Phosphodiesterase inhibitors
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A description of various phosphodiesterase inhibitors and their pharmacology.
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Phosphodiesterase inhibitors
- 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.
- 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