Phosphodiesterase inhibitors dosing

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. 

Fleischhacker, W.W., Hinterhuber, H., Bauer, H., Pflug, B., Berner, P., Simhandl, C., Wolf, R., Gerlach, W., Jaklitsch, H., Sastre-y-Hernandez, M., Schmedlng-Wlegel, H., Sperner-Unterweger, B., Voet, B., and Schubert, H. (1992) A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology 26 59-64. 

The many LH-dose and -time correlations that have been shown between the levels of cyclic AMP and steroid production and the positive effects of phosphodiesterase inhibitors have been interpreted as strong evidence that cyclic AMP is directly involved in the regulation of steroid production. However, there are several observations that do not fit this general concept. 

MACROUDES PHOSPHODIESTERASE TYPE 5 INHIBITORS t phosphodiesterase type 5 inhibitor levels with erythromycin, and possibly clarithromycin and telithromycin Inhibition of metabolism 1 dose of these phosphodiesterase inhibitors (e.g. start vardenafil at 5 mg)... 

None of the available oral phosphodiesterase inhibitors has become established in routine therapy, because the short-term benefit of the increased contractility has been offset by an increased mortality (presumably due to arrhythmias) on chronic dosing. A similar fate befell flosequinan, a positive inotrope which acted through the phosphatidylinositol system. Their use is restricted to short-term symptom control prior to, for example, transplanation. 

On the premise that phosphodiesterase inhibitors also inhibit the production of cytokines, milrinone has been used in the treatment of nine patients with the systemic inflammatory response sjmdrome and compared with seven patients with congestive heart failure (4). In both groups mikinone significantly altered cardiac index, pulmonary capillary wedge pressure, and left ventricular stroke work index. In the patients with cardiac failure it also reduced systemic vascular resistance index, and the dose of adrenaline had to be increased substantially during milrinone infusion to counteract vasodilatation. 

The usual oral doses of the phosphodiesterase inhibitors are listed in Table 84-4. The agents vary as to whether doses mnst be adjnsted for elderly patients (over age 65) and compromised hepatic or renal func-... 

Most adverse effects of the phosphodiesterase inhibitors are nfild or moderate and self-limited, rarely reqniring treatment discontinuation. In usual doses the most common adverse effects are headache, facial flushing, dyspepsia, nasal congestion, and dizziness, all of which result from inhibition of phosphodiesterase isoenzyme type 5 in extragenital tissues. ... 

Unlike the other two marketed phosphodiesterase inhibitors, tadalafil does inhibit type 11 phosphodiesterase, which is found in skeletal muscle. It is believed that this is linked to back and muscle pain, which occurs in a dose-related fashion in 7% to 30% of patients treated with doses of 10 to 100 mg. " ... 

Priapism is a rare adverse effect of phosphodiesterase inhibitors, particularly sildenafil and vardenafil, which have shorter plasma half-lives than tadalafil. When priapism has occurred, this has been associated with excessive doses of the phosphodiesterase inhibitor or concomitant therapy involving other erectogenic drugs. 

One of the proposed mechanisms by which OA exerts its regulatory actions is via an adenylate cyclase (12-18). In a preliminary test male CL were treated with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), alone and with OA. The dose of OA (10 ug/g) was one that induced little or no effect on male sensitivity (see Figure 1). Results showed that when treated with IBMX alone (10 Ug/g) male response to a low dosage of pheromone (0.01 mg) was not significantly enhanced over that observed with controls, or OA alone (20 vs. 15% source contacts respectively). However, when treated with 10 Ug/g OA and 10 Ug/g IBMX, 78% of the males successfully reached the source. IBMX clearly potentiated the effect of a low dose of OA on male sensitivity to pheromone ... 

The xanthine theophylline has been used for several decades in the treatment of asthma. This compound produces different effects at the cellular level, including phosphodiesterase isoenzyme inhibition, adenosine antagonism, catecholamine secretion enhancement, and the modulation of calcium fluxes. Recently, theophylline was found to have both immunomodulatory and anti-inflammatory properties therefore, interest in its use in patients with asthma has been renewed [103]. Recent studies have thus discovered that at low doses, theophylline is able to decrease airway inflammation, accelerate eosinophil apoptosis, and decrease recruitment of lymphocytes and neutrophils to the lungs. Although it is classified as a phosphodiesterase inhibitor, its exact therapeutic mechanism of action remains undetermined [104]. Of the new mechanisms that have been included in the potential mode of action of theophylline, one is the apoptosis of inflammatory cells. In eosinophils and lymphocytes, for example, this effect is due to the compound s ability to inhibit phosphodiesterase, which leads to an even more pronounced increase in intracellular cAMP levels than that which occurs when adenylate cyclase, the enzyme that synthesizes cAMP, is activated. This inhibition and the resulting cAMP level increase thus lead to... 

Smaller doses of sodium nitroprusside might be required in patients receiving antihypertensive drugs. There is a risk of severe hypotension if phosphodiesterase inhibitors (e.g. sildenafil, tadaiafil and vardenafil) are used with sodium nitroprusside. 

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