Medical Pharmacology and Therapeutics, 4e

16. Erectile dysfunction

Physiology of erection

Erectile dysfunction

Management of erectile dysfunction

Oral phosphodiesterase inhibitors

Alprostadil

Physiology of erection

Achieving and maintaining an erection is a spinal reflex that involves a complex series of interactions between the central nervous system, the autonomic nervous system and local mediators. Psychological, visual, olfactory and tactile stimuli are all important. The primary erectile innervation is the parasympathetic nervous system. There are four phases in achieving full penile erection.

Phase 1. Parasympathetic stimulation relaxes both arterial smooth muscle and the smooth muscle that forms bands (trabeculae) with connective tissue in the highly vascular erectile tissues of the penis (corpus cavernosa and corpus spongiosum). These actions increase the influx of blood into the sinusoidal spaces of the corpus cavernosa, which become engorged (Fig. 16.1). Conversely, sympathetic stimulation inhibits erection by increasing vascular smooth muscle tone.

image

FIG. 16.1 Cross-section of the penis, showing structures involved in erection.

This diagram shows only part of the rich nervous and vascular filling and drainage system in the penis. The left-hand area shows the situation in the flaccid penis and the right-hand area the erect penis. The rising pressure during erection limits the venous outflow, thus maintaining the erection. The penis contains three cylinders of erectile tissue: two corpora cavernosa and the corpus spongiosum. The corpus spongiosum contains the urethra. The cylinders of erectile tissue are divided into spaces known as sinusoids or lacunae, which are lined by vascular epithelium. The walls of these spaces are made up of thick bundles of smooth muscle cells within a framework of fibroblasts, collagen and elastin (trabeculae). The erectile tissues are supplied with blood from the cavernosal and helicine arteries, which drain into the sinusoidal spaces. Blood is drained from the sinusoidal spaces through emissary veins. The venules join together to form larger veins that drain into the deep dorsal vein or other veins at different parts of the penis. Arterial and sinusoid dilation is important for erection, while swelling is limited by the inelastic tunica albuginea.

Phase 2. Pressure rises within the corpus cavernosum and the sinusoids expand. The penis elongates and widens.

Phase 3. The rise in pressure in the sinusoids compresses the venous plexus and reduces venous outflow, thus maintaining the erection (the corporeal veno-occlusive mechanism).

Phase 4. The pudendal nerve (part of the parasympathetic innervation) stimulates the ischiocavernous muscle. This squeezes the crura at the base of the penis and stops both arterial inflow and venous outflow, maintaining full erection. Muscle fatigue eventually allows return of perfusion.

There are also many locally produced mediators that appear to be involved in achieving and maintaining an erection. Nitric oxide (NO) synthesised by blood vessel endothelial cells and released from non-adrenergic non-cholinergic (NANC) nerves in the corpora appears to be crucial for cavernosal smooth muscle relaxation. Nitric oxide generates intracellular cGMP, which activates protein kinase G. cGMP is degraded to GMP by phosphodiesterase type 5 (PDE5) (see Table 1.1), terminating its effects. Inhibition of PDE5 is a primary target for the pharmacological treatment of erectile dysfunction (see below). Other vasodilators that are involved in modulating penile vascular smooth muscle relaxation and blood flow include vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and prostaglandin E1, but their precise roles are less well understood. Numerous central facilitatory mediators have been identified, including dopamine, acetylcholine and a variety of peptides. These are involved in the psychological preparedness that is essential for an erection to occur.

Erectile Dysfunction

Erectile dysfunction is defined as the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It is a common problem, affecting up to 20% of adult men, with up to 10% over the age of 40 years having complete erectile dysfunction. Any disease process that affects penile neural supply, arterial inflow or venous outflow can produce erectile dysfunction. There is a physical cause in about 80% of cases (Box 16.1) but a psychological component often coexists. Psychogenic erectile dysfunction is more common in younger men. Drugs are an important cause of erectile dysfunction, particularly antihypertensive, psychotropic and ‘recreational’ drugs, and account for up to 25% of cases. Drugs can also affect libido and therefore arousal, or inhibit ejaculation in those who achieve an erection (Table 16.1).

Box 16.1  Common causes of erectile dysfunction

Diabetes

Vascular disease

Prostate surgery

Drugs (see Table 16.1)

Substance abuse, e.g. nicotine, alcohol, recreational drugs

Testosterone deficiency, e.g. hyper- or hypothyroidism

Neurological disease, e.g. multiple sclerosis, Alzheimer's disease, epilepsy

Spinal cord injury

Psychological factors (20% as a primary cause, more commonly secondary to physical problems)

Table 16.1

Drugs that commonly cause male sexual dysfunction

image

Management of erectile dysfunction

A number of strategies can be used in the management of erectile dysfunction. Initially there should be an assessment and treatment of any underlying psychological cause or physical disease or if possible withdrawal of a causative drug. Treatment options for persistent dysfunction include:

image pharmacological, using the drugs described below,

image mechanical aids, such as the vacuum constriction device: these are usually advised for older people who do not respond to pharmacological treatment and do not wish to have surgery,

image penile implants using a malleable or inflatable prosthesis,

image testosterone-replacement therapy for hypogonadism (Ch. 46), an uncommon cause of impotence.

