Phosphodiesterase, drugs inhibiting

Among the methylxanthines, aminophylline is most commonly used drug in the treatment of bronchial asthma. It is a stable mixture of theophylline and ethylenediamine. These drugs inhibit the enzyme phosphodiesterase, this inhibition results in higher concentration of intracellular cyclic AMP. 

A frequently cited mechanism of action for these agents is phosphodiesterase (PDE) inhibition and the associated antiplatelet effects that accompany increases in intracellular cyclic adenosine monophosphate (cAMP). In fact, the effects of these drugs go far beyond their direct effect on PDE inhibition or platelet function. This chapter discusses (/) cyclic nucleotides, PDE, and PDE inhibitors (if) the mechanisms of action of dipyridamole and cilostazol (Hi) drug issues and (iv) current clinical applications for dipyridamole and cilostazol, including recent clinical trials that may have changed our perception of the possible utility of these agents for percutaneous intervention. 

Catecholamines inhibit phosphodiesterase from beef heart [44] and guinea-pig lung [45], and so does N, 2 -0-dibutyryl cyclic AMP [47] which has been used to mimic cyclic AMP effects as it is more lipid-soluble and, therefore, assumed to penetrate cell membranes more readily than cyclic AMP [6,46]. A large number of other drugs inhibit the phosphodiesterase activity of rat brain and cat heart [48]. 

Figure 7.2. Some intracellular processes that may be affected by calcium channel blocking drugs. Calcium channel blocking drugs inhibit calmodulin-dependent sarcolemmal Ca2 -A TPase (7), myosin light-chain kinase (MLCK) (2) and phosphodiesterase (PDE) (7). Passive Na -Ca2 exchange (4) may also be inhibited, whilst (Na +K )-ATPase (J) is stimulated. Ca2 release from mitochondria (MIT) in exchange for Na ( ) may be inhibited, but the effect of calcium channel blocking drugs on Ca2 uptake into sarcoplasmic reticulum (SR) via Ca2 -ATPase (7) is variable.

Dipyridamole was briefly mentioned in Chapter 10. In addition to vasodilator effects, the drug inhibits phosphodiesterase, thereby increasing intraplatelet c-AMP. Although these events do lead to decreased platelet aggregation, the drug s effectiveness clinically seems poor unless synergistically combined with either aspirin or warfarin. 

These drugs inhibit the actions of cellular phosphodiesterase, resulting in increased levels of cyclic adenosine monophosphate (cAMP). The actions are tissue-specific and mimic tor potentiate) the effects of sympathetic beta agonists. Other bronchodilatory actions may also be present, but as yet are undefined. 

By studying the effect of combinations of this drug with catecholamines, propranolol, and methylxanthlnes, it was shown that dlethylcarbamazlne apparently acts as an inhibitor of phosphodiesterase. Dlsodlum cromo-glycate, by contrast, could not be shown to Interact with any of the components of the cyclic AMP system, and it is therefore concluded that it must inhibit mediator release at a different step in the biochemical sequence leading to release.In fact, it has been suggested that this drug inhibits the action of the phospholipase A which has been postulated by Hdgberg and UvnSs, to be Involved in the release sequence. 

Mehtylxanthines are naturally occurring drugs, including theophylline, theobromine and caffeine. Methylxanthines at relatively high doses inhibit phosphodiesterases, which results in an increase in intracellular cAMP... 

Theophylline is also considered an alternative to inhaled corticosteroids for the treatment of mild persistent asthma however, limited efficacy compared to inhaled corticosteroids, a narrow therapeutic index with life-threatening toxicity, and multiple clinically important drug interactions have severely limited its use. Theophylline causes bronchodilation through inhibition of phosphodiesterase and antagonism of adenosine and appears to have anti-inflammatory and immunomodulatory properties as well.36... 

But now, a strategy, used for the synthesis of derivative (622) (lit. synthesis (622) see in Ref. 555), which is the most efficient analog of the commercial drug rolipram with a broad spectrum of action (in particular, anti-inflammatory, antidepressant, neuroprotective, and immunodepressing effects), is presented in Scheme 3.286. (The principle action of rolipram is based on selective inhibition of adenosine monophosphate (AMP)-specific phosphodiesterase.) Derivative (622) is almost 10 times more efficient than rolipram, but the biological activity of (622) was determined only for the racemate (555). 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

The enzyme phosphodiesterase (PDE) converts cyclic GMP to GMP. The Pfizer scientists wanted to develop a drug to inhibit PDE so that the level of cyclic GMP remains high, so that the last mechanism step can proceed. 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

The mechanism of action of these drugs is not completely understood. However, it is very likely that they inhibit cellular phosphodiesterase of the myocardium, which leads to an elevation in the cellular level of cyclic AMP, which in turn facihtates contraction of myocardial cells. It is clear that these drags are not 8-adrenoreceptor antagonists, and that their effect is not mediated by inhibition of (Na -K+) ATPase. They simultaneously increase the flow of calcium ions into the cell. They are used for short-term control of patients that inadequately react to cardiac glycosides, diuretics, and coronary vasodilating agents. 

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

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