PHOSPHODIESTERASE INHIBITORS IN THERAPEUTICS

ROAD MAP

Introduction

Classification and distribution of enzymes Phosphodiesterase inhibitors in therapeutics

Recent advances

Summary

INTRODUCTION

Phosphodiesterase (PDE) enzyme that breaks phosphodiester bond.

Cyclic nucleotide PDE cleaves the bond in 2nd messenger molecules cAMP and cGMP.

Important regulators of signal transduction mediated by 2nd messenger molecules.

CLASSIFICATION

There are 12 subtypes of PDE. Based on:

Amino acid sequence Substrate specificity Regulatory properties Tissue distribution Pharmacological properties

PDE 1 Also called Ca2+ or calmodulin dependent PDE; calmodulin activates

it in a Ca2+ dependent manner; is affected by phosphorylation of isoenzymes.

3 isoenzymes- PDE1A, PDE1B, PDE1C Degrade both cAMP & cGMP(PDE1A & 1B cGMP; PDE1C both). Functions as a mechanism for integrating cell pathways (mediated

by cAMP & cGMP) with those that regulate intracellular Ca2+ channels.

Isoform Localization

PDE1A Smooth muscle, heart, lung, brain, sperm

PDE1B Neurons, lymphocytes, smooth & skeletal muscle, brain, heart,

PDE1C Brain, heart, testes, olfactory epithelium

PDE 2

Hydrolyses both cGMP and cAMP.

Thought to be involved in different intracellular processes such as (i) Aldosterone secretion from adrenal gland

(ii)Long term memory etc.

Indicated in inflammatory responses in microvessels but not larger vessels.

One isoenzyme- PDE2A.

PDE 3 Clinically significant regulates heart muscle and platelet

aggregation. More affinity for cAMP than cGMP. 2 isoforms PDE3A & PDE3B; regulated by phosphorylation

via protein kinases A & B PDE3B mediates antilipolytic and antiglycogenolytic effect

of insulin on adipose and liver tissues. Activation of PDE3B ’d concentration of cAMP ’d

protein kinase A lipolysis.

Isoform Localization

PDE3A (membrane associated/ cytosolic)

Heart, smooth muscle, oocyte, platelets, kidney

PDE3B(membrane associated)

Vascular smooth muscle, adipocytes, hepatocytes, kidney , β cells.

PDE 4 Role in host defence targeted in treatment of inflammation. Inhibition immunosuppression (due to role in inhibiting

infiltration of neutrophils into airway)

PDE 5

Accepts cGMP & breaks it down. Chemical reduction relieves auto inhibition of enzyme function

in allosteric cGMP binding & catalytic activities. Expressed in human colonic cells & in intestinal tissues. Also found in human corpus carvernosum smooth muscles & in

platelets, visceral and vascular smooth muscle and skeletal muscle.

PDE 6 Expressed in the retinal rod cells; important role in regulation of

rod cell membrane current . In dark adapted human eye, steady state membrane potential of

rods -30mV

Maintained due to partially opened state of ligand gated Na+ channel

Ligand cGMP; binds to channel (concentration dependent)

Active rhodopsin + transducin conformational change

exchange of GDP for GTP

PDE6 hydrolyses cGMP to 5’-GMP ’d cGMP & ’d no. of open channels & more hyperpolarization.

PDE 7 Insensitive to agents that inhibited other PDE’s. Isolated in T-cells role in immunity.

PDE 8 Target for chemotaxis of activated lymphocytes. In CNS cortex, striatum & hippocampus

PHOSPHODIESTERASE INHIBITORS IN THERAPEUTICS

NON SELECTIVE INHIBITORS

Papaverine: Opium alkaloid; devoid of narcotic

properties. Pharmacokinetics: High protein binding

(90%) and bioavailability (80%); metabolised in liver, excreted in urine.

Given orally, rectally, i.m. and i.v. Side effects: Polymorphic ventricular

tachycardia, constipation. Uses:(i) Erectile dysfunction (ii) Spasms of GIT, bile duct &

ureter.

NON SELECTIVE INHIBITORS

Theophylline: Methylxanthine related to caffeine and theobromine.

