1. 1. By Dr.Elza Emmannual JR 1 Dpmt. Of Pharmacology Govt. Medical College ,Kottayam PHOSPHODIESTERASE INHIBITORS
2. 2. HISTORY Phosphodiesterases isolated from rat brains by Uzunov and Weiss in 1972 The phosphodiesterase (PDE) story begins with the work of Henry Hyde Salter in 1886. An asthmatic he noted that when he drank a strong cup of coffee on an empty stomach, his breathing eased, an effect attributed to the bronchodilator properties of caffeine.
3. 3. Henry Hyde Salter
4. 4. PHOSPHODIESTERASES Breaks phosphodiester bond in the second messenger molecules cAMP and cGMP c cGMP PDE 5GMP
5. 5. Ca Ca calmodulin complex MLCK MLCK* MLC MLC PO4* Actin Contraction MLC-(PO4)2 cAMP + + + + MLC cGMP+ 5AM PPDE 5GM P Relaxation
6. 6. cAMP cGMP ATP AC GC GTP PDE 5AMP 5GMP
7. 7. PDE enzyme The superfamily of PDE enzymes - 12 families, namely PDE1-PDE12. PDE 4,7,8 selective for cAMP PDE 5,6,9 selective for cGMP Others both
8. 8. Nomenclature Family - Arabic numeral Familys gene - Capital letter splice variant - A second Arabic numeral (e.g., PDE1C3 = family: 1, gene: C, splicing variant: 3).
9. 9. PDE 1 Mainly cytosolic 3 subtypes Sites Brain Smooth muscle heart Lung Drugs Vinpocetine PDE 1 PDE 1A PDE 1B PDE 1C
10. 10. PDE 2 Membrane bound or cytosolic Sites Platelet macrophages endothelial cells heart etc Drug Anagralide PDE 2A PDE 2A1 PDE 2A2 PDA 2A3
11. 11. PDE 3 PDE 3 PDE 3A PDE 3B Membrane bound or cytosolic Sites Heart Vascular smooth muscle Platelets Drugs Inamrinone, Cilastazol
12. 12. PDE 4 Membrane bound or cytosolic Sites smoot h muscl e cardiovasc ular tissues Brain inflammato ry cells Drugs Drotaverin e Roflumilas t Cilomilast. PDE 4 PDE 4A PDE 4B PDE 4D
13. 13. PDE 5 PDE 5 PDE 5A PDE 5B Cytosolic Sites Corpus cavernosum Retina Drugs Sildinafil, Dipyridamol
14. 14. ENZYME SITES PDE 6 Retinal rods & cones PDE 7 B lymphocytes,brain,heart PDE 8 Testes PDE 9 Spleen, small intestine,brain PDE 10 Brain, thyroid, testes PDE 11 Testes, prostate
15. 15. PHOSPHODIESTERASE INHIBITORS
16. 16. Nonselective Xanthine alkaloids Selective PDE 1 Vinpocetine PDE 2 Anagralide PDE 3 Inamrinone,Milrenone,Cilastozol PDE 4Rolipram,Drotaverine PDE 5Sildinafil,Vardinafil,Dipyridamole PDE 6Zaprenast,Dipiridamole PDE 7Quinazoline PDE 10Papaverine PDE inhibitors
17. 17. Nonselective PDE inhibitors Caffeine Theophylline Theobromine Pentoxyfylline
18. 18. Theophylline Uses COPD & asthma ADRNarrow margin of safety, Therapeutic range -8-15mcg/ml ADR Proposed Mechanism Nausea,vomitimg PDE 3 inhibition headache PDE 3 inhibition Gastric discomfort PDE 3 inhibition Diuresis Adenosine antagonism Cardiac Arrhythmia PDE 3 inhibition Seizures Adenosine antagonism
19. 19. PENTOXIFYLLINE Improves microcirculation in ischaemic areas Reduces blood viscosity Rheological effect on RBC. Use Intermittant claudication -PVD Nonhemorrhagic stroke Chronic cerebrovascular insufficiency Trophic leg ulcers Diabetic neuropathy
20. 20. SELECTIVE PDE INHIBITORS
21. 21. VINPOCETINE Semisynthetic derivative of alkaloid vincamine,an extract of periwinkle plant. Enhance plasticity,improves memory Vasodilator & antiinflammatory property. Therapeutic use Parkinsons & Alzheimers PDE 1 INHIBITORS
22. 22. PDE 2 INHIBITORS Anagralide EHNA BAY 60-7550 Oxindole PDP
