2019-09-24

ED is a symptom of another, underlying problem. ED is not considered normal at any age, and may be associated with other problems that interfere with sexual intercourse, such as lack of desire and problems with orgasm and ejaculation.

Erectile dysfunction (ED) is one of the most common conditions affecting middle-aged and older men. Nearly every primary care physician, internist and geriatrician will be called upon to manage this condition or to make referrals to urologists, endocrinologists and cardiologists who will assist in the treatment of ED. This article will briefly discuss the diagnosis and management of ED. In addition, emerging concepts in ED management will be discussed, such as the use of testosterone to treat ED, the role of the endothelium in men with ED and treating the partner of the man with ED. Finally, future potential therapies for ED will be discussed.

PHYSIOLOGY OF ERECTION

If viewed in cross section, the glans of the penis reveal that the penis consists of three tube-like projections of spongy tissue, the corpus spongiosum, located ventrally and the paired corpi cavernosi located dorsally. In each of the latter is the deep artery of the penis which carries blood over the length of the penis into the open channels that make up the corpus cavernosum. The blood carried out of the corpi cavernosi empties into the dorsal vein of the penis which then returns the blood to the body. It is thought that the level of rigidity of the penis is due to the relationship between arterial inflow and venous outflow in the penis. This means that the larger the calibre of the arteries, the more blood enters the corpus cavernosum and enlarges the penis, and the larger the calibre of the veins, the more blood is shunted away from the penis. An erection is an involuntary action controlled by the autonomic nervous system which consists of the sympathetic and parasympathetic pathways. In general, sympathetic stimulation leads to the constriction of smooth muscle surrounding the arteries (reducing the calibre) and parasympathetic stimulation induces smooth muscle relaxation (larger artery). When stimulated sexually, the sympathetic stimulation of the penis decreases and the parasympathetic stimulation increases. It is the terminal of the axons of the parasympathetic nerves that release NO. The mechanism that causes erection is then the one shown above. The engorged sinusoids of the corpi cavernosi compress the penile veins, which reduces blood outflow from the penis. Blood is therefore trapped in the penis, which maintains the erection.

Sidenafil is selective for the enzyme phosphodiesterase of type 5 : its effect is more potent on PDE5 than on the other known PDE enzymes. It is 80-fold more selective for PDE5 than PDE1 and over 1000-fold more selective for PDE5 than for PDE2, PDE3 and PDE4. However, its selectively is only 10-fold as potent for PDE5 compared to PDE6 (found in the retina) which could be the basis for abnormalities related to colour vision (blue, green) which have been talked about a lot in the media. PDE5 is also found in lower concentrations in the platelets, vascular and visceral smooth muscle and skeletal muscle. Sildenafil inhibits PDE5 in these tissues as well, which is the cause of several side effects which are believed to be due to Viagra. There are 7 types of phosphodiesterases (or isozymes). They catalyse the same reaction, but the isozymes show show different behaviour when subjected to physical biochemical techniques. Those 7 types of PDE are summerised in the table below. The Km values are equivalent to measurements of the tightness of binding (or affinity) of enzyme (PDE) to substrate (cGMP). The smaller the Km value, the more tightly the substrate binds to the enzyme.

Medications which may cause erectile dysfunction (ED) Erectile dysfunction (ED) is a common side effect of a number of prescription drugs. While these medications may treat a disease or condition, in doing so they can affect a man's hormones, nerves or blood circulation, resulting in ED or increasing the risk of ED. If you experience ED and think that it may be a result of the medication you are using, DO NOT stop taking the medication. If the problem persists, contact your doctor and he or she may be able to prescribe a different medication. Common medications that may list ED as a potential side effect include:

• Diuretics (pills that cause increase urine flow) 
• Antihypertensives (high blood pressure drugs) 
• Antihistamines 
• Antidepressants • Parkinson's disease drugs 
• Antiarrhythmics (drug for irregular heart action) 
• Tranquilizers 
• Muscle relaxants • Nonsteroidal anti-inflammatory drugs 
• Histamine H2-receptor antagonists 
• Hormones 
• Chemotherapy medications 
• Prostate cancer drugs 
• Anti-seizure medications Other substances or drugs that can cause or lead to ED include these recreational and frequently abused drugs: 
• Alcohol
 • Amphetamines
 • Barbiturates 
• Cocaine 
• Marijuana 
• Methadone 
• Nicotine 
• Opiates

