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A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), therefore preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), by the respective PDE subtype(s).

Contents 1 History 2 Classification 2.1 Non-selective phosphodiesterase inhibitors 2.2 PDE1 selective inhibitors 2.3 PDE2 selective inhibitors 2.4 PDE3 selective inhibitors 2.5 PDE4 selective inhibitors 2.6 PDE5 selective inhibitors 3 References

History

The different forms or subtypes of phosphodiesterase were initially isolated from rat brains by Uzunov and Weiss in 1972^[1] and were soon afterwards shown to be selectively inhibited in the brain and in other tissues by a variety of drugs.^[2][3] The potential for selective phosphodisterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait.^[4] This prediction meanwhile has proved to be true in a variety of fields.

Classification

Non-selective phosphodiesterase inhibitors

• caffeine, a minor stimulant
• theophylline, a bronchodilator
• IBMX (3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research

PDE1 selective inhibitors

• Vinpocetine

PDE2 selective inhibitors

• EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine)

PDE3 selective inhibitors

Main article: PDE3 inhibitor

• Enoximone and milrinone, used clinically for short-term treatment of cardiac failure. These drugs mimic sympathetic stimulation and increase cardiac output.

PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase.

PDE4 selective inhibitors

• Mesembrine, an alkaloid from the herb Sceletium tortuosum
• Rolipram, used as investigative tool in pharmacological research
• Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor depending on the dose.

PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD and rhinitis. They suppress the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects^[5] and have also recently been proposed for use as antipsychotics.^[6][7]

PDE5 selective inhibitors

Main article: PDE5 inhibitor

• Sildenafil, tadalafil and vardenafil, and the newer udenafil and avanafil selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunction, as well as having some other medical applications such as treatment of pulmonary hypertension.
• Dipyridamole also inhibits PDE5. This results in added benefit when given together with NO or statins.

References

v • d • e Selective Phosphodiesterase inhibitors (C01CE, G04BE) PDE1 Vinpocetine PDE2 EHNA PDE3 Amrinone • Bucladesine • Cilostazol • Enoximone • Milrinone • RPL-554 PDE4 Cilomilast • Drotaverine • Etazolate • Glaucine • HT-0712 • Ibudilast • Mesembrine • Roflumilast • Rolipram • RPL-554 PDE5 Acetildenafil • Avanafil • Icariin • Sildenafil • Tadalafil • Thiomethisosildenafil • Udenafil • Vardenafil PDE10A Papaverine • PF-2545920 • Tofisopam

v • d • e Cardiac stimulants excluding cardiac glycosides (C01C) Adrenergic and dopaminergic agents Adrenergic agonists α Metaraminol • Phenylephrine • Methoxamine • Norfenefrine • Oxedrine • Midodrine • Mephentermine β Dobutamine • Arbutamine • Isoprenaline • Prenalterol mixed EPINEPHRINE • Norepinephrine • Etilefrine Dopamine agonists Fenoldopam Both DOPAMINE • Dopexamine • Ibopamine • Octopamine Unknown/ungrouped Dimetofrine • Gepefrine • Cafedrine • Theodrenaline Phosphodiesterase inhibitors (PDE3I) Amrinone • Milrinone • Enoximone • Bucladesine Other cardiac stimulants Angiotensinamide • Xamoterol • Levosimendan

v • d • e Pharmacology: enzyme inhibition Class Competitive inhibition - Uncompetitive inhibition - Non-competitive inhibition - Suicide inhibition - Mixed inhibition Substrate Oxidoreductase (EC 1): Aromatase inhibitors - Lipoxygenase inhibitor - Monoamine oxidase inhibitors - COX-2 inhibitor Transferase (EC 2): Integrase inhibitor - Protein kinase inhibitors - Reverse transcriptase inhibitors - COMT inhibitors Hydrolase (EC 3): Acetylcholinesterase inhibitors - Phosphodiesterase inhibitors - Protease inhibitors (ACE inhibitor, Trypsin inhibitor) - Histone deacetylase inhibitor Lyase (EC 4): Carbonic anhydrase inhibitors

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• This page was last modified on 11 September 2008, at 17:37.

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