Genitourinary Agents
Impotence Agents

Hormones and Hormone Modifiers

Description: Alprostadil is naturally occurring prostaglandin E1. Alprostadil and other prostaglandins in the E series are naturally present in the seminal vesicles and cavernous tissues of males and in the placenta and ductus arteriosus of the fetus. Alprostadil is used to treat impotence in adult males and to maintain the patency of the ductus arteriosus in neonates up until the time of corrective or palliative surgery. The efficacy of alprostadil in treating impotence varies with the cause. The response rate is generally lower in patients with impotence due to mixed etiologies compared to those with impotence due to neurogenic, psychogenic, or vasculogenic causes. Two dosage forms are marketed for treating impotence: a transurethral product (Muse®) which uses a medicated pellet administered into the urethra and an injection (Caverject® or Edex®) that is directly injected into the corpus cavernosa. Other dosage forms such as a topical gel and a non-invasive liposomal delivery system are under investigation. Topiglan™ is one such investigational topical formulation of alprostadil under development by MacroChem ( The company expects the licensee of the product to conduct phase III trials in order to pursue marketing. Prostin VR Pediatric® is the commercial intravenous preparation of alprostadil used in neonates for maintaining the patency of the ductus arteriosus. The drug is generally more effective in those neonates with low pretreatment blood PO2 and who are 4 days old or less. Intravenous alprostadil requires respiratory monitoring during administration because apnea develops in 10—12% of neonates. Prostin VR Pediatric® was approved by the FDA in 1981, Caverject® in July 1995, MUSE® in October 1996, and Edex® in June 1997.

Mechanism of Action: For the treatment of impotence, alprostadil relaxes the smooth muscles of the corpus cavernosum; however, the exact mechanism of action is unknown. It appears that the effects are due to increasing the intracellular concentrations of cyclic AMP. Alprostadil interacts with specific membrane-bound receptors that stimulate adenylate cyclase and elevate intracellular cyclic AMP, leading to activation of protein kinase and resultant smooth muscle relaxation. This action is in contrast to papaverine which inhibits oxidative phosphorylation mediated inactivation of cyclic AMP and interferes with calcium mobilization during muscle contraction. Alprostadil may also antagonize the vasoconstrictive actions of norepinephrine by preventing the neuronal release of norepinephrine and may enhance the actions of nonadrenergic, noncholinergic vasodilatory neurotransmitters. In treating impotence, alprostadil induces erection by relaxing trabecular smooth muscle and dilating cavernosal arteries and their branches. Dilation of the cavernosal arteries is accompanied by increased arterial inflow velocity and increased venous outflow resistance. As a result, the lacunar spaces expand and blood becomes entrapped secondary to compression of venules against the tunica albuginea. To achieve adequate tumescence and rigidity, the tunica albuginea must be sufficiently stiff to compress the venules penetrating it and thus block venous outflow. This process is also referred to as the corporal veno-occlusive mechanism. Alprostadil does not directly affect ejaculation or orgasm.

In the treatment of ductus arteriosus-dependent congenital heart defects, alprostadil maintains ductal patency by relaxing the smooth muscles of the ductus arteriosus. Alprostadil is only effective if given prior to complete anatomic closure of the ductus arteriosus. Administration of alprostadil to neonates with cyanotic congenital heart defects (restricted pulmonary blood flow) results in an increase in pulmonary blood flow and/or increase in mixing between the systemic and pulmonary circulation which leads to a temporary increase in arterial oxygen partial pressure (PaO2) and oxygen saturation. The response of the cyanotic neonate to alprostadil therapy is also inversely related to pretreatment PO2. The greatest response appears to be in those neonates with low pretreatment PaO2 (< 20 torr), narrowing ductus arteriosus, and who are 4 days old or younger. Neonates with PaO2 values of 40 torr or more usually have little response to alprostadil.

In neonates with restricted systemic blood flow, administration of alprostadil can result in prevention or correction of acidemia, increased cardiac output with increased systemic blood pressure, increased femoral pulse volume, increased renal blood flow and function, decreased gradient of descending to ascending aortic blood pressures (in neonates with coarctation of the aorta), and/or decreased ratio of pulmonary artery pressure to descending aortic pressure (in neonates with interruption of the aortic arch). Unlike in cyanotic neonates, the efficacy of alprostadil in acyanotic neonates does not depend on age or pretreatment PaO2.

Pharmacokinetics: Alprostadil is administered by intravenous infusion, intracavernosal injection, or via an urethral suppository. Intravenous administration of alprostadil requires a continuous infusion of the drug because approximately 80% of the dose is metabolized in one pass through the lungs, mostly by beta- and omega-oxidation. After intracavernosal or intraurethral administration, minimal systemic absorption occurs. Any alprostadil absorbed by these routes is rapidly metabolized. Alprostadil given via the urethra is delivered directly to the urethral lining for transfer via the corpus spongiosum to the corpora cavernosa. The onset of effect is within 5—10 minutes after urethral administration and the duration of effect is approximately 30—60 minutes and will vary from patient to patient. Following intracavernosal administration, erection usually occurs within 2—25 minutes and may last for about 1 to several hours. Tolerance to the beneficial vascular effects does not appear to occur.

Once in the systemic circulation, alprostadil is bound primarily to albumin (81%). No significant binding to erythrocytes or white blood cells occurs. Alprostadil is completely metabolized to several metabolites which are primarily excreted in the urine. There is no evidence of tissue retention of alprostadil or its metabolites following IV administration.

Drug Information Provided by
Gold Standard Inc. � 2007