23. 23. ANAGRALIDE Inhibits maturation of platelets from megakaryocytes Also inhibits PDE 3 & phospholipase A2 USES Essential thrombocytosis ADR Headache, diarrhoea, fatigue, nausea, dizziness, hairloss. Less common side effects MI, CHF, cardiomyopathy
24. 24. Other PDE 2 Inhibitors EHNA-Erythro-9-(2-hydroxy-3-nonyl)adenine anti-viral, anti-tumour and anti-arrhythmic effects BAY 60-7550 is an analog of EHNA. PDP (9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4- dimethoxybenzyl)-purin-6- 5) and Oxindole . No clinical use Used as investigative tool in pharmacological research
25. 25. Inamrinone, milrinone and Enoximone (inodilator) Cardiac stimulantion force of contraction, HR Vasodilatation Use short-term treatment of cardiac failure. Cilostazol Vasodilator & anti aggregatory Use intermittent claudication. Pimobendan - for veterinary use in the treatment of heart failure in animals. PDE 3 INHIBITORS
26. 26. PDE 4 INHIBITORS Drotaverine used to alleviate renal colic pain, hasten cervical dilatation in labor Roflumilast,Cilomilast COPD Ibudilast a neuroprotective and bronchodilator drug used in asthma and stroke. Apremilast psoriasis and psoriatic arthritis Rolipram, Piclamilast investigative tool in pharmacological research
27. 27. Phosphodiesterase-5 inhibitors Sildenafil (Viagra) 50mg, 100mg Tadalafil (Cialis) 5mg, 10mg, 20mg Vardenafil (Levitra) 10mg, 20mg Udenafil (Zydena, DA 8159) 100mg, 200mg Mirodenafil (Mvix, SK3530) 100mg
28. 28. Phosphodiesterase-5 inhibitors Action on 1. Corpus cavernosum (highly selective) 2. Bladder neck 3. Urethra 4. Prostate Tadalafil more potent & longer acting, slow onset
29. 29. ADRs Headache, nasal congestion, flushing, hypotension Disturbance in colour vision due to inhibition of PDE 6 in retina. Ability to potentiate NO use cautiously in patients on nitrates Vardanafil prolongs Q-T interval
30. 30. Uses Erectile dysfunction Pulmonary hypertension. possible benefits BPH Cystic fibrosis Systemic hypertension
31. 31. Future trends in PDE 5 inhibitors Premature ejaculation Female sexual arousal disorder Raynauds phenomenon Stroke
32. 32. DIPYRIDAMOLE MOA Inhibits PDE5 & 6. Also inhibits cellular uptake of adenosine Actions Coronary vasodilator used in the treatment of angina Antiplatelet action Uses Post MI (to prevent coronary thrombosis) Prosthetic valves (+Warfarin) Post stroke (+Aspirin) ADR Coronary steal
33. 33. PDE7 selective inhibitors Quinazoline type PDE7 inhibitor - potent anti- inflammatory and neuroprotective agent. PDE10 selective inhibitors Papaverine, an opium alkaloid PDE10A is almost exclusively expressed in the striatum Use Erectile dysfunction (PIPE therapy)
34. 34. Summary PDE Inhibitors exerts its action by preventing the degradation of second messenger molecules thereby augmenting their effect in various tissues causing smooth muscle relaxation,increased neuronal plasticity,antiplatelet action etc. Many more PDE Inhibitors are yet to come Selective PDE inhibitors are being investigated in a wide range of diseases including the use of PDE2 inhibitors in sepsis; PDE5 inhibitors to treat sexual dysfunction in females, cardiovascular disease and pulmonary hypertension; and PDE4 inhibitors to treat asthma, COPD, allergic rhinitis, psoriasis, multiple sclerosis, depression, Alzheimer's disease and schizophrenia.
35. 35. THANKYOU