Erectile Dysfunction: Causes, Evaluation, and Treatment

• Erectile dysfunction (ED) is the inability to attain or sustain an erection for sexual intercourse.
• ED can impact the quality of life.
• Most ED is related to vascular, neurologic, psychologic, and hormonal disorders, but drug use can also cause ED.
• Evaluation for ED typically includes screening for underlying disorders and measuring testosterone levels.
• Treatment options for erectile dysfunction include oral phosphodiesterase inhibitors, intra-urethral or intra-cavernosal prostaglandins, vaccum erection devices, and surgical implants.

Learning Objectives

• Describe the physiological mechanisms of normal penile erection
• Name examples of drugs that can cause erectile dysfunction
• Describe clinical pharmacology of drugs used in the treatment of erectile dysfunction

Physiological Mechanisms of Normal Penile Erection

• Parasympathetic nerves S2-4 mediate erection.
• Sympathetic nerves T11-L2 control ejaculation and detumescence.
• Stimulation of the penile shaft by the nervous system leads to secretion of nitric oxide (NO)
• Acetylcholine acts on muscarinic receptors
• Nitric oxide diffuses into cavernosal smooth muscle cells, activating guanylate cyclase
• Guanylate cyclase converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP).
• Cyclic GMP relaxes smooth muscle, resulting in vasodilation.
• Erectile tissues in the corpus cavernosa fill with blood, causing a penile erection.
• Phosphodiesterase type 5 (PDE5) exists primarily in the corpora cavernosa and stops the effect of cGMP.
• PDE5 degrades cGMP, resulting in vasoconstriction of erectile tissues leading to loss of erection.
• Loss of an erection occurs after orgasm and ejaculation of sperm in normal males.

Drugs Associated with Erectile Dysfunction

• Anti-hypertensive drugs and diuretics can cause ED, like spironolactone and thiazides.
• Beta blockers and centrally acting drugs (e.g. methyldopa), anxiolytics like Benzodiazepines are also implicated.
• Antipsychotics such as Phenothiazines, and psychotropic drugs, including Alcohol, Opiates, Amphetamines, Cocaine, and Cannabis, are further risks.
• ED can also be caused by antidepressants such as tricyclic antidepressants, MAO inhibitors and SSRIs
• Anti-muscarinic drugs and other drugs such as lipid-lowering agents.
• NSAIDs, cytotoxic drugs, anti-androgens, estrogens, ketoconazole, and cimetidine are further causes for ED.

Drugs Used in the Treatment of Erectile Dysfunction

• Oral agents include Phosphodiesterase type 5 inhibitors (PDE-5 inhibitors).
• Alprostadil can be injected intra-cavernosally or intra-urethrally.

PDE-5 INHIBITORS

• PDE-5 inhibitors include sildenafil, vardenafil, and tadalafil.
• These are the first-line drugs in managing erectile dysfunction.
• PDE-5 inhibitors selectively inhibit cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE-5).
• PDE-5 is the predominant phosphodiesterase isoform in the pelvis.
• By preventing the hydrolysis of cGMP, these drugs promote the cGMP-dependent smooth muscle relaxation that is essential for normal erection
• Fatty food reduces the effect of PDE-5 inhibitors.
• All three drugs work regardless of the cause of ED but require sexual stimulation for activation.
• In comparative clinical trials, these drugs show comparable efficacy of 60 to 75%.
• Vardenafil and tadalafil are more selective for the penile vasculature than sildenafil.
• Clinic responses and adverse effects of the drugs are similar.

PDE-5 Inhibitors: Adverse Effects

• Adverse effects include nasal congestion, dizziness, flushing, visual abnormalities, abnormal color perception (blue haze), hearing loss, dyspepsia, and headache.
• The use of tadalafil has been linked with myalgias.
• Nonarteritic ischemic optic neuropathy has been associated with PDE-5 inhibitor use, but a causal relationship has not been established.
• PDE5 inhibitors can, rarely, cause priapism.

PDE-5 Inhibitors: Contraindications

• Contraindications include hypotension and recent cardiovascular events (stroke or myocardial infarction)
• Anatomical deformity (angulation, cavernosal fibrosis, Peyronie's) and predisposition to prolonged erection can mean you can't use them (sickle cell disease, multiple myeloma, and leukaemia)

PDE-5 Inhibitors: Drug Interactions

• All PDE-5 inhibitors cause direct coronary vasodilation and potentiate the hypotensive effects of organic nitrates.
• Concomitant use of nitrates and PDE-5 inhibitors can be dangerous and should be avoided.
• All PDE5 inhibitors should be administered cautiously and at lower initial dosages to patients receiving a-blockers due to the risk of hypotension.
• Patients taking an a-blocker should wait at least 4 hours before using a PDE-5 inhibitor.
• Cytochrome P450 inhibitors (e.g. ritonavir, cimetidine, ketoconazole, erythromycin) increase the effects of PDE-5 inhibitors (inhibit the metabolism of PDE-5 inhibitors).

Erectile Dysfunction Second Line Treatments: Alprostadil

• Alprostadil is a vasoactive prostaglandin E₁.
• Alprostadil causes blood vessels to dilate, increasing blood flow to the penis.
• This helps facilitate an erection with a mean duration of 30 to 60 min.
• Alprostadil is self-administered via intraurethral insertion or intracavernosal injection.
• Intracavernosal injection produces satisfactory erection in up to 90% of men and has an almost immediate onset of action.
• Intraurethral therapy is less effective, and produces satisfactory erections in up to 60% of men.
• Alprostadil is more effective when used in combination with phentolamine and papaverine (vasodilators).
• This combination has an extremely high rate of efficacy at 92%.
• Adverse effects include penile pain, prolonged erections, priapism, and fibrosis.
• Contraindications include bleeding disorders, sickle cell anaemia, multiple myeloma, and leukaemia.