Inhibiting Phosphodiesterase

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... 

Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of thrombocytopenia seen with inamrinone. 

Sildenafil (Viagra ), tadalafil (Cialis ), and vardenafil (Levitra ) act by selectively inhibiting phosphodiesterase (PDE) type 5, an enzyme that breaks down cGMP. By inhibiting the breakdown of cGMP, smooth muscle relaxation is... 

Although caffeine is known to mobilize intracellular calcium, to inhibit phosphodiesterase activity, and to increase in vitro 5-HT and NE concentrations in the brainstem (Garrett and Griffiths 1997 Berkowitz et al. 1970 Carter et al. 1995 Solinas et al. 2002), it is now widely accepted that the mechanism of action of caffeine on wakefulness, at least at the dose range produced by voluntary caffeine intake, is via the antagonism of adenosine receptors. 

Milrinone is a bipyridine derivative that inhibits phosphodiesterase 111 and produces positive inotropic and arterial and venous vasodilating effects hence, milrinone has been referred to as an inodilator. It has supplanted use of amrinone, which has a higher rate of thrombocytopenia. 

Theophylline appears to produce bronchodilation by inhibiting phosphodiesterases, which may also result in antiinflammatory and other nonbronchodilator activity through decreased mast cell mediator release, decreased eosinophil basic protein release, decreased T-lymphocyte proliferation, decreased T-cell cytokine release, and decreased plasma exudation. 

For a wide variety of 6-aryl-3(2//)-pyridazinones (including those discussed in the chapter on cardiotonic agents and antithrombotics [1]), bronchodila-tor activity has been claimed in patents [104,114-116,129,423,424]. Thus, for instance, the bronchospasmolytic effects (guinea-pig tracheal-chain preparations) of compounds of type (99) have been found to exceed those of xanthines [425]. The therapeutic index of these compounds (which inhibit phosphodiesterase at lower concentrations than xanthines and do not interact with adenosine receptors) is larger than that of xanthines. 

These compounds competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP (see Box 14.3) and subsequent release of adrenaline. This leads to the major effects a stimulation of the central nervous system (CNS), a relaxation of bronchial smooth muscle, and induction of diuresis. These effects vary in the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine. 

It is believed that theophylline can inhibit phosphodiesterase, which in turn can lead to elevated levels of cellular cyclic adenosine monophosphate, and subsequently, to the weakening of smooth musculature of the respiratory tract. However, theophylline is not a powerful phosphodiesterase inhibitor, and the necessary concentrations for this cannot be achieved in vivo. 

Mectianism of Action A cardiac inotropic agent that inhibits phosphodiesterase, which increases cyclic adenosine monophosphate and potentiates the delivery of calcium to myocardial contractile systems. Therapeutic Effect Relaxes vascular muscle, causing vasodilation. Increases cardiac output decreases pulmonary capillary wedge pressure and vascular resistance. 

Mechanism of Action An erectile dysfunction agent that inhibits phosphodiesterase type 5, the enzyme responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpus cavernosum of the penis and pulmonary vascular smooth muscle, resulting in smooth muscle relaxation and increased blood flow. Therapeutic Effects Facilitates an erection, produces pulmonary vasodilation. 

The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect calcium sensitivity in vitro. Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. 

Inamrinone (previously called amrinone) and milrinone are bipyridine compounds that inhibit phosphodiesterase isozyme 3 (PDE-3). They are active orally as well as parenterally but are available only in parenteral forms. They have elimination half-lives of 3-6 hours, with 10-40% being excreted in the urine. 

These compounds inhibit phosphodiesterase resulting in the prolonged activation of... 

Theoretical explanations for the stimulatory activity of the methyl xanthines. These compounds inhibit phosphodiesterase reaulting in the prolonged activ of metabolic enzymes.Adenylate cyclase activity is modulated by the bindin free adenosine. The methyl xanthines are antagonists to adenosine but the bindings do not produce its modulating (inhibitory, attenuating) response. Therefore the end result is stimulatory in relation to cAMP activity. 

Figure 23-43 The light-activated transducin cycle. In step a photoexcited rhodopsin (R ) binds the GDP complex of the heterotrimeric transducin (T ). After GDP—GTP exchange (step b) the activated transducin T GTP reacts with the inhibited phosphodiesterase (PDEapY2) to release the activated phosphodiesterase (PDEap). Based on scheme by Stryer528 and other information.

Sildenafil increases the release of nitric oxide and increases the levels of cyclic guanosine monophosphate (cGMP), a smooth muscle relaxant. Sildenafil enhances the effects of nitric oxide by inhibiting phosphodiesterase 5, an enzyme found primarily in the penis that degrades cGMP. As a result, increased levels of cGMP in the corpus cavemosum enhance smooth muscle relaxation, the inflow of blood, and erection. Sildenafil has no effect in the absence of sexual stimulation (see Figure 60.1). 

Tolbutamide, N-[(butylamino)carbonyl]-4-methylbenzenesulphona-mide N-(butylamino) carbonyl-p-toluene sulphonamide is a sulphonlylurea that is orally active as a hypoglycemic agent. The drug stimulates the poncreatic islet beta cells to release extra insulin. It also inhibits phosphodiesterase, which preserves cyclic AMP and thus favor glycogenolysis in a number of tissues. 

In Table II of his comments, Dr. Laduron points out differences between bovine and human parathyroid cells. Several of these are in error. Prostaglandins affect both human and bovine parathyroid cells. Phosphodiesterase inhibitors have not been tested directly in human parathyroid cells, although dibutyryl cyclic AMP, which may act in part by inhibiting phosphodiesterase, stimulated PTH release in fragments of human parathyroid glands (6). 

All of the following actions of nitrovasodilators are correct except a they inhibit phosphodiesterase... 

These drugs enhance the effect of nitric oxide by inhibiting phosphodiesterase type 5. Tadalafil has cross-reactivity with phosphodiesterase type 11, which may cause back pain and myalgia. The approximately 4000-fold selectivity for phosphodiesterase type 5 versus type 3 is important because type 3 is involved in the control of cardiac contractility. 

Sildenafil, tadalafil and vardenafil have similar, although not identical, mechanisms of action and structural similarity, and are metabolized primarily by the CYP3A4 isoenzymes, Vardenafil is 32-fold more potent than sildenafil in inhibiting phosphodiesterase type 5. Tadalafil has a quicker onset of action and a longer duration of action - around 36 hours - hence the need to be aware of the potential for adverse drug interactions for nearly 2 days after the intake of a single tablet. 

Sildenafil and vardenafil inhibit phosphodiesterase types 6 and 1 (found in the brain, heart and vascular smooth muscle) more than tadalafil. Type 5 inhibition can result in an increase of the Q-T interval and a risk of life-threatening ventricular arrhythmias with class 1A and class III antiarrhythmics, this risk being greater with tadalafil and vardenafil. 

Theophylline produces bronchodilation possibly by inhibiting phosphodiesterase isomers, has some anti-inflammatory effect and reduces muscle tone in the diaphragm. Theophylline is a positive inotrope and chronotrope, and is associated... 

Therapeutic approaches directed at the CFTR channel protein are also being considered. Elucidation of the mechanism of action of the CFTR has also led to the initiation of pharmacological strategies to correct the basic defect in CFTR. Elevation of intracellular cAMP has been shown to activate many mutant forms of CFTR. Thus, agents which increase cAMP levels by stimulating adenyl cyclase or inhibiting phosphodiesterases would be useful in therapy. Similarly, phosphatase inhibitors, which increase the net phosphate groups on the CFTR, may also be useful in therapy (Collins, 1992). 

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