MARK R. LICHT, MD
`Head, Section of Sexual Dysfunction and Prosthetic Surgery,
`Cleveland Clinic Florida, Ft. Lauderdale
`
`Sildenafil (Viagra)
`for treating male erectile dysfunction
`Ia ILDENAFIL
`ITRATE (Viagra ) was recen tly
`Dl app roved by
`the Food and Drug
`Administration for treating ma le erectile dys(cid:173)
`fun ction. The manufacture r, Pfizer Inc,
`is
`aggre ively marketing the drug directly to
`pati nts, and media coverage h as bordered on
`sensationalism .
`
`• ABSTRACT
`Sildenafi I, 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.
`
`• KEY POINTS
`
`The usual dosage of sildenafil is 50 mg by mouth, 1 hour
`before initiating sexual activity.
`
`Sildenafi I is strictly contraindicated 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.
`
`See editorial, page 33 I
`
`N ot urprisingly, early sales h ave been out(cid:173)
`stand ing. In fact, patients are aggress ive ly
`dema nding the drug from physic ians in a fren(cid:173)
`zy never before seen with the re lease of a new
`medication.
`The sudden popularity of sildenafil may
`have taken many physic ian s by surprise.
`Howeve r,
`it remains incum be nt upon th e
`phy ician to perform a thorough history and
`physical examinati n before prescribing silde(cid:173)
`nafil, as well as to discuss r alistic expectations
`of th drug's effectiveness with the patient.
`This article review th pharmacology and
`use of sildenafil.
`
`• ERECTILE DYSFUNCTION
`IS COMMON
`
`By one estimate, 52% of m n between the ages
`of 40 and 70 have o me impa irment in erectile
`function.! Many treatments h ave been tried,
`including vacuum erect ion dev ices, prosthetic
`imp lants, and vasoactive drugs that are either
`inj ected into the corpus cavernosum or insert(cid:173)
`ed into the urethra. A lthough th ese th erapies
`can improve or restore erectile function, each
`of them eith er requires the use of mechanical
`dev ices or is invas ive. Up to now, no oral med(cid:173)
`ications for erectile dysfunction have been
`successful.
`
`CLEVELAND CLIN IC JOURNAL OF MED IC INE
`
`VO LU ME 65 • NUMBER 6
`
`JUNE 1998 301
`
`Page 1
`
`ARGENTUM EX1016
`
`

`

`SILDENAFIL
`
`LICHT
`
`Did treatment improve your erections?
`Results of sildenafil in 416 men with
`erectile dysfunction
`
`100
`
`"' ~ 80
`en
`c
`"0
`c
`0
`0.
`
`"' ~
`+-' c
`Q) :.:
`Q)
`c..
`
`Placebo
`
`5 mg
`
`25 mg 50 mg 100 mg
`Si ldenafi I
`
`Did treatment improve your ability
`to achieve or maintain erections?
`
`• Abi lity to achieve erections
`• Ab ility to maintain erections
`
`5
`
`4
`
`3
`
`2
`
`-1<
`~
`0
`u
`"' c
`
`C1l
`Q)
`
`2
`
`Placebo
`
`5 mg
`
`50 mg 100 mg
`25 mg
`Sil denafil
`
`* 1 =never or almost never; 5 = almost always or always
`
`SOURCE: DATA FROM LUE ET AL, REFERENCE 4
`
`FIGURE 1
`
`• PHYSIOLOGY OF ERECTIONS
`AND SILDENAFIL ACTION
`
`In its flaccid state the penis receives minimal
`blood flow. Smooth muscle cells within the
`paired corpora cavernosa-
`the erectile cham(cid:173)
`bers of the penis-are normally in a contract(cid:173)
`ed state under sympathetic nervous system
`control. Sexual arousal stimulates the parasym(cid:173)
`pathetic nervous system, which initiates relax(cid:173)
`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 ) Nitric oxide (NO) diffuses into
`smooth muscle cells, where it activates the
`guanylate cyclase enzyme. This increases the
`intrace llular
`level of cyclic guan os ine
`monophosphate (cGMP), and smooth muscle
`relaxation ensues. Thus, the neuronal N O(cid:173)
`cGMP system is the main mechanism for cor(cid:173)
`poral smooth muscle relaxation and develop(cid:173)
`ment of an erection.
`The erection subsides when phosphodi(cid:173)
`esterase (POE) enzymes catalyze the break(cid:173)
`down of cGMP ( SEE HOW SILFENADIL POTENTIATES
`ERECTIONs ). One of the POE enzymes, POES, is
`the active isoenzyme involved in the metabo(cid:173)
`lism of cGMP in the penis. S ildenafil citrate is
`a selective inhibitor of PDES . By inhibiting
`cGMP breakdown in a dose-dependent fash(cid:173)
`ion in penile smooth muscle, sildenafi l has
`been shown in vitro to potentiate the natural
`process leading to penile erection)
`
`• CLINICAL TRIALS WITH SILDENAFIL
`
`In trials to date, sildenafil appeared to be
`effective and well-tolerated and had few sig(cid:173)
`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(cid:173)
`afil in various doses or placebo to 416 patients
`with erectile dysfunction. T he 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
`
`302
`
`CLEVELAND CLINIC JOURNAL OF MEDICINE
`
`VOLUME 65 • NUMBER 6
`
`JUNE 19 98
`
`Page 2
`
`

