NCLEX: Drugs for Urologic Disorders

Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) are common urologic disorders in males. ED is the inability to maintain penile erection for the successful performance of sexual activity. ED has many physical and psychological causes, including vascular disease, diabetes, medications, depression, and sequelae to prostatic surgery. It is estimated to affect more than 30 million men in the United States. BPH is nonmalignant enlargement of the prostate, which occurs naturally as men age. As the prostate grows in size, lower urinary tract symptoms develop, which can significantly impact a patient’s quality of life.

Drugs for Urologic Disorders

Drugs for Urologic Disorders: DRUGS USED TO TREAT ERECTILE DYSFUNCTION

Focus topic: Drugs for Urologic Disorders

Therapy for ED includes penile implants, intrapenile injections of alprostadil, intraurethral suppositories of alprostadil, and oral phosphodiesterase-5 (PDE-5) inhibitors. Because of the efficacy, ease of use, and safety of PDE-5 inhibitors, these drugs are now considered first-line therapy for ED. Four PDE-5 inhibitors (sildenafil, vardenafil, tadalafil, and avanafil) are approved for the treatment of ED. [Note: Sildenafil and tadalafil are also indicated to treat pulmonary hypertension, although the dosage regimen differs for this indication.]

A. Phosphodiesterase-5 inhibitors

Focus topic: Drugs for Urologic Disorders

All four PDE-5 inhibitors, sildenafil [sil-DEN-a-fil], vardenafil [var-DENna-fil], tadalafil [ta-DAL-a-fil], and avanafil [a-VAN-a-fil], are equally effective in treating ED, and the adverse effect profiles of the drugs are similar. However, these agents differ in the duration of action and the effects of food on drug absorption.

1. Mechanism of action: Sexual stimulation results in smooth muscle relaxation of the corpus cavernosum, increasing the inflow of blood. The mediator of this response is nitric oxide (NO). NO activates guanylyl cyclase, which forms cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP produces smooth muscle relaxation through a reduction in the intracellular Ca2+ concentration. The duration of action of cyclic nucleotides is controlled by the action of phosphodiesterase (PDE). At least 11 isozymes of PDE have been characterized. Sildenafil, vardenafil, tadalafil, and avanafil inhibit PDE-5, the isozyme responsible for degradation of cGMP in the corpus cavernosum. The action of PDE-5 inhibitors is to increase the flow of blood into the corpus cavernosum at any given level of sexual stimulation. At recommended doses, PDE-5 inhibitors have no effect in the absence of sexual stimulation.

2. Pharmacokinetics: Sildenafil and vardenafil have similar pharmacokinetic properties. Both drugs should be taken approximately 1 hour prior to anticipated sexual activity, with erectile enhancement observed for up to 4 hours after administration. Thus, administration of sildenafil and vardenafil must be timed appropriately with regard to anticipated sexual activity. The absorption of both drugs is delayed by consumption of a high-fat meal. Vardenafil is also available in an orally disintegrating tablet (ODT) formulation, which is not affected by a high-fat meal. However, the bioavailability of the ODT formulation may be decreased by water, and therefore the ODT should be placed under the tongue and not administered with liquids. The vardenafil ODT provides a higher systemic bioavailability than the vardenafil film-coated oral tablet, and these products are not interchangeable. Tadalafil has a slower onset of action than sildenafil and vardenafil, but a significantly longer half-life of approximately 18 hours. As such, it is approved for once-daily dosing (in addition to as-needed dosing). This results in enhanced erectile function for up to 36 hours. Furthermore, the absorption of tadalafil is not clinically influenced by food. The timing of sexual activity is less critical for tadalafil because of its prolonged duration of effect. Of all the PDE-5 inhibitors, avanafil has the quickest onset of action. It should be taken 30 minutes prior to sexual activity. All PDE-5 inhibitors are metabolized by the cytochrome P450 3A4 (CYP3A4) isoenzyme. Dosage adjustments are recommended in patients with hepatic dysfunction. For patients with severe renal dysfunction, the dose of sildenafil and tadalafil should be reduced, and daily-dose tadalafil and avanafil are contraindicated in these patients.

3. Adverse effects: The most frequent adverse effects of the PDE-5 inhibitors are headache, flushing, dyspepsia, and nasal congestion. These effects are generally mild, and men with ED rarely discontinue treatment because of side effects. Disturbances in color vision (loss of blue/green discrimination) may occur with PDE-5 inhibitors, probably because of inhibition of PDE-6 (a PDE found in the retina that is important in color vision). Tadalafil, however, does not appear to disrupt PDE-6, and reports of changes in color vision have been rare with this medication. The incidence of these reactions appears to be dose dependent. Sudden hearing loss has also been reported with the use of PDE-5 inhibitors, perhaps due to changes in sinus pressure because of vasodilation. Tadalafil has been associated with back pain and myalgias, likely because of inhibition of PDE-11, an enzyme found in skeletal muscle. There is an inherent cardiac risk associated with sexual activity. Therefore, PDE-5 inhibitors should be used with caution in patients with a history of cardiovascular disease or those with strong risk factors for cardiovascular disease. PDE-5 inhibitors should not be used more than once per day. All of the PDE-5 inhibitors have the potential to cause priapism (a painful, prolonged erection). Although this is a rare side effect, it is a medical emergency.