These drugs not only affect and often suppress the central nervous system, but can also cause serious damage to the blood vessels, leading to permanent ED. Brief history of the treatment of ED Impotence treatments were discussed in the oldest Chinese text, The Yellow Emperor’s Classic of Internal Medicine, which describes traditional Chinese medicine during the time of the Yellow Emperor’s rule which ended around 2600 BC. One of the treatments for impotence discussed is a potion with 22 ingredients. Nearly 1000 years later, the Egyptian Papyrus Ebers, a medical Egyptian document dated 1600 BC, describes a cure for impotence in which baby crocodile hearts were mixed with wood oil and applied topically to the penis. In 1973, Dr Brantley Scott from Baylor College of Medicine reported on the implantable inflatable prosthesis that urologists still use today. The major breakthrough occurred in 1998 when sildenafil became the first oral drug to be approved to treat ED. This was followed by the use of tadalafil and vardenafil as similar phosphodiesterase-5 inhibitor oral medications for treating ED.

There are hundreds of medications that have the side effect of ED and/or decreased libido. Examples of drugs implicated as a cause of ED include hydrochlorothiazides and beta-blocking agents. Medications used to treat depression, particularly the SSRIs such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Prozac Weekly, Sarafem), fluvoxamine (Luvox, Luvox CR), paroxetine (Paxil, Paxil CR, Pexeva) and sertraline (Zoloft), may also contribute to ED. Bupropion (Wellbutrin) which has a predominant effect on blocking the reuptake of dopamine is an antidepressant with lower incidence of ED. The side effects of 5ARIs occurring in fewer than 5% of patients can include gynaecomastia, ED, loss of libido and ejaculatory dysfunction. Men being treated for prostate cancer with treatments such as radical prostatectomy, radiation therapy or the use of Lutenizing hormone-releasing hormone (LHRH) agonists and antagonists can expect that ED may accompany these treatments.

Smoking, excessive use of alcohol and illicit drugs are also associated with ED. A study in 2005 suggests that ED is not only more likely among men who smoked compared with those who never did, but that in younger men with ED, cigarette smoking is very likely the cause of their impotence. Also, it is important to remember that there are psychogenic issues such as performance-related issues, traumatic past experiences, relationship problems, anxiety, depression and stress that can certainly cause or be considered a comorbid condition contributing to ED. Bullet point: Ageing and comorbidities as well as polypharmacy factor greatly influence the development of ED.

TREATMENT- • 

PDE5 inhibitors Sidenafil is selective for the enzyme phosphodiesterase of type 5 : its effect is more potent on PDE5 than on the other known PDE enzymes. It is 80-fold more selective for PDE5 than PDE1 and over 1000-fold more selective for PDE5 than for PDE2, PDE3 and PDE4. However, its selectively is only 10-fold as potent for PDE5 compared to PDE6 (found in the retina) which could be the basis for abnormalities related to colour vision (blue, green) which have been talked about a lot in the media. PDE5 is also found in lower concentrations in the platelets, vascular and visceral smooth muscle and skeletal muscle. Sildenafil inhibits PDE5 in these tissues as well, which is the cause of several side effects which are believed to be due to Viagra. There are 7 types of phosphodiesterases (or isozymes). They catalyse the same reaction, but the isozymes show show different behaviour when subjected to physical biochemical techniques. Those 7 types of PDE are summerised in the table below. The Km values are equivalent to measurements of the tightness of binding (or affinity) of enzyme (PDE) to substrate (cGMP). The smaller the Km value, the more tightly the substrate binds to the enzyme.

• NON- PDE5 

INHIBITORS Newer pharmacological treatments are focused on targeting alternative pathways in the erectile process, both centrally and peripherally. Dopaminergic agents. Dopamine operates in the brain as a neurotransmitter and in the periphery it functions like a local messenger. Apomorphine (Uprima) is a dopaminergic agent activating dopamine receptors D1 and D2 at a central level within the paraventricular nucleus of the brain.

Melanocortin receptor agonists. Melanocortins are involved in many processes, and their role in controlling sexual function was first reported in the 1960s. They are linked to the induction of penile erection and the regulation of sexual behavior. Two well-studied melanocortin receptor agonists are melanotan II and bremelanotide.

Soluble guanylate cyclase stimulators and activators. PDE5-I efficacy depends on the production of cGMP, which in turn is dependent on nitric oxide (NO) activation of soluble guanylate cyclase (sGC). In some patients, especially post-prostatectomy and DM patients, this pathway is disturbed because of varying amounts of nerve damage and the effectiveness of PDE5-Is is reduced significantly. There are two types of compounds that can stimulate sGC: heme-dependent stimulators (BAY 63-2521 and BAY 60-4552) and heme-independent activators (BAY 58-2667).

