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The Best of Pill Pushing - Viagra - Impotence used to be a hard nut to crack - (11/13/2017)

Pill Pushing
The ways in which medications have changed our culture
Ron Gasbarro, PharmD
The drug in question: Viagra (sildenafil)
The culture at that time: Following the sexual revolution of the 1960s and 1970s and the impact that the media had on subjects once considered taboo, people were more relaxed to take on topics of sexual dysfunction and the like. Impotence was one of those matters. For example, in a 1971 episode of CBS’ All in the Family, Meathead (Rob Reiner) has become impotent due to anxiety over his final college exams, so he goes to his father-in-law Archie (Carroll O’Connor) for advice. The cure: a fantastic report card. 
In 2000, the popular HBO hit series Sex and the City explored the difference between psychological impotence and physical erectile dysfunction. When the married couple Charlotte (Kristin Davis) and Trey (Kyle MacLachlan) are unable to consummate their relationship, Charlotte investigates whether Trey's erection wakes up when he goes to sleep. She did this by winding postage stamps around his penis when he was asleep to see if the band broke by morning. The cure: divorce.
In fact, as early as the late 16th century in France, male impotence was considered a crime, as well as legal grounds for a divorce [Roach, 2009]. Even today, impotence is a specific fault ground for divorce in some states, although, many states have no-fault divorces whereby the wife can file for dissolution of the marriage without specifically stating why. Thus, in real life, events do not always go so flawlessly in the bedroom. The National Institutes of Health (NIH) estimates that as many as 30 million men in the United States have erectile dysfunction or impotence. Erectile dysfunction may affect 30% to 50% of men aged 40 to 70 years, with age, smoking, and obesity being the main risk factors, although 20% of cases have psychological causes [Khera, 2011]. Obviously, there’s a big market for a treatment. 
The good, the bad, and/or the ugly: There have been many attempts to treat erectile dysfunction. Creams, penile injections, vacuum pumps, prosthetic implants, and alternative treatments such as yohimbine, as well as herbal concoctions, have been used with a modicum of success, depending on the contributing factors to impotence. Dr. John R. Brinkley initiated a boom in male impotence cures in the US in the 1920s and 1930s. His radio programs recommended expensive goat gland implants and mercurochrome injections to restore male potency [Lee, 2002]. A breakthrough of sorts in modern pharmacotherapy for erectile dysfunction made a significant advance in 1983 when British physiologist Giles Brindley dropped his trousers and demonstrated to a shocked Urodynamics Society audience his papaverine-induced erection [Klotz, 2005]. The drug Brindley injected into his penis was a non-specific vasodilator, an alpha-blocking agent, and the mechanism of action was clearly corporal smooth muscle relaxation. The effect that Brindley discovered established the fundamentals for the later development of specific, safe, orally effective drug therapies. 
Sildenafil in the pre-Viagra years was being tested in patients with hypertension and angina pectoris. Studies done at that time suggested the drug had scant effect on chest pains, but it could induce marked penile erections [Boolell, 1996a; Boolell, 1996b]. Millions of men around the world owe a salute to the 12 hard-working stiffs in the Welsh village of Merthyr Tydfil where, in 1992, their work testing this new drug produced firm evidence of its unexpected sex enhancing power [Boolell, 1996]. 
To understand how Viagra works, an understanding of how an erection works is helpful. Nitric oxide (NO) dilates blood vessels and is released with sexual stimulation from nerve endings in the corpus cavernosum (or shaft) of the penis. An enzyme then converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP) to produce the energy needed to produce an erection. cGMP causes the smooth muscle of the penis to relax, which causes an inflow of blood which then leads to an erection. cGMP is then hydrolyzed back to the inactive GMP by the magical enzyme phosphodiesterase type 5 (PDE5). Now all you need is candlelight, Mantovani, and you’re all set. 
What does Viagra have to do with the PDE5 enzyme? Men who suffer from erectile dysfunction often produce abnormally small amounts of NO. This means that the amount of cGMP they produce is broken down at the same rate and therefore does not have the time to accumulate and cause a prolonged erection. Viagra works by inhibiting PDE5. This means that cGMP is not broken down as fast, allowing the smooth muscle to relax and tumescence ensues [drugs.com, 2015]. Now that wasn’t so hard, was it? 