4. Drug interactions: Because of the ability of PDE-5 inhibitors to potentiate the hypotensive activity of NO, administration of these agents in patients taking any form of organic nitrates (for example, nitroglycerin products, isosorbide dinitrate, or isosorbide mononitrate) is contraindicated. PDE-5 inhibitors may produce additive blood pressure–lowering effects when used in patients taking α-adrenergic antagonists (used to treat hypertension and/ or alleviate symptoms associated with BPH). The combination of PDE-5 inhibitors and α-adrenergic antagonists should be used with caution. Patients should be on a stable dose of the α-adrenergic antagonist prior to the initiation of the PDE-5 inhibitor, and the PDE-5 inhibitor should be started at a low dose if this combination is to be used. Doses of PDE-5 inhibitors may need to be reduced in the presence of potent inhibitors of CYP3A4, such as clarithromycin, ritonavir, and other protease inhibitors.

Drugs for Urologic Disorders
Drugs for Urologic Disorders
Drugs for Urologic Disorders

B. Alprostadil

Focus topic: Drugs for Urologic Disorders

Alprostadil [al-PRAHST-uh-dill] is synthetic prostaglandin E1 (PGE1). In the penile tissue, PGE1 allows for relaxation of the smooth muscle in the corpus cavernosum. Alprostadil is available as an intraurethral suppository and an injectable formulation. Although PDE-5 inhibitors are considered first-line therapy for the treatment of ED, alprostadil may be used for patients who are not candidates for oral therapies. In contrast to oral agents, alprostadil acts locally, which may reduce the occurrence of adverse effects.

1. Mechanism of action: Alprostadil causes smooth muscle relaxation by an unknown mechanism. It is believed that alprostadil increases concentrations of cyclic AMP (cAMP) within cavernosal tissue. As a result, protein kinase is activated, allowing trabecular smooth muscle relaxation and dilation of cavernosal arteries. Increased blood flow to the erection chamber compresses venous outflow, so that blood is entrapped and erection may occur.

2. Pharmacokinetics: Systemic absorption of alprostadil is minimal. If any alprostadil is systemically absorbed, it is quickly metabolized. The onset of action of alprostadil is 5 to 10 minutes when given as a urethral suppository and 2 to 25 minutes when administered by injection. The resulting erection may last for 30 to 60 minutes, or longer, depending upon the particular patient.

3. Adverse effects: Since alprostadil is not systemically absorbed, adverse systemic effects are rare. However, hypotension or headache is a possibility due to PGE1-induced vasodilation. Locally, adverse effects of alprostadil include penile pain, urethral pain, and testicular pain. Bleeding from the insertion or injection of alprostadil is rare. Hematoma, ecchymosis, and rash are possible from alprostadil injection, although these adverse effects are also rare. Alprostadil administration may lead to priapism.

Drugs for Urologic Disorders: BENIGN PROSTATIC HYPERPLASIA

Focus topic: Drugs for Urologic Disorders

Three classes of medications are used to treat BPH: α1-adrenergic antagonists, 5-α reductase inhibitors, and phosphodiesterase-5 (PDE-5) inhibitors.

A. α1-Adrenergic antagonists

Focus topic: Drugs for Urologic Disorders

Terazosin [ter-AY-zoe-sin], doxazosin [dox-AY-zoe-sin], tamsulosin [tam-SUE-loh-sin], alfuzosin [al-FUE-zoe-sin], and silodosin [sil-oh-DOE-sin] are selective competitive blockers of the α1 receptor. All five agents are indicated for the treatment of BPH. Prazosin is an α-blocker that is used off-label in the treatment of BPH. However, current guidelines do not endorse the use of prazosin for BPH. Please refer to Chapter 7 for a discussion of α-blockers in the setting of hypertension.

1. Mechanism of action: α1A receptors are found in the prostate, α1B receptors are found in the prostate and vasculature, and α1D receptors are found in the vasculature. By blocking the α1A and α1B receptors in the prostate, the α-blockers cause prostatic smooth muscle relaxation, which leads to improved urine flow. Doxazosin, terazosin, and alfuzosin block α1A and α1B receptors, whereas tamsulosin and silodosin are more selective for the α1A receptor. Because doxazosin, terazosin, and alfuzosin block α1B receptors, these agents decrease peripheral vascular resistance and lower arterial blood pressure by causing relaxation of both arterial and venous smooth muscle. In contrast, tamsulosin and silodosin have less of an effect on blood pressure because they are more selective for the prostate-specific α1A receptor. In general, α-blockers cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate.

