Phosphodiesterase inhibitor, effects

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

Effectiveness of the three available phosphodiesterase inhibitors is essentially comparable, but differences exist in duration of action, and to a small degree, incidence of side effects and drug interactions. 

Unless otherwise stated, general information applies to the entire class of phosphodiesterase inhibitors. Sildenafil is highlighted because it was the first to be marketed and is the most thoroughly studied. The newer agents tadalafil and vardenafil have different pharmacokinetic profiles (Table 83-3), drug-food interactions, and adverse effects. 

Phosphodiesterase inhibitors are selective for isoenzyme type 5 in genital tissue. Inhibition of this isoenzyme in nongenital tissues (e.g., peripheral vascular tissue, tracheal smooth muscle, and platelets) can produce adverse effects. 

Martin prepared 5-trimethylstannylindole and effected coupling with bromobenzene to give 5-phenylindole [125], In a search for new cAMP phosphodiesterase inhibitors, Pearce prepared the furylindole 190 from 5-bromoindole and 5-ferr-butoxy-2-trimethylstannylfuran [196a], Benhida and co-workers explored Stille couplings of 6-bromo- and 6-iodoindole, and methyl 6-iodoindol-2-ylacetate with a variety of heteroarylstannanes and vinylstannanes [196b]. 

Horowski, R. and SastreHernandez, Y.M., Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients global evaluation of the preliminary reports, Curr. Ther. Res. Clin. Exp., 38, 23, 1985. 

Phosphorylation of cardiac calcium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phosphodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentration and elicit effects resembling those of epinephrine. 

Visuai disturbances Single oral doses of phosphodiesterase inhibitors have demonstrated transient, dose-related impairment of color discrimination (blue/green), with peak effects near the time of peak plasma levels. The findings were most evident 1 hour after administration, diminishing but still present 6 hours after administration. 

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. 

A small controlled trial suggests that the phosphodiesterase inhibitor tadalafil was effective in preventing HAPE but not AMS dexamethasone reduces the risk of both HAPE and AMS. 

Griebel G, Misslin R, Vogel E, Bourguignon J (1991) Behavioral effects of rolipram and structurally related compounds in mice behavioral sedation of cAMP phosphodiesterase inhibitors. J Neurochem 58 321-323... 

The immediate effect of increasing intracellular cAMP levels is an increase in contractility. This has been observed repeatedly in acutely ill patients in the intensive care unit with the intravenous infusion of either (3-adrenergic agonists (e.g., dobutamine) or the phosphodiesterase inhibitors milrinone (Corotrope) and am-rinone (Inocor). Binding of dobutamine to cardiac myocyte adrenoceptors results in G-protein coupling, activation of adenylyl cyclase, and the conversion of ATP to cAMP. 

Positive inotropic compounds can be classified into three groups cAMP generators, intracellular calcium regulators, and modulators of ion channels or pumps [11]. The cAMP generators such as dopamine, dobutamine, and milrinone (a phosphodiesterase inhibitor) may worsen ischemia, cause arrhythmias, and increase mortality [2,6]. Intracellular calcium modulators have not reached clinical use, possibly because of additional effects such as vasoconstriction,... 

Lam, S.C.T. Packham, M.A. Isolation and kinetic studies of nucleoside diphosphokinase from human platelets and effects of cAMP phosphodiesterase inhibitors. Biochem. Pharmacol., 35, 4449-4455 (1986)... 

The addition of phosphodiesterase inhibitors such as isobutylmethylxanthine (IBMX) and cyclic AMP analogs such as the 8-bromo- and dibutyryl-derivatives resulted in a stimulation of synthesis which could not be blocked by the co-addition of opiates. This implies that opiates are exerting their effect at the level of adenylate cyclase activation. The actual effect of these drugs on cellular cyclic AMP levels was determined by radioimmunoassay as shown in Table III. 

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