PHOSPHODIESTERASES AS DRUG TARGETS

K. Upendra Reddy 2010H146037H

Phosphodiesterases are the large group of enzymes with diverse expression patterns, cellular localizations, substrate specificities and modes of regulation.

Play a major role in cell signaling and function by regulating levels of secondary messengers cAMP and cGMP.

PDE 5 Inhibitors• Three drugs are currently approved:– Sildenafil (Viagra)

Doses: 25mg, 50mg, 100mg Most patients start at 50mg and it can be taken anytime from 1/2 to 4

hours before sexual activity Max frequency is once per day Maybe best to take it on an empty stomach

– Vardenafil (Levitra)Doses: 2.5mg, 5mg, 10mg, and 20mg

Most patients start at 10mg taken ~60minutes before sexual activity High fat meals can reduce the plasma concentration by 18-50% (on an

empty stomach is not a bad idea)

– Tadalafil (Cialis)Doses: 5mg, 10mg, 20mg

Most patients start on 10mg and it can be taken without regard to food Maximum dosing frequency is once per day

Mechanism of Action

• They inhibit phosphodiesterase V, which is responsible for the breakdown of cGMP– cGMP relaxes the smooth muscle and increases blood flow

to the corpus cavernosum.

• Note: These drugs do not cause a chemical erection. Sexual stimulation is still needed to cause the initial release of nitric oxide, which stimulates the synthesis of cGMP.

The figure below shows the mechanism of action of Viagra, and the other PDE5 inhibitors, on the nitric oxide cycle.

Side Effects

• Sildenafil:– Headache and flushing– Dyspepsia– Nasal congestion– Abnormal vision (blue halo around lights)

Side Effects• Vardenafil:– Headache and flushing– Rhinitis– Dyspepsia

• Tadalafil:– Headache and flushing– Dyspepsia– Nasal congestion– Back pain--unique to Cialis– Myalgia

Drug-Drug Interactions for the PDE 5 Inhibitors

Contraindications for PDE 5 Therapy

• Nitrates:– Patients using nitrates regularly or intermittently

should not use any of the PDE-5 Inhibitors.• Applies for any form of nitrates (sublingual,

transdermal, etc)• Patients can get extreme hypotension

• Hypersensitivity to any of the components of the tablet.

Use with Caution:

• Alpha-Blockers:– In the past these drugs were contraindications,

but recent evidence suggests that they can be used together

– Patients should be stabilized on either the alpha-blocker or the PDE-5 inhibitor first before the other is added on at the lowest possible dose.

Sildenafil:

• Drug-Drug Interactions:– Amiodarone– Amlopdipine– Aspirin– Atazanavir– Bosentan– Cimetidine– Ciprofloxacin– Clarithromycin– Darunavir/ritonavir

– Delavirdine– Erythromycin– Fluvoxamine– Grapefruit juice– Indinavir– Nelfinavir– Ritonavir (initially)– S-warfarin– Saquinavir– Saquinavir/ritonavir– tacrolimus

Tadalafil :

• Drug-Drug Interactions:– Amlodipine– Aspirin– Atazanavir– Bendrofluazide– Darunavir/ritonavir– Doxazosin– Enalapril– Ethanol-acute

– Ketoconazole– Lovastatin– Midazolam– Rifampin– S-warfarin– Tamsulosin– Theophylline

Treatment of CHF:

• PDE-III inhibitors are useful for the treatment of CHF.

• Increases the myocardial cAMP and transmembrane influx of calcium.

• Decreases the peripheral vascular resistance.

• Example: Amrinone Milrinone

Anti inflammatory & CNS applications:

PDE enzymes are present in variety of inflammatory cells including eosinophils, neutrophils, macrophages and fibroblast.

Due to the broad immuno modulatory action, it has been proposed that efficacious for skin disorders such as dermatitis & psoriasis.

Highly selective PDE4 inhibitors are currently under evaluation for the asthma & Chronic Obstructive Pulmonary Disease.

Ex : ROLIPRAM,ROFLUMILAST(advanced inhibitors phase –III stage)

Problems associated while drug targeting:

It is important to pay attention to PDE selectivity in order to minimize the potential side effects associated with inhibition of other enzymes.

Visual disturbances are associated with inhibition of PDE 6

Nausea ,emesis, gastric acid production associated with PDE4

Cardiac arrhythmia associated with inhibition of PDE3

CONCLUSION

For PDE drug development target selectivity is critical to avoid side effects, resulting from the inhibition of other PDEs.

Effective assays for identification ,characterization of compounds modulating specific PDE activities are crucial components of drug discovery efforts in most therapeutic areas.

References:

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Kalsi JS, Kell PD. Update on the oral treatments for male erectile dysfunction. Eur Acad Dermatol Venereol 2004;18:267–74.

Conti, M., and Jin, S.-L. C. (1999) The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol.63, 1-38

J Nandhakumar, et al., Characterization of the Effects of Phosphodiesterases (PDEs) Isozyme Inhibitors in Animal Models. Life Sciences and Me.dicine Research, Volume 2010: LSMR-7.

• Conti, M. & Beavo, J. Annu. Rev. Biochem. 76, 481–511(2007).