Phosphodiesterase inhibitors work by preventing the breakdown of cyclic nucleotides like cAMP and cGMP. There are 12 families of PDE enzymes that are involved in breaking down these second messenger molecules. Selective PDE inhibitors have been developed that target specific PDE families for conditions like erectile dysfunction, pulmonary hypertension, heart failure, and asthma. Future research is exploring more selective PDE inhibitors for diseases including sepsis, female sexual dysfunction, cardiovascular issues, and neurological disorders.

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