Erectile Dysfunction & BPH Winter 2024-2-2.pdf

Erectile Dysfunction David M. Gazze PhD Winter 2024 Physiology of the Penile Erection Involvement of Cerebral Sex Centers in the Physiology of Erection: Nitrergic neuron sinusoids S sinusoids expand, , the the The Physiology of Penile Erection In the penile vessels and the smooth muscle of the corpo...

Erectile Dysfunction David M. Gazze PhD Winter 2024 Physiology of the Penile Erection Involvement of Cerebral Sex Centers in the Physiology of Erection: Nitrergic neuron sinusoids S sinusoids expand, , the the The Physiology of Penile Erection In the penile vessels and the smooth muscle of the corpora cavernosa, the balance between contractant and relaxant factors controls the degree of tone of the penile vasculature and of the smooth muscle. This in turn determines the functional state of the penis: detumescence and flaccidity, tumescence and erection. *Nitric Oxide Acetylcholine Acts at Muscarinic Receptors on Vascular Endothelial Cells to Increase the Production of Nitric Oxide The Role of Nitric Oxide in Vascular Smooth Muscle Relaxation Note: the “cGMP-specific kinase”depicted in green in this illustration is more commonly called: “Protein Kinase G” = PKG Fazio, Luke Brock, Gerald CMAJ 170 p.1429 1437 (2009) Actions of Protein Kinase G (PKG) Leading to Relaxation of Penile Vascular Smooth Muscle Opens K+ channels on the plasma membrane of vascular smooth muscle cells, thus hyperpolarizing the smooth muscle cell The above action inhibits membrane depolarization required for the opening of voltage gated - Ca+ channels on the plasma membrane of the vascular smooth muscle cells Increases sequestration of Ca++ in the endoplasmic reticulum of the vascular smooth muscle cell Activates the myosin light chain phosphatase leading to the detachment of the myosin head from actin. This prevents smooth muscle contraction leading instead to muscle relaxation. Mechanisms of Nitric Oxide/c-GMP Pathway in Penile Vascular Smooth Relaxation Myosin light chain kinase Tissue Distribution of the Various Subtypes of Phosphodiesterase Tissue Distribution of the Phosphodiesterase Subtypes FYI Chemical Structures of PDE5 Inhibitors Avanafil Mechanism of Action of PDE5 Inhibitors Used in the Treatment of Erectile Dysfunction PKG Bern and Levy, Physiology, 6th edition figure 43-12b p.786 Comparison of PDE5 Inhibitors Pharmacokinetics of PDE5 Inhibitors FYI Pharmacokinetics of PDE5 Inhibitors Comprehensive Pharmacokinetic Summary of PDE5 Inhibitors FYI PDE5 Inhibitors: General Side Effects Mostly vasodilation effects: Headache (16%) Flushing (10%) Heartburn Visual effects (3%) -generally transient and mild-to-moderate. PDE5 inhibitors are associated with several visual side effects, including blurred vision, changes in color vision, extreme sensitivity to light, and in extreme cases, damage to the optic nerve that relays optical signals to the brain (NAION) Sinus Pressure Common Adverse Effects of PDE5 Inhibitors: PDE5 Inhibitors: Side Effects and Cautions Contraindications/ Cautions Associated with PDE5 Inhibitors PDE5 Inhibitors can potentiate the hypotensive effects of nitrates. Therefore, PDE5 inhibitors are contraindicated in patients who are using any form of organic nitrate either regularly and/or intermittently b/c of the risk of severe hypotension. PDE5 inhibitors can potentiate the vasodilation of nitrates and result in potentially dangerous hypotension. Caution is advised when PDE5 inhibitors are co-administered with alphaadrenergic receptor antagonists b/c both have vasodilatory effects, and an additive effect on blood pressure lowering effects can be anticipated. The longer half-life of tadalafil imposes increased risk for drug interactions in individuals taking potent CYP450 inhibitors (e.g., erythromycin, clarithromycin, azole antifungals, cimetidine, protease inhibitors, grapefruit juice). Rare but serious reports of prolonged erections lasting less than 4 hours and priapism (painful erections lasting more than 6 hours) have been reported with PDE5 inhibitors. Priapism carries with it significant risks of structural damage to the penis and permanent erectile dysfunction. Potential Remedies for Lack of Response to PDE5 Inhibitors Empty stomach No alcohol No fatty food (tadalafil absorption is not affected) Leave appropriate time for absorption → AT LEAST 60 minutes for men using sildenafil (Viagra®) and valdenafil (Levitra®) and up to 2 hours for men using tadalafil (Cialis® as needed) b/c peak plasma concentration of tadalafil is not reached for approx. 2 hours. Cialis® once daily is taken regularly and therefore dose not require a “kick-in” time. Adequate dose Indications for PDE5 Inhibitors FYI Hormonally –induced erectile dysfunction with EITHER of the following: erectile dysfunction persists despite correction of an abnormal testsosterone, prolactin, or thyroid level correction of the hormone deficiency is contraindicated due to comorbitity (e.g., treatments lowering testosterone levels in a man with prostate cancer) Neurogenic erectile dysfunction such as resultant from spinal cord injury, multiple sclerosis, pituitary microadenoma, cerebral vascular accident (CVA), diabetes, radical prostatectomy or surgically-induced impotence Vascular-genic erectile dysfunction such as resultant from aortic aneurysm, atherosclerosis, hypertension, hyperlipidemia, or peripheral vascular disease Indications (cont’d) FYI Pelvic trauma-induced erectile dysfunction such as resultant from compression injuries or radiation Pharmacologically-induced erectile dysfunction where the patient has tried ONE alternate, non-erectile dysfunction-causing medication and erectile dysfunction persists, OR there is a contraindication to making medication changes Mediators of Vascular Smooth Relaxation: Alprostadil Please note that activation of the prostaglandin