Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in the Treatment of Erectile Dysfunction

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Individual Agents

The pharmacological agents useful in this disorder may be grouped under five broad categories of treatment.

INDIVIDUAL AGENTS

 

The pharmacological agents useful in this disorder may be grouped under five broad categories of treatment (Table 64.2). Such a classification system takes into ac-count the mode of drug action, the route of administra-tion, and the means by which target organ selectivity is achieved.


 

Oral medication for treatment of ED is relatively new. Earlier measures often employed the intracavernosal injection of a vasoactive agent or a systemic mode of drug administration. 

Local injections or dermal ap-plications were frequently required for satisfactory pharmacological actions upon the vascular smooth mus-cles of the penis. Compounds with relatively short dura-tion of action were found to be less than satisfactory in maintaining penile erections.

 

Combinations of drugs have sometimes been used to take advantage of the differing onset and duration of action of the individual compounds. A rapid onset of ac-tion and a sufficient duration are important characteris-tics of drugs used in the treatment of ED. Vasoactive agents that are orally effective have been available for about 20 years, but sildenafil and apomorphine (buccal) have significantly improved upon the therapeutic effi-cacy of orally active agents.

 

Alprostadil

 

Alprostadil (prostaglandin E1 [PGE1]; Edex, Topiglan) exerts a number of effects, including systemic vasodila-tion, inhibition of platelet aggregation, and stimulation of intestinal motility. PGE1 relaxes isolated smooth muscle cells contracted by norepinephrine. It has be-come widely used in the treatment of ED. Alprostadil binds with PGE receptors and results in a cyclic adeno-sine monophosphate (cAMP) mediated smooth muscle relaxation. Little is known about the pharmacokinetics of PGE1, but it is believed that as much as 80% is me-tabolized in one pass through the lungs. Such rapid degradation probably accounts for its lack of significant cardiovascular side effects when administered intracav-ernosally. PGE1 can also be metabolized in the penis.

 

PGE1 is not orally effective. Its therapeutic success depends on its being injected intracavernosally or ad-ministered transurethrally or intraurethrally. PGE1 has also been used in combination with other agents, such as papaverine. The injection does not appear to produce any long-term side effects on penile smooth muscle. Transurethral therapy with alprostadil, such as MUSE (alprostadil urethral suppository or medicated urethral system for erection) is also an effective therapeutic technique, and there may be a role for this form of ad-ministration in selected patients with ED. The intracav-ernosal injection of alprostadil (e.g., alprostadil alfadex; Edex, Viridal) is safe and effective in patients with ED when sildenafil is ineffective. Both of these delivery sys-tems have been used in the treatment of ED. MUSE can also be used in conjunction with a penile constrictor de-vice (e.g., ACTIS).

 

Apomorphine

 

Apomorphine (Uprima) is a short-acting central and pe-ripheral dopamine receptor agonist that can elicit male sexual responses. Dopamine appears to have an impor-tant role in normal erectile function. Apomorphine is a D1-like, D2-like dopamine receptor agonist.Apomorphine is not a new drug, and it has been used with limited suc-cess in ameliorating the symptoms of Parkinson’s disease and to induce emesis. It is not orally active except for a special buccal formulation, but it can be given parenter-ally, usually subcutaneously. Apomorphine is rapidly cleared from the kidney because of its high lipid solubility, its large volume of distribution, and its rapid metabolism.

 

Aside from sildenafil, apomorphine is one of the few orally active (buccal route) pharmacological agents used in the treatment of ED. Apomorphine stimulates penile erection in both normal men and in men who are impotent. Apomorphine can be the drug of choice in patients with coexisting benign prostatic hyperplasia (BPH), coronary artery disease, and hypertension.

When formulated into a controlled release sublin-gual capsule, apomorphine becomes a very effective orally active drug representative of a new class of cen-trally acting drugs useful in the treatment of ED. It has a narrow range (2 to 6 mg) of effective doses for its erectogenic actions, with the higher doses being more effective in inducing erections. Apomorphine can cause nausea, emesis, drowsiness, and dizziness.

 

Androgens: Testosterone

 

Androgen deficiency can lead to decreases in nocturnal erections and libido. Hypogonadism is associated with impotence, yet erection in response to visual stimula-tion is preserved in men with hypogonadism, suggesting that androgens are not essential for erection. Although androgens can enhance male sexual function, testos-terone therapy for the treatment of ED should be dis-couraged unless the cause is clearly related to hypogo-nadism. Androgen therapy in normal men may enhance sexual behavior but is without significant effect upon erectile function.