Rho-kinase inhibitors. As mentioned above, endothelial-derived NO plays a critical role in the relaxation of corporal tissue and this pathway is impaired in diabetic patients, which leads to poor erectile function. Phosphorylation of myosin light chain kinase regulates the contraction of smooth muscle in the corpora and dephosphorylation is mediated by smooth muscle myosin phosphatase enzyme. A key regulator of this phosphatase is the serine/threonine kinase Rho-kinase.

Low-intensity shockwave therapy

Extracorporeal low-intensity shockwave therapy (LIST) to the penis has recently emerged as a novel and promising treatment modality for ED. LIST has been previously used to treat a wide variety of urological and non-urological conditions. The mechanism of action for this treatment consists of sending acoustic waves that generate pressure impulses, which can treat patients with kidney stones, tendinitis, and peripheral vascular disease. For the treatment of ED, it is hypothesized that LIST causes cell membrane microtrauma and mechanical stress, which causes an upregulation of angiogenic factors such as vascular endothelial growth factor (VEGF), NO synthase, and von Willebrand factor, which increase angiogenesis and vascularization of tissues.

Stem cell transplant Stem cell therapy is a new treatment option that offers the potential to reverse the underlying causes of ED and reduce patient reliance on the transitory effects of PDE5-I medications. It has been studied in several animal models in subjects who poorly respond to PDE5-Is (cavernous nerve injury and DM). Stem cell regenerative therapy is based on the rationale that stem cells can differentiate into a wide variety of cells including endothelial cells, Schwann cells, smooth muscle cells, and neurons. In ED research, three types of stem cells are commonly used: adipose tissue-derived stem cells, bone marrow-derived stem cells, and muscle-derived stem cells. These can all differentiate into various cell types within the mesodermal germ line. It is hypothesized that multipotent stem cells have beneficial effects on damaged or diseased tissues by releasing various molecular mediators, which lead the host tissue to initiate a regenerative or healing response to diseased or injured tissue responsible for ED

 It is important to understand that in most cases

ED is a symptom of another, underlying problem. ED is not considered normal at any age, and may be associated with other problems that interfere with sexual intercourse, such as lack of desire and problems with orgasm and ejaculation.

Erectile dysfunction (ED) is one of the most common conditions affecting middle-aged and older men. Nearly every primary care physician, internist and geriatrician will be called upon to manage this condition or to make referrals to urologists, endocrinologists and cardiologists who will assist in the treatment of ED. This article will briefly discuss the diagnosis and management of ED. In addition, emerging concepts in ED management will be discussed, such as the use of testosterone to treat ED, the role of the endothelium in men with ED and treating the partner of the man with ED. Finally, future potential therapies for ED will be discussed.

PHYSIOLOGY OF ERECTION

If viewed in cross section, the glans of the penis reveal that the penis consists of three tube-like projections of spongy tissue, the corpus spongiosum, located ventrally and the paired corpi cavernosi located dorsally. In each of the latter is the deep artery of the penis which carries blood over the length of the penis into the open channels that make up the corpus cavernosum. The blood carried out of the corpi cavernosi empties into the dorsal vein of the penis which then returns the blood to the body. It is thought that the level of rigidity of the penis is due to the relationship between arterial inflow and venous outflow in the penis. This means that the larger the calibre of the arteries, the more blood enters the corpus cavernosum and enlarges the penis, and the larger the calibre of the veins, the more blood is shunted away from the penis. An erection is an involuntary action controlled by the autonomic nervous system which consists of the sympathetic and parasympathetic pathways. In general, sympathetic stimulation leads to the constriction of smooth muscle surrounding the arteries (reducing the calibre) and parasympathetic stimulation induces smooth muscle relaxation (larger artery). When stimulated sexually, the sympathetic stimulation of the penis decreases and the parasympathetic stimulation increases. It is the terminal of the axons of the parasympathetic nerves that release NO. The mechanism that causes erection is then the one shown above. The engorged sinusoids of the corpi cavernosi compress the penile veins, which reduces blood outflow from the penis. Blood is therefore trapped in the penis, which maintains the erection.

