The document summarizes phosphodiesterases (PDEs), which are important regulators of signal transduction mediated by the second messengers cAMP and cGMP. There are 11 PDE families with over 50 isoforms that degrade these cyclic nucleotides in different tissues. PDE inhibitors prevent degradation of cAMP and cGMP, classified as non-selective or selective. Selective PDE5 inhibitors like sildenafil are used to treat erectile dysfunction by potentiating the effect of nitric oxide in the penis.

3. • 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

10. MAINTISSUE LOCALIZATIONPDE
Brain, heart, vascular smooth muscle1
Adrenal cortex, brain, heart, corpus cavernosum2
Heart, corpus cavernosum, vascular smooth muscle, platelets, liver pancreas3
Lung, mast cells, vascular smooth muscle4
Corpus cavernosum, lung, vascular smooth muscle, platelets, brain, esophagus5
Retina6
Skeletal muscle,T cells7
Testis, thyroid8
Broadly expressed, not well characterized9
Brain, testes10
Skeletal muscle, prostate, liver, kidney, pituitary, testis11

12. • 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.

13. A) Nonselective phosphodiesterase inhibitors

15. B) Selective phosphodiesterase inhibitors

16. PDE4 selective inhibitors
• Mesembrine, Rolipram, Ibudilast, Piclamilast, Luteolin,
Drotaverine.
PDE5 Inhibitors
• Sildenafil, Tadalafil, Vardenafil (10 times more potent
than sildenafil) Udenafil , Avanafil, Lodenafil

18. Adverse drug reaction Proposed Mechanism
Nausea,Vomitting PDE 3 inhibition
Headache PDE 3 inhibition
Gatric Discomfort PDE 3 inhibition
Diuresis Adenosine antagonism
CardiacArrhythmias PDE 3 inhibition
Seizures Adenosine antagonism

26. Approved PDE3 inhibitors include the following:
• Amrinone
• Cilostazol
• Milrinone
• Enoximone
• Also referred as nonglycoside nonsympathomimetic
ionotropic agents.
• Positive ionotropic on heart, vasodilatation of vessels.

32. • Apremilast
Cilomilast
Ibudilast

33. Piclamilast
Roflumilast

35. • 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).

37. 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
to erection.

38. • PDE-5 inhibitors do not increase the nitric oxide level, but
they potentiate the nitric oxide effect to stimulate
erection.
• Without sexualarousal, these inhibitors are ineffective