Hyperprolactinaemia impairs erection; it is most commonly caused by drug therapy (e.g. with phenothiazines) and can be improved by oral dopamine agonists (Ch. 43) if the cause cannot be treated.

Oral Phosphodiesterase Inhibitors

Examples

sildenafil, tadalafil, vardenafil

Endothelial-derived nitric oxide increases the synthesis of cGMP that acts via protein kinases to cause blood vessel dilation (see Ch. 5Fig. 5.3). cGMP is broken down in penile tissue by PDE5. Sildenafil, tadalafil and vardenafil are orally active analogues of cGMP that selectively inhibit the enzyme. PDE5 is also found in lower concentrations in other vascular and visceral smooth muscles, and in skeletal muscle and platelets. Sexual stimulation resulting in the release of nitric oxide is a prerequisite for these drugs to produce an erection, and the drug will then prolong the vasodilator effect of nitric oxide on penile vascular smooth muscle. If an appropriate dose of the drug is used, about 60% of men with erectile dysfunction will achieve erections sufficient to permit intercourse. The response is often better if precipitating factors are also treated, such as depression or excess alcohol consumption.

Sildenafil and tadalafil are also used to treat pulmonary hypertension (Ch. 6).

Pharmacokinetics

Sildenafil is relatively well absorbed orally, but vardenafil and tadalafil are less well absorbed. The median time to onset of action for all is about 30 min. The absorption of sildenafil and vardenafil is delayed by a fatty meal, whereas the absorption of tadalafil is rapid and unaffected by food. All are eliminated by hepatic metabolism mediated primarily by CYP3A4. Sildenafil and vardenafil have half-lives of less than 6 h, and should be taken 30–60 min before sexual activity for maximum benefit. The half-life of tadalafil is longer (17 h), and its duration of action is up to about 24–36 h; therefore, planning of sexual activity (and its timing in relation to drug dosage) is less relevant with this drug. Sildenafil and vardenafil both have active metabolites, but tadalafil does not.

Unwanted effects

image Dyspepsia, nausea, vomiting.

image Hypotension, dizziness, flushing, headache and nasal congestion from systemic vasodilation.

image Myalgia, back pain.

image PDE6 (involved in phototransduction in the eye) is inhibited by high doses of sildenafil, but less so by tadalafil or vardenafil. This can cause visual disturbance (enhanced perception of bright lights, or a ‘blue halo’ effect) and raised intraocular pressure. Ischaemic optic neuropathy can cause sudden visual impairment.

image Priapism, a painful and sustained erection, can occur rarely.

image Drug interactions: oral PDE5 inhibitors should not be used together with nitrates or nicorandil (see Ch. 5), because of a synergistic effect on vascular nitric oxide with exaggerated vasodilator effects. Several antiviral drugs, such as saquinavir (Table 2.7 and Ch. 51), inhibit the CYP3A4 isoenzyme that metabolises oral PDE5 inhibitors, and can potentiate their effects.

Alprostadil

Intracavernosal injection of alprostadil is effective if arterial flow is normal, such as with neurogenic and psychogenic impotence. It should not be used if the person has bleeding tendencies, and may be problematic if there is poor manual dexterity or morbid obesity. The injection is made into the side of the penis, directly into the corpus cavernosum.

Alprostadil is a synthetic prostaglandin E1 analogue. It vasodilates by acting on smooth muscle cell surface receptors to increase intracellular cAMP, which in turn reduces the intracellular Ca2+ concentration. Local pain after injection is a common unwanted effect, reported by one-third of users, and can be reduced by the addition of a local anaesthetic such as procaine (Ch. 18). Rapid local metabolism of alprostadil minimises unwanted systemic effects. Priapism (prolonged painful erection) is the most worrying complication, and may require aspiration and lavage of the corpora.

High doses of intra-urethral alprostadil can be given as a pellet using a plastic applicator, but are less effective than the injection. In responders, an erection develops within 15 min and lasts for 30–60 min. Because of the uterine-stimulant activity of alprostadil, a condom is recommended if the partner is pregnant.

Self-Assessment

True/false questions

1. Sildenafil should not be taken by men already taking nitrates.

2. Sexual stimulation is a prerequisite for sildenafil to cause an erection.

3. Phosphodiesterase (PDE) type 5 is only found in the vasculature in the penis.

4. Increased parasympathetic outflow to the penis causes a failure of erection.

5. Erections caused by injected drugs such as alprostadil are not easy to control.

6. Impotence caused by hypogonadism can be treated with oestrogen.

7. Diabetes can cause impotence.

8. The duration of the biological actions of sildenafil and tadalafil is similar.

9. Sildenafil inhibits the breakdown of cAMP.

10. Alprostadil reduces prostaglandin synthesis by inhibiting cyclo-oxygenase-1.

One-best-answer (OBA) question

Which statement concerning drug action and erectile dysfunction is the least accurate?

A Alcohol can cause erectile difficulties.

