prn8099 - Number 24, August 1999

Treading Slowly with Viagra

Although Viagra officially made its inaugral appearance in April 1999, its name is not entirely new to Malaysia. Since March 27, 1998 when "Viagra" was first approved by the US Food and Drug Administration, the National Poison Centre at Universiti Sains Malaysia has recorded more than 350 articles about the drug in five local newspapers. In other words, Malaysians on average have been getting their daily dose of Viagra news and it is expected to go on in the months ahead. The number of items that have appeared in the local media can be considered unprecedented. In a way it is ironic in the sense that never has a product that is yet to be made available "legally" in the market has had so much publicity. This is even more worrying considering the fact that much of the reporting is brief, and some carry unbalanced and incomplete information. Some even bordered on sensationalism. This raises concern that there are bound to be misconceptions as reported in other countries as well. The concern is felt even more considering that Malaysia has a vibrant young population who are sexually active.

Indeed, Viagra has raise the curiosity of many segments of society, generating discussions and jokes. The mood is one of cautious optimism. The Health Minister is correct when he was quoted as saying we should be concerned about the adverse effects this drug can bring, despite recognising its usefulness. Given the prevailing situation about the scarcity of accurate information, this statement cannot be overemphasised.

The death toll related to Viagra as of November 1998 stands at 130 cases, although many more deaths were allegedly being reported in other countries. Not surprisingly some the post-marketing information released to date does show that there are cases of "misuse" due to a lack of information or otherwise caused by "drug misadventure" on the part of the patients.

Although the product is still regarded as "safe" this is only in the context of proper and correct usage.

The withdrawal of the anti-obesity drugs "Fen-phen" just a few months before should continue to remind us that no drugs are safe until they are used as directed with full understanding of their implications.

To this end, the FDA has instructed stronger warnings to be labelled on the product in attempting to avert further deaths. Malaysians had the full benefit of such safety measures due to the long time taken to register the drug in the country.

Even then, labelling alone is not a foolproof measure because Malaysians are not accustomed to reading labels and the general awareness about medicines is rather low.

Moreover, in many cases, medicines have never been properly labelled and little information is "dispensed" with the medicine. This has not bothered the patients at all. Yet for Viagra all these will make a difference. And the difference could be between life and death. It is therefore vital that the public be exposed to all the necessary precautions as soon as possible in the form of public education on the use of Viagra, if not all medicines. The role model set by the government hospitals with their drug counselling services is indeed a good point to start.

Whatever the merit of the case, it is indeed heartening to learn that to date there’s has been no major untowards incidences involving the drug since it has being registered. Indeed, the sales too has not shown any unusual trend. This is rather encouraging given the media type surrounding the product.

For its part, the National Poison Centre attempted to play its role in redressing the situation by creating a locally available website named VIAGRALERT since December 1998. It is aimed at redirecting the consumers and professionals to a number of selected websites about the product. The response to date have been encouraging.

In so doing, it is hoped more active and comprehensive self-directed learning about the subject would continue. Apart from links to other prominent websites, quizzes and moderated discussion have been added where users can actively participate in keeping themselves well-informed.

There is also a regular news update that will bring the latest reliable information to the public. For the professionals, a free search engine has been integrated enabling them to source the latest research in the field.

All these are intended to alert Malaysians on the need to be fully informed about their medication, particularly on drugs like Viagra. A full blown colour image and description of the tablets are also incorporated so that patients can as far as possible distinguish them from fakes and counterfeit products.

 VIAGRALERT (http://prn.usm.my/viagra.html) is divided into five basic sections. The news update resources for consumers featuring less technical information on all effects of the drugs, resources for professionals, search and selected readings giving access to a free search engine to databases at the National Institutes of Health in the US, and articles and books on related subjects and special section on erectile dysfunction (or impotence) are also featured.

There is also a section on alternative solutions. Some of these alternatives have been tried and proven to be effective albeit they work quite differently from Viagra. A Bahasa Malaysia version is also available.

Viagra Fresh Flower

Cut flowers stay fresh-looking if Viagra is put in their water, according to a report in the medical publication Arzte Zeitung, citing research at Bar Ilan University in Ramat Gan, Israel, as well as Newcastle University in Australia.

PRN CONSULT

Review on

Sildenafil (Viagra)

A potential threat or breakthrough for erectile dysfunction

by Ayesha Faiq Ahmad MSc

Male erectile dysfunction (ED) is a common problem encountered in men between the ages of 40-70 years. It is defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Until the 1970s it was traditionally referred to as impotence and all too often, patients were given reassurances that they are "over-the-hill" and their days of sexual intimacy are over. Significant morbidity is associated with ED. It impairs the quality of life, and is associated with depression, increased anxiety and poor self-esteem in affected patients’. In-spite of this, seems to be a very sensitive issue and most individuals do not wish to be made aware. And our social setup and religious beliefs play an important role in several men not seeking effective treatment of this curable symptom.

But dramatic changes have occurred in the treatment of erectile dysfunction. Existing treatments include use of vacuum devices, implants, intracaver-nosal injections and intrauretheral suppositories. Men experiencing impotence have long hoped for a pill that would allow them to have normal erections and with the launching of Viagra, dreams seem to have come true.

