Pharmacotherapy of
Pharmacological Treatment Options for ___Erectile Dysfunction___________
Barry VanDenHeuvel, PharmD Candidate 2007
| |Therapeutic Class/Agents |Therapeutic Class/Agents |
| |Phospodiesterase Type 5 (PDE5) Inhibitors |Alprostadil |
|Product Availability |Sildenafil (Viagra) |Alprostadil (Caverject, Muse) |
|Generic (Brand) |Vardenafil (Levitra) | |
| |Tadalafil (Cialis) | |
|Mechanism |Does not directly cause penile erections, but affects the response to sexual stimulation. |Causes vasodilation by means of direct effect on vascular and ductus arteriosus smooth muscle; |
|of Action |The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in|relaxes trabecular smooth muscle by dilation of cavernosal arteries when injected along the |
| |the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate |penile shaft, allowing blood flow to and entrapment in the lacunar spaces of the penis (ie, |
| |cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), |corporeal veno-occlusive mechanism) |
| |producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil| |
| |enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is | |
| |responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation | |
| |causes local release of NO, inhibition of PDE-5 by sildenafil causes increased levels of | |
| |cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to| |
| |the corpus cavernosum; at recommended doses, it has no effect in the absence of sexual | |
| |stimulation. | |
|EFFICACY |Because of their apparent effectiveness, convenient route of administration, and |Indication: Treatment of erectile dysfunction of vasculogenic, psychogenic, or neurogenic |
| |comparatively low incidence of serious side effects, Phosphodiesterase inhibitors are |etiology; adjunct in the diagnosis of erectile dysfunction |
|(Indication/Use, |considered first-line therapy for erectile dysfunction, particularly in younger patients. | |
|Clinical Data Support) | |The initial trial dose of alprostadil intra-urethral suppositories should be administered under |
| |Indication: Treatment of erectile dysfunction. |healthcare provider supervision due to the risk of syncope. Physicians who prescribe |
| | |intracavernous injection therapy should (1) inform patients of the potential occurrence of |
| |In the presence of sexual stimulation and in doses of 25 to 100mg, sildenafil produces |prolonged erections, (2) have a plan for the urgent treatment of prolonged erections and (3) |
| |satisfactory erections in 56% to 82% of patients, independent of the etiology of erectile |inform the patient of the plan. |
| |dysfunction. Similar values are documented in the product labeling for the other two | |
| |agents in this class (65% to 80% for vardenafil and 2% to 77% for tadalafil). The | |
| |effectiveness of all three appears to be dose related. |In various controlled and uncontrolled studies, the overall efficacy of intracavernosal |
| | |alprostadil is 70% to 90%. The efficacy is dose related over a range of 2.5 to 20mcg. The |
| |Approximately 30% to 40% of patients fail to respond to PDE5 inhibitors. For sildenafil, |mean duration of erection is directly related to dose and ranges from 12 to 44 minutes. |
| |approximately 55% of nonresponders can be salvaged with education on proper use of the |Tolerance does not appear to develop with continued use. |
| |medication. |Despite effectiveness, many patients discontinue use at home due to inconvenience, an unnatural,|
| |Education includes: |nonspontaneous erection, needle phobia, loss of interest, and cost. |
| |patients must engage in sexual stimulation | |
| |should be taken on an empty stomach. | |
| |taken with a fatty meal will reduce absorption, except tadalafil. | |
| |should try 5 to 8 doses before declaring failure. | |
| |Some patients mar require dosage titration up to 100mg (sildenafil), or 20mg (vardenafil | |
| |and tadalafil). | |
| | | |
| |Should not be used by patients without erectile dysfunction and should not be used in | |
| |combination with other forms of therapy for erectile dysfunction, as this may lead to | |
| |prolonged erection. | |
|SAFETY |Contraindications Hypersensitivity to sildenafil or any component of the formulation; |Contraindications Hypersensitivity to alprostadil or any component of the formulation; hyaline |