 

Usefulness of oral methyltestosterone is limited in men with hypogonadal impotence. Improvement follow-ing transdermal testosterone may require several months of therapy. Androgen replacement regimens for treating male hypogonadism include long-acting intramuscular injections (e.g., testosterone enanate, testosterone cypi-onate) and oral preparations (e.g. methyltestosterone, fluoxymesterone). Transdermal patches (Testoderm, Androderm) and topical testosterone gel (Androgel) are also available. Transdermal testosterone also may im-prove sexual function and psychological well-being in women who have undergone oophorectomy and hys-terectomy. Transdermal delivery systems can provide a more constant serum testosterone level than do intra-muscular injections, but they are more expensive.

 

Papaverine

 

Papaverine (Pavabid) is a nonspecific phosphodi-esterase inhibitor that increases cAMP and cGMP lev-els in penile erectile tissue. Papaverine is particularly known as a smooth muscle relaxant and vasodilator. Its principal pharmacological action is as a nonspecific va-sodilator of smooth muscles of the arterioles and capil-laries. Various vascular beds and smooth muscle re-spond differently to papaverine administration both in intensity and duration. Papaverine decreases the resist-ance to arterial inflow and increases the resistance to venous outflow.

 

Papaverine is highly effective in men with psy-chogenic and neurogenic ED but less effective in men with vasculogenic ED. Papaverine–phentolamine com-binations have been used in self-injection procedures. Papaverine doses may range from 15 to 60 mg. Papa-verine treatment in patients with severe arterial or ve-nous incompetence is usually unsuccessful, but autoin-jections using low doses sufficient to achieve an erection are safe and efficient.

 

Major side effects associated with papaverine ther-apy include priapism, corporeal fibrosis, and occasional increases in serum aminotransferases. Intracorporeal scarring may be related to the low pH of the vehicle that is necessary to solubilize papaverine. Attempts to buffer papaverine to render it more suitable for intracaver-nosal injection have not been entirely satisfactory, and such delivery may still lead to intracorporeal scarring.

 

Phentolamine

 

Human erectile tissue has a population of membrane receptors that are predominantly of the α-adrenoceptor subtype. Phentolamine (Vasomax) is a nonselective α- adrenoceptor blocking agent , and like other such agents, it has been used to treat ED. Nonselective adrenoceptor antagonists may provoke a reflex that increases both sympathetic outflow and the release of norepinephrine.

 

Phentolamine has been used orally and intracaver-nosally in the treatment of ED. Following oral adminis-tration, phentolamine has a plasma half-life of about 30 minutes and a duration of action of 2 to 4 hours. An in-tracavernosal injection of phentolamine results in the drug reaching maximum serum levels in about 20 to 30 minutes. It is rapidly metabolized.

 

Phentolamine has been used in combination with papaverine, chlorpromazine, and vasoactive peptides in the treatment of ED.

 

Side effects of phentolamine are dose related. It may cause orthostatic hypotension, reflex tachycardia, cardiac arrhythmias, and rarely, myocardial infarction. Phentolamine also may reduce sperm motility in vitro.

 

Other α-adrenoceptor receptor antagonists include yohimbine, phenoxybenzamine, and thymoxamine. Yo-himbine is an α2-adrenoceptor antagonist, and thymox-amine is a competitive and relatively selective blocking agent for α1- adrenoceptors. Phenoxybenzamine blocks both α1- and α2-adrenoreceptors, although it has a greater affinity for the α1-subtype. All three of these β -receptor blocking drugs can induce penile erection, but their ef-fects are generally less consistent and less effective than those of phentolamine. Yohimbine is only moderately ef-fective in treating patients with organic impotence, and side effects may include postural hypotension, heart pal-pitations, fine tremors, and cavernosal fibrosis, especially following intracavernosal injections.

 

Sildenafil

 

Sildenafil (Viagra) was developed more than 10 years ago as an antihypertensive and antianginal drug. It proved ineffective in these applications but was shown to affect the smooth muscles of the penis.

 

Sildenafil is a selective inhibitor of cGMP-specific PD-5 and therefore inhibits the degradation of cGMP. PD-5, the predominant type in the corpus cavernosum, also is present in other tissues (e.g., lungs, platelets, and eye). The selective inhibition of this enzyme facilitates the release of nitric oxide and smooth muscle relaxation of the corpus cavernosa. Sildenafil enhances erection by augmenting nitric oxide–mediated relaxation pathways. It has been suggested that sildenafil’s mechanism of action is due to cross-talk between cGMP- and cAMP-dependent transduction pathways within the cavernous muscles.

 

Sildenafil is readily absorbed after oral administra-tion and reaches peak plasma levels after about an hour. It undergoes hepatic metabolism and has a termi-nal half-life of about 4 hours. An initial dose of 50 mg is taken about an hour prior to sexual activity to induce penile erection.

 

Orally administered sildenafil is an effective and well-tolerated treatment for men with ED, including those with diabetes mellitus. It has also been used for so-called salvage therapy in men who do not respond to intracorporeal injections of other agents.

