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 5GMP
5. Ca Ca calmodulin complex MLCK MLCK* MLC MLC PO4* Actin
Contraction MLC-(PO4)2 cAMP + + + + MLC cGMP+ 5AM PPDE 5GM P
Relaxation
6. cAMP cGMP ATP AC GC GTP PDE 5AMP 5GMP
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 Familys gene - Capital
letter splice variant - A second Arabic numeral (e.g., PDE1C3 =
family: 1, gene: C, splicing variant: 3).
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
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 Parkinsons & Alzheimers 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
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
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.