Sildenafil, adverse effects

In a randomised, plaeeho-eontrolled, double-blind, crossover study, 28 healthy subjects were given sildenafil 100 mg before and after taking ritonavir for 7 days (300,400 and 500 mg twice daily on days 1, 2 and 3 to 7, respectively). It was found that the sildenafil AUC was increased 11-fold and the maximum serum levels 3.9-fold by ritonavir, but the inci-denee and severity of the sildenafil adverse effects and the steady-state levels of ritonavir remained unchanged. However, the clinical significance of this interaction is highlighted by a case report of a 47-year-old man, with no cardiovascular risk factors apart from smoking, who had a fatal heart attack when he took sildenafil 25 mg while he was also taking ritonavir and saquinavir. One hour after the ninth dose, he had an onset of severe ehest pain, and died soon after. ... 

The most dramatic difference between the three agents is tadalahl s extended duration of action, earning it the nickname the weekender drug. While sildenafil and vardenafil have average half-lives of 3 to 4 hours, tadalafil s half life is approximately 18 hours.18 The extended half-life allows for more spontaneous sexual activity over a couple of days, but may increase the duration of adverse effects and liklihood of drug interactions or sildenafil. 

A patient with no history of prior disease and taking sildenafil might develop which of the following adverse effects ... 

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. 

Sildenafil and vardenafil decrease systolic/diastolic blood pressure by 8 to 10/5 to 6 mm Hg for 1 to 4 hours after a dose. Although most patients are asymptomatic, multiple antihypertensives, nitrates, and baseline hypotension increase the risk of developing adverse effects. Although tadalafil does not decrease blood pressure, it should be used with caution in patients with cardiovascular disease because of the inherent risk associated with sexual activity. 

Sildenafil has other minor adverse effects, such as headache, nasal congestion, and flushing. There are no clinically significant drug interactions between sildenafil and apomorphine. Apomorphine, like sildenafil, is orally active. However, unlike sildenafil, it exerts its action through the central nervous system. Apomorphine can produce dizziness, nausea, pallor, and hypotension, and in the presence of ethanol, it purportedly increases... 

T effects OF amiodarone, astemizole, atorvastadn, barbiturates, bepridil, bupropion, cerivastatin, cisapride, clorazepate, clozapine, clarithromycin, desipramine, diazepam, encainide, ergot alkaloids, estazolam, flecainide, flurazepam, indinavir, ketoconazole, lovastatin, meperidine, midazolam, nelfinavir, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, simvastatin, SSRIs, TCAs, terfenadine, triazolam, troleandomycin, zolpidem X effects W/ barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, St. John s wort, tobacco X effects OF didanosine, hypnotics, methadone, OCPs, sedatives, theophylline, warfarin EMS T Effects of amiodarone, diazepam, midazolam and BBs, may need X- doses concurrent use of Viagra-type drugs can lead to hypotension X- effects of warfarin concurrent EtOH use can T adverse effects T glucose ODs May cause an extension of adverse SEs symptomatic and supportive Rivasrigmine (Exelon) [Cholinesterase Inhibitor/Anri ... 

Tadalafil has also been extensively evaluated in patients with cardiovascular disease and has a similar safety and efficacy profile to sildenafil (45). Studies have shown no adverse effects on cardiac contraction, ventricular repolarization, or ischemic threshold. A similar hypotensive effect has been recorded with a dose of doxazosin 8 mg so caution is needed. As hypotension does not occur in the supine position and as tadalafil has a long half-life it is suggested that tadalafil is taken in the morning and doxazosin in the evening. There is no interaction of tadalafil with the selective a-adrenoceptor antagonist tamsulosin, which can, therefore, be prescribed as an alternative to doxazosin for symptomatic benign prostate hypertrophy (46). 

Sexual dysfunction is a common adverse effect of SSRIs and various treatments have been proposed, of which sildenafil is the only strategy with consistent support from controlled trials. Sildenafil is metabolized by CYP3A4, which is inhibited by fluvoxamine. The effects of fluvoxamine (100 mg/day for 10 days) on the pharmacokinetics of sildenafil (50 mg orally) has been evaluated in 12 healthy men (mean age 25 years) using a doubleblind, placebo-controlled, crossover design (46). Fluvoxamine increased the AUC of sildenafil by about... 

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... 

The main adverse effects reported in chnical studies were flushing, headache, dyspepsia, visual disturbances, and rhinitis, some of which show that vasodilatation is not confined to the corpora cavernosa. They were mUd, and only 1-2% of the patients discontinued sildenafil because of adverse effects. 

The adverse effects of a single dose of sildenafil 50 mg have been evaluated in a placebo-controlled study in 40 young healthy volunteers (3). The most commonly reported adverse effects with sildenafil and placebo respectively were flushing (75 and 0%), headache (50 and 5%), and dyspepsia (15 and 5%). This adverse effects profile was similar to that observed in chnical trials. Heart rate changed significantly, but blood pressure did not. 

The interpretation of these sporadic cases is controversial, although some have argued that the reported cardiovascular adverse effects occur more often with sildenafil than with other pharmacological treatments of erectile dysfunction. It is at present unclear whether there is an increased risk with sildenafil. For example, in placebo-controlled trials there have been no differences in the incidences of myocardial infarction, angina, or coronary artery disorders between sildenafil and placebo (9). Exclusion criteria in clinical trials may have prevented the inclusion of patients who are at increased risk of adverse events. On the other hand, sexual activity itself increases cardiac workload and the risk of myocardial infarction. Patients with cardiovascular disease should be cautious in their use of sildenafil. 

Pharmacological interactions are adverse effects that occur due to combined pharmacological activities, leading to exaggerated pharmacological effects. An example of pharmacological interactions is serious, sometimes fatal drop in blood pressure due to coadministration of nitroglycerin and sildenafil.3... 

Adverse Effects. Sildenafil is well tolerated in patients with normal cardiovascular function. Most of the side effects reported in the clinical trials at a higher rate than placebo are mild and are related to the drug s vasodi-latory effect. They include headache, flushing, and nasal congestion. Other frequent side effects include abnormal vision (impairment of color discrimination) and dyspepsia. The... 

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. 

Visual adverse effects occur less frequently with vardenafll when compared with sildenafil (less than 0.1% versus 10%, respectively). Tadalafil has minimal to no inhibitory activity against type 6 phosphodiesterase, and no visual adverse effects have been reported. 

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. 

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