 

Headache is a common side effect, as are flushing and rhinitis. More serious side effects include definite or suspected myocardial infarctions and cardiac arrest.

 

Trazodone

 

Trazodone (Apothecon) is also classified as an antide-pressant agent. It is a selective serotonin reuptake in-hibitor (SSRI), partial agonist at postsynaptic 5-HT1A receptors, and exhibits α-adrenoceptor blocking ac-tions.

 

Trazodone may cause priapism and enhance libido, and it prolongs nocturnal erections. This drug has been used both orally and by intracavernosal injection. It can be used alone or in combination with yohimbine. Overall, trazodone has not been as effective in treating ED as other available agents. However, it may be an op-tion for selected patients, particularly those with per-formance anxiety or low libido.

 

Other Agents

 

Many other drugs and herbals exhibit varying degrees of potency with respect to penile erection. Some have undergone limited clinical trials, while others are asso-ciated with anecdotal reports. Generally, these agents are not particularly effective and are not widely used among mainstream therapeutic options for ED.

 

Linsidomine (SIN-1) is an active metabolite of the antianginal drug molsidomine. Its mechanism of action upon the corpus cavernosum involves the release of ni- tric oxide. Injected intracavernosally it can produce pe-nile erections, but its clinical usefulness has not been fully established.

 

Nitroglycerin (also isosorbide nitrate) relaxes iso-lated strips of human corpus cavernosum. Its mecha-nism involves the stimulation of guanylate cyclase. Clinically, nitroglycerin has been of limited use in the treatment of ED.

 

Minoxidil, an antihypertensive agent, produces arte-riolar vasodilation by an unknown mechanism. In lim-ited clinical studies, minoxidil increases penile rigidity and has been used in the long-term treatment of organic impotence.

 

Naltrexone, an orally active opioid receptor antago-nist, restores erectile function in some patients with id-iopathic ED.

 

Calcitonin gene–related peptide (CGRP) induces a dose-related increase in penile arterial inflow, cav-ernous smooth muscle relaxation, cavernous outflow occlusion, and an erectile response. CGRP plus PGE1 may be an alternative to penile implants in selected pa-tients.

 

Forskolin, an herbal, relaxes smooth muscle. In-jected intracavernosally, forskolin has been of limited use in the treatment of vasculogenic impotence.

 

Other herbal remedies or so-called natural products purportedly can enhance male sexual activity. Some may contain yohimbine. Natural prosexual agents of herbal origin include Epidemicum sagthatum, Tribulas terrestris, and Murira puama. Their use in folk medicine in China and other countries is likely due to their sexual stimulating properties and their aphrodisiac effects. Ginkgo biloba extract also has been used in the therapy of ED and sexual dysfunction.

 

Drug Interactions

 

Orally active agents used in the treatment of ED are more affected by aging and disease processes than are those injected intracavernosally. In addition, alterations in hepatic metabolism and/or renal clearance in the eld-erly man  influence the frequency of ap-pearance of adverse reactions between several coad-ministered drugs in the treatment of ED. For example, the concomitant use of sildenafil and nitroglycerin is contraindicated by cardiovascular complications. Also, the use of testosterone in the presence of androgen-dependent tumors may promote tumor growth.

 

Sildenafil has other minor adverse effects, such as headache, nasal congestion, and flushing. There are no clinically significant drug interactions between sildenafil and apomorphine. Apomorphine, like sildenafil, is orally active. However, unlike sildenafil, it exerts its ac-tion through the central nervous system. Apomorphine can produce dizziness, nausea, pallor, and hypotension, and in the presence of ethanol, it purportedly increases the incidence of these side effects. Such a synergy caused by ethanol and apomorphine coadministration is not unique and would likely be present with other agents that induce mild hypotension.

 

The concomitant intake of grapefruit juice increases the concentration of many drugs (e.g., testosterone, sildenafil) in humans. Such actions appear to be medi-ated mainly by the suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine. The resultant di-minished first-pass metabolism and increased bioavail-ability can lead to increased drug levels in the blood. Because sildenafil is metabolized by CYP3A and to a lesser extent by CYP2C9, grapefruit juice can reduce the clearance of this drug. Other drugs can either in-crease or decrease serum levels of sildenafil. Admin-istration of cimetidine, erythromycin, or ritonavir can lead to increases in serum concentrations of sildenafil, while rifampin diminishes blood levels of sildenafil.

 

Therapy with phentolamine may result in reflex tachycardia, arrhythmias, and hypotension; the latter ef-fect can be exacerbated by other vasodilatory drugs and by the simultaneous ingestion of ethanol. The pharma-cological actions of trazodone can be reduced by parox-etine and possibly other SSRIs.

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