Effectively relaxes airway smooth muscle by inhibiting PDE

Additional mechanisms blockade of adenosine receptor mediated bronchoconstriction AND inhibition of synthesis & release of inflammatory mediators from mast cells, basophils etc.

THEOPHYLLINE…

Pharmacokinetics: -Readily absorbed orally/ parenterally. -Absorption is slowed by presence of food. -Widely distributed; crosses placenta and into breast milk.

-Plasma protein binding ’s in newborns & adults with hepatic cirrhosis.

-Marked inter individual variation in daily dosing. -Therapeutic ranges 1st order kinetics. Higher concentrations 0 order kinetics

THEOPHYLLINE…

Other pharmacological actions: CNS- Stimulation; dose dependent CVS- Direct stimulation; ’d force of contraction and cardiac

output; constriction of cranial vessels and dilatation of systemic blood vessels.

Kidney-Mild diuretic action Skeletal muscles- Contraction Stomach- ’d gastric secretion.

THEOPHYLLINE..

Uses:Asthma and COPD bronchodilator. Nocturnal asthma is relieved by

theophylline slow release preparations.

Apnoea of pre-term infants Oral/ i.v. theophylline; 4-8 g/ml.

Pentoxyfilline lower extremity claudication. Adverse effects: Dose dependent - Rapid i.v. aminophylline cardiac arrhythmias -Headache, dizziness, palpitation, nausea, hypotension. -Seizures above 40g/ml; treatment diazepam (prophylactic)

DIPYRIDAMOLE

Vasodilator, inhibits platelet function by inhibiting adenosine uptake & cGMP PDE activity.

Has no beneficial effect alone combination with aspirin to prevent cerebrovascular ischaemia.

Also in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves.

Adverse effects: -Nausea & abdominal discomfort

-Headache, -Myocardial ischaemia & angina in patients having CAD.

PDE 1 SELECTIVE INHIBITORS

Vinpocetine: Semi synthetic alkaloid derivative of

vincamine- extract from periwinkle plant.

’s cGMP levels vasorelaxant effect on cerebral smooth muscles

Said to have neuroprotective effects due to additional mechanisms

Side effects indigestion, nausea, insomnia; agranulocytosis.

Supplement for vasodilatation; nootropic for improvement of memory

Safety in pregnancy is to be evaluated.

PDE 2 SELECTIVE INHIBITORS

Anagrelide: ’s cGMP levels Additional action on megakaryocytes essential

thrombocytosis. Side effects headache, dizziness, diarrhoea. Not first line in thrombocytosis.

EHNA: Erythro-9(2-hydroxy-3-nonyl) adenine

PDE 3 SELECTIVE INHIBITORS

Inamrinone/ amrinone and milrinone: Chemically, bipyridine derivatives. Directly stimulate myocardial contractility Balanced arterial & venous dilatation ’d systemic & pulmonary

vascular resistance. ’d myocardial contractility in cardiac output. This in addition

to in ventricular afterload greater in cardiac output with milrinone than nitroprusside.

Used in CHF. Adverse effect agranulocytosis (only inamrinone), marked hypotension

PDE 3 SELECTIVE INHIBITORS

Cilostazol: Promotes accumulation of intracellular cAMP especially in

platelets ’d platelet aggregation and vasodilatation.

Improves symptoms of claudication.

PDE 4 SELECTIVE INHIBITORSRolipram: Anti inflammatory drug being researched as a possible

alternative for current antidepressants May improve long term memory, wakefulness & afford

neuroprotection.

Roflumilast: Long acting. Has anti inflammatory effects & has potential in asthma,

COPD & emphysema. Effective during clinical trials; dose limiting side effects

nausea, diarrhoea, headache.

PDE 4 SELECTIVE INHIBITORS

Ibudilast: Inhibits PDE 4 to the greatest extent. Anti inflammatory; additional bronchodilator effect; inhibits

platelet aggregation Crosses blood brain barrier & suppresses glial activation

neuropathic pain. Main use asthma.

Luteolin: Flavonoid; possible role as an anti inflammatory agent.

Mesembrine: Alkaloid present in Sceletium tortuosum.

