Case sildenafil

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

Lee M, Min DI. Determination of sildenafil citrate in plasma by high-performance liquid chromatography and a case for the potential interaction of grapefruit juice with sildenafil citrate. Ther Drug Monit 2001 23(l) 21-26. 

Up to 2001, AERS indicated up to 39 case reports of possible drug interactions between St. John s wort and a prescription drug. In these case reports, the potential drug interactions occurred mostly with oral contraceptives, antidepressants, cyclosporine, and sildenafil. All cases were reported between 1997 and 2000. Most of the reported cases were in females (24),... 

Four cases of lack of effect or impotence were reported in patients using sildenafil while on St. John s wort and other concomitant drugs (what are they Are any of them significant from the standpoint of drug interaction ). The age range of the four male patients was between 55 to 73 years. Viagra... 

The available case reports in the FDA AERS support the published literature that there are pharmacokinetic interactions between St. John s wort and CYP3A4 and/or p-glycoprotein substrates, such as cyclosporine, levonorgestrel/estradiol and sildenafil, and pharmacodynamic interactions with the SSRIs or MAOI. Subsequent clinical studies including those conducted via a CDER clinical pharmacology research cooperative agreement (14—16) provided mechanistic basis of many of these interactions (refer to Chapter 4). 

The E-factors of different types of chemical processes are shown in Table 13.4.32 In general, processes performed on a larger scale tend to involve fewer operations and form simpler products. Both facets help lead to lower E-factor values. Remarkably, oil refining generates approximately 10-fold more product than waste. In contrast, pharmaceutical processes can be less than 1% efficient based on waste production. The commercial process of sildenafil (13.73), highlighted in the Case Study below, has been optimized more extensively than the typical pharmaceutical synthesis. 

Nonsteroidal anti-inflammatory medications (NSAIDs) are used for many aches and pains and are available over the counter in such forms as ibuprofen (brand names Motrin and Advil, as well as a generic form), naproxen (brand name Aleve and a generic form), and others. There have been reports of depression, anxiety, paranoia, psychosis, and confusion with these medications. Sildenafil (brand name Viagra), used for male sexual dysfunction, has been reported to cause aggression, delusions, hallucinations, mania, paranoia, and confusion in rare cases. Therapists will treat patients who are taking steroids, over-the-counter NSAIDs, and Viagra. When these patients have mental health symptoms, they need to be evaluated by their physician to see if the medication is contributing to the psychiatric symptoms. 

There have been several case reports of the use of sildenafil to ameliorate rebound pulmonary hypertension (4). 

The authors suggested that in this case the effect of sildenafil may have been reduced by impaired gastrointestinal absorption. They speculated that exogenous nitric oxide inhibits nitric oxide sjmthase activity, with a consequent reduction in pulmonary vascular smooth muscle cGMP concentration. Phosphodiesterase type V inhibitors, such as sildenafil, increase cGMP concentration and ameliorate the rebound effect... 

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. 

Clinical trials of sildenafil have not shown increased risks of stroke or myocardial infarction. However, postmarketing drug surveillance programs have mentioned strokes associated with sildenafil, and case reports have been published. 

Several other cases of non-arteritic ischemic optic neuropathy have been reported in men taking sildenafil (26,27). 

Whereas priapism has not been reported with sildenafil in controlled clinical trials, it is being mentioned in postmarketing drug surveillance programs, and two case reports have appeared in a healthy young man and a patient with sickle cell trait (29,30). 

Hamzavi J, Schmetterer L, Formanek M. Vestibular symptoms as a compheation of sildenafil a case report. Wien Klin Wochenschr 2002 114(l-2) 54-5. 

Boshier A, Pambakian N, Shakir SA. A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil. Int J Chn Pharmacol Ther 2002 40(9) 422-3. 

There is no established pharmacokinetic or pharmacodynamic interaction between the phosphodiesterase type-5 inhibitors and warfarin, and no warfarin dose adjustment would therefore be expected to be needed on concurrent use. However, in pulmonary hypertension, sildenafil appears to increase the risk of nosebleeds, and this may be greater in patients taking coumarins. Similarly, the two possible cases with acenocoumarol and warfarin, although not conclusive, do introduce a note of caution. 

The use of phosphodiesterase inhibitors (e.g. sildenafil, tadaiafil and var-denafil) with sodium nitroprusside is contraindicated by the manufacturers, due to the risk of severe hypotension. See also Phosphodiesterase type-5 inhihitors +Nitrates , p.l272. A case report describes the therapeutic use of sildenafil to enhance the hypotensive effect of sodium nitroprusside and other antihypertensives in a patient with a hypertensive crisis. ... 

In an open label, randomised study in 12 healthy subjects, ketoconazole 200 mg daily increased the AUC of a single 10-mg dose of tadalafil by twofold, and ketoconazole 400 mg daily increased the AUC fourfold. The manufacturers predict that itraconazole will interact similarly. This prediction has been borne out by a case report of a 56-year-old man who was taking itraconazole 400 mg daily for 7 days each month. Within a few hours of his first 10-mg dose of tadalafil he developed priapism, which lasted for more than 4 hours. The same reaction occurred when he took tadalafil during the following month. He had seemingly previously taken sildenafil with itraconazole without adverse effect. ... 

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. ... 

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