Erectile Dysfunction (ED)

Erectile Dysfunction (ED)

• Erectile dysfunction (ED), also know as impotence, is the consistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse.
• The incidence of ED increases with age, but it's relatively low in men under 40.
• Penile anatomy features two corpora cavernosa composed of interconnected sinusoids, and a single corpus spongiosum.
• Open pore capillaries are within the sinusoids.
• Erection happen with filling the sinusoid with corpus cavernosa with blood.
• The following occurs in a flaccid state: cavernosal smooth muscle cells contract; sinusoids contract; arterial inflow = venous outflow.
• The following occurs during an erection: sexual arousal stimulates Nitric Oxide (NO) and Vasoactive Intestinal Peptide (VIP)
• NO and VIP released from parasympathetic NANC neurons on cavernosal smooth muscle cells
• Release of NO and VIP initiates and sustains cavernosal smooth muscle relaxation
• Blood flow through helicine arterioles fills sinusoids, sinusoids expand, expanding sinusoids compress penile emissary veins against the tunica albuginea.
• Arterial inflow becomes much greater than venous outflow, leading to a rigid penis.

Etiology of ED

• ED can arise from abnormalities in the four systems crucial for normal penile erection.
• About 80% of ED cases are organic, and can be classified as: Vascular, Neurologic, or Hormonal in origin.
• Vascular causes include hypertension and arteriosclerosis.
• Neurologic causes include spinal cord injury and diabetes mellitus.
• Hormonal causes involve endocrine disorders.
• Psychogenic ED is also a cause: associated with malaise, depression, performance anxiety, Alzheimer's, and other mental disorders.

Medical Conditions and Drugs that Cause ED

• Medical conditions such as arteriosclerosis and hypertension reduce vascular flow to corpora cavernosum can cause ED.
• Spinal cord injury and stroke, which impair nerve conduction to the brain, can cause ED.
• Diabetes mellitus, by impairing peripheral nerve conduction to the penile vasculature, can cause ED.
• Primary or secondary hypogonadism can cause subphysiologic levels of testosterone leading to ED.
• Drugs such as diuretics, beta-blockers, and Ca2+ channel blockers, which decrease penile blood flow, can cause ED.
• CNS depressants suppress psychogenic stimuli, and anticholinergic agents can cause ED.
• Estrogens and anti-androgens suppress testosterone-mediated stimulation of libido, leading to ED.

Pharmacologic Therapy

• PDE5 inhibitors Sildenafil (Viagra), Vardenafil, and Tadalafil are used to treat ED.
• Alprostadil, a synthetic PGE1 analog, is also used.
• Testosterone may be prescribed.

NO-Mediated Muscle Relaxation Pathway

• Nitric oxide (NO) is released from NANC neurons on cavernosal smooth muscle cells resulting in Intracellular Ca2+ store and stimulates muscle relaxation.
• NO stimulates guanylate cyclase, increasing cGMP levels.
• Increased cGMP reduces Ca2+-calmodulin complex .
• Lower Ca2+-calmodulin complex activates Myosin-LC kinase to relax Smooth muscle.
• NO-cGMP is therefore an important transmitters for erection onset & maintenance.

Deactivation of cGMP, cAMP by PDEs

• Phosphodiesterases (PDEs) deactivates cGMP leading to relaxation.
• PDE inhibitors increase cGMP promoting relaxation that helps in erection.
• There are more than 11 PDE families each with different selectivity for cAMP and/or cGMP.

PDE5 Inhibitors

• PDE5 inhibitors include sildenafil, vardenafil, and tadalafil and are used to treat ED: they block cGMP degradation.
• PDE5 is highly selective in smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis.
• PDE5 inhibitors competitively and reversibly inhibit PDE5.
• Most patients (30-40%) are irresponsive to the PDE5 inhibitors
• Concomitant ingestion of alcohol is an ADR that can cause orthostatic hypotension.
• Severe hypotension can result, particularly in patients taken with nitrates or riociguat
• Vision changes are possible because PDE6 on retinal rods and cones is inhibited by PDE5 inhibitors.
• Sildenafil > Vardenafil > Tadalafil cause blurred vision cyanopsia (blue vision)
• Rare priapism may occur specifically with Sildenafil.
• PDE5 inhibitors are contraindicated with nitrates to avoid hypotension.