Impact of the drug on culture: Is Viagra a true medication used to treat a medical condition? Or is it just another “lifestyle” drug like marijuana, or even like prescription drugs such as norethindrone to postpone menstruation and minoxidil (Rogaine) to correct baldness? While humans have been searching for the fountain of youth since the time of Egyptian pharaohs and their quest to reverse time so they could enjoy their wealth and power, we do the same thing today. Only now, Big Pharma is involved and it knows a cash cow when one slams head on into it. 
People attempt to solve their problem in a very simple way. We are conditioned by the media to expect that every simple health problem can be relieved with a pill. This quirk of the human psyche has further been exploited by the pharmaceutical industry, which salivates knowing that people will buy all sorts of pills.
In a 2010 article by Rahman and colleagues on the way medications impact society, the researchers commented that our lifespan is increasing and hence the demand for many lifestyle drugs is also burgeoning in a large scale. Fueled by ample and frequent direct to consumer advertising, these lifestyle drugs could have some devastating consequences on the young, vibrant and ambitious population. The blatant advertisements and unceasing flaunting of products with supposed improvement in the physical, mental and sexual performances lead to an assault on the fragile mind of youngsters. This is a matter of serious psycho-sociological concern. While Viagra has some legitimate medical indications, a recent study shows that recreational use of Viagra is growing rapidly in men under 45 years of age. In a 4-year period, the use of Viagra in these relatively young men tripled, said the study, which looked at 5 million insured American males. What this study indicates is that Viagra is being used as a recreational drug, not as a drug to treat a medical condition. Thus, it belongs more in the category of pot and cocaine rather than being a medicinal pharmaceutical.
Where the drug is today: Viagra continues to be heavily advertised television and in print. And of course, your spam box is filled with emails beckoning you to buy whatever counterfeit cut-rate form of the drug that is being sold by off-shore hacks. “Little blue pill” jokes are a permanent feature of the pop culture landscape. According to drugs.com, Pfizer sold $1.165 billion worth of the little blue pill in 2013 [drugs.com, 2015]. 
Where would Viagra be without its longtime competitors Cialis (tadalafil) and Levitra (vardenafil) – both approved in 2003? All three drugs work the same way. But the entry of these later medications eroded the marketplace which was up to that time the leader. In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction drugs [Keith, 2000]. By 2007, Viagra's global share had plummeted to approximately 50% [McGuire, 2007]. Besides the availability of 2 other ED medications, along with several counterfeits and clones, reports of vision loss in people taking this class of drugs have scared away many potential users [Berenson, 2005].
But give the pharmaceutical industry credit for being creative. Viagra is being sold as a chewing gum in some countries – but not in the United States – under the name Viagra Jet. One study that compared the oral tablet with the chewable form showed that there was no perceivable difference in efficacy or onset of action [Rubio-Aurioles, 2012]. However, there were some negative comments. Many study participants complained about the taste, which some said left a residue in the mouth or produced discomfort in the throat. One patient also said that his partner complained about the taste. Patients also complained that the chewable tablet turned their tongues blue, was too large, and sometimes required obtaining a glass of water anyway.
A so-called “female Viagra” – the little pink pill for girls – is flibanserin (proposed names Girosa and Addyi), is being studied as a non-hormonal treatment for pre-menopausal women with hypoactive sexual desire disorder. Although it works in a completely different way than Viagra, it works to balance the chemicals in the brain (neurotransmitters) to evoke a healthy sexual response. Once considered a new form of antidepressant, this potentially huge moneymaker (at least in the eyes of hapless males) has not yet been approved for female dysfunction as of 2015. 
In 2014, a study was published in a Journal of the American Medical Association suggesting that the use of Viagra was linked to melanoma, a deadly form of skin cancer [Li, 2014]. Those men in the group who were Viagra takers had almost double the risk of developing melanoma than those who had never taken the drug, while those who were currently taking the drug had an 84% higher risk of developing melanoma, revealed the preliminary study. Researchers cautioned that the findings need to be further investigated but caution that this is another reason why people should protect themselves from the sun’s harmful rays. 
In a curious note, Israeli and Australian researchers discovered that 1 mg of Viagra dissolved in a vase of water can extend the shelf life of cut flowers, making them stand up straight for up to a week beyond their natural lifespan [Siegel, 1999]. The drug also slows down the ripening of delicate produce; tests were done strawberries, legumes, roses, carnations, broccoli, and other perishables. In this case, Viagra increases the vase life of the flowers by slowing the breakdown of cGMP, a pathway similar to how the drug produces erections of the penis. 
Ron Gasbarro, PharmD is a pharmacist, medical writer, and principal at Rx-Press.com. Write him at ron@rx-press.com.
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