Lipid Lowering Medication

Fibrates (clofibrate, gemfibrozil, and less frequently bezafibrate and fenofibrate) are lipid-lowering medications that have long been associated with medication-induced sexual dysfunction.

A case­control study of 339 age­matched men revealed that there were more impotent men in the group of patients treated with lipid-lowering medications (12% vs. 5.6%); and multivariate anal-ysis showed that fibrates and statins were independent risk factors for erectile dysfunction.

A contemporary systematic review was recently carried out by a group in England evaluating the evidence associating lipid lowering therapies, including statins, with the onset of ED. While there are multiple trials that do not show and increased rate of sexual dysfunction in patients taking lipid lowering medications versus placebo, the authors report several studies in which the initiation of clofibrate, gemfibrozil, and multiple statins was associated with ED. While it remains unclear what the true rates of sexual adverse events with hypolipidemics, the mechanism in which this occurs is thought to be through decreased synthesis of sex steroid hormones derived from cholesterol, namely, testosterone. In addition to their known effects on serum lipid levels, statins have been hypothesized to mediate anti-inflammatory effects through several different pathways, including the inhibition of NOS activity. Thus, it is possible that statins might potentiate erectile dysfunction via decreased nitric oxide levels.

Miscellaneous and Kamagra Australia

Case reports of sexual side effects from metoclopramide, baclofen, amicar (epsilon-amino-car-poic acid), disulfiram, and carbonic anhydrase inhibitors have been associated with ED. Cytotoxic drugs have also been implicated in drug­related ED include methotrexate and thalidomide. Digoxin is yet another drug that has been suggested to induce ED. The mechanism it thought to be via blockade of the Na⁺, K⁺­ATPase pump, resulting in a net increase in intracellular calcium and increased corporal smooth muscle tone. Others have also suggested that the chemical structure of digoxin is similar to sex steroids leading to antiandrogen activity.

Immunomodulators

Decreased libido and ED are commonly reported side effects experienced by male patients during antiviral therapy for chronic hepatitis C. This effect was studied in 34 male patients being treated with interferon and ribavirin. Free and total testosterone decreased significantly during antiviral therapy while depression scores increased during therapy.

Certain agents used in renal transplantation have been implicated in erectile function as well. The immunosuppressive agents’ target of rapamycin inhibitors (i.e., sirolimus and everolimus) have been shown to result in decreases in serum testosterone levels, increases in levels of luteinizing hormone, and a disruption of spermatogenesis. The impairment of gonadal function is reported to elicit ED in patients receiving these drugs.

Hormonal Agents

Androgens are known to increase libido, but their exact role in erectile function remains unclear. Normal levels of testosterone appear to be important for erectile function, particularly in older males. It has been shown that androgen replacement therapy can improve depressed erectile function when ED is secondary to hypogonadism. As such, it is not surprising that any drug that interferes with testosterone production or action might lead to sexual dysfunction. Estrogens, GnRH agonists, LHRH agonists, and corticosteroids can cause ED by suppressing gonadotropin production. Certain drugs like spironolactone, cypoterone acetate, ketoconazole, aminoglutethimide, and other similar drugs have also been shown to have antiandrogen activity and have each been linked to drug-induced sexual dysfunction. These agents often resemble the molecular structure of testosterone and compete with native testosterone for binding to androgen receptors; they have also been shown to induce hyperprolactinemia. Multiple reports have linked H₂ blockers to sexual dysfunction. Ranitidine and cimetidine have both been shown to increase prolactin levels and act as antiandrogens.

5a (alpha)-reductase inhibitors

The potential sexual side effects, including ED, decreased libido and ejaculatory problems, which have been reported with 5a-reductase inhibitors (dutasteride and finasteride) are of particular relevance to the urology patient. These drugs block the con-version of testosterone to the more potent androgen, dihydrotestosterone (DHT). Animal models have demonstrated decreased NOS activity with decreased DHT, and thus, it has been proposed that 5a-reductase inhibitors elicit sexual dysfunction by indirectly attenuating NOS activity. Sexual adverse events have been reported in clinical trials at rates of 2.1–38%. The most common complaint is ED, followed by ejaculatory dysfunction and decreased libido. It appears that these effects occur early in the initiation of therapy and decrease over time. The results of these studies, however, have been questioned as the high incidence of drug-induced sexual dysfunction reported in some clinical tri-als does not seem to correlate with clinician experience. In a more recent study, two groups of blinded, randomized patients received 5 mg of finasteride with and without counseling regarding the potential for sexual side effects. The incidence of ED, decreased libido and ejaculatory problems were significantly reduced in patients who did not receive sexual side effect counseling. The authors conclude that a “nocebo” effect, an adverse effect that is not a direct result of the specific pharmacological action of the drug, should be taken into account when managing patients with reported sexual side effects. This latter study elucidates a common problem encountered by any physician attempting to counsel their patients regarding the potential side effects caused by the drugs mentioned in this chapter. This psychological priming can be a particularly difficult challenge in the management of sexual dysfunction in the setting of drug use.

