1. By
Dr.Elza Emmannual
JR 1
Dpmt. Of Pharmacology
Govt. Medical College ,Kottayam
PHOSPHODIESTERASE
INHIBITORS

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. Henry Hyde Salter

4. PHOSPHODIESTERASES
 Breaks phosphodiester bond in the second
messenger molecules cAMP and cGMP
 c
cGMP PDE
5’GMP

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. cAMP
cGMP
ATP
AC
GC
GTP
PDE
5’AMP
5’GMP

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. 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. PDE 1
 Mainly cytosolic
 3 subtypes
 Sites
Brain
 Smooth muscle
 heart
 Lung
 Drugs
 Vinpocetine
PDE 1
PDE 1A PDE 1B PDE 1C

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. PDE 3
PDE 3
PDE 3A PDE 3B
 Membrane bound or
cytosolic
 Sites
Heart
Vascular smooth
muscle
 Platelets
 Drugs
 Inamrinone, Cilastazol

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. PDE 5
PDE 5
PDE 5A PDE 5B
 Cytosolic
 Sites
Corpus
cavernosum
 Retina
 Drugs
 Sildinafil,
Dipyridamol

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. PHOSPHODIESTERASE
INHIBITORS

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. Nonselective PDE inhibitors
•Caffeine
•Theophylline
•Theobromine
•Pentoxyfylline

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. 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. SELECTIVE PDE INHIBITORS

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. PDE 2 INHIBITORS
 Anagralide
 EHNA
 BAY 60-7550
 Oxindole
 PDP

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. 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.  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. 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. 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. 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. 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. Uses
 Erectile dysfunction
 Pulmonary hypertension.
 possible benefits
 BPH
 Cystic fibrosis
 Systemic hypertension

31. Future trends in PDE 5 inhibitors
 Premature ejaculation
 Female sexual arousal disorder
 Raynauds phenomenon
 Stroke

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. 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. 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. THANKYOU