The VIP and PGE1-Mediated Muscle Relaxation Pathway

• VIP and PGE1 from NANC neurons/cavernosal smooth muscle cells, leading to muscle relaxation.
• VIP and PGE1 increase cAMP by activating adenylate cyclase.
• Higher cAMP levels lead to relaxation.
• VIP/PGE1-cAMP plays a minor role compared with NO-cGMP in this process.

Alprostadil

• Alprostadil (synthetic PGE1 analog) stimulates adenylate cyclase, increasing cAMP level leading to penile muscle relaxation.
• Administered via intracavernous injection with the following ADRs: cavernosal plaques, and corporal fibrosis at injection sites.
• Given by intraurtheral insertion with the following ADRs: uthreal stricture and severe hypospadias.
• Priapism can happen: an involuntary, prolonged erection (> 4 hrs).
• Blood can become trapped in the erection chamber
• Ischemia gangrene can result.
• Treatment involves injecting an a₁ agonist (phenylephrine) into the penis to cause detumescence.

Enhanced NO, VIP/PGE1-Mediated Relaxation

• NO and VIP are stored and simultaneously released from NANC nerve terminals with sexual arousal.
• Intracellular Ca²⁺ decreases as vascular smooth muscle relaxes.
• MLCK decreases activating the Myosin light chain kinase and initiating muscle relaxation and erection maintenance.

Testosterone

• Testosterone has the following mechanism in the male body: stimulates libido.
• Testosterone is active as "free floating" at 2%.
• Testosterone binds to sex hormone-binding globulin (Inactive) at 50-60%
• Testosterone reversibly bound to albumin in equilibrium is the remainder.
• Normal levels of testosterone help erection.
• High age decreases testosterone triggering hypogonadism in about 1/3 of men.
• Subphysiologic levels of subnormal serum testosterone lead to loss of energy, loss of muscle strength, depressive mood, and decreased libido
• Low testosterone causes libido to decrease, with the patient losing ability to develop erection.

Testosterone Replacement

• Used to stimulate androgen receptors in CNS.
• Used to Maintain normal sexual drive.
• Used to Stimulate nitric oxide synthase.
• Used for ED due to confirmed presence of decreased libido and low serum testosterone resulted from primary or secondary hypogonadism.
• Potential ADR, sodium retention is a possible ADR, leading to weight gain, exacerbate hypertension, congestive heart failure, and edema.
• Can cause gynecomastia.
• Contraindicated for patients with breast cancer and untreated prostate cancer

Benign Prostatic Hyperplasia (BPH)

• BPH is the most common benign neoplasm in American men.
• BPH is nearly ubiquitous among elderly men.
• Only about 50% of elderly men experience clinical symptoms.

Prostate Anatomy

• The prostate is a heart-shaped, chestnut-sized gland located below the bladder, surrounding the urethra.
• Prostate consists of the peripheral, central and transitional zone
• The prostate consists of three tissue types: Epithelial tissue, Strumal tissue and Capsule tissue
• Glandular epithelium is surrounded by fibromuscular stroma, and is innervated by sympathetic nerve with alpha1 receptor.

Hyperplasia

• Normal prostate weighs 20-30 g.
• Enlarged prostate weighs 60-100 g.
• At surgery prostate may be greater than 100g.
• Nonmalignant prostate growth causes enlargement of the prostate gland
• Hyperplasia happens predominantly in the transition-zone where nodular gland arises.
• Compression of the urethra leads to urethral stricture and lower urinary tract obstruction.

Clinical Manifestations

• There may be no distress unless severe complications of BPH are present.
• Irritative voiding symptoms and urge UI characterize moderate stages.
• Obstructive symptoms and overflow UI characterize advanced stages.

