General Pharmacology of cAMP-Dependent Phosphodiesterase Inhibitors (PDE3)
Heart
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
www.rxlist.com 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.
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