This article will look at the potential be-nefits and risks associated with the use of Sildenafil in the treatment of erectile dysfunction. The approach is to provide information for improved decision making when prescribing the drug.

Erectile dysfunction and its causes

The process starts with the brain registering a sexual stimulus. The brain then orchestrates a cascade of nerve signals that run through the spinal cord to the penis. Here, the cavernosal nerves release nitric oxide, a gas that quickly penetrates the smooth muscle cells that form the penis’ spongy tissue. The nitric oxide causes the cells to produce a substance called the cyclic guanosine monophosphate (cGMP), which has an expansive, relaxing effect. The arteries feeding the penis expand and the smooth muscle relaxes, opening up tiny sacs in the erectile tissue that then swell with blood. The two main chambers of the penis, the corpus cavernosa, fill and the organ becomes so engorged that the veins that usually drain away blood are pressed shut against the tough outer membrane of the erectile chambers. The result is erection.

However, nature, recognising the disadvantage of having to experience a permanent erection, has provided an enzyme called the phosphodiesterase type 5 (PDE5), that breaks down the cGMP. When the sexual signal decreases, the PDE5 levels supersede those of the declining cGMP levels and the erection returns to the flaccid state.

In men with diagnosed ED, the smooth muscle never relaxes enough for the penis to get hard and remain so until satisfactory performance of the sexual act.

Several studies have been conducted to determine the cause of ED. ED is reportedly the most common sexual problem in men after premature ejaculation. In the U.S alone accounting for more than 30 million men are affected. Some of the causes are elaborated in Table 1.

Risk Factors Associated

Although considerable advances have been made in the diagnosis and treatment of ED, there remains a significant underdiagnosis of the condition. The NIH Development Panel Conference on impotence report and the Massachusetts Male Aging study remain to date the most useful sources of information of ED.

Increasingly it is recognised that maintaining quality of life has profound implications for an individual’s health. Men with ED have an impaired quality of life compared with unaffected men. It isknown that the prevalence of ED increases with age affecting 5% of 40 years old, 20% of 60 years old and 40% of 80 years old and the risk factors associated with ED increase with age and overlap extensively with risk factors associated with cardiovascular diseases such as hypertension, smoking and hypercholesterolemia. However, there is little or no information on the prevalence of ED in relation to the ethnicity or socioeconomic status. Anecdotal evidence suggests variation in the attitude towards sexuality between cultures but there is no data to support this.

Patients reluctance to seek treatment maybe due to mistaken beliefs about its causes and potential for treatment, feeling of embarrassment, or the perception that, compared to other medical problems, ED is a low priority concern.

Although age is associated with increased likelihood of many of the risk factors for ED (table 2), the assumption that ED is a natural concomitant of the aging process is not justified.

Diagnosis

Evaluation and management can be readily integrated into a physician’s office practice based on an appreciation of a wide variety of pathologies and other risk factors associated with ED. The physician can determine, through careful, sensitive questioning, physical examination and a few diagnostic tests the exact cause and risk factors associated with ED.

As many as 40% of male patients over 50 years experience some degree of ED. Therefore, the importance of obtaining a detailed sexual history cannot be over estimated because, in addition to providing almost all of the needed information, it assures a patient that physicians are dealing with the problem seriously. Indeed, selecting the most appropriate therapy, considering the risk factors for the condition and the desires of the couple, can often be achieved without the need to undertake extensive testing. In this context, a variety of questionnaires designed to evaluate male sexual dysfunction are available that the physicians may find useful, for example, the International Index of Erectile Dysfunction and from "The practical approach to the evaluation and treatment of erectile dysfunction: a private practitioner’s viewpoint".

Some diagnostic tests used are listed below.

Diagnostic tests for Erectile Dysfunction

Treatment

A detailed appraisal of some of the classical therapies is given in the American Urological Association Erectile Dysfunction Clinical Guidelines. These guidelines although, written with an urologist in mind are nevertheless useful for practitioners also.

In deciding what treatment options to discuss with the patients and their partners, primary care physicians need to bear in mind that ED will often involve a mixture of causes and that the psychological factors will usually be present in some degree. A goal directed approach is recommended, in which patients and their partners determine the most appealing treatment option in consultation with the physician. Treatment rarely needs to be invasive. Information on the effectiveness, possible complications, and cost of each alternative should also be provided. Some patients may benefit from counseling or psychotherapy. A patient’s drug profile must be reviewed with a view to eliminating unnecessary medication although that will rarely affect erectile function.

Although as yet there is no universal applicable medical treatment for ED, in appropriately selected patients medical treatment can be most effective.

Sildenafil citrate (Viagra)

Since the introduction of Viagra in March ’98, first line therapy for ED has changed dramatically. Although traditional treatments still maybe appropriate, nowadays, most men presenting with ED are seeking a prescription for Viagra.

