Health & Medicine
• The cyclic nucleotide phosphodiesterases degrade the phosphodiester bond in the second messenger cAMP and cGMP.
• PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules.
• When referring to phosphodiesterases we usually refers to cyclic nucleotide phosphodiesterases which have great clinical implications.
• PDE family: 11 isoenzymes families (PDE 1-PDE 11) with over 50 isoforms
MAIN TISSUE LOCALIZATIONPDE
Brain, heart, vascular smooth muscle1
Adrenal cortex, brain, heart, corpus cavernosum2
Heart, corpus cavernosum, vascular smooth muscle, platelets, liver pancreas 3
Lung, mast cells, vascular smooth muscle4
Corpus cavernosum, lung, vascular smooth muscle, platelets, brain, esophagus5
Skeletal muscle, T cells7
Broadly expressed, not well characterized9
Skeletal muscle, prostate, liver, kidney, pituitary, testis11
• Drugs that block subtypes of the enzyme phosphodiesterase (PDE).
• Therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s).
• They are classified into non-selective PDE inhibitors and selective PDE.
A) Nonselective phosphodiesterase inhibitors
B) Selective phosphodiesterase inhibitors
PDE4 selective inhibitors
• Mesembrine, Rolipram, Ibudilast, Piclamilast, Luteolin, Drotaverine.
• Sildenafil, Tadalafil, Vardenafil (10 times more potent than sildenafil) Udenafil , Avanafil, Lodenafil
Adverse drug reaction Proposed Mechanism
Nausea, Vomitting PDE 3 inhibition
Headache PDE 3 inhibition
Gatric Discomfort PDE 3 inhibition
Diuresis Adenosine antagonism
Cardiac Arrhythmias PDE 3 inhibition
Seizures Adenosine antagonism
Approved PDE3 inhibitors include the following:
• Also referred as nonglycoside nonsympathomimetic ionotropic agents.
• Positive ionotropic on heart, vasodilatation of vessels.
• PDE5 has only one subtype, PDE5A, of which there are 4 isoforms in humans called PDE5A1-4.
• PDE5 enzyme is specific for cGMP which means it only hydrolyzes cGMP but not cAMP, the selectivity is mediated through network of hydrogen bonding which is favorable for cGMP but unfavorable for cAMP in PDE5.
• PDE5 is responsible for the degradation of cGMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis, which leads to erectile dysfunction (ED).
Cyclic GMP in turn activates a
specific protein kinase which
results in the opening of the
potassium channels and
hyperpolarization and causes
sequestration of intracellular
calcium and blocks calcium
influx. As a result of this drop in
cytosolic calcium, smooth
muscle relaxation occurs leading
• PDE-5 inhibitors do not increase the nitric oxide level, but
they potentiate the nitric oxide effect to stimulate
• Without sexual arousal, these inhibitors are ineffective