Phosphodiesterase Inhibitors

General Pharmacology of cAMP-Dependent Phosphodiesterase Inhibitors (PDE3)


Intracellular concentrations of cAMP play an important second messenger role in regulating cardiac muscle contraction. Activation of sympathetic adrenergic to the heart releases the neurotransmitter norepinephrine and increases circulating catecholamines (epinephrine and norepinephrine). These catecholamines bind primarily to beta1-adrenoceptors in the heart that are coupled to Gs-proteins. This activates adenylyl cyclase to form cAMP from ATP. Increased cAMP, through its coupling with other intracellular messengers, increases contractility (inotropy), heart rate (chronotropy) and conduction velocity (dromotropy). Cyclic-AMP is broken down by an enzyme called cAMP-dependent phosphodiesterase (PDE). The isoform of this enzyme that is targeted by currently used clinical drugs is the type 3 form (PDE3). Inhibition of this enzyme prevents cAMP breakdown and thereby increases its intracellular concentration. This increases cardiac inotropy, chronotropy and dromotropy. PDE3 inhibitors can be thought of as a backdoor approach to cardiac stimulation, whereas β-agonists go through the front door to produce the same cardiac effects. 

Blood vessels

Cyclic-AMP also plays an important role in regulating the contraction of vascular smooth muscle. Beta2-adrenoceptor agonists such as epinephrine stimulate the Gs-protein and the formation of cAMP . Unlike cardiac muscle, increased cAMP in smooth muscle causes relaxation. The reason for this is that cAMP normally inhibits myosin light chain kinase, the enzyme that is responsible for phosphorylating smooth muscle myosin and causing contraction. Like the heart, the cAMP is broken down by a cAMP-dependent PDE (PDE3).Therefore, inhibition of this enzyme increases intracellular cAMP, which further inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation). 

Other actions

PDE3 inhibitors also decrease platelet aggregation by increasing platelet cAMP. However, only cilostazol (see below) is used for this purpose in the treatment of intermittant claudication (ischemic leg pain associated with leg movement).

General Pharmacology of cGMP-Dependent Phosphodiesterase Inhibitors (PDE5)

There is a second isoenyme form of PDE in vascular smooth muscle that is a cGMP-dependent phosphodiesterase. The type 5 isoform of this enzyme (PDE5) 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 (NO). Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation .
NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.  Therefore, inhibitors cGMP-dependent phosphodiesterase, by increasing intracellular cGMP, enhance smooth muscle relaxation and vasodilation, and cause penile erection. 

Specific Drugs

Several different PDE inhibitors are available for clinical use:  (Go to for specific drug information)
  • PDE3 inhibitors
    • milrinone
    • inamrinone (formerly amrinone)
    • cilostazol
  • PDE5 inhibitors
    • sildenafil
    • tadalafil
The PDE3 inhibitors (except cilostazol) are used for treating acute, decompensated heart failure, whereas the PDE5 inhibitors are used for treating male erectile dysfunction. Note that the PDE3 inhibitors used in acute heart failure end in "one," whereas the PDE5 inhibitors end in "fil".
Inhibition of platelet aggregation, along with vasodilation, is an important mechanism of action for cilostazol, which is used in the treatment of intermittant claudication in peripheral arterial disease. Cilostazol appears to have less cardiostimulatory effects than milrinone.

Side Effects and Contraindications

PDE3 inhibitors

Milrinone and inamrinone are not used in the treatment of chronic heart failure because clinical trials have shown that long-term use of these drugs worsen outcome. The most common and severe side effect of PDE3 inhibitors is ventricular arrhythmias in about 12% of patients, some of which may be life-threatening. Headaches and hypotension occur in about 3% of patients. These side effects are not uncommon for drugs that increase cAMP in cardiac and vascular tissues, other examples being β-agonists.

PDE5 inhibitors

The most common side effects for PDE5 inhibitors include headache and cutaneous flushing, both of which are related to vascular dilation caused by increased vascular cGMP. There is clinical evidence that nitrodilators may interact adversely with PDE5 inhibitors. The reason for this adverse reaction is that nitrodilators stimulate cGMP production while PDE5 inhibitors inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary perfusion.