Sidenafil is selective for the enzyme phosphodiesterase of type 5 : its effect is more potent on PDE5 than on the other known PDE enzymes. It is 80-fold more selective for PDE5 than PDE1 and over 1000-fold more selective for PDE5 than for PDE2, PDE3 and PDE4. However, its selectively is only 10-fold as potent for PDE5 compared to PDE6 (found in the retina) which could be the basis for abnormalities related to colour vision (blue, green) which have been talked about a lot in the media. PDE5 is also found in lower concentrations in the platelets, vascular and visceral smooth muscle and skeletal muscle. Sildenafil inhibits PDE5 in these tissues as well, which is the cause of several side effects which are believed to be due to Viagra. There are 7 types of phosphodiesterases (or isozymes). They catalyse the same reaction, but the isozymes show show different behaviour when subjected to physical biochemical techniques. Those 7 types of PDE are summerised in the table below. The Km values are equivalent to measurements of the tightness of binding (or affinity) of enzyme (PDE) to substrate (cGMP). The smaller the Km value, the more tightly the substrate binds to the enzyme.

Medications which may cause erectile dysfunction (ED) Erectile dysfunction (ED) is a common side effect of a number of prescription drugs. While these medications may treat a disease or condition, in doing so they can affect a man's hormones, nerves or blood circulation, resulting in ED or increasing the risk of ED. If you experience ED and think that it may be a result of the medication you are using, DO NOT stop taking the medication. If the problem persists, contact your doctor and he or she may be able to prescribe a different medication. Common medications that may list ED as a potential side effect include:

• Diuretics (pills that cause increase urine flow) 
• Antihypertensives (high blood pressure drugs) 
• Antihistamines 
• Antidepressants • Parkinson's disease drugs 
• Antiarrhythmics (drug for irregular heart action) 
• Tranquilizers 
• Muscle relaxants • Nonsteroidal anti-inflammatory drugs 
• Histamine H2-receptor antagonists 
• Hormones 
• Chemotherapy medications 
• Prostate cancer drugs 
• Anti-seizure medications Other substances or drugs that can cause or lead to ED include these recreational and frequently abused drugs: 
• Alcohol
 • Amphetamines
 • Barbiturates 
• Cocaine 
• Marijuana 
• Methadone 
• Nicotine 
• Opiates

These drugs not only affect and often suppress the central nervous system, but can also cause serious damage to the blood vessels, leading to permanent ED. Brief history of the treatment of ED Impotence treatments were discussed in the oldest Chinese text, The Yellow Emperor’s Classic of Internal Medicine, which describes traditional Chinese medicine during the time of the Yellow Emperor’s rule which ended around 2600 BC. One of the treatments for impotence discussed is a potion with 22 ingredients. Nearly 1000 years later, the Egyptian Papyrus Ebers, a medical Egyptian document dated 1600 BC, describes a cure for impotence in which baby crocodile hearts were mixed with wood oil and applied topically to the penis. In 1973, Dr Brantley Scott from Baylor College of Medicine reported on the implantable inflatable prosthesis that urologists still use today. The major breakthrough occurred in 1998 when sildenafil became the first oral drug to be approved to treat ED. This was followed by the use of tadalafil and vardenafil as similar phosphodiesterase-5 inhibitor oral medications for treating ED.

There are hundreds of medications that have the side effect of ED and/or decreased libido. Examples of drugs implicated as a cause of ED include hydrochlorothiazides and beta-blocking agents. Medications used to treat depression, particularly the SSRIs such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Prozac Weekly, Sarafem), fluvoxamine (Luvox, Luvox CR), paroxetine (Paxil, Paxil CR, Pexeva) and sertraline (Zoloft), may also contribute to ED. Bupropion (Wellbutrin) which has a predominant effect on blocking the reuptake of dopamine is an antidepressant with lower incidence of ED. The side effects of 5ARIs occurring in fewer than 5% of patients can include gynaecomastia, ED, loss of libido and ejaculatory dysfunction. Men being treated for prostate cancer with treatments such as radical prostatectomy, radiation therapy or the use of Lutenizing hormone-releasing hormone (LHRH) agonists and antagonists can expect that ED may accompany these treatments.

Smoking, excessive use of alcohol and illicit drugs are also associated with ED. A study in 2005 suggests that ED is not only more likely among men who smoked compared with those who never did, but that in younger men with ED, cigarette smoking is very likely the cause of their impotence. Also, it is important to remember that there are psychogenic issues such as performance-related issues, traumatic past experiences, relationship problems, anxiety, depression and stress that can certainly cause or be considered a comorbid condition contributing to ED. Bullet point: Ageing and comorbidities as well as polypharmacy factor greatly influence the development of ED.

