Drugs for Erectile Dysfunction and Benign Prostatic Hyperplasia

Erectile Dysfunction ED, also known as impotence Ø Persistent inability to achieve or sustain an erection suitable for satisfactory sexual performance Affects up to 30 million men ED commonly associated with chronic illnesses Risk for ED increases with advancing age

Treatment for ED Drugs Oral agents: PDE 5 inhibitors • Sildenafil, vardenafil, and tadalafil Ø Nonoral agents • Papaverine plus phentolamine, and alprostadil Ø Psychotherapy Surgical implantation of penile prosthesis

Sildenafil (Viagra) Phosphodiesterase type 5 (PDE 5) inhibitor I First oral agent for ED: introduced in 1998 Generally well tolerated Ø ED effects discovered by accident Ø Can be dangerous if used concurrently with certain vasodilators (alpha-adrenergic blockers and nitrates) Originally developed as cardiac medicine Only enhances normal erectile response in the presence of stimuli Ø Ø Ø No significant impact on men who do not have ED Not approved for women Approved in 2005 as Revatio to treat pulmonary arterial hypertension

Sildenafil (Viagra) Adverse effects Hypotension Priapism Headache, dyspepsia, flushing, nasal congestion, diarrhea, rash, dizziness, mild transient visual disturbances, intensification of obstructive sleep apnea Ø Rare side effects • Nonarteritic ischemic optic neuropathy • Sudden hearing loss Ø Ø Ø

Sildenafil (Viagra) Absorption slowed by high-fat meals Drug interactions Nitrates • Could cause life-threatening hypotension • 24 hours in between these medications for safety Ø Alpha blockers • Can cause symptomatic postural hypotension Ø Inhibitors of cytochrome P 450 (CYP 3 A 4) • Can suppress metabolism of sildenafil Ø

Sildenafil (Viagra) Drug should be used with caution by men with the following conditions: MI, stroke, and life-threatening dysrhythmia within the last 6 months Ø Resting hypotension (BP below 90/50 mm Hg) Ø Resting hypertension (BP above 170/110 mm Hg) Ø Heart failure Ø Unstable angina Ø Sildenafil should not be used at all by men taking nitroglycerin or any other drug in the nitrate family

Vardenafil (Levitra) PDE 5 inhibitor II Relaxes arterial and trabecular smooth muscle in the penis Ø Adverse effects • Headache and flushing • Rhinitis and dyspepsia • Can prolong QT interval • Can lower blood pressure • Can also be associated with sudden hearing loss and vision loss from nonarteritic ischemic optic neuropathy (NAION)

Vardenafil (Levitra) Drug interactions Nitrates • Could cause life-threatening hypotension • 24 hours in between these medications for safety Ø Alpha blockers • Can cause symptomatic postural hypotension Ø Inhibitors of cytochrome P 450 (CYP 3 A 4) • Can suppress metabolism of vardenafil Ø

Tadalafil (Cialis) PDE 5 inhibitor II Relaxes penile and arterial and trabecular smooth muscle Ø Effects last up to 36 hours (longest of the three PDE 5 inhibitors) Ø Also now approved for daily dosing if activity anticipated twice weekly Ø

Tadalafil (Cialis) Adverse effects Headache, dyspepsia, back pain, myalgia, limb pain, flushing, nasal congestion Ø Can also be associated with sudden hearing loss and vision loss from NAION Ø Drug interactions Ø Ø Nitrates Alpha blockers (except tamsulosin [Flomax])

Other Drugs for ED Treatment Papaverine (smooth muscle relaxant) plus phentolamine (alpha-adrenergic blocking agent) Increased arterial flow and decreased venous outflow in the penis Ø Used to counteract impotence Ø Administration • Injected directly into the corpus cavernosum Ø Adverse effects • Priapism • Painless fibrotic nodules in the corpus cavernosum • Orthostatic hypotension with dizziness Ø

Other Drugs for ED Treatment Alprostadil (prostaglandin E 1) Ø Administration • Injected directly into the corpus cavernosum • Increased arterial flow and decreased venous outflow in the penis • Should not be used more than 3 times per week or once in 24 hours Ø Adverse effects • Burning sensations, prolonged erection, priapism, and penile fibrosis Ø Transurethral—alprostadil pellets (Muse) • Do not use more than twice in 24 hours • No priapism or penile fibrosis

Benign Prostatic Hyperplasia Nonmalignant prostate enlargement Caused by excessive growth of epithelial (glandular) cells and smooth muscle cells Signs and symptoms Ø Ø Ø Urinary hesitancy Urinary urgency Increased frequency of urination Dysuria Nocturia

Benign Prostatic Hyperplasia Signs and symptoms Ø Ø Straining to void Postvoid dribbling Decreased force and caliber of the urinary stream Sensation of incomplete bladder emptying

Benign Prostatic Hyperplasia Treatment modalities Surgery Watchful waiting Drug therapy 5 -Alpha-reductase inhibitors (mechanical obstruction) • Finasteride • Dutasteride Ø Alpha 1 -adrenergic antagonists (dynamic obstruction) Ø Ø

Finasteride (Proscar) Inhibits 5 -alpha-reductase Most effective in patients with a very large prostate (mechanical obstruction) Also sold at lower dosages as Propecia for male pattern baldness Adverse effects Ø Ø Ø Decreases ejaculate volume and libido Gynecomastia Decreases levels of prostate-specific antigen (PSA)

Dutasteride (Avodart) Inhibits 5 -alpha-reductase Similar to finasteride but with three differences: Ø Ø Ø Reduction in circulating DHT is more complete Harmful to a developing male fetus Extremely long half-life (5 weeks)

Alpha 1 -Adrenergic Antagonists Four are approved for the treatment of BPH: Ø Ø Terazosin (Hytrin) Doxazosin (Cardura) Tamsulosin (Flomax) Alfuzosin (Uroxatral) Blockade of alpha 1 receptors relaxes smooth muscle in the bladder neck (trigone and sphincter)

Alpha 1 -Adrenergic Antagonists Impact on blood pressure Tamsulosin (Flomax) and alfuzosin (Uroxatral) • Selective for alpha 1 receptors in the prostate Ø Terazosin (Hytrin) and doxazosin (Cardura) • Also block alpha receptors in the blood vessels • Promote vasodilation and can lower blood pressure Ø

Alpha 1 -Adrenergic Antagonists Adverse effects Ø Tamsulosin (Flomax) and alfuzosin (Uroxatral) • Less likely to cause the effects of terazosin and doxazosin • Tamsulosin cause abnormal ejaculation Ø Terazosin (Hytrin) and doxazosin (Cardura) • Hypotension, fainting, dizziness, somnolence, and nasal congestion Ø These drugs do not decrease PSA levels

Alpha 1 -Adrenergic Antagonists Drug interactions Exercise caution with other blood pressure– lowering medications Ø Organic nitrates, antihypertensive drugs, PDE 5 inhibitors used for ED Ø Inhibitors of CYP 3 A 4 Ø

Other Drugs for BPH Saw palmetto Ø Ø Used widely Effectiveness not supported Tolterodine (Detrol) PDE 5 inhibitors Botulinum toxin