| |concurrent use of organic nitrates (nitroglycerin) in any form (potentiates the hypotensive|membrane disease or persistent fetal circulation and when a dominant left-to-right shunt is |
|(Major Drug |effects) |present; respiratory distress syndrome; conditions predisposing patients to priapism (sickle |
|Interactions, | |cell anemia, multiple myeloma, leukemia); patients with anatomical deformation of the penis, |
|Pre-cautions, |Adverse effects: Headache, dyspepsia, flushing, dizziness, insomnia, blurred vision or |penile implants; use in men for whom sexual activity is inadvisable or contraindicated; |
|Contra-indications, |sensitivity to light, |pregnancy |
|Adverse Effects, | | |
|Pregnancy Risk Category)|Warnings: Decreases in blood pressure may occur due to vasodilator effects; use caution in |Adverse effects: Penile pain, Headache, dizziness, prolonged erection, injection site reactions|
| |patients with resting hypotension (BP 170/110), fluid depletion,|(bruising, itching) |
| |severe left ventricular outflow obstruction, or autonomic dysfunction, and patients | |
| |receiving alpha-blockers or other antihypertensive medication. Not recommended for use with|Warnings: priapism, syncope after first administration. |
| |pulmonary veno-occlusive disease. | |
| |Use caution in patients with cardiovascular disease, including cardiac failure, unstable |Interactions: Risk of hypotension and syncope may be increased with antihypertensives. |
| |angina, or a recent history (within the last 6 months) of myocardial infarction, stroke, or| |
| |life-threatening arrhythmia. Use caution in patients receiving concurrent bosentan. Use |Pregnancy category: X |
| |caution in patients with bleeding disorders or with active peptic ulcer disease; safety and| |
| |efficacy have not been established. | |
| |There is a degree of cardiac risk associated with sexual activity; therefore, physicians | |
| |may wish to consider the cardiovascular status of their patients prior to initiating any | |
| |treatment for erectile dysfunction. Sildenafil should be used with caution in patients with| |
| |anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie's | |
| |disease), or in patients who have conditions which may predispose them to priapism (sickle | |
| |cell anemia, multiple myeloma, leukemia). | |
| |Rare cases of nonarteritic ischemic optic neuropathy (NAION) have been reported; risk may | |
| |be increased with history of vision loss. Other risk factors for NAION include low | |
| |cup-to-disc ratio ("crowded disc"), coronary artery disease, diabetes, hypertension, | |
| |hyperlipidemia, smoking, and age >50 years. | |
| |The safety and efficacy of sildenafil with other treatments for erectile dysfunction have | |
| |not been established; use is not recommended. May cause dose-related impairment of color | |
| |discrimination. Use caution in patients with retinitis pigmentosa; a minority have generic | |
| |disorders of retinal phosphodiesterases (no safety information available). Safety and | |
| |efficacy in pediatric patients have not been established. | |
| |Interactions: Drug Interactions Substrate of CYP2C9 (minor), 3A4 (major); Inhibits CYP1A2 | |
| |(weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak), 3A4 (weak) | |
| |Azole antifungals: May increase the serum concentrations of sildenafil; reduce starting | |
| |dose to 25 mg. | |
| |Alpha-blockers (doxazosin): Concomitant use may lead to symptomatic hypotension in some | |
| |patients. Patient should be stable on an alpha-blocker prior to initiation of PDE-5 | |
| |inhibitor. Sildenafil should be started at 25 mg. If patient is taking an optimal dose of | |
| |PDE-5 inhibitor, alpha-blocker should be initiated at lowest dose. | |
| |Bosentan: May decrease serum concentration and effect of sildenafil. | |
| |CYP3A4 inhibitors: May increase the levels/effects of sildenafil. Example inhibitors | |
| |include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib,| |
| |isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, | |
| |telithromycin, and verapamil. | |
| |Macrolide antibiotics: May increase serum concentrations of sildenafil; reduce starting | |
| |dose of Viagra® to 25 mg if used with clarithromycin, erythromycin, telithromycin, or | |
| |troleandomycin. No adjustments with Revatio™ are required. | |
| |Nitroglycerin (other nitrates): Concurrent use with sildenafil is contraindicated due to | |
