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By
Dr.Elza Emmannual
JR 1
Dpmt. Of Pharmacology
Govt. Medical College ,Kottayam
PHOSPHODIESTERASE
INHIBITORS
HISTORY
 Phosphodiesterases isolated from rat brains by
Uzunov and Weiss in 1972
 The phosphodiesterase (PDE) story begi...
Henry Hyde Salter
PHOSPHODIESTERASES
 Breaks phosphodiester bond in the second
messenger molecules cAMP and cGMP
 c
cGMP PDE
5’GMP
Ca
Ca – calmodulin complex
MLCK MLCK*
MLC MLC –PO4*
Actin
Contraction
MLC-(PO4)2
cAMP
+
+
+
+
MLC
cGMP+
5’AM
PPDE
5’GM
P
R...
cAMP
cGMP
ATP
AC
GC
GTP
PDE
5’AMP
5’GMP
PDE enzyme
 The superfamily of PDE enzymes - 12 families,
namely PDE1-PDE12.
 PDE 4,7,8  selective for cAMP
 PDE 5,6,9...
Nomenclature
 Family - Arabic numeral
 Family’s gene - Capital letter
 splice variant - A second Arabic numeral (e.g.,
...
PDE 1
 Mainly cytosolic
 3 subtypes
 Sites
Brain
 Smooth muscle
 heart
 Lung
 Drugs
 Vinpocetine
PDE 1
PDE 1A PDE...
PDE 2
 Membrane bound or cytosolic
 Sites
 Platelet
 macrophages
 endothelial cells
 heart etc
 Drug
 Anagralide
P...
PDE 3
PDE 3
PDE 3A PDE 3B
 Membrane bound or
cytosolic
 Sites
Heart
Vascular smooth
muscle
 Platelets
 Drugs
 Inamr...
PDE 4
•Membrane
bound or
cytosolic
• Sites
• smoot
h
muscl
e
• cardiovasc
ular tissues
• Brain
• inflammato
ry cells
•Drug...
PDE 5
PDE 5
PDE 5A PDE 5B
 Cytosolic
 Sites
Corpus
cavernosum
 Retina
 Drugs
 Sildinafil,
Dipyridamol
ENZYME SITES
PDE 6 Retinal rods & cones
PDE 7 B lymphocytes,brain,heart
PDE 8 Testes
PDE 9 Spleen, small intestine,brain
P...
PHOSPHODIESTERASE
INHIBITORS
 Nonselective
 Xanthine alkaloids
 Selective
 PDE 1  Vinpocetine
 PDE 2  Anagralide
 PDE 3 Inamrinone,Milrenone,C...
Nonselective PDE inhibitors
•Caffeine
•Theophylline
•Theobromine
•Pentoxyfylline
Theophylline
 Uses  COPD & asthma
 ADRNarrow margin of safety, Therapeutic
range -8-15mcg/ml
ADR Proposed Mechanism
Na...
PENTOXIFYLLINE
 Improves microcirculation in ischaemic areas
 Reduces blood viscosity
 Rheological effect on RBC.
 Use...
SELECTIVE PDE INHIBITORS
VINPOCETINE
 Semisynthetic derivative of alkaloid vincamine,an
extract of periwinkle plant.
 Enhance plasticity,improves...
PDE 2 INHIBITORS
 Anagralide
 EHNA
 BAY 60-7550
 Oxindole
 PDP
ANAGRALIDE
 Inhibits maturation of platelets from
megakaryocytes
 Also inhibits PDE 3 & phospholipase A2
 USES
 Essent...
Other PDE 2 Inhibitors
 EHNA-Erythro-9-(2-hydroxy-3-nonyl)adenine
 anti-viral, anti-tumour and anti-arrhythmic effects
...
 Inamrinone, milrinone and Enoximone
(inodilator)
 Cardiac stimulantion
 ↑ force of contraction, ↑HR
 Vasodilatation
...
PDE 4 INHIBITORS
 Drotaverine
 used to alleviate renal colic pain, hasten cervical
dilatation in labor
 Roflumilast,Cil...
Phosphodiesterase-5 inhibitors
Sildenafil (Viagra) 50mg, 100mg
Tadalafil (Cialis) 5mg, 10mg, 20mg
Vardenafil (Levitra) 10m...
Phosphodiesterase-5 inhibitors
Action on
1. Corpus cavernosum (highly selective)
2. Bladder neck
3. Urethra
4. Prostate
Ta...
ADRs
 Headache, nasal congestion, flushing,
hypotension
 Disturbance in colour vision due to inhibition of
PDE 6 in reti...
Uses
 Erectile dysfunction
 Pulmonary hypertension.
 possible benefits
 BPH
 Cystic fibrosis
 Systemic hypertension
Future trends in PDE 5 inhibitors
 Premature ejaculation
 Female sexual arousal disorder
 Raynauds phenomenon
 Stroke
DIPYRIDAMOLE
 MOA
 Inhibits PDE5 & 6.
 Also inhibits cellular uptake of adenosine
 Actions
 Coronary vasodilator used...
PDE7 selective inhibitors
 Quinazoline type PDE7 inhibitor - potent anti-
inflammatory and neuroprotective agent.
PDE10 s...
Summary
 PDE Inhibitors exerts its action by preventing the
degradation of second messenger molecules thereby
augmenting ...
THANKYOU
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Phosphodiesterase inhibitors

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Phosphodiesterase inhibitors

  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 5’GMP
  5. 5. Ca Ca – calmodulin complex MLCK MLCK* MLC MLC –PO4* Actin Contraction MLC-(PO4)2 cAMP + + + + MLC cGMP+ 5’AM PPDE 5’GM P Relaxation
  6. 6. cAMP cGMP ATP AC GC GTP PDE 5’AMP 5’GMP
  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  Family’s 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 4Rolipram,Drotaverine  PDE 5Sildinafil,Vardinafil,Dipyridamole  PDE 6Zaprenast,Dipiridamole  PDE 7Quinazoline  PDE 10Papaverine PDE inhibitors
  17. 17. Nonselective PDE inhibitors •Caffeine •Theophylline •Theobromine •Pentoxyfylline
  18. 18. Theophylline  Uses  COPD & asthma  ADRNarrow 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 – Parkinson’s & Alzheimer’s 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

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