TREATMENT- • 

PDE5 inhibitors Sidenafil is selective for the enzyme phosphodiesterase of type 5 : its effect is more potent on PDE5 than on the other known PDE enzymes. It is 80-fold more selective for PDE5 than PDE1 and over 1000-fold more selective for PDE5 than for PDE2, PDE3 and PDE4. However, its selectively is only 10-fold as potent for PDE5 compared to PDE6 (found in the retina) which could be the basis for abnormalities related to colour vision (blue, green) which have been talked about a lot in the media. PDE5 is also found in lower concentrations in the platelets, vascular and visceral smooth muscle and skeletal muscle. Sildenafil inhibits PDE5 in these tissues as well, which is the cause of several side effects which are believed to be due to Viagra. There are 7 types of phosphodiesterases (or isozymes). They catalyse the same reaction, but the isozymes show show different behaviour when subjected to physical biochemical techniques. Those 7 types of PDE are summerised in the table below. The Km values are equivalent to measurements of the tightness of binding (or affinity) of enzyme (PDE) to substrate (cGMP). The smaller the Km value, the more tightly the substrate binds to the enzyme.

• NON- PDE5 

INHIBITORS Newer pharmacological treatments are focused on targeting alternative pathways in the erectile process, both centrally and peripherally. Dopaminergic agents. Dopamine operates in the brain as a neurotransmitter and in the periphery it functions like a local messenger. Apomorphine (Uprima) is a dopaminergic agent activating dopamine receptors D1 and D2 at a central level within the paraventricular nucleus of the brain.

Melanocortin receptor agonists. Melanocortins are involved in many processes, and their role in controlling sexual function was first reported in the 1960s. They are linked to the induction of penile erection and the regulation of sexual behavior. Two well-studied melanocortin receptor agonists are melanotan II and bremelanotide.

Soluble guanylate cyclase stimulators and activators. PDE5-I efficacy depends on the production of cGMP, which in turn is dependent on nitric oxide (NO) activation of soluble guanylate cyclase (sGC). In some patients, especially post-prostatectomy and DM patients, this pathway is disturbed because of varying amounts of nerve damage and the effectiveness of PDE5-Is is reduced significantly. There are two types of compounds that can stimulate sGC: heme-dependent stimulators (BAY 63-2521 and BAY 60-4552) and heme-independent activators (BAY 58-2667).

Rho-kinase inhibitors. As mentioned above, endothelial-derived NO plays a critical role in the relaxation of corporal tissue and this pathway is impaired in diabetic patients, which leads to poor erectile function. Phosphorylation of myosin light chain kinase regulates the contraction of smooth muscle in the corpora and dephosphorylation is mediated by smooth muscle myosin phosphatase enzyme. A key regulator of this phosphatase is the serine/threonine kinase Rho-kinase.

Low-intensity shockwave therapy

Extracorporeal low-intensity shockwave therapy (LIST) to the penis has recently emerged as a novel and promising treatment modality for ED. LIST has been previously used to treat a wide variety of urological and non-urological conditions. The mechanism of action for this treatment consists of sending acoustic waves that generate pressure impulses, which can treat patients with kidney stones, tendinitis, and peripheral vascular disease. For the treatment of ED, it is hypothesized that LIST causes cell membrane microtrauma and mechanical stress, which causes an upregulation of angiogenic factors such as vascular endothelial growth factor (VEGF), NO synthase, and von Willebrand factor, which increase angiogenesis and vascularization of tissues.

Stem cell transplant Stem cell therapy is a new treatment option that offers the potential to reverse the underlying causes of ED and reduce patient reliance on the transitory effects of PDE5-I medications. It has been studied in several animal models in subjects who poorly respond to PDE5-Is (cavernous nerve injury and DM). Stem cell regenerative therapy is based on the rationale that stem cells can differentiate into a wide variety of cells including endothelial cells, Schwann cells, smooth muscle cells, and neurons. In ED research, three types of stem cells are commonly used: adipose tissue-derived stem cells, bone marrow-derived stem cells, and muscle-derived stem cells. These can all differentiate into various cell types within the mesodermal germ line. It is hypothesized that multipotent stem cells have beneficial effects on damaged or diseased tissues by releasing various molecular mediators, which lead the host tissue to initiate a regenerative or healing response to diseased or injured tissue responsible for ED