PDE 5 SELECTIVE INHIBITORS

Sildenafil: Highly selective Pharmacokinetics: -Well absorbed orally; reaches

peak in blood in 30-120min. -t ½ = 4hrs. -Food may delay onset/ offset of

effect. -Metabolised in kidney; excreted

by liver and kidney.

SILDENAFIL

Adverse effects: -Short lived and dose related. - Headache, flushing, nasal congestion,

dyspepsia. - High doses inhibits PDE 6 transient

colour vision disturbances. Contraindications: - Nitrates. - Men for whom sexual intercourse is

inadvisable. - Hypotension; severe hepatic/ renal impairment

SILDENAFIL Uses: Erectile dysfunction: -Inability to achieve/ maintain penile erection sufficient enough

to permit satisfactory sexual intercourse.

-Release of neurotransmitters from endothelial cells of penis smooth muscle relaxation (arteries, arterioles, trabeculae of erectile tissue)

- ’d blood flow & rapid filling of sinusoids and corpora cavernosum compression of venous plexus draining almost total cessation of venous outflow leading to erection of penis.

SILDENAFIL- Neurotransmitter involved is nitric oxide (NO)

SILDENAFIL Pulmonary hypertension: Sildenafil relaxes arterial wall ’d pulmonary arterial resistance & pressure ’d workload of right ventricle of heart Improves symptoms of right sided heart failure

Sildenafil selectively causes vasodilatation in heart and penis (location of PDE 5) without causing it in other areas of the body.

TADALAFIL

Mechanism of action similar to that of sildenafil; but has

longer duration of action.

Found to be associated with vision impairment related to Non-arteritic anterior ischaemic optic neuropathy (NAION); most patients had underlying anatomic or vascular risk factors.

Recently studied for it’s effect on pulmonary hypertension.

VARDENAFIL

Closely related in function & mechanism to sildenafil &

tadalafil. Indicated for erectile dysfunction Specific side effect nausea; heart attack possible,

but rare

Udenafil and Avanafil newer agents developed for erectile dysfunction

PDE 6 INHIBITORS

Most PDE 5 selective inhibitors also inhibit PDE6 at concentrations other than their therapeutic concentrations.

Vardenafil is more potent.

Zaprinast only drug that inhibits PDE 6 more potently

Found to augment central immune/ inflammatory reactions possibly via production of TNF and IL1 by activated microglial cells.

RECENT ADVANCES

PDE 7 targeted for it’s role in neurological & inflammatory disorders. Inhibitors are being studied in T-cell related diseases, airway diseases and even CNS disorders.

In a study conducted at the University of Connecticut Health Centre, Connecticut, USA, PDE 8 was investigated and it was found that inhibition of this enzyme inhibited chemotaxis of activated lymphocytes inflammation

RECENT ADVANCES

Studies on PDE 9 activity carried out at the Eleibiniz Institute Of Neurobiology, Germany showed a novel PDE 9 inhibitor BAY 73-6691 improves learning and memory in rodents.

Inhibition treating memory deficits associated with ageing & neurodegenerative disorders.

PDE10 inhibitors preclinical trials as a new approach for treatment of schizophrenia

RECENT ADVANCES

PDE12 negative regulator of antiviral and antitumour functions induced by interferons. Suppression in viral replication.

PDE role in gastric motility; related to soluble guanylyl cyclase which is principal target of NO

SUMMARY

REFERENCES

Goodman and Gilman’s The Pharmacological Basis of Therapeutics-Laurence. L. Brunton, John. S. Lazo, Keith. L. Parker; 11th edition.

Braunwald’s Heart Disease, A Textbook of Cardiovascular medicine; 8th edition; 604-05

Basic and Clinical Pharmacology; Betram G Katzung; 10th edition; 556-57

Textbook of Biochemistry With Clinical Correlations; Thomas M Devlin; 4th edition, 942-44

Pentoxyfillne, Dipyridamole; Cardiovascular Drug therapy; Messerli; 2nd edition; 1604-05, 1451-53

Essentials of Medical Pharmacology-K.D Tripathi; 6th edition.

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