phosphodiesterase_inhibitors

by QHA
 * Phosphodiesterase Inhibitor: Serendipity in action **

What is a phosphodiesterase inhibitor and why is itrelevant to us? When we approach acomplicated idea, it is better to explain it in simpler terms and concepts inorder to deliver the overarching ideas. We can use this technique to understand the pharmaceutical aspect ofphosphodiesterase (PDE) inhibitors and their functions. The first phosphodiesterase inhibitor Theophyllinewas discovered in 1962. By the seventies1-methyl-3-isobutylxanthine was developed. The xanthines were the first class of nonspecific PDE inhibitors (1). In the last decade there have been tremendousprogresses in producing new inhibitors for the ever growing market. Our story starts with a signal and its response. An example of this would be the photoreceptorin your eyes responding to light or sensory and mechanoreceptor response tostimulation. These signals cause chemicalmessages to be relayed to cells in order to prepare the body for a reactionsuch as the opening of Ca+ channel. Themessage, once arrived would bind to receptors embedded on the cellularmembrane. These cellular receptors wouldattach GTP (similar to ATP) to G-protein activating it (2). G-protein would then initiate the enzyme adenylylcyclase, which has the ability to change ATP into adenosine 3’, 5’–cyclicmonophosphate (cAMP) and GTP into guanosine 3’, 5’ –cyclic monophospate (cGMP) (3) Their function is to amplify the signal sothat it can be relayed to the enzymes, organelles, ion channels, etc. withincells to coordinate the appropriate response. These facts about cAMP/cGMP can be placed into a more relatable contextif you think of cAMP/cGMP as a gossip. After hearing a juicy rumor, he or she is now able to spread informationto large population of people. Cyclic AMPperforms the same function; it is the preferred cascade messenger to relayinformation throughout the cell. After the message reaches its target site,phosphodiesterases comprising of a superfamily of hydrolase (4), wouldbreak cAMP into AMP the non-responsive version. The superfamily of phosphodiesterase contained eleven members whichperform different functions throughout the body (5). The body uses phosphodiesterase in order toregulate the activity of cAMP. Figure1 Figure 2 The varieties of phosphodiesterases are a tribute totheir extensive roles throughout the body. These phosphodiesterases have functions dealing with the brain (PDE 1, 2,4, 10, somewhat with 8, 9), the retina in PDE6, and smooth muscle activities ofPDE 3, 4, and 5. The extensive classesof phosphdiesterases are matched by the inhibitors, preventing their activitiesand prolonging the effect of cAMP/cGMP. Phosphodiesterasetype 1 inhibits the PDE1 which acts on calcium channel within the brain, especiallywith the cerebellum, hippocampus, caudate, and Purkinje cells (motor control,coordination of short, long term memory, learning memory, motor coordination). PDE inhibitor type 2 has heart and lungfunctions (6).Type 3, 4 and 5 will be focus on later. PDE inhibitor type 6 has similarcharacteristic to that of type 5 (which maybe why there is the wives talesabout masturbation and blindness), but its main area of focus is on theretina. Finally, the last 4 types ofinhibitors do not have sufficient research to be discussed (7). The most extensive research data are found on PDEinhibitor 3, 4, 5 which have been extensively studied, both academically and bypharmaceutical corporations. Theinterests in these inhibitors are due to their profitability as pharmaceuticalagents. From 1980s to the 90s there werepervasive research done on isolating a PDE 3 inhibitor which would help withheart failure (8). PDE 3 inhibitor was founded to have effect onplatelets’ cAMP (9)which would then suggest that it could help with heart problem. But the research into PDE 3 inhibitor andheart failure stopped because it can cause arrhythmias (which is changes heartrhythm; from too fast, slow or irregular). It is now investigated as medication for anticoagulant andvasodilatation such as Cilostazol which is used for peripheral arteries disease (10). Figure 3 There has also been a lot of study done for PDE type4 inhibitor which functions in the brains, inflammatory and cardiovasculartissues. In the brain PDE 4 inhibitorhas been linked to antidepressants for example Rolipram (11). PDE type 4 also has anti-inflammatoryfunctions, through their work