and vasodilation.⁵
• Dipyridamole increased intracellular cGMP and cAMP levels, resulting in reversible platelet inhibition.⁶

• Milrinone is available only in intravenous or inhaled formulations due to poor oral bioavailability.
• Pharmacokinetics for dipyridamole have been described for the oral route of administration.
• Cilostazol is only available as an oral formulation.

Metabolism and Elimination

• All PDE3 inhibitors are hepatically metabolized.
• Milrinone’s elimination half-life is significantly influenced by creatinine clearance.
• Milrinone’s duration of action can be significantly increased in the setting of impaired renal clearance.

Systemic Effects

Cardiovascular

• PDE3 inhibition in the myocardium results in increased inotropy, improved lusitropy, and increased cardiac output.¹⁰
• Milrinone is a non-selective venous and arterial vasodilator.
• Milrinone does not increase myocardial oxygen demand in patients with a history of heart failure.
• Dipyridamole can result in coronary vasodilation by increasing adenosine levels through inhibition of its cellular reuptake and adenosine deaminase-mediated breakdown.⁹

Pulmonary

• Inhaled milrinone can directly cause pulmonary vasodilation, decreasing pulmonary vascular resistance (PVR) and potentially improving (right ventricular) RV function.

Hematologic

• Both cilostazol and dipyridamole inhibit platelet aggregation.

Clinical Uses

• Common PDE 3inhibitors used in clinical practice include cilostazol, milrinone, amrinone, and dipyridamole.

Peripheral Arterial Disease⁵

• Cilostazol has been shown to improve the quality of life in patients with ischemic rest pain.
• Cilostazol may also reduce the risk of arterial re-stenosis after a surgical intervention.

Postoperative Thromboembolic Prophylaxis

• Dipyridamole is FDA-approved only for adjunctive anticoagulation in patients with mechanical cardiac valves and for thallium nuclear stress testing.
• It is commonly combined with aspirin for postoperative thromboembolic prophylaxis or for patients with cerebrovascular disease, although these uses are off-label.

Heart Failure¹⁰

• There is strong evidence that supports the use of milrinone to enhance inotropy in acute decompensated heart failure.
• Milrinone has become a common option for long-term outpatient inotropic therapy.
• Milrinone is beneficial for treating right ventricular failure by decreasing PVR and improving contractility; however, it must be used cautiously due to the risk of hypotension.

Cardiac Surgery

• Milrinone can serve as a bridge to orthotopic heart transplantation or to evaluate pulmonary vascular reactivity in transplant candidates, aiding in determining the need for right ventricular support after graft implantation.
• It may reduce the risk of vasospasm in coronary artery bypass grafts.
• It can be used in valvular surgery for patients with pre-existing pulmonary hypertension.
• It can be useful in improving inotropy, improving diastolic filling, and reducing PVR in patients undergoing pulmonary thromboendarterectomy.
• Milrinone is commonly combined with a vasopressor to maintain adequate coronary perfusion pressure.

Guidelines for Regional Anesthesia¹¹

• Cilostazol should be held for 2 days before neuraxial or deep plexus blocks.
• Dipyridamole should be held for 1 day before neuraxial or deep plexus blocks.
• Both drugs can be given postoperatively 6 hours after removal of a neuraxial and/or deep plexus block catheter.

Side Effects^5,6,10

• Hypersensitivity reactions can occur with any PDE3 inhibitor.
• The side effects of commonly used PDE3 inhibitors are summarized in Table 2.