The FDA website give details of the reports of 130 cases of patients who have died after being prescribed Viagra inspite of detailed placebo controlled studies which describe the safety of the drug in most groups of men. Other studies have also shown that there is whatsoever no relationship between sildenafil and the cardiovascular effects with which the people have reportedly died of. Therefore, in the midst of all the development, it is crucial to consider Viagra a breakthrough medication or a potential risk for the treatment of ED.

A Breakthrough Medication

Sildenafil is indeed a significant breakthrough in therapy for erectile dysfunction. The study by I. Golgstein et al provided the much needed data for scrutiny by the medical community with regard to the efficacy, pharmacokinetics, dosing and side effects of sildenafil. Some other studies have been carried out in the double blind crossover fashion in patients with diabetes and those with a mean age of 47.9 years to determine the efficacy and safety of oral sildenafil.

Sildenafil is a selective inhibitor of (PDE5) and was originally investigated as an anti-anginal medication. It has considerable effect on the biochemical pathway mediating erection. PDE5, found in high concentrations in the penile corpus cavernosum, is responsible for the breakdown of cGMP but does not catabolize cyclic adenosine monophosphate. As an inhibitor of PDE5, sildenafil produces elevated levels of cGMP in the corpus cavernosa, generated through the nitric oxide-cGMP pathway only under conditions of sexual stimulation. The increase in the cGMP results in smooth muscle relaxation in both the penile arterial vessels and corpora cavernosa, leading to improved erectile function in patients from erectile dysfunction.

It is effective in improving the erectile dysfunction. It is available in three doses of 25mg, 50 mg and 100 mg tablet. The drug is rapidly absorbed and has a short half-life. Therapeutic dose is achieved in 0.5-2.0 hours when taken 1 hour before having sex. The onset of action is 20 minutes and the effect can last 8 hours or longer. It is 96% plasma protein bound, metabolized in the liver and has a terminal half-life of 4.0 hours. It does not have appear to have a high affinity for the other PDEs (PDE1- PDE6) found elsewhere in the bodies except for PDE5.

Dose escalation studies have shown that the effectiveness is dose related (p<0.001); evaluated by responses to questions 3 and 4 of the International Index of Erectile dysfunction, a validated, multidimensional and self administered questionaire use in another study by the author and the global-efficacy question (Did the treatment improve your erection?). Of the 532 men involved in the study 69% were successful at attempting sexual intercourse as compared with only 22% receiving the placebo.

Recognising the fact that in most men ED is a multifactorial problem, the study enrolled men with a variety of causes of the disorder and conducted the study in their normal environment. The therapeutic efficacy was found to be independent of the case of the ED. The safety studies showed that on 8% of men discontinued due to different adverse effects that were eliminated with discontinuation of therapy. This proved that sildenafil was well tolerated. Since the study involved men aged 20-87, it was concluded that it could generally be used in all age groups of men.

Potential risk factors

With the development of new and effective treatments for ED, awareness and consideration need to be given to these overlapping risk factors. Since the introduction of sildenafil into the market as an effective oral therapy for ED, reports indicating the adverse effects of the drug associated with cardiovascular problems has prompted a more strict screening process to be adopted before prescribing the drug. The risk factors listed in Table 2 give a detailed insight into the potential risks that the physicians can look for when a patient walks in with ED. However, some consideration needs to be given to the overall cardiovascular profile of sildenafil.

Some researcher (Zusman et al) consider the following groups of patients as being at high risk.

            3. Special risk groups

Commonly observed adverse effects

Carefully controlled studies in patients treated with 25-100mg doses of sildenafil show that the common cardiovascular adverse effects are:

Inhibition of PDE5 in the vascular smooth muscle is considered to be the mechanism responsible for these events.

There are some other common noncardiovascular adverse events after oral adminstration of sildenafil. These adverse events are consistent with the known pharmacological properties of sildenafil and/or tissue specific locations of PDE5.

Because several important groups have been excluded from most clinical trials, safety data is limited for patients who

Therefore, prescriptions for sildenafil for any of these groups should be done with caution.

Conclusion

ED is a common medical condition that shares a number of risk factors with cardiovascular diseases. Sildenafil is first of a new class of orally active drugs designed to treat ED. Sildenafil is rapidly absorbed, has a short plasma half life, and is selective at inhibiting PDE5. This inhibition results in increased levels of cGMP, which induces the smooth muscle relaxation, vasodilation, and restores the effective erectile function in men with ED.

ED and adverse cardiovascular events are common in older men and are associated with multiple double risk factors, such as smoking, hypertension, diabetes and hyperlipidemia. Consequently, strokes, heart attacks, and deaths are more likely to occur among the population of men most at risk of ED. The distribution of these risk factors in the patients taking sildenafil since the drug was launched is broadly in consistence with the clinical trials (risk groups and groups of patients excluded from the trials).

Extensive clinical testing with the duration of therapy of up to 1 year has shown that overall treatment with sildenafil, taken up to once daily as needed, is well tolerated. But despite the data present, physicians, urologists and endocrinologists should nontheless assess a patients ability as well as coexisting risk factors especially the cardiovascular system before prescribing the medication.N

Table 1 Types of erectile dysfunction and their prevalence

Table 2 Some risk factors associated with erectile dysfunction