Phosphodiesterase inhibitors adverse effects

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. 

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. 

The adverse effects of atazanavir include fever, jaundice/scleral icterus, myalgia and diarrhea. Its coadministration is not recommended with the drugs that induce cytochrome P-450 isoenzyme CYP3A4. Ritonavir increases plasma concentrations of atazanavir. It is an inhibitor of isoenzymes CYP3A4, CYP2C8 and UGT1A1. The coadministration of atazanavir with calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 inhibitors should be carefully monitored. 

Q10 Other bronchodilator agents include nebulized ipratropium. Ipratropium is a muscarinic receptor antagonist that helps to relax bronchial smooth muscle which has contracted via parasympathetic stimulation. The xanthines theophylline and aminophylline (theophylline ethylenediamine) are alternative bronchodilator agents. These agents may act as phosphodiesterase inhibitors and, although they have been used as bronchodilators for many years, adverse CNS, GI and cardiovascular effects may limit their usefulness. 

CICLOSPORIN PHOSPHODIESTERASE TYPE S INHIBITORS-SILDENAFIL t plasma concentrations of cidosporin, with risk of adverse effects Competitive inhibition of CYP3A4-mediated metabolism of cidosporin Be aware. Sildenafil is taken intermittently and is unlikely to be of clinical significance unless concomitant therapy is long term... 

CIMETIDINE PHOSPHODIESTERASE TYPE 5 INHIBITORS -SILDENAFIL t efficacy and adverse effects of sildenafil Inhibition of metabolism via CYP3A4 Consider a starting dose of 25 mg of sildenafil... 

PHOSPHODIESTERASE TYPE 5 INHIBITORS (e.g. sildenafil, tadalafil, vardenafil) GRAPEFRUIT JUICE Possibly t efficacy and t adverse effects, e.g. hypotension Small t in bioavailability, t variability in pharmacokinetics, i.e. interindividual variations in metabolism Safest to advise against intake of grapefruit juice for at least 48 hours prior to intending to take any of these preparations. When necessaiy, the starting dose of sildenafil should not exceed 25-50 mg and that of tadalafil 10 mg. Avoid co-administration with vardenafil... 

Enoximone is an inhibitor of phosphodiesterase type III, and has a positive inotropic effect. Its most common adverse effects are gastrointestinal and cardiac. The gastrointestinal effects include anorexia, nausea, vomiting, and diarrhea (1,2). 

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. 

Because of their apparent effectiveness, convenient route of administration, and comparatively low incidence of serious adverse effects, phosphodiesterase inhibitors are considered first-line therapy for erectile dysfunction, particularly in younger patients. 

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. ... 

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. 

When treatments for erectile dysfunction are needed, the least invasive forms of treatment should be used first, as they produce the lowest incidence of serions adverse effects. VEDs or phosphodiesterase inhibitors are therefore considered first-line treatments. If these fail, intracavemosal alprostadil injection therapy can be initiated. If this fails, the patient can be tried on a combination of intracavemosal alprostadil pins VED, combination intracavemosal therapy, or intra-nrethral alprostadil. If this fails, the patient may require insertion of a penile prosthesis. 

The interaction of the macrolides with the phosphodiesterase type-5 inhibitors is established, although most of the studies concern the use of erythromycin. These interactions are expected to result in both increased efficacy and increased incidence of adverse effects. 

Platelet inhibitors are widely used in the treatment and prevention of coronary artery disease. In addition to acetic salicylic acid (ASA), two major groups of platelet inhibitors are used phosphodiesterase inhibitors, including dipyridamole, and thienopyridines. Clopidogrel is the most widely used antiplatelet agent and in combination with ASA, it is the standard-of-care (SoC) for acute coronary s5mdromes and percutaneous coronary interventions. However, the mechanisms of action include pathways that affect the metabolic activity of bone cells and pharmacologic modulation of these pathways may have adverse effects on the bones. 

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