with leukocytes (12). This function has been greatly exploited bypharmaceutical companies, using it to treat inflammatory diseases like asthma. PDE 4 like that of type 3 and 5 also haveeffects in smooth muscle especially, that of the airway passages. The way that PDE 4 (also PDE 5) is able toachieve this feat is through regulating the amount of intracellular cAMP. This has lead to development of PDE 4inhibitors to also treat chronic pulmonary disease (COPD) (13). Treatment in the early days with PDE 4inhibitors (in example Piclamilast) did have adverse effects on users. The mostprominent of which is nausea and vomiting (14). New varieties of PDE 4 inhibitors have beenproduced to lessen the emetic effects. Learning about the varieties of phosphodiesterase inhibitorsmay be informative and somewhat interesting. It may be relevant to a far futurelecture in another class or a research project which might cause recollectionof a presentation on PDE inhibitors, but the majority of people will onlyremember the discussion about PDE 5 inhibitor. This inhibitor is most well known, not only for its function, but alsobecause it has received much publicities and advertisements over the year. Figure 4 The history of PDE 5 inhibitor is as serendipitousas penicillin. The first version of aPDE 5 inhibitor was zapirnast the precursor to later varieties of PDE 5inhibitor. It was intended for thetreatment of angina (chest pain resulting from muscles in the chest not gettingenough oxygen). They quickly realizedthat it has other functions, especially with erectile dysfunction (ED). It was discovered by Peter Dunn and AlbertWood, who synthesized it in 1989 in a Pfizer research institute in Kent,England (15)and patented by Nicholas Terrett in 1991 as an angina medication. By 1998 PDE Inhibitor type 5 was on the fasttrack to be approved by the FDA as the first drug taken orally to treaterectile dysfunction. In the family of phosphodiesterase inhibitor, myprimary effects are working with phosphodiesterase type 5 (PDE 5). Sildenafil is now considered the first lineof defense in managing ED. How it worksis through the regulation of arterial smooth muscle. In the body Nitric Oxide (commonly confusedwith Nitrous Oxide used as laughing gas and racing propellant) is a vasodilator,which means it dilates blood vessels (16). Nitric Oxide is a neurotransmitter created inresponse to sensory stimulus, and has affect arteries. Nitric oxide would then react with guanylylcyclase, converting GTP (similar to ATP) to cGMP the secondary chemicalmessenger. The effect of cGMP is torelax arterial smooth muscle found in the penis causing an erection. This process is confusing for some because itis not intuitive that relaxation can cause excitation, but there is a simpleexplanation for this. We will proceedwith a little anatomy and physiology explanation. The penis is similar to a hydraulic pumpwhich is pressurized into movement. Themale genitalia have a similar function. The arteries to the penis are usually constricted which allows minimalblood flow causing it to be flaccid. CyclicGMP causes dilation of the arteries and blood to flow into the two corpuscavernosum, filling it causing an erection. This reaction does not last forever evident by the fact that theerection is not permanent, because cGMP is then hydrolyzed by PDE 5 whichconverted to its inactive GMP form. Phosphodiesterase type 5 inhibitors such as sildenafil or cialis work toinhibit hydrolyzing of cGMP by phosphodiesterase 5 (17). As a result more of the secondary messengers(cGMP) are present causing prolonged dilation of arteries and increasing thevolume of blood to the genitalia causing the erection. Figure 5 Figure 6 Because PDE inhibitors 5 and 6 have similar effectsthere are some visual side effects which can be experienced with in sildenafil,such as blue tinting in your vision (18). Recently, other PDE 5 inhibitors have beencreated, which are stronger alternatives to Viagra. Two of which are vardenafil (Levitra) andtadalafil (Cialis –which I think has the best name ever). The studies done comparing sildenafil versustadalafil has been reviewed in the “Current Pharmaceutical Design” issues 2009and the research data although inconclusive due to a variety in experimentalprocedure and adherence to treatment, do show that most patients in the studyprefers tadalafil over that of sildenafil (19).

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