`

`II
`
`• 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. ---------"''~;:o-------~ ....
`
`NITRIC OXIDE activates the enzyme - - - - ----"'t--- - --
`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. - -- - cGMP
`
`PHOSPHODIESTERASE 5 (PDES) breaks - --
`down cGMP into inactive products, causing
`smooth muscle cells to resume their usual
`contracted state.
`
`- - - ~ ! M~
`
`Metabolites
`
`SILDENAFIL blocks the action of PDES, allowing cG MP
`to accumulate and potentiatin g and maintaining penile
`erections.
`
`to grade their ability to ach ieve and maintain
`an erection on a scale of 1 to 5, in which 1 rep(cid:173)
`resented "never or almost never" , and 5 repre(cid:173)
`sented "always or almost always" (FIGURE 1) .
`A gain, all differences were statistically signifi(cid:173)
`cant from placebo (P < .0001).
`A dverse effects were few and mild, and
`included:
`• H eadaches (reported by up to 11 % of
`the men)
`• Vasodilation (8.5%)
`• Dyspepsia (8.5 %)
`• Diarrhea (4.9%)
`• Visual disturbances (a blue tinge to
`
`vision, sensit ivity to brigh t light, and blu rred
`vision, all mild and tran i nt, experienced by
`a few pat ients).
`The authors concluded that sildenafil is
`an effective and well-tolerated treatmen t for
`erectile dysfunction of differen t etiologies.
`
`Long-term study
`Buvat et alS recently reported on the results of
`a 1-year open-label extension study using
`sildenafi l in 3 17 patients with erectile dys(cid:173)
`function of no known organ ic cause. They
`found that 27 1 patients (87.1 %) cont inued to
`benefit from taking sildenafi l after 1 year.
`
`CLEVELAND C LI NIC JOURNAL OF MEDICINE
`
`VOLUME 65 • N UMBER 6
`
`JUN E 1998
`
`303
`
`Page 3
`
`

`

`SILDENAFIL
`
`LICHT
`
`II
`
`Only 13 patients (4.2% ) withdrew from the
`study because of lack of drug efficacy, and only
`3 patients (1 %) h ad adverse events attribut(cid:173)
`able to sildenafil; these included headache,
`facial flush ing, 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(cid:173)
`eral vascular disease, or pelvic surgery.
`Patients should undergo a complete his(cid:173)
`tory and physical examination . A sexual his(cid:173)
`tory should also be obtained. Routine labora(cid:173)
`tory testing hould include a serum testos(cid:173)
`terone level.
`
`• CONTRAINDICATED WITH NITRATES
`
`in
`strictly contraindicated
`i
`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(cid:173)
`disiac, nor does it initiate a rapid-onset erec(cid:173)
`tion as is achieved with a pharmacological
`inj ection . 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(cid:173)
`cal response and adverse effects. Patients with
`cirrhosis or severe renal insufficiency should
`start at a 25 mg dose.
`Si ld en afil is expensive: approx imately
`$8 to $ 10 per pi ll . Therefore, I reco mmend
`that the patient try 50 mg for three doses .
`If he cannot achieve an erection sufficient
`for intercourse at this dose, then h e should
`try 100 mg for three doses. If the patient is
`still unable to achieve intercourse while
`being treated with sild en afil, he should
`exp lore o ther treatment options with his
`physician.
`The manufacturer currently does not rec(cid:173)
`ommend the use of sildenafil together with
`any other form of pharmacological treatment
`for erectile dysfunction. However, as physi(cid:173)
`cians learn about the efficacy of the drug and
`its limitations, sildenafil may eventually be
`used as an adj unct to improve the effects of
`other forms of therapy in patients whose erec-
`tile dysfunction is difficult to treat.
`Ill
`
`• REFERENCES
`1. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ,
`McKinlay JB. Impotence and its medica l and psychosocial
`correlates: Results of the Massachusetts Male Aging
`Study. J Urol1994; 151 :54-61 .
`2. Palmer RMJ, Ferrige AG, Moncada 5. Nitric oxide re lease
`accounts for the biological activity of endothelium(cid:173)
`derived relaxing factor. Nature 1987; 327:524-526 .
`3. Ballard SA, Burslem FMF, Gingell CJC, et al. In vitro pro(cid:173)
`f ile of UK-92,480, an inhibitor of cyc lic GMP-specific phos(cid:173)
`phodiesterase 5 for the treatm ent of ma le erectile dys(cid:173)
`function (abstract). J Urol 1996; 155:676A.
`lue TF, and t he Sildenafil Study Group. A study of si lde(cid:173)
`nafil (Viagra), a new oral agent for the treatment of
`male erecti le dysfunction (abstract). J Urol 1997:
`157:181A.
`5. Buvat J, Gingell CJ, Jardin A, et al. Sildenafil (Viagra), an
`ora l treatment for erecti le dysfunction: A 1-year, open(cid:173)
`label, exten sion study (abstract). J Urol 1997; 157:204A.
`
`4.
`
`ADDRESS: Mark R. Licht, MD, Section of Sexual Dysfunction
`and Prosthetic Surgery, Cleveland Clinic Florida, 3000 West
`Cypress Creek Road, Ft. Lauderdale, FL 33309.
`
`One Hour Category I CME Credit is now
`available ONLINE 1 at the
`Cleveland Clinic Journal of Medicine
`Web site:
`www.ccf.org/pc/gim/cme/opencme.htm
`
`Sildenafil is
`not an
`aphrodisiac
`
`I
`
`304
`
`CLEVELAND CLINIC JOURNAL OF MEDICINE
`
`VOLUME 65 • NUMBER 6
`
`JUNE 1998
`
`Page 4
`
`