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208 Albersen et al

ral Phannacotherapy

Although many treatment modalities are available lar ED, this article mainly locuses onoral pharmacotherapy, which will efficienlly Ireat most palienls experiencing ED.When oral Iherapies lail, relerral lo a specialist should be considered except whenIhe primary care provider has a particular interest and co mlort in dealing wilh sexualilyissues.

PDE5 specific inhibitorsPDE5-specilic inhibilors (PDE5Is) are nonhydrolyzable analogs 1 cGMP and exerttheir beneficial effects on smooth muscle relaxation through competitively bindingto the catalytic sile 1 PDE5. Through slowing Ihe degradation 1 cGMP, these drugsproduce an intracellular accumulation of cGMP in smooth muscle cells in the arteriesand trabeculae of the corpus cavernosum ( Vi Fig. 1), resulting in relaxation of thesmooth muscle, increased arterial blood flow, and penile tumescence. 1 ;

Treatment of E with P ESI

In current treatment guidelines, PDE51s are recommended as the preferred pharmacotherapy far ED. 1IJ Numerous trals have established on-demand efficacy rates of 60to 70% in the general population, and postmarketing data confirms excellent safetyprofiles of the three compounds currently available in the United States (sildenafil, vardenalil, and tadalalil). , , Allhough a large crossover sludy showed an overall equivalence in the subjective perception of treatment benefits among all PDE5Is, the threecurrently available drugs differ from each other in time to onset of action and duration

1 aclion (sildenalil and vardenalil up lO 5 hours and ladalalil up lo 24-36 hours).' Thechoice of appropriate drug is based on patient and partner preference guided byphysician advice.: Jfl

Before intiation of treatment, patients should be informed that sexual stimulation isessential far the efficacy 1 the drugs. Although sorne men may experience limited efficacy a fter a first trial, these patients should be informed that results generally improvewith repeated dosing, and a minimum of six attempts should be made before treat

ment is considered a failure. The recommended starting doses are 50 mg for sildenafiland 1 mg lar vardenalil and tadalalil. The unique pharmacokinelic properties 1 ladalalil have led lo the approval 1 this drug as a daily Irealment lar ED al 2.5- and 5-mgdoses; this regimen may be best for patients who have frequent intercourse or thosewho desire to separate the act of taking the drug from sexual interactions. The lowesttherapeulic doses (25 mg 1 sildenalil and 5 mg 1 vardenalil and tadalalil on-demand)should be used when liver ar kidney failure is present or when the patient uses mediealion that inhibils the CYP34A palhway. Examples 1 Ihese drugs are keloconazole,itraconazole, erythromycin, clarithromycin, and HIV protease inhibitors. 1U However,patients taking medications that potentiate the CYP34A pathway, such as rjfampin,phenobarbital, phenytoin, and carbamazepine, may need higher doses for efficacy.lO

Safety profilePostmarketing surveillance has not shown increased myocardial infarction rates inpatients using PDE51s compared wilh age-malched controls.' However. eertainheart-relaled precautions must be considered in men laking PDE5Is. PDE51s are relatively contraindicated in patients with unstable angina pectoris, recent myocardialinfarction, certain arrhythmias, and poorly controlled hypertension. These patientsshould undergo cardiovascular examination and treatment fortheir heart-related candition befare initiating ED treatment. 1ll Furthermore, patients treated with nitrates ornitrale-donars should not take PDE5Is, and, use 1 PDE51s with certain ,,-blockers

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Evaluation and Treatment o Erectile Dysfunct ion 209

may result in postural hypotension. 1 \ Patients taking .-blockers tor prostate symptomsor blood pre s sur e con1rol should take POE51S with at least a 4-hour window betweendosing because of a theoretical risk of orthostatic hypotension, although so me

e vidence suggests 1hat the ris k is low in patien1s on long-term b l o c k e rtherapy . 1Patient s with prolongation of the QTc interval should not b e treated with vardenafil . .

