IE 3: Pathophysiology of ED

What is erectile dysfunction?

• The consistent or recurrent inability of a man to attain and/or maintain an erection sufficient for sexual performance

  • Recurrent is 3 months or longer occurring on regular or recurrent basis

What is impotence?

• Broad term including problems of libido, erection, and orgasm

Normal penile erection is regulated by what 3 components?

• Psychogenic + neural

• Vascular

• Hormonal

What is the psychogenic + neural component?

• Visual, olfactory, imaginative inputs to pre optic area of hypothalamus

For the psychogenic + neural component, what is the primary erectogenic NT in hypothalamus?

• Primary erectogenic neurotransmitter in hypothalamus is dopamine → Erectogenic efferent parasympathetic nerves (S2-2S4) to penile tissue to release acetylcholine

For the psychogenic + neural component, what is the inhibitory effects mediated through?

• Inhibitory effects are mediated through α2 receptors → inhibitory efferent sympathetic nerves (T1-L2) to penile tissue to release norepinephrine

What can also cause erection through spinal pathways?

• Tactile stimuli to penile tissue or some other inputs can also cause erection through spinal pathways

The penile tissue consists of what sinusoid (blood capillaries) rich structures?

• Two corpora cavernosa

• One corpora spongiosum

In terms of the vascular component, neuronal stimulation releases what?

• Neuronal stimulation releases Acetylcholine which in turn releases NITRIC OXIDE which causes smooth muscle relaxation of walls of sinusoids which fills them with blood to cause erection

In the vascular component, what happens in the flaccid penis?

• In flaccid penis: Arterial inflow and venous outflow balances out

In the vascular component, what happens in the erect penis?

• In erect penis: Arterial inflow and rigidity drastically decreases venous outflow

Activation of the muscarinic receptors by acetylcholine on endothelial cells causes what?

• Activation of muscarinic receptors by acetylcholine on the endothelial cells causes release of nitric oxide (NO)

What does NO stimulate?

• NO stimulates guanylyl cyclase which converts GTP to cGMP

What does cGMP cause?

• cGMP causes dephosphorylation of myosin filaments thus relaxing the smooth muscles of blood vessels which results in vasodilatation

What does the enzyme phosphodiesterase break down?

• breaks down cGMP to inactive form GMP

Normal levels of testosterone is needed for what?

• For normal development and growth of penile tissue

• Maintenance of libido

What is the pathophysiology of ED

• Psychogenic causes

  • NO identifiable physical cause

What are the organic causes of ED? (80% cases)

• Vascular

  • Hypertension, PAD, Arteriosclerosis

• Neurologic

  • Spinal cord injury, Stroke, Diabetes

• Hormonal

  • Primary or secondary hypogonadism leading to low testosterone levels
    

What can be another cause of ED?

• Drug induced

What are drugs that can cause ED?

• Drugs that can affect neural and psychogenic components: Antidepressants, Antipsychotics, BZDs, Metoclopramide, Diphenhydramine, TCA, alpha 2 agonist, barbiturate, opioid

• Drugs that can affect the vascular component: Beta-blockers, diuretics

• Drugs that affect the hormonal component: Spironolactone, Ketoconazole, 5-alpha reductase inhibitors

What are nonpharm ways of ED management?

• Vacuum devices, penile prosthesis

What are pharm ways to manage ED?

• PDE5 inhibitors

• Alprostadil

• Testosterone

• Off label:

  • Trazodone, Yohimbine, Papaverine

What are the PDE5 inhibitors?

• Sildenadil (Viagra)

• Vardenafil (Levitra)

• Tadalafil (Cialis)

• Avanafil (Stendra)

What is the MOA of PDE5?

• Isoform 5 of enzyme PDE is expressed in penile tissue

• PDE5 metabolizes cGMP to inactive GMP

• PDE5 inhibitors inhibit cGMP metabolism to its inactive form

• Thus prolonging cGMP actions (vasodilation and facilitating penile erection)

Which PDE 5 inhibitor has longest half life?

• Tadalafil and the effect can last days (called weekend pill)

What are the PDE5 inhibition in peripheral vascular tissue and vasodilation based SE?

• Headache, Facial flushing, Nasal Congestion, Hypotension, Nonarteritic anterior ischemic optic neuropathy (NAION)

What are the PDE6 SE in rods and cones?

• Cynaopisa (blue tinge in the vision)

What are the PDE11 in striated muscles SE?

• Myalgia muscle pain

Organic nitrates can cause what life threatening SE? How?

• Life threatening hypotension with organic nitrates

  • Nitrates are NO donors and PDE5 inhibitors will cause excessive levels of cGMP when Co administered with nitrates

What is Alprostadil?

• Prostaglandin E1 → available for intracavernosal injection or intraurethral admin

What is the MOA of Alprostadil?

• Causes activation of prostaglandin receptors which activates adenylate cyclase and increases cAMP results in penile vasodilatation & penile erection

What is the onset of alprostadil and how is it metabolized? What is systemic absorption?

• Onset of action 5-15 minutes

• Metabolized locally by 15-hydroxy dehydrogenase

• Systemic absorption minimal

For non-FDA approved drugs, what is the MOA of Trazodone?

• Alpha receptor antagonism in penile tissue. Causes a predominance of cholinergic effects and facilitates erection

For non-FDA approved drugs, what is the MOA of Yohimibine?

• Alpha2 receptor antagonist. Thought to be centrally acting to cause mood elevation

For non-FDA approved drugs, what is the MOA of Papaverine?

• Nonspecific PDE inhibitor. Causes increased cAMP levels and causes smooth muscle relaxation