| |the potential for severe, potentially fatal, hypotensive responses. | |
| |Protease inhibitors: May increase the serum concentrations of sildenafil; reduce dose of | |
| |Viagra® to 25 mg/24 hours; use of Revatio™ is not recommended. | |
| | | |
| |Pregnancy category: B | |
|Dosage & Administration |Viagra®: |Caverject®, Edex®: Intracavernous: Individualize dose by careful titration; doses >40 mcg |
| |For most patients, the recommended dose is 25-50 mg taken as needed, approximately 1 hour |(Edex®) or >60 mcg (Caverject®) are not recommended: Initial dose must be titrated in |
|(Include renal and/or |before sexual activity. However, sildenafil may be taken anywhere from 30 minutes to 4 |physician's office. Patient must stay in the physician's office until complete detumescence |
|hepatic adjustments) |hours before sexual activity. Based on effectiveness and tolerance, the dose may be |occurs; if there is no response, then the next higher dose may be given within 1 hour; if there |
| |increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum |is still no response, a 1-day interval before giving the next dose is recommended; increasing |
| |recommended dosing frequency is once daily. |the dose or concentration in the treatment of impotence results in increasing pain and |
| | |discomfort. |
| |Administer orally 1 hour before sexual activity (may be used anytime from 4 hours to 30 |Vasculogenic, psychogenic, or mixed etiology: Initiate dosage titration at 2.5 mcg, increasing |
| |minutes before). |by 2.5 mcg to a dose of 5 mcg and then in increments of 5-10 mcg depending on the erectile |
| | |response until the dose produces an erection suitable for intercourse, not lasting >1 hour; if |
| |Dosage adjustment for patients >65 years of age: Hepatic impairment (cirrhosis), severe |there is absolutely no response to initial 2.5 mcg dose, the second dose may be increased to 7.5|
| |renal impairment (creatinine clearance 1 hour |
| |Cialis®: |Maintenance: Once appropriate dose has been determined, patient may self-administer injections |
| |10 mg prior to anticipated sexual activity (dosing range: 5-20 mg); to be given as one |at a frequency of no more than 3 times/week with at least 24 hours between doses |
| |single dose and not given more than once daily. Note: Erectile function may be improved for|Administration: Use a 1/2 inch, 27- to 30-gauge needle. Inject into the dorsolateral aspect of |
| |up to 36 hours following a single dose; adjust dose. |the proximal third of the penis, avoiding visible veins; alternate side of the penis for |
| | |injections. |
| |Dosage adjustment in renal impairment: |Muse® Pellet: Intraurethral: |
| |Clcr 31-50 mL/minute: Initial dose 5 mg once daily; maximum dose 10 mg not to be given more|Initial: 125-250 mcg |
| |frequently than every 48 hours. |Maintenance: Administer as needed to achieve an erection; duration of action is about 30-60 |
| |Clcr 4 hours;|hypertension, chest pain, palpitations, irregular heartbeat); flushing, fever, flu-like |
| |or other adverse reactions. |symptoms; respiratory difficulty or wheezing; or other adverse reactions. Refer to prescriber |
| | |every 3 months to ensure proper technique and for dosage evaluation. Pregnancy precautions: |
| | |Consult prescriber about use of contraceptives. Do not give blood while taking this medication |
| | |and for 1 month following discontinuance. |
|Cost |(Cialis) |Injection (reconstituted) (Caverject) |
|(1-month) |5 mg (10): $120.99 |40 mcg (6): $219.53 |
| |10 mg (10): $120.99 |Kit (Caverject Impulse) |
| |20 mg (10): $120.99 |10 mcg (2): $56.99 |
| |(Viagra) |20 mcg (2): $70.99 |
| |25 mg (10): $99.99 |Pellet (Muse) |
| |50 mg (10): $99.99 |125 mcg (6): $130.65 |
| |100 mg (10): $99.99 |250 mcg (6): $137.42 |
| |(Levitra) |500 mcg (6): $146.70 |
| |5 mg (10): $101.55 |1000 mcg (6): $158.36 |
| |10 mg (10): $98.98 | |
| |20 mg (10): $103.94 | |
|References |American Urological Association: Guidelines on the Management of Erectile Dysfunction |American Urological Association: Guidelines on the Management of Erectile Dysfunction |
|(Guidelines, Drug Info | | |
|Sources) |Lexicomp Online |Lexicomp Online |
| | | |
| |DiPiro, JT, et al., Pharmacotherapy, A Pathophysiologic Approach, Sixth Edition. |DiPiro, JT, et al., Pharmacotherapy, A Pathophysiologic Approach, Sixth Edition. |
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