A phosphodiesterase is any enzyme that breaks a phosphodiester bond.<\/li>
There are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNAses, RNAses, and restriction endonucleases<\/li>
Usually, people speaking of Phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance.<\/li>
The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP.<\/li>
PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules.<\/li><\/ul>\n\n\n\n
Historical aspects<\/strong><\/p>\n\n\n\n
The phosphodiesterase (PDE) story begins with the work of Henry Hyde Salter in 1886<\/li><\/ul>\n\n\n\n
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<\/li>
Although the mechanism of action at the time was unknown, it has since been shown that caffeine was acting as a non-selective PDE inhibitor<\/li><\/ul>\n\n\n\n
The classification is based on:<\/strong><\/p>\n\n\n\n
PDE substrate specificities by enzyme family
Some are cAMP selective hydrolases(PDE 4, 7 and 8)<\/li><\/ul>
cGMP selective(PDE 5, 6 and 9)<\/li><\/ul>
Hydrolyse both cAMP and cGMP (PDE 1, 2, 3, 10,11)<\/li><\/ul><\/li>
Inhibition of PDE2 by EHNA potentiates NMDA receptor activated increase in cGMP, but has no effect on cAMP concentrations<\/li>
Also EHNA is a potent inhibitor of adenosine deaminase. This dual inhibition (PDE plus ADA) leads to the accumulation of the two inhibitory metabolites, adenosine and cGMP, which may act in synergy to mediate diverse pharmacological responses including anti-viral, anti-tumour and antiarrhythmic effect<\/li><\/ul>\n\n\n\n
USE:<\/p>\n\n\n\n
Study implication of PDE2 in calcium control in cardiac myocytes<\/li>
Shown to be effective to reverse hypoxic pulmonary vasoconstriction in perfused lung models<\/li><\/ul>\n\n\n\n
Drug used for the treatment of essential thrombocytosis or overproduction of blood platelets.<\/li>
Also has been used in the treatment of chronic myeloid leukemia<\/li><\/ul>\n\n\n\n
Mechanism of action: <\/strong><\/p>\n\n\n\n
Inhibiting the maturation of platelets from megakaryocytes inhibitor of phosphodiesterase-II.<\/li>
It inhibits PDE-3 and phospholipase A2.<\/li><\/ul>\n\n\n\n
Uses: <\/strong><\/p>\n\n\n\n
Combination of anagrelide and aspirin for the initial management of ET<\/li><\/ul>\n\n\n\n
ADRs: <\/strong><\/p>\n\n\n\n
Headache, diarrhea, unusual weakness\/fatigue, hair loss, nausea and dizziness.<\/li>
Less common side effects include: congestive heart failure, myocardial infarction, cardiomyopathy<\/li><\/ul>\n\n\n\n
Contraindications<\/strong><\/p>\n\n\n\n
Severe hepatic function impairment.<\/li>
Dose:0.5 mg \/day<\/li><\/ul>\n\n\n\n
Inamrinone, Milrinone — Mechanism of action:<\/strong><\/li>
Selectively inhibits PDE 3, located in heart \u00e0 Increased cAMP<\/li>
Enhances relaxation of the left ventricle by increasing Ca++-ATPase activity on the cardiac sarcoplasmic reticulum which increases calcium ion uptake<\/li>
Positive ionotropic on heart<\/li>
Vasodilatation of vessels (Ionodilator)<\/li>
used in the management of heart failure only when conventional treatment with vasodilators and diuretics has proven insufficient due to the potentially fatal adverse effects of milrinone, including ventricular arrhythmias<\/li>
Prolonged half-life (2.5 hrs) \u00e0This can result in a prolonged weaning and possible adverse outcomes from stopping this medication rapidly.<\/li>
Only used IV for acute heart failure cases, dihydropyridazinone<\/strong> \u00e0first orally active, potent, and selective PDE3B inhibitor.<\/li><\/ul>\n\n\n\n