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USRF Research

Erectile Dysfunction (ED) update, 2003

Viagra vs the new PDE-5 Inhibitors: Levitra and Cialis

Leonard S. Marks, M.D.
Medical Director, USRF

Forbes Magazine Compares Viagra & Levitra

Hope for Men who Fail Viagra?

4th Quarter, 2003--- Two new ED drugs, vardenafil (Levitra, Bayer) and tadalafil (Cialis, Lilly/ICOS), have completed extensive clinical testing, and both drugs have gained FDA's approval. Both are inhibitors of type 5 phosphodiesterase (PDE-5), thus sharing the same basic mechanism of sildenafil (Viagra, Pfizer), which was approved in March, 1998. All three are taken orally prior to planned sexual activity, acting to increase blood flow in the penis in response to sexual stimulation. However, there are important differences between the three, differences that could influence safety, specificity, duration of action, and ultimately, public acceptance within this class of drug.

Giles Brindley and Drug Therapy for ED
Cardura (doxazosin) Modern drug therapy for ED was advanced enormously in 1983 when British physiologist Giles Brindley, Ph.D. dropped his trousers and demonstrated to a shocked AUA audience his phentolamine-induced erection. 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, ie, PDE-5 inhibitors.

PDE Inhibition and Smooth Muscle Relaxation
Phosphodiesterase (PDE) is an enzyme that causes breakdown of cyclic GMP, which is the direct intracellular mediator in the nitric oxide (nonadrenergic, noncholinergic) pathway. Discovery of this pathway led to a Nobel Prize in 1998 for the scientists responsible. The nitric oxide system causes relaxation of smooth muscle in blood vessel walls, ie, vasodilation, in various organ systems.

The direct intracellular mediator of the nitric oxide pathway is cGMP. PDE catalyzes the degradation of cGMP. This pathway is active in numerous organ systems, and as of this writing, a number of different PDEs are known. The various PDEs differ in their physiologic roles and tissue distribution. Type 5 PDE is concentrated in the penile smooth muscle of the corpus cavernosum, where its normal function is to inhibit erection by degradation of cGMP, the mediator of erection. Viagra and the new drugs Cialis and Levitra all inhibit PDE-5, which is an inhibitor for corporal smooth muscle relaxation, resulting in increased blood flow in the penis in response to sexual stimulation.

Comparison of Viagra, Cialis, & Levitra
No head-to-head trial comparing the 3 PDE inhibitors has been performed. However, some differences between the 3 are basic: a table has been created to illustrate the major differences. An obvious proviso is that extensive data are available on Viagra (more than 20 million men treated, more than 1100 peer-reviewed articles as of Feb. ’03), but only limited data on Cialis and Levitra. Drs. Gresser and Gleiter from the U. Tubingen in Germany have compared the three drugs via literature review (Eur. J. Med. Res. 7:435, 2002)

In brief, efficacy is approximately 70% with all 3 drugs. The side effect profile is similar among the 3 drugs, except that blue discoloration of vision (overlap with PDE-6 in the retina) is seen only with Viagra (<0.5%) and muscle aches only with Cialis (~5%). Otherwise, vasodilatory side effects (headaches, nasal congestion, flushing) are common with all, but are mild, and only rarely cause men to drop out of clinical trials (2-3% quit rate). All 3 will carry a contra-indication in men using organic nitrates. Otherwise, the long half-life of Cialis (17.5 hours) is noteworthy, earning this drug the nickname ‘weekender,’ as a single dose taken on Friday would still be exerting an effect Sunday (or even Monday).

Conclusion
Alternative PDE-5 inhibitors Cialis and Levitra will soon be in competition with Viagra, and the launch of these new drugs is certain to bring many men with ED into doctors’ offices. Aside from the long half-life of Cialis, and the excellent track record of Viagra, the differences between the 3 drugs are not great. All appear to be effective and safe, provided concomitant nitrates are avoided,. A potential for serious hypotension exists should an organic nitrate be used along with any of these three PDE-5 inhibitors.


 

 

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