Adverse eventsThe most c a mman adverse event s from PDE51s inelude heada e he , facial and ocularhypere m ia . na s al c ongest iono m yalgia, dyspepsia , and baek pain. These side effectsare attributable to specific inhibition 01 PDES and subsequen vasodHatation in tissues01her than the penis .' 1 Cangestion and flushing are more c a mman with s ildenafilrelative to the other PDESls, whereas myalgias and dyspepsia are more strongly associated with tadalatil and vardenafil. respectively. Other les s -common adverse eventsinvolve visu a l disturbances, most often at ributable to the inhibition 01 PDE6 in theco ne s of the retin a.; Ad ve rs e events a cc o unt far ap proximatel y 2 5 % of patientswho di s continue PDESI U5e, wher ea s th e mo s t common reason for discontinuationof PDE 5 s is lack of effic ac y.: 1 More s e rious ad ver se e vents are rare and nclude

s eizur e s, nonarteritie ischemi e optie neuritis, and acute hearing 1055, alth o ugh thee xact r o le af PDE Sls in these condltions i s deb a table and reports are n e c d o t l/ ~Palient s can generally be rea ss ured ttlat the ris k of serious long -term adverse eventsis low in appropriately s elected candidates fm PDE 51 herap y.

NonrespondersOf the patients who do no experience an initial response to POESI, between 30 and5 0 may be converted to respond e rs through re-education on proper dosing te c hnique and through d o se ~e s l t i o n Patients who discontinue tadala1il because ofside effects may benefit lrom the daily-dosing option (2.5 or 5 mg/d).26 ' Furtherm ore , addlti o n of exogenous te s tosterane supplementation may enhan c e PDESItherap y in individuals in whom hypogonadism is confirmed. ; ;] Because the efficacyof POE SI depends on the integrity 01 the NO pathwa y in producing cGMP. patientsin whom this pathway is disturbed will benelit far less from POESI treatment compared

with the general populati o n. Oisease states that diminish NO availability include denervation of the erectile ti ss ue after radical prostatectomy; severe diabetes: and downregulation of NOS express on, as may be seen in atherosclerosis , metaboliesy ndrome. aging , and hypogonadism. ; These difficult-to-treat patients benelit fromreferral to a sexual medicine specialist ar urologist for second-line treatment.

Alternative Oral Pharmacotherapy

Apomorphine SLApomorphine is a centrally acting nonselective dopamine agonist that exhibits D2-likeeffect s. It aets by binding to dopamine receptors in the hypothalamus and enhancesnaturally occurring pro-erectile signals.:\( ) t is available in 2 - or 3-mg doses but has notbeen approved in the Uniled Sta es far the treatment of ED. 1 ' It is rapidly absorbedthrough the sublingual route of administration and results in the development of anereetion within 20 minutes in more than two-thirds of patients. : O Apommphine has

lower efficacy and satisfaction rate s than POE5Is, and is mast effective in patientswith mild to moderate ED . H l It also is a valid alternative to PDESls ter patients inwhom psychogenie ED is suspected and in those who have contraindications toPOESls, such as those taking nitrates. The mosl common adverse events are eausedby nonspee ifie binding lo other subtypes af Ihe dopamine receptor and neludenausea , headache , and dizziness. :l l These efteets occur with relative high frequency,and have limited the usefulnes s of this drug.