2. Pharmacokinetics: The α-blockers are well absorbed following oral administration. When taken with food, the absorption of tamsulosin, alfuzosin, and silodosin is increased. Therefore, for best efficacy, these agents should be taken with meals (typically supper). Doxazosin, alfuzosin, tamsulosin, and silodosin are metabolized through the cytochrome P450 (CYP450) system. Silodosin is also a substrate for P-glycoprotein (P-gp). Terazosin is metabolized in the liver, but not through the CYP system. In general, the α-blockers have a half-life of 8 to 22 hours, with peak effects 1 to 4 hours after administration. Silodosin requires dosage adjustment in renal impairment and is contraindicated in patients with severe renal dysfunction.

3. Adverse effects: α-Blockers may cause dizziness, a lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension (although to a lesser degree than that observed with phenoxybenzamine and phentolamine). Tamsulosin and silodosin inhibit the α1A receptors found on the smooth muscle of the prostate. This selectivity accounts for relatively minimal effects on blood pressure, although dizziness and orthostasis may occur. These drugs do not affect male sexual function as severely as phenoxybenzamine and phentolamine. However, by blocking α receptors in the ejaculatory ducts and impairing smooth muscle contraction, inhibition of ejaculation and retrograde ejaculation have been reported. Tamsulosin has a caution about “floppy iris syndrome,” a condition in which the iris billows in response to intraoperative eye surgery.

4. Drug interactions: Drugs that inhibit CYP3A4 and CYP2D6 (for example, verapamil, diltiazem) may increase the plasma concentrations of doxazosin, alfuzosin, tamsulosin, and silodosin, while drugs that induce the CYP450 system (for example, carbamazepine, phenytoin, and St. John’s wort) may decrease plasma concentrations. Alfuzosin may prolong the QT interval, so it should be used with caution with other drugs that cause QT prolongation (for example, class III antiarrhythmics). Since silodosin is a substrate for P-gp, drugs that inhibit P-gp, such as cyclosporine, may increase silodosin concentrations.

Drugs for Urologic Disorders

B. 5-α reductase inhibitors

Focus topic: Drugs for Urologic Disorders

Finasteride [fin-AS-ter-ide] and dutasteride [doo-TAS-ter-ride] inhibit 5α-reductase. Compared to the α-blockers, which provide patients with relief from BPH symptoms within 7 to 10 days, these agents may take up to 12 months to relieve symptoms.

1. Mechanism of action: Both finasteride and dutasteride inhibit the enzyme 5-α reductase, which is responsible for converting testosterone to the more active dihydrotestosterone (DHT). DHT is an androgen that stimulates prostate growth. By reducing DHT, the prostate shrinks and urine flow improves. Compared to finasteride, dutasteride is more potent and causes a greater decrease in DHT. In order for the 5-α reductase inhibitors to be effective, the prostate must be enlarged. Thus, it is appropriate to use a 5-α reductase inhibitor in combination with an α-blocker when the prostate is enlarged. Finasteride and dutasteride are also used for alopecia, since a reduction in scalp and serum DHT prevents hair loss.

2. Pharmacokinetics: Food does not affect the absorption of either agent. Both are highly protein bound. Finasteride and dutasteride are metabolized by the CYP450 system. The mean plasma elimination half-life of finasteride is 6 to 16 hours, while the terminal elimination half-life of dutasteride is 5 weeks once steady-state concentrations are achieved, which is typically after 6 months of therapy.

3. Adverse effects: The 5-α reductase inhibitors cause sexual side effects, such as decreased ejaculate, decreased libido, ED, gynecomastia, and oligospermia. Finasteride and dutasteride have teratogenic potential. Women who are pregnant or of childbearing age should not handle or ingest either agent, as this may lead to serious birth defects involving the genitalia in a male fetus. Although both agents are metabolized by the CYP450 system, drug interactions are rare. It is not ideal to use a 5-α reductase inhibitor with testosterone, since both finasteride and dutasteride inhibit the conversion of testosterone to its active form, DHT.

Drugs for Urologic Disorders
Drugs for Urologic Disorders

C. Phosphodiesterase-5 inhibitor

Focus topic: Drugs for Urologic Disorders

Tadalafil is the only PDE-5 inhibitor approved for the treatment of BPH. PDE-5 is present in the prostate and bladder. As such, inhibition of PDE-5 by tadalafil allows for vasodilation and relaxation of the smooth muscle of the prostate and bladder, which thereby improves symptoms of BPH.

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