HIV therapy

HIV and the polypharmacy standardin the care of HIV patients have been associated with sexual dysfunction. A recent cross­sectional study of HIV patients in England estimated the prevalence of moderate to severe ED to be 33% and moderate to severe impairment of sexual desire to be 24%. While multivariate analysis found sexual dysfunction to be common in both patients receiving antiretroviral therapy and those naïve to the drugs, ED was found to be associated with long duration of HIV therapy. A survey among a different group of HIV patients from ten different European countries demonstrated decreased libido and potency in men receiving drug regimens containing protease inhibitors as compared to protease inhibitor naïve patients, specifically identifying protease inhibitors as a drug leading to sexual dysfunction among HIV patients. Studies have shown that antiretroviral therapy is associated with increased aromatization of testosterone leading to increases serum levels of estradiol in men. It is hypothesized that the sexual dysfunction reported by patients taking antiretrovirals is secondary to these hormonal imbalances. Various hormonal replacement strategies have recently been under investigation. While testosterone has been well studied in the treatment of HIV-related wasting syndromes several more recent reports specifically address sexual function. Letrozole, an aromatase inhibitor, and both parenteral and topical forms of testosterone have both been shown not only to increase serum levels of testosterone, but also to improve patient reported sexual function.

Psychotropic Medications

Psychotropic agents – particularly neuroleptics, tricyclics, and serotonin reuptake inhibitors (SRIs) – are associated with erectile, ejacula­ tory, orgasmic, and sexual desire difficulties. Mental illness and the management of mental disorders are a significant cause of sexual dysfunction in men. A recent population study reported a fivefold increase in odds of self-reported complete ED among men who used selected antidepressant therapy (principally selective SRIs and tricyclics) which exceeded the risk of ED attributed to depression symptoms or diagnosis. Antidepressant­associated ED is reported to occur with prevalence rates from 30 to 90%. Worsening or the initiation of sexual dysfunction has been reported with agents for all antidepressant classes, including mono-amine oxidase inhibitors, tricyclic antidepressants, and SRIs. Bupropion, nefazodone, and mirtazapine appear less likely to cause sexual dysfunction. A number of molecularpathways have been implicated in antidepressant-induced sexual adverse events. Serotonin has been hypothesized to inhibit normal sexual response by decreasing dopamine-enhanced libido, arousal and erection and increasing prolactin release from the hypothalamus. SRIs have also been shown to be potent inhibitors of NOS.

Given the high prevalence of antidepressant-induced sexual dysfunction, a prospective, parallel group, randomized, doubleblind, placebo-controlled trial was undertaken to evaluate the safety and efficacy of PDE­5 inhibitors in the treatment of this disorder. Ninety male outpatients at three different university medical centers with major depression in remission and sexual dysfunction associated with either selective or nonselective SRI antidepressant treatment were randomly assigned to take sildenafil at a flexible dose (50–100 mg) for 6 weeks. Multiple different validated and unvalidated questionnaires were administered, including the IIEF. Based on several analyses, the authors concluded that sildenafil was well tolerated and significantly improved erectile function and overall sexual satisfaction in men with SRI­associated ED. These data provide Level 1 evidence that a PDE­5 inhibitor may be success-fully used to treat Antipsychotic medications are associated with both erectile and ejaculatory dysfunction in up to 50% of patients. Certain antipsychotics, in particular the typical antipsychotics, can exhibit a1 adrenergic antagonism and lead to the unwanted effects of retrograde ejaculation and priapsim. Atypical antipsychotics at high­ doses have been implicated in retrograde ejaculation and priapism as well. Dopamine is considered a key target of neuroleptic medications and is known to have multiple effects in the central nervous system. It is well established that dopamine inhibits prolactin release. Decreases in dopamine action thus lead to hyperprolactinemia. Increased serum levels of prolactin may decrease libido by suppressing gonadotropinreleasing hormone (GnRH) and decreased testosterone levels, resulting in decreased libido, anorgasmia, and ED. In addition, many drugs that produce central nervous system sedation or depression, such as anxiolytics and tranquilizers, are also thought to lead to ED potentially via CNS antidopaminergic effects and increased prolactin release.

CNS sedatives are also known to have residual anticholinergic effects. While acetylcholine plays a significant role in normal erectile function, the use of anticholinergic agents has not been associated with ED as frequently as one might expect. ED has, however, been reported with the anticholinergic antiarrhythmic drug disopyramide. In addition, many of the antidepressants, namely, tricyclics and select SRIs, maintain residual anticholinergic properties. It is possible that the sexual dysfunction from these medications is mediated in part by their anticholinergic properties.