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210 Albersen et al

YohimbineYohimbine is a natural peripheralJy and cen tralJ y acting 'J blocker. Ho wev er . litUeevidence shows its efficacy in tre a ting EO. and therefar e it is not currently re co mmended

in ma st guidelines for management of ED. It may have a role in patients who prefer naturalprodu e ts but s t1auld not be considered a recommended mainstream medical therapy. ;"

Vacuum onstriction Devices

The vacuum constriction device (VeO) creates negative pre ssure around the penis.the reby init iating passi ve engorgement of the sinusoidal spaces and creal ing an ereelion. Maintenan ce of ereetion is facilitated by application of a rubber cuff worn aroundthe base 1 the penis. Although efteetive in up to 90 % 1 patients, the use 1 a vaeuumde vice might b e percei ved as di sru pti ve. especiaUy b y yau nger men . O Local sideeffects are relatively minar and include bruising. some discomfort, and ejaculatoryobstru c tion. It is advised to limit the use of th e constriction band to 30 minutes to avaidski n necrosis. Contr aindica tions to veo use indude bleeding diso rders and the use ofanticoagulants. t

SecondLine TreatmentIntracavernous nd intraurethral therapyBefare the adve nt of PDE51,s intra cav ernous and intraurethral administration were theonly nonsurgic a l treatment aptions tor ED. The mast commanly used substance, andeurrently the only one approved by the U .S . Food and Orug Administration as a treatment 1 EO, is prostaglandin El PGE 1). PGE 1 activates adenylate eyelase and therebyraises intraeellular eAMP , with efleets analogous to those 1 cGMP (see Fig. 1). Theseelfeets are independent of the NO -eGMP pathway, making thi s treatment an exeellentaption for patients who do not experience response to PDE51 therapy. : Intraea ve mousPGEl therapy h as an overall satisf ae tion rate 1 approximately 80 .' '''

Ph en tolamine, papaverine, and vasaactive intestinal peptid e are also available farintraca ve rnou s injectian , although their role is limited t o combination therap y(commonly referre d to as bimix or trimix . PGE1 is also available far intraurethral

administration (medieated urethral system lar ereetion [MUSE]).Adverse events from these therapies include priapism , variable degrees of pain withinjecti on in approximatel y half of patients, and penile fibrosis after long-term use. :\Patients are advised to co nsult their physi c ian i1 they experience prolonged penilepain or an erection lasting up to or more than 4 hours, because aspiration of cavernousblood may be necessary for penile decompression . n Relative contraindications toinjeetion therapy include a history af priapism or bleedin -g disorders. Befare nitiationof therapy, pati e nts follow a short in-office training program. MUSE has many sideeffeets in common with intracavernous PGE1 , although it is less likely lo cause priapismand may ha ve marginal effic acy in many cases. MUSE has al so been associated wi thhypotension, syneope. urethral burning or paln, and vaginal irritation in the p r t n e r

Third-Line Therapy Surgery)

Implantation of a penile prosthesis. which can be either inflatable or malleable, is indi

cated far men in whom pharmacologic therapy is not etfective. Implantation of a penileprosthesis has satisfaction rates of 70 to 90 . but patients should b e aware of thedefinitive and irreversible nature 1 this surgery. 1 Adverse events include mechanicalfailure after several years of use (50% after a 1Oyear interval), in fection 1 -3 ), and,rarely, erosior1. . 1 \

Other surgical options available for ED include penile revascularization and venausligation. Outcomes 1 these surgeries in the general population 01 patients with ED are

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Evaluation and Treatment of Erectile Dysfun ction 211

poor. These surgeries should be reserved t r a select group 01 primarily youngpatient s and should b e pert o rmed in specialized centers only. 1

SUMMARY

ED is a pfevalent and important disease that has been associated with vari o us comor-bidities . The evaluation 01 pa1ients with ED should include a general health assess-ment lollo we d b y a di sc ussio n 01 reve rsibl e lact o rs and hf esty le changes that mighth e lp preserve erectile capacity. Numerous effective treatment options are currentlyavailable. A frank discussion about use and side effects 01 these therapies is requiredto optimize success. Although oral pharmacologic treatm en ts can be initiated andmonitored b y the primary car e physician, patients who d o not experience respons eto these tre a tments may be best served by referral to a sexua l medicine spe c iali stt r further assessment and consideration 01 other treatment options.

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