phosphodiesterase inhibitors

• 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

Retina6

Skeletal muscle, T cells7

Testis, thyroid8

Broadly expressed, not well characterized9

Brain, testes10

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.

PDE5 Inhibitors

• 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:

• Amrinone

• Cilostazol

• Milrinone

• Enoximone

• Also referred as nonglycoside nonsympathomimetic ionotropic agents.

• Positive ionotropic on heart, vasodilatation of vessels.

• Apremilast

Cilomilast

Ibudilast

Piclamilast

Roflumilast

• 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

to erection.

• PDE-5 inhibitors do not increase the nitric oxide level, but

they potentiate the nitric oxide effect to stimulate

erection.

• Without sexual arousal, these inhibitors are ineffective