Complications of Untreated BPH

• Untreated BPH can lead to the following: urinary incontinence, chronic renal failure, gross hematuria, recurrent urinary tract infection, bladder stones, and bladder diverticulum.

Treatment for BPH

• Treatment includes: 5a-reductase inhibitor, a1-adrenergic antagonists, and PDE5 inhibitor (Tadalafil only).

Pathophysiology of BPH

• Free testosterone levels decease with aging.
• Potential prostate enlargement with gram (g) increases with aging.
• By middle age, approximately 30-40% of men have BPH symptoms.
• Dihydro-testosterone (DHT) converted from testosterone is more potent than testosterone and stimulates hyperplasia in the epithelial tissue to cause BHP.
• BPH is dependent on the following: 5a-reductase: Prostatic DHT levels remain high, even if testosterone decreases in aging male. The androgen receptor levels also remain high.

Types of reductase

• T1: Localized in the Scalp, skin all over body, sebaceous glands, liver. Presence of Increased Acne and hair growth. Absence is unknown.
• T2: Localized in Prostate at the Genital tissue and scalp. Presence is Male pattern baldness and hyperplasia. Absence is Degeneration of prostate and ambiguous genitalia in newborns.

5α-Reductase Inhibitors

• Finasteride is Type II selective.
• Dutasteride is Non-selective
• Reduce prostate size by 25%.
• Has a delayed effect, 6-12 months.
• Decreases libido, ED, sperm disorder, ejaculation disorder, and decreased ejaculate volume as side effects.
• It is a teratogenic on a male fetus : pseudohermaphroditic offspring with ambiguous genitalia are possible.
• Avoid during pregnancy or when seeking to be pregnant.
• Personnel should not handle tablets without gloves.
• Avoid contact with semen from men on the medication

a₁-Adrenergic Receptor-Mediated Smooth Muscle Cell Contraction

• Norepinephrine binds to alpha1 receptor which triggers contractions in vasculature
• Contraction in vascular smooth muscle increases intracellular Calcium and stimulating smooth muscle contraction.
• PtdIns(4,5)P2 increases as Phosphatidylinositol Bisphosphate (PIP2) goes up.
• Inositol triphosphate (IP3) leads to diacylglycerol (DAG).

Pathophysiology of BPH via Hyperplastic Stroma

• Excessive a₁-adrenergic tone in the capsule, stroma and bladder neck.
• Higher Stromal to epithelial tissue ratio in BPH (5:1 ) with normal ratio is 2:1
• Higher NE causes: smooth muscle contraction in prostate and bladder neck which further increase urethra Lumen, resistance with pressure which further increase urinary bladder.

Pharmacological Therapy for BPH with a₁-Adrenergic Antagonists

• These include Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin, and Silodosin.
• MOA: Decreased resistance to urine flow by blocking receptors to loosen the bladder and prostate.
• Terazosin (Hytrin®) is a reversible is a₁ selective and is used to treat hypertension and BPH.
• Has a half-life of 9-12 hrs.
• Doxazosin (Cardura®) is longer half life of 22hrs.
• Alfuzosin is relatively uroselective
• Tamsulosin (Flomax®) blocks a₁₁-adrenergic receptors
• Silodosin (Rapaflo®) most imp receptors mediate smooth muscle contraction and is used for BPH

ADR of with a₁-Adrenergic Antagonists

• The "first-dose syncope" can be orthostatic hypotension.
• There is risk of intraoperative floppy iris syndrome (IFIS) and postoperative dilation complications of cataract surgery.
• Specifically, Tamsulosin and Silodosin causes blocking a₁₁-adrenergic receptors.
• Iris dilator muscle relaxes, with construction of the iris causing higher risk of IFIS due to intraoperative miosis and postoperative compilations and retinal detachment.
• Stop Tamsulosin 14 days prior to eye surgery.
• Retrograde ejaculation is possible with Silodosin.

