Phosphodiesterase (PDE) enzymes break down cyclic nucleotides like cAMP and cGMP. There are many families of PDEs that regulate these second messenger molecules in different tissues. PDE inhibitors prevent the inactivation of cAMP and cGMP, prolonging their cell signaling effects. Some PDE inhibitors are used to treat conditions like pulmonary hypertension and erectile dysfunction by increasing cyclic nucleotide levels. The document then provides examples of specific PDE inhibitors and their therapeutic applications.

1. Bhagya Siripalli,
Department of pharmacology, SVIPS

2.  A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester
bond. Usually, phosphodiesterase refers to cyclic
nucleotide phosphodiesterases.
 However, there are many other families of phosphodiesterases,
including phospholipases C and D, autotaxin, sphingomyelin
phosphodiesterase, DNases, RNases, and restriction endonucleases (which
all break the phosphodiester backbone of DNA or RNA), as well as
numerous less-well-characterized small-molecule phosphodiesterases.
 The cyclic nucleotide phosphodiesterases comprise a group of enzymes that
degrade the phosphodiester bond in the second
messenger molecules cAMP and cGMP.
 They regulate the localization, duration, and amplitude of cyclic nucleotide
signaling within subcellular domains.
 PDEs are therefore important regulators of signal transduction mediated by
these second messenger molecules.

9. PDE MAINTISSUE LOCALIZATION
1 Brain,heart, vascular smooth muscle
2 Adrenal cortex,brain, heart, corpus cavernosum
3 Heart, corpus cavernosum, vascular smooth muscle, platelets, liver pancreas
4 Lung, mast cells,vascular smooth muscle
5 Corpus cavernosum, lung, vascular smooth muscle,platelets, brain, esophagus
6 Retina
7 Skeletalmuscle,T cells
8 Testis,thyroid
9 Broadly expressed,not wellcharacterized
10 Brain,testes
11 Skeletalmuscle, prostate, liver,kidney,pituitary,testis

11. • 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 PDEsubtype(s).
• They are classified into non-selective PDE inhibitors and
selective PDE.

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

16.  PDE inhibitors have been identified as new potential therapeutics in areas
such as pulmonary arterial hypertension, coronary heart
disease, dementia, depression, asthma, COPD, protozoal infections
(including malaria) and schizophrenia.
 PDE also are important in seizure incidence. For example, PDE
compromised the antiepileptic activity of adenosine. In addition, using of a
PDE inhibitor (pentoxifylline) in pentylenetetrazole-induced seizure
indicated the antiepileptic effect by increasing the time latency to seizure
incidence and decreasing the seizure duration in vivo.
 Cilostazol (Pletal) inhibits PDE3. This inhibition allows red blood cells to
be more able to bend. This is useful in conditions such as intermittent
claudication, as the cells can maneuver through constricted veins and
arteries more easily.

17.  Dipyridamole inhibits PDE-3 and PDE-5. This leads to intraplatelet
accumulation of cAMP and/or cGMP, inhibiting platelet aggregation.
 Zaprinast inhibits the growth of asexual blood-stage malaria parasites (P.
falciparum) in vitro with an ED50 value of 35 μM, and inhibits PfPDE1, a P.
falciparum cGMP-specific phosphodiesterase, with an IC50 value of 3.8
μM.
 Xanthines such as caffeine and theobromine are cAMP-phosphodiesterase
inhibitors. However, the inhibitory effect of xanthines on
phosphodiesterases are only seen at dosages higher than what people
normally consume.
 Sildenafil, Tadalafil and Vardenafil are PDE-5 inhibitors and are widely
used in the treatment of erectile dysfunction.

21.  Phosphodiesterase enzymes have been shown to be different in different
types of cells, including normal and leukemic lymphocytes and are often
targets for pharmacological inhibition due to their unique tissue distribution,
structural properties, and functional properties.
 Inhibitors of PDE can prolong or enhance the effects of physiological
processes mediated by cAMP or cGMP by inhibition of their degradation by
PDE.
 Sildenafil (Viagra) is an inhibitor of cGMP-specific phosphodiesterase type
5, which enhances the vasodilatory effects of cGMP in the corpus
cavernosum and is used to treat erectile dysfunction. Sildenafil is also
currently being investigated for its myo- and cardioprotective effects, with
particular interest being given to the compound's therapeutic value in the
treatment of Duchenne muscular dystrophy and benign prostatic
hyperplasia.
 Paraxanthine, the main metabolite of caffeine, is another cGMP-specific
phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring
phosphodiesterase. PDE9 is expressed as high as PDE5 in the corpus
cavernosum.