C U R R E NT D R UG T H E R A PY
`
`D O N A LD G.
`
`MARK R. LICHT, MD
`Head, Section of Sexual Dysfunction and Prosthetic Surgery,
`Cleveland Clinic Florida, Ft. Lauderdale
`
`Sildenafil (Viagra)
`for treating male erectile dysfunction
`
`ABSTRACT
`Sildenafil, the first oral drug for treating male erectile
`dysfunction, appears effective and well tolerated. However,
`more time and experience will be needed to establish this
`drug's true efficacy and safety.
`K EY POINTS
`The usual dosage of sildenafil Is 50 mg by mouth, 1 hour
`before initiating sexual activity.
`
`Sildenafil is strictly contralndicated In patients using oral or
`transdermal nitrates, as It dangerously potentiates the
`hypotensive effects of these drugs.
`
`Patients should understand that sildenafil only potentiates
`penile tumescence: it Is not an aphrodisiac and does not
`produce Instant erections.
`
`ILDENAF1L C I T R A TE (Viagra) was recently
`approved by
`the Food and Drug
`Administration for treating male erectile dys-
`function. The manufacturer, Pfizer Inc,
`is
`aggressively marketing the drug directly
`to
`patients, and media coverage has bordered on
`sensationalism.
`
`See editorial, page 331
`
`Not surprisingly, early sales have been out-
`standing. In fact, patients are aggressively
`demanding the drug from physicians in a fren-
`zy never before seen with the release of a new
`medication.
`The sudden popularity of sildenafil may
`have
`taken many physicians by surprise.
`However,
`it remains
`incumbent upon
`the
`physician to perform a thorough history and
`physical examination before prescribing silde-
`nafil, as well as to discuss realistic expectations
`of the drug's effectiveness with the patient.
`This article reviews the pharmacology and
`use of sildenafil.
`
`• ERECTILE DYSFUNCTION
`IS C O M M ON
`
`By one estimate, 52% of men between the ages
`of 40 and 70 have some impairment in erectile
`function.1 Many treatments have been tried,
`including vacuum erection devices, prosthetic
`implants, and vasoactive drugs that are either
`injected into the corpus cavernosum or insert-
`ed into the urethra. Although these therapies
`can improve or restore erectile function, each
`of them either requires the use of mechanical
`devices or is invasive. Up to now, no oral med-
`ications for erectile dysfunction have been
`successful.
`
`CLEVELAND CLINIC JOURNAL OF MEDICINE
`
`VOLUME 65 • NUMBER 6
`
`JUNE 1998
`
`3 01
`
`ATI 1025-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`SILDENAFIL
`
`LICHT
`
`i m p r o ve y o ur e r e c t i o n s?
`D id t r e a t m e nt
`Results of s i l d e n a f il
`in 416 m en w i th
`e r e c t i le d y s f u n c t i on
`
`100
`
`R
`
`01
`CI
`c
`-O
`c
`o
`a.
`
`01
`Q_
`
`80
`
`60
`
`40
`
`20
`
`5 mg
`
`50 mg
`25 mg
`Sildenafil
`
`100 mg
`
`Placebo
`
`i m p r o ve y o ur a b i l i ty
`D id t r e a t m e nt
`to a c h i e ve or m a i n t a in e r e c t i o n s?
`
`Ability to achieve erections
`Ability to maintain erections
`
`i ® 3 . 60
`
`3.28 ¿ 32
`
`2.93 2.95
`
`2.00 2.05
`
`1
`
`Placebo
`
`5 mg
`
`50 mg
`25 mg
`Sildenafil
`
`100 mg
`
`*1 = never or almost never; 5 = almost always or always
`
`SOURCE: DATA FROM LUE ET AL, REFERENCE 4
`
`FIGURE 1
`
`• PHYSIOLOGY OF ERECTIONS
`A ND SILDENAFIL ACTION
`
`In its flaccid state the penis receives minimal
`blood flow. Smooth muscle cells within the
`paired corpora cavernosa—the erectile cham-
`bers of the penis—are normally in a contract-
`ed state under sympathetic nervous system
`control. Sexual arousal stimulates the parasym-
`pathetic nervous system, which initiates relax-
`ation of smooth muscle cells in the corpora
`
`cavernosa and arteries. The rapid increase in
`arterial blood flow to the penis fills the spongy
`tissue within the corpora cavernosa, leading to
`penile tumescence. Full rigidity occurs and is
`maintained when veins exiting the corpora are
`compressed, limiting outward blood flow.
