Phosphodiesterase inhibitors drug interactions

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. 

Drugs that may interact with nitrates include alcohol, alteplase, aspirin, beta-blockers, calcium channel blockers, dihydroergotamine, heparin, nondepolarizing muscle relaxants, phenothiazines, phosphodiesterase inhibitors (eg, sildenafil, tadalafil, vardenafil), and vasodilators. 

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. 

ED and vascular disease commonly coexist. They share the same risk factors and endothelial dysfunction is the common denominator. ED may develop in an otherwise asymptomatic male and be an important predictor of subsequent acute or chronic cardiac events. ED may therefore offer an opportunity for risk assessment and therapeutic intervention to reduce the chance of a subsequent cardiac presentation. Cardiac patients with ED need a careful assessment to judge the safety of sexual activity and suitability for ED treatment. Properly assessed and counselled patients can safely enjoy sexual activity. ED therapy with phosphodiesterase type five inhibitors is safe and effective providing the patient and partner are advised on their use and the importance of avoiding drug interactions, especially with nitrates. 

The three marketed phosphodiesterase inhibitors differ in their pharmacokinetic profiles, drug-food interactions, and adverse effects, and precautions are necessary in patients with cardiovascular disease (Table 81-5). Because sildenafil has been marketed longer and is better studied, it is emphasized in this section, with important differences among the three drugs highlighted as appropriate. 

Several newer approaches to antiplatelet drug development have been recently discovered (122). These include inhibitions of the vWf/GPIb interaction, the platelet/collagen interaction, and the thrombin-induced platelet activation. Other approaches to platelet inhibition include the use of serotonin antagonists (because serotonin induces platelet aggregation), nitric oxide-donating antiplatelet agents, phosphodiesterase inhibitors, and inducers of adenyl cyclase. 

An experimental study into the mechanism of action of enoximone in 14 patients with ischaemic or idiopathic dilative cardiomyopathy found that pretreatment with intravenous aminophylline 7 mg/kg given over 15 minutes reduced the beneficial haemodynamic eflects of intravenous enoximone 1 mg/kg given over 15 minutes. This appears to occur because each drug competes for inhibition of cAMP specific phosphodiesterases in cardiac and vascular smooth muscle. Milrinone, another phosphodiesterase inhibitor similar to enoximone, would be expected to interact in the same way. However, there are, at present, no published reports of a possible interaction with milrinone, and no case reports of a problem occurring with the concurrent use of either drug with theophylline. The clinical importance of this study therefore awaits evaluation. 

Pentyala S, Rahman A, Mishra S, Muthiki S, Hughes E, Bikkani A, Cervo K, Maruso C, Khan S (2011) Pharmacokinetic drug interactions of phosphodiesterase inhibitors mediated by cytochrome 3A4 isoform. Int J Med Med Sci 3 22-31... 

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... 

Rolipram is a racemic selective inhibitor of cAMP phosphodiesterase that has been used in the treatment of endogenous depression. The R(—)-enantiomer possesses the majority of the therapeutic eflect. After separate administration of the enantiomers by the oral and intravenous routes (Tables 1 and 2), no stereoselectivity appeared in plasma concentrations or in calculated pharmacokinetic [146]. However, it is not known whether this is also true after the administration of the racemate, because enantiomer-enantiomer interactions may affect the enantiomeric plasma concentration ratios of a number of chiral drugs. 

No clinically relevant interactions appear to occur between sildenafil, tadalafil or vardenafil and most antihypertensive drugs. The exceptions may be diltiazem and verapamil. The potentially serious interactions of sildenafil, tadalafil and vardenafil with the alpha blockers and nitrates are discussed elsewhere. See Phosphodiesterase type-5 inhibitors + Alpha blockers , p.l268 and Phosphodiesterase type-5 inhibitors -I- Nitrates , p.l272. 

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. 

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