Twenty years ago last month, a medication called sildenafil was approved by the FDA. It is perhaps better known by its brand name of Viagra. Very few medications have enjoyed such widespread pop-culture attention. Sildenafil was mentioned in numerous TV shows, , and was the subject of a huge marketing campaign. In the early 2000’s it was almost impossible to watch TV without seeing a Viagra ad.
Sildenafil netted Pfizer billions of dollars in revenue, even though it was almost a failure. It was initially supposed to be a medication to treat angina, but it was largely ineffective. Pfizer almost abandoned the drug until a review of the patient interviews revealed that men who participated in the trials reported more and longer lasting erections. It was not a very effective treatment for heart disease, but this discovery raised new possibilities. It was re-packaged, re-studied, and re-branded as Viagra.ĚýĚýÂ Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â ĚýĚý
Sildenafil has had its fair share of criticism, mainly that people created the disease only to sell the cure. Prior to its approval by the FDA, erectile dysfunction (ED) was not really considered a serious medical condition that needed treatment. ED was seen as either a consequence of age, the result of stress or attributed to the rather nebulous concept of “performance anxiety.” Its marketing campaign also heralded the current age of direct to consumer advertising from the pharmaceutical industry. It is worth noting that direct to consumer advertising of pharmaceuticals is not permitted in Canada, although US commercials inevitably reach us anyway.
But the introduction of sildenafil did lead to a number of new realizations in the medical community. Even though people rarely discussed the problem with their physicians, ED was a far more common problem than anyone seemed to realize. It also demonstrated that sexual dysfunction in men was in fact a biologic problem and not psychological in origin as previously assumed. So while heavy marketing obviously played a role in the drug’s wild popularity, the initial and continued success sildenafil, as well as related medications like tadalafil (Cialis) or vardenafil (Levitra), demonstrated a genuine need on the part of patients that was previously being unmet.
Amazingly though, despite much ink having been spilt on the topic of sildenafil and its chemical cousins, many misconceptions persist. Firstly, sildenafil is not an aphrodisiac. It does nothing to increase sexual desire. Its main mechanism of action is to inhibit an enzyme called phosphodiesterase-5 (PDE-5), which causes the smooth muscle around blood vessels to relax and thereby increase blood flow. It was initially though that this would increase blood flow to the heart, but sildenafil ended up being more specific to the blood vessels supplying the corpus cavernosum, which controls erectile action. As such, it does not make someone want to have sex, it simply allows them to do so.
The other persistent misconception regarding the PDE-5 inhibitors is that they are potentially dangerous in patients with heart disease. The concern was first raised within a year of the drug’s approval by the FDA. By November of 1998, the FDA had received 130 reports of men who had . However, given that tens of thousands of prescriptions for sildenafil had been written, proportionally this number was actually quite small.
Nevertheless, the idea that the “little blue pill” was dangerous for men with a history of heart disease permeated into the popular culture. This idea was helped by the many movies and TV shows that found that the medication was a useful plot device. Indeed, comedy writers inevitably found that sex pills were funnier than diabetes medication ever could be.
The association however was ill founded. Of the reports made to the FDA, roughly 70% of the men had pre-existing heart disease and so the use of sildenafil may have been unrelated to their deaths. Subsequent data bore this out. A 1999 report in the found no increased cardiac risk with sildenafil and neither did a subsequent . Another study in the showed when men with stable heart disease took sildenafil it did not affect their exercise capacity or cause any symptoms of ischemia.
Sildenafil has even found a second life as a cardiovascular treatment. Although it failed in its initial role as a treatment of angina, it is now used to treat another condition called primary pulmonary hypertension. Primary pulmonary hypertension occurs when the pressure in the blood vessels leading from the heart to the lungs becomes elevated. Sildenafil, since it relaxes the smooth muscles around blood vessels, can improve blood flow, lower the pressure in the lungs and serve as a useful treatment for those with mild disease (in more severe cases other medications are generally preferred). Thus rather than being contraindicated in cardiovascular disease, it is sometimes used as a treatment (albeit in this rather rare condition).
There is one potential risk when it comes to sildenafil and the other PDE-5 inhibitors. If combined with nitrates they can result in a sudden and severe drop in blood pressure. The problem stems from the fact that nitrates and sildenafil act via the same mechanism to lower blood pressure. Therefore, using both together leads to a synergistic effect. In one , the combination of sildenafil with oral nitroglycerin (specifically isosorbide mononitrate or ISMN) resulted in a substantial drop in blood pressure to near dangerous levels. Combining sildenafil with nitro spray resulted in a lesser, but still important, drop in blood pressure. Thus the combination of PDE-5 and nitrates is strongly contraindicated. The combination of sildenafil with seems to be well tolerated and generally not dangerous.
Fortunately, nitrates are used much less frequently today than they were in decades past. Essentially, nitrates are helpful in relieving angina symptoms but do not really prevent future events. Thus they have been de-emphasized from current cardiovascular treatment in favor of medications that confer a mortality benefit. So while they are still used today, fewer patients find themselves taking nitrates on a daily basis.
Despite the numerous trials demonstrating that sildenafil does not provoke heart attacks, the idea remains fixed in the public awareness, no doubt helped along by the many TV shows and movies that suggest it does. Indeed, many pieces of cinematic fiction like to perpetuate the idea that sexual activity is dangerous and can bring on a heart attack when it is most convenient to the plot. In fact, this issue has been studied in the which evaluated whether sexual activity could trigger a myocardial infarction. It did find that the risk of a cardiac event was increased in the 2 hours after sexual activity but, in absolute terms, the risk was . It amounted to roughly a 0.01% increase in low risk individuals and 0.1% increase in high risk individuals. It’s also worth noting that regular exercise reduces that risk.
While anxiety regarding sexual activity in the setting of cardiac disease continues to exist, much of that fear is unfounded. The risk of a myocardial infarction during or immediately after sexual activity is very small and patients would be better served by working on other traditional risk factors like smoking, diabetes, blood pressure, cholesterol, an unhealthy diet and a sedentary lifestyle. The use of sildenafil and other drugs for erectile dysfunction is also generally safe and well tolerated with the only major contraindication being their combination with nitrates and the drop in blood pressure.
So much of our preconceptions regarding cardiac risk and sexual activity are derived from TV and movies, and they are often quite wrong. Cardiac patients can generally take sildenafil provided their physician reviews their medications to make sure no interactions will result. But as for suddenly keeling over while in the throws of passion, while it makes for a great plot twist on TV, it’s not particularly good science.
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