`At a molecular level, nitric oxide released
`by neurons is the mediator of smooth muscle
`relaxation.2 Nitric oxide (NO) diffuses into
`smooth muscle cells, where it activates the
`guanylate cyclase enzyme. This increases the
`intracellular
`level of
`cyclic
`guanosine
`monophosphate (cGMP), and smooth muscle
`relaxation ensues. Thus, the neuronal NO-
`cGMP system is the main mechanism for cor-
`poral smooth muscle relaxation and develop-
`ment of an erection.
`The erection subsides when phosphodi-
`esterase (PDE) enzymes catalyze the break-
`down of cGMP
`(SEE HOW SILFENADIL POTENTIATES
`ERECTIONS). One of the PDE enzymes, PDE5, is
`the active isoenzyme involved in the metabo-
`lism of cGMP in the penis. Sildenafil citrate is
`a selective inhibitor of PDE5. By inhibiting
`cGMP breakdown in a dose-dependent fash-
`ion in penile smooth muscle, sildenafil has
`been shown in vitro to potentiate the natural
`process leading to penile erection.5
`
`• CLINICAL TRIALS WITH SILDENAFIL
`
`In trials to date, sildenafil appeared to be
`effective and well-tolerated and had few sig-
`nificant side effects or drug interactions. The
`true efficacy and safety of the drug, however,
`will not be completely known until it is on the
`market for 6 months to a year.
`
`Short-term study
`In a double-blind study, Lue et al4 gave silden-
`afil in various doses or placebo to 416 patients
`with erectile dysfunction. The etiology of the
`dysfunction was organic in 73% of the patients,
`psychogenic in 9%, and mixed in 18%.
`At
`the end of 8 weeks of treatment,
`patients answered a questionnaire. Asked if
`their erections had improved, significantly
`more men receiving sildenafil at any dose
`answered yes than did men receiving placebo
`(P <
`.0001). Further, response to the drug
`increased with dose (FIGURE 1 ).
`The men responded similarly when asked
`
`3 02
`
`CLEVELAND CLINIC JOURNAL OF MEDICINE
`
`VOLUME 65 • NUMBER 6
`
`JUNE 1998
`
`ATI 1025-0002
`
`

`

`• How sildenafil potentiates erections
`
`PARASYMPATHETIC NERVE FIBERS,
`in response to sexual stimulation, release
`nitric oxide, which diffuses into smooth
`muscle cells in the corpus cavernosum.
`
`NITRIC OXIDE activates the enzyme
`guanylate cyclase (GC), which catalyzes the
`conversion of guanosine triphosphate (GTP)
`to cyclic guanosine monophosphate (cGMP).
`
`CYCLIC GUANOSINE MONOPHOSPHATE
`(cGMP) causes smooth muscle fibers
`to relax; this relaxation allows arterial
`blood to flow into the corpus cavernosum.
`
`PHOSPHODIESTERASE 5 (PDE5) breaks
`d o wn cGMP into inactive products, causing
`smooth muscle cells to resume their usual
`contracted state.
`
`Metabolites
`
`Lacunar spaces
`of corpus
`cavernosum
`
`SILDENAFIL blocks the action of PDE5, allowing cGMP
`to accumulate and potentiating and maintaining penile
`erections.
`
`to grade their ability to achieve and maintain
`an erection on a scale of 1 to 5, in which 1 rep-
`resented "never or almost never", and 5 repre-
`sented "always or almost always"
`(F I G U RE 1 ).
`Again, all differences were statistically signifi-
`cant from placebo (P < .0001).
`Adverse effects were few and mild, and
`included:
`• Headaches (reported by up to 11% of
`the men)
`• Vasodilation (8.5%)
`• Dyspepsia (8.5%)
`• Diarrhea (4.9%)
`• Visual disturbances (a blue tinge to
`
`vision, sensitivity to bright light, and blurred
`vision, all mild and transient, experienced by
`a few patients).
`The authors concluded that sildenafil is
`an effective and well-tolerated treatment tor
`erectile dysfunction of different etiologies.
`
`Long-term study
`Buvat et al5 recently reported on the results of
`a 1-year open-label extension study using
`sildenafil in 317 patients with erectile dys-
`function of no known organic cause. They
`found that 271 patients (87.1%) continued to
`benefit from taking sildenafil after 1 year.
`
`CLEVELAND CLINIC JOURNAL OF MEDICINE
`
`VOLUME 65 • NUMBER 6
`
`JUNE 1998
`
`3 03
`
`ATI 1025-0003
`
`

`

`SILDENAFIL
`
`LICHT
`
`Only 13 patients (4-2%) withdrew from the
`study because of lack of drug efficacy, and only
`3 patients (1%) had adverse events attribut-
`able to sildenafil; these included headache,
`facial flushing, and indigestion.