B Cimetidine can exacerbate the potential for sildenafil to cause headache.

C Nicorandil is safe when taken together with tadalafil.

D Amitriptyline can cause impotence.

E Sildenafil prevents the breakdown of cGMP.

Case-based questions

Mr JA, aged 56 years, presented with erectile dysfunction of gradual onset over the last 2–3 years. He was hypertensive, with a blood pressure of 160/96 mmHg, and was being treated with atenolol and bendroflumethiazide. There was a family history of coronary artery disease. He smokes 30 cigarettes a day and drinks four pints of beer a night. Investigation revealed that he was hypercholesterolaemic and there were signs of coronary artery disease. Tests for liver function and testosterone were normal and no organic reason for the dysfunction was found. Mr JA also has recurrent heartburn, for which he is taking cimetidine on most days.

It was decided not to prescribe a pharmacological agent for his erectile dysfunction at this stage, but a number of suggestions and recommendations were made.

After 3 months, during which time Mr JA followed the advice he was given, his blood pressure was within normal limits and his cholesterol was lower. He was regularly taking cimetidine. However, his erectile dysfunction persisted.

Following discussions, it was decided that Mr JA should try sildenafil.

A Which of the above factors could contribute to his erectile dysfunction and what recommendations would you suggest?

B From his history, what precautions should be taken in prescribing sildenafil and what advice should Mr JA be given?

True/false answers

1. True. Nitrates result in increased nitric oxide production and this elevates cGMP. Sildenafil elevates cGMP by blocking its breakdown, and the combination with nitrates can lead to additive unwanted effects, particularly hypotension.

2. True. Sildenafil and other PDE type 5 inhibitors prolong the vasodilator action of NO produced as a result of sexual stimulation.

3. False. PDE type 5 is found in some other blood vessels and tissues, which can result in unwanted effects when sildenafil is given.

4. False. Parasympathetic stimulation enhances erection, and drugs known to inhibit the parasympathetic outflow (e.g. tricyclic antidepressants) can cause erectile failure.

5. True. Painful priapism with erections lasting many hours can occur with intracavernosal drugs.

6. False. Testosterone can be useful if the impotence is due to hypogonadism.

7. True. Diabetes mellitus probably causes erectile problems through vascular dysfunction.

8. False. Tadalafil has a much longer biological half-life than sildenafil, allowing it to be taken up to 12 hours before sexual activity.

9. False. Sildenafil inhibits the breakdown of cGMP, not cAMP.

10. False. Alprostadil is a synthetic prostaglandin E1 analogue, which vasodilates by increasing cAMP.

OBA answer

Answer C is the least accurate.

A True. Alcohol use is a recognised cause of erectile dysfunction.

B True. Cimetidine inhibits the isoenzyme CYP3A4 that metabolises sildenafil, enhancing its vasodilator effects, including headache.

False. Nicorandil is a K+ channel opener (Ch. 5) that also has a nitrate structure; this increases cGMP formation and would add to the effects of tadalafil, with the potential for increased unwanted effects.

D True. Amitriptyline has antimuscarinic actions that could decrease blood vessel dilation in the penis, thereby inhibiting erection.

E True. Blocking the breakdown of cGMP is the main mechanism of action of sildenafil, leading to vasodilation.

Case-based answers

A The contribution of psychological factors in Mr JA's erectile dysfunction needs to be assessed and dealt with if they are present. Vascular disease, smoking and alcohol consumption may also contribute and Mr JA should be helped to manage these. Because of the evidence of coronary artery disease, which is known to be associated with erectile dysfunction, it would be advisable to be more intensive in treating his high blood pressure and reducing his cholesterol levels. Although this is unlikely to restore erectile function, it may improve the patient's well-being and have a psychological benefit. Beta-adrenoceptor antagonists (atenolol) and thiazide diuretics (bendroflumethiazide) can contribute to erectile problems; Mr JA could be treated with an ACE inhibitor, such as enalapril, which has not been shown to contribute to impotence.

B Cimetidine is an inhibitor of hepatic CYP3A4 (Table 2.7) that metabolises sildenafil, so the initial dose of sildenafil should be reduced. Alternatively, Mr JA could use ranitidine, which does not inhibit CYP3A4. Studies of sildenafil in patients with a history of cardiovascular disease have shown that the simultaneous use of nitrates is an absolute contraindication. Mr JA should be told about the dangers of drug interactions and possible unwanted effects.

Compendium: drugs used to treat erectile dysfunctiona

image

aAll drugs in this table should be used with caution in people with cardiovascular disease.

Further reading

Andersson, K-E. Pharmacology of penile erection. Pharmacol Rev. 2001;53:417–450.

Corbin, JD, Francis, SH. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract. 2002;56:453–459.

McVary, KT. Erectile dysfunction. N Engl J Med. 2007;357:2472–2481.

Morgentaler, A. Male impotence. Lancet. 1999;354:1713–1718.

Sivalingam, S, Hashim, H, Schwaibold, H. An overview of the diagnosis and treatment of erectile dysfunction. Drugs. 2006;66:2339–2355.



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!