Urinary Incontinence (UI) & Nocturia

• Urinary Incontinence (UI) is the involuntary leakage of urine.
• This happens when in bladder that connects to the Kidneys experiences anatomical malfunction.
• The Inner lining that is in contact with the internal organs is the Mucosal
• The outer serosal layer consists of urinary tubes that flows from ureters, which leads to the opening to release, urinary orifice.
• Bladder under involuntary control and is innervated by the external urethral

Low Innervation Tract

• Under Involuntary control the following must be true:
• Internal urethral sphincter controls Bladder neck and bladder detrusor muscle.
• The Urethra requires a fully functioning Peritoneum and Medium umbilical ligament.

Sympathetic Control of Urinary Function

• Sympathetic Control which has Alpha 1 activity triggers contractions in Bladder which causes.
• Receptors are stimulated bladder relaxed with beta3 in the bladder and causes urinary retention
• Parasympathetic releases M3 and increases contractility and increases relaxation of bladder walls to pee External contracts requires ACH to pee.
• If not possible there is urine retention.
• Regulation of Muscle in the Bladder triggers with detrusor

Regulation of Muscle in Bladder

• Is achieved due to pressure.
• Multilayer creates a void within the bladder.
• Parasympathetics nerve endings release Ach (urination with cholinergic blockers that trigger retention.
• A Muscle around the hollow organ acts as barrier which requires a Sphincter
• Internal contraction increases bladder neck due to alpha 1 contractions of the bladder that leads to Urinary Retention.
• External contraction in Skeletal reinforcement allows for pressure.

Sympathetic Nervous System vs Parasympathetic Control

• Alpha 1 receptors at the bladder with retention contract when activated.
• Alpha receptors are inhibited when Bladder is not fully activated for Urination.
• Beta 3 receptors, allow bladder to relax to get volume.
• M3 Receptors in bladder urethra contracts and facilitates urination.
• If inhibited The The urethra contract releases the volume.

Types of UI

• Stress – Due to gland removal and damage with stress from compression.
• Urge: Overactive contractions causes high pressure and Urge to pee.
• Normal: When the bladder expands in a Normal state.
• Overflow: (Blocked urethra) Over expansion with small drips of urine over time.

Etiology of Urge UI (Bladder Overactivity)

• Idiopathic in the majority of older adults.
• In Moderate stages BPH is associated with increased bladder activity
• If there a recurring UTI bladder control has a problem.
• If there neurological diseases such parkinson's or stroke can affect bladder's function.

Characteristics of UI

• In storing urine with bladder function becomes ineffective and hypo sensitive.
• Small amounts of urine begin the bladder emptying.
• More than 8 times a day you release volume often. Urgency creates a GOT TO GO urgency.
• There is Bed wetting from inability to release over time.

Oxybutynin

• It is Anticholinergic that is Muscarinic antagonist.
• M3 In urethra there is retention.
• Vision becomes a problem: Ciliary muscle Obstructs drainage with introcular pressure increasing.
• Saliva becomes restricted.
• There is constriction within the the Gl mobility.
• Avoid during Gl obstruction and retention.

Beta 3-Adrenergic Agonist UI treatment

• Mirabgiron is drug.
• Activates receptor is is a Urinary retention.
• It is Hypertension and raises heart rate as result
• Avoid during uncontrolled hypertension.
• Over time there is Decompensation with non Muscle Specific Caldesmon creating an irregular Bladder.
• Patient will have to physically apply pressure to force the bladder.

Treatment for UI

• Alpha 1 blockers reduces pressure.
• a-Adrenergic also assist since it promotes Contractions
• provokes running lifting coughs
• the pelvic region loses strength with no feeling within urethra
• Alpha adrenic assist increase

UI with pseudoephedrine

• No Catechol ring prevents urination.
• Activateren Receptors creates Stimulate with NE for contraction.
• Increases BP and causes headache.
• Avoided with cardio issues.

Desmopresson

• AVP is used for antureic treatment that can increase bladder function.
• Synthesizer release that helps kidneys reabsorb.
• Increases adenyline to regulate peeing
• There is hyponatremia and seizure as ADR and should be avoided.