`
`• WHO WILL BENEFIT FROM SILDENAFIL?
`
`Given the limited data from clinical trials, few
`conclusions can be reached regarding
`the
`effectiveness of treatment of specific causes of
`erectile dysfunction. Generally, patients with
`psychogenic erectile dysfunction or
`those
`with mild organic causes are most likely to
`benefit from sildenafil. The drug may not be
`as effective in patients with diabetes, periph-
`eral vascular disease, or pelvic surgery.
`Patients should undergo a complete his-
`tory and physical examination. A sexual his-
`tory should also be obtained. Routine labora-
`tory testing should include a serum testos-
`terone level.
`
`• CONTRAINDICATED WITH NITRATES
`
`in
`contraindicated
`is strictly
`Sildenafil
`patients using oral or transdermal nitrates, as
`it dangerously potentiates the hypotensive
`effect of these drugs.
`
`• DOSAGE AND USE
`
`To allow time for absorption, patients should
`take sildenafil 1 hour before initiating sexual
`activity. Sexual stimulation is then required
`for onset of action. The drug is not an aphro-
`disiac, nor does it initiate a rapid-onset erec-
`tion as is achieved with a pharmacological
`injection. Sildenafil can be effective for up to
`4 hours after it is ingested.
`The usual dosage is 50 mg by mouth,
`which can be increased to a maximum of 100
`
`mg or decreased to 25 mg depending on clini-
`cal response and adverse effects. Patients with
`cirrhosis or severe renal insufficiency should
`start at a 25 mg dose.
`Sildenafil is expensive: approximately
`$8 to $10 per pill. Therefore, 1 recommend
`that the patient try 50 mg for three doses.
`If he cannot achieve an erection sufficient
`for intercourse at this dose, then he should
`try 100 mg for three doses. If the patient is
`still unable to achieve
`intercourse while
`being
`treated with sildenafil, he should
`explore other treatment options with his
`physician.
`The manufacturer currently does not rec-
`ommend the use of sildenafil together with
`any other form of pharmacological treatment
`for erectile dysfunction. However, as physi-
`cians learn about the efficacy of the drug and
`its limitations, sildenafil may eventually be
`used as an adjunct to improve the effects of
`other forms of therapy in patients whose erec-
`tile dysfunction is difficult to treat.
`E3
`
`•
`
`REFERENCES
`1. Feldman HA, Goldstein 1, Hatzichristou DG, Krane RJ,
`McKinlay JB. Impotence and its medical and psychosocial
`correlates: Results of the Massachusetts Male Aging
`Study. J Urol 1994; 151:54-61.
`2. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release
`accounts for the biological activity of endothelium-
`derived relaxing factor. Nature 1987; 327:524-526.
`3. Ballard SA, Burslem FMF, Gingell CJC, et al. In vitro pro-
`file of UK-92,480, an inhibitor of cyclic GMP-specific phos-
`phodiesterase 5 for the treatment of male erectile dys-
`function (abstract). J Urol 1996; 155:676A.
`4. Lue TF, and the Sildenafil Study Group. A study of silde-
`nafil (Viagra), a new oral agent for the treatment of
`male erectile dysfunction (abstract). J Urol 1997:
`157:181 A.
`5. Buvat J, Gingell CJ, Jardin A, et al. Sildenafil (Viagra), an
`oral treatment for erectile dysfunction: A 1-year, open-
`label, extension study (abstract). J Urol 1997; 157:204A.
`
`ADDRESS: Mark R. Licht, MD, Section of Sexual Dysfunction
`and Prosthetic Surgery, Cleveland Clinic Florida, 3000 West
`Cypress Creek Road, Ft. Lauderdale, FL 33309.
`
`Sildenafil is
`not an
`aphrodisiac
`
`D i U l h U ^l
`S i ' J JH Z i i B Dl
`" f B z j 'f
`
`
`
`f
`
`One Hour Category I CME Credit is now
`available ONLINE i at the
`Cleveland Clinic Journal of Medicine
`Web site:
`www.ccf.org/pc/gim/cme/opencme.htm
`
`I
`
`3 04
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`C L E V E L A ND CLINIC JOURNAL OF MEDICINE
`
`V O L U ME 65 • NUMBER 6
`
`JUNE
`
`1998
`
`ATI 1025-0004
`
`