PDE-5 Inhibitors for the Treatment of ED

Pharmacy Times
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Erectile dysfunction (ED) is a disorderthat affects more than halfof men >40 years of age.1 ED isdefined as the inability to achieve anerection adequate for sexual intercourse.It is more likely to occur in thepresence of increased age, diabetesmellitus, cigarette smoking, hyperlipidemia,hypertension, depression, andcardiovascular disease.2,3

ED is associated with a decreasedquality of life. It often goes untreatedbecause the sensitive nature of theissue leads to patient embarrassmentand underreporting.4 With recentadvances in oral therapy and publicattention paid to the problem, however,more patients are now seeking helpand using medications to treat ED.


Psychological, neurologic, hormonal,and vascular disorders all may contributeto ED. Nitric oxide (NO)-mediatedsmooth muscle relaxation of thecavernosal tissue and arterioles of thepenis is required for penile erection.3NO is released as a result of sexualstimulation. It then increases intracellularcyclic guanosine monophosphate(cGMP), decreases intracellularcalcium in the smooth muscle, andcauses relaxation of the cavernosalsmooth muscle and penile arterioles.5This action allows for increased bloodflow to the corpora cavernosa, leadingto tissue engorgement and penile erection.In ED, psychogenic and organicfactors alter the release of NO, decreasesmooth muscle relaxation, anddiminish the ability of the penis toachieve erection.5


Before selecting a treatment for ED,a full medical workup and a medicationhistory are necessary to determinethe etiology of the disorder.Medications must be reviewed toensure that the disorder is not druginducedbefore another treatmentoption is initiated. Some medicationsthat inhibit sexual function are betablockers,calcium channel blockers,selective serotonin reuptake inhibitors,and antipsychotics.6

Several agents are used to treat ED,including trazodone, alprostadil,yohimbine, testosterone, bromocriptine,pergolide, papaverine, and phentolamine.Many have unwanted sideeffects, however, and their use maynot be ideal for most patients.

Phosphodiesterase type 5 (PDE-5)inhibitors have become more favorablebecause of their efficacy and theiravailability in oral formulations. Thesemedications work by blocking thedegradation of cGMP by phosphodiesteraseenzymes, therefore potentiatingpenile smooth muscle relaxation.7Three of these agents are currentlyavailable by prescription: sildenafil(Viagra), tadalafil (Cialis), and vardenafil(Levitra).

Sildenafil was the first PDE-5 agent,released in 1998. It has a half-life of 4hours and reaches peak concentrationsin 1 hour. Administration with a highfatmeal leads to decreased absorptionand delayed onset of action.

Sildenafil is metabolized via thecytochrome (CYP) P450 3A4 isoenzyme,and it may interact with medicationsthat also utilize that metabolicpathway. Therefore, lower doses areneeded when it is given concomitantlywith ketoconazole, erythromycin, andsaquinivir, due to CYP 3A4 inhibitionleading to increased plasma levels ofsildenafil.8 Common side effects includeheadache, flushing, and dyspepsia.The use of sildenafil is contraindicatedwith the use of nitrates, and itshould not be taken within 4 hours ofan alpha-blocker.

A starting dose of 50 mg of sildenafiltaken 1 hour prior to sexual activity isrecommended for most patients, althougha dose of 25 mg is recommendedin patients >65 years of age.8,9Sildenafil should not be taken morethan once per day, with a maximumdaily dose of 100 mg.8 Like all PDE-5agents, the use of sildenafil alone willnot produce an erection; sexual stimulationis needed for a therapeuticeffect. Sildenafil is available in 25-, 50-,and 100-mg tablets.

Tadalafil is the most lipophilic of the3 available PDE-5 inhibitors. It reachespeak concentrations in 2 hours andhas a half-life of 17.5 hours.9,10 Unlikesildenafil or vardenafil, its absorptionis not altered by food intake. One benefitthat tadalafil has over the otheragents is a duration of action of 36hours, which may allow for more sexualspontaneity.5

Common side effects of tadalafilinclude headache, dyspepsia, and backpain.10 It is contraindicated with theconcomitant use of nitrates, and itshould be used with caution in patientstaking alpha-blockers, with theexception of tamsulosin.10

A starting dose of 10 mg of tadalafilis needed for most patients, and nodosage adjustment is required for those>65 years of age. Patients with moderaterenal impairment (creatinine clearanceof 30-50 mL/min) should startwith a 5-mg dose, with a maximum of10 mg every 48 hours.9,10 Patients taking3A4 inhibitors, such as ketoconazoleor ritonavir, should not exceed10 mg of tadalafil once every 3 days.Tadalafil is available in 5-, 10-, and 20-mg tablets.

Vardenafil is the most potent of thePDE-5 inhibitors.3 It reaches peak concentrationswithin 45 minutes and hasa half-life of 4 hours. Vardenafil is only15% bioavailable and has decreasedabsorption with a high-fat meal, whichmay cause patient variability withregard to efficacy.7,9

Like sildenafil, vardenafil is metabolizedby CYP 3A4, and it interacts withdrugs such as ketoconazole, erythromycin,and protease inhibitors.11 It iscontraindicated with the use ofnitrates and alpha-blockers due tohypotensive effects, and it is not recommendedin patients with retinaldegenerative disorders.9,11 Commonside effects include headache, dyspepsia,and dizziness. No dosage adjustmentis needed for renal impairment,although no information is availablefor dialysis patients.

A starting dose of 10 mg of vardenafil1 hour prior to sexual activity isneeded for most patients, although adose of 5 mg is recommended for men>65 years of age and those with moderatehepatic impairment.9,11 Vardenafilis available in 2.5-, 5-, 10-, and 20-mgtablets.

Due to the vasodilatory properties ofPDE-5 inhibitors, the risk of hypotensionmust be considered when they areprescribed. As stated above, all 3 agentsare contraindicated with the use ofnitrates, because nitrates also increasecGMP and potentiate smooth musclerelaxation. The concomitant use ofPDE-5 inhibitors with nitrates can leadto excessive hypotension and possiblesyncope. It also can lead to myocardialischemia in patients who suffer fromcoronary heart disease.2 Vardenafil iscontraindicated and tadalafil must beused with caution when coadministeredwith alpha-blockers, becausethere may be additive hypotensiveeffects.9,11 Tadalafil also must be usedwith caution in patients with coronaryheart disease because of its long durationof action.


ED is a common disorder that canhave serious effects on the quality oflife of the men it touches. PDE-5inhibitors may be an option forpatients who do not take nitrates oneither a regular or intermittent basisand have no other contraindicationsto such therapy.

Pharmacists can assist patients withED by screening their medication profilesto uncover any drug-induced reasonsfor ED. Pharmacists also can helpby counseling patients on the importanceof avoiding nitrates, and remindingthem to report the use of PDE-5inhibitors to all health care professionalsto avoid any potential drug interactions.Patients should also be awarethat sexual stimulation is needed for atherapeutic effect, and that if they getan erection lasting >4 hours theyshould seek medical help as soon aspossible.

Dr. Hajjar is an assistant professor of clinicalpharmacy at Philadelphia College ofPharmacy, University of the Sciences inPhiladelphia.

For a list of references, send a stamped, self-addressedenvelope to: References Department,Attn. A. Stahl, Pharmacy Times,241 Forsgate Drive, Jamesburg, NJ 08831; orsend an e-mail request to: astahl@ascendmedia.com.

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