E1 receptor increases c-AMP production which activates Protein Kinase A to decrease intracellular Ca2+ levels by several mechanisms. Alprostadil is an agonist at the E1 prostaglandin receptor. Alprostadil Intracavernous Injection for Treatment of ED receptor agonist Alprostadil: Adverse Effects months Penile fibrosis is the formation of a scar on the surface of the penis. It is an inflammatory process that occurs in the tunica albuginea, which is the thick sheath of tissue covering the corpora cavernosa. This results in a loss of elasticity of the penis. Cavernous fibrosis is a process that decreases the number or function of the corporal smooth muscle cells. Alprostadil Injection FYI Treatment of Benign Prostatic Hypertrophy (BPH) David M. Gazze Winter 2024 Consequences of Untreated Clinical BPH Acute urinary retention Urinary tract infection Bladder calculi Renal impairment Bladder damage Hematuria Anatomy of the Prostate Gland vas Static versus Dynamic Factors Associated With BPH BPH may cause physical compression of the urethra and result in anatomic bladder outlet obstruction (BOO) through two distinct mechanisms: an increase in prostate volume, termed the STATIC component, in which the hyperplastic prostatic tissue compresses the urethra an increase in stromal smooth muscle tone, termed the DYNAMIC component: the bladder neck (output) and prostate are richly supplied with alpha-1 adrenergic receptors which increase smooth muscle tone, promoting obstruction to the flow of urine Lower Urinary Tract Symptoms (LUTS) Associated With BPH When symptomatic, BPH presents with lower urinary tract symptoms (LUTS). Typical manifestations of LUTS/BPH include: Storage (irritative) symptoms – Urinary frequency, urgency, nocturia and incontinence Voiding symptoms – Slow urinary stream, straining to void, urinary intermittency (stream starting and stopping during micturition) or hesitancy, splitting of the voiding stream, and terminal dribbling Storage symptoms are often more bothersome than voiding symptoms Glandular Epithelial Cells and the Surrounding Stroma Histology of the Prostate Gland Anatomy of the Prostate The prostate has four distinct regions: a non-glandular anterior fibromuscular zone and the glandular peripheral, central and transitional zones. Within the glandular zones are secretory acini and associated ducts. The prostate has two basic compartments: the glandular (secretory) epithelium and the supporting stroma. This supporting stroma is comprised of fibroblasts, myofibroblasts, smooth muscle cells, vascular endothelial cells, autonomic nerve cells and inflammatory cells BPH occurs when both stromal and secretory epithelial cells of the prostate (mainly in the transitional zone surrounding the urethra) proliferate by processes that are thought to be influenced by inflammation and sex hormones, causing prostate enlargement. Unfortunately, as noted above, most of the hyperplasia occurs in the transitional zone of the prostate. Because this is the tissue that surrounds the urethra, BPH can slow the flow of urine even if the overall size of the gland is nearly normal. Relevant Physiology of the Prostate Gland: Androgens Testosterone (produced in the testes) diffuses into stromal and epithelial cells of the prostate. Testosterone and DHT interact with the cytoplasmic androgen receptor (AR), which upon binding dimerizes and translocates to the nucleus whereupon the dimer binds to an androgen response element (ARE), promoting the expression of genes encoding various growth factors. In stromal cells, most of the testosterone is converted to dihydrotestosterone (DHT), which then acts in an autocrine manner to promote stromal proliferation. DHT can also diffuse into an adjacent epithelial cell to act in a paracrine manner. DHT produced peripherally in the liver and the skin can also diffuse from the circulation into the prostate to act in an endocrine manner. Relevant Physiology of the Prostate Gland: Androgens DHT acts on prostate cells mainly via paracrine or autocrine mechanisms and plays a key part in regulating the homeostasis between apoptosis and cell proliferation. DHT binding to androgen receptors leads to the expression of genes for certain growth factors. Growth factors stimulated by DHT, including epidermal growth factor (EGF), keratinocyte growth factor (KGF) and insulin-like growth factors (IGFs), modulate cellular proliferation in the prostate in humans. The expression of transforming growth factor-β (TGFβ) which modulates apoptosis, is also influenced by DHT Testicular androgens are required in the prostate for the development of BPH. The enzyme steroid 5α-reductase (mainly Type II) converts testosterone into dihydrotestosterone (DHT), the principal androgen in the prostate accounting for 90% of total prostatic androgen DHT: Activation of the Androgen Receptor FYI DHT is a potent agonist of the AR, and is in fact the most potent endogenous ligand of the receptor. It has an affinity (Kd ) of 0.25 to 0.5 nM for the human AR, which is about 2- to 3-fold higher than that of testosterone (Kd = 0.4 to 1.0 nM) and 15–30 times higher than that of adrenal androgens (e.g., DHEA). In addition, the dissociation rate of DHT from the AR is 5-fold slower than that of testosterone. The EC50 of DHT for activation of the AR is 0.13 nM, which is about 5-fold stronger than that of testosterone (EC50 = 0.66 nM). In bioassays, DHT has been found to be 2.5- to 10-fold more potent than testosterone. The elimination half-life of DHT in the body (53 minutes) is longer than that of testosterone (34 minutes), and this may account for some of the difference in their potency. A study of transdermal DHT and testosterone treatment reported terminal half-lives of 2.83 hours and 1.29 hours, respectively Physiology of the Androgen Receptor DHT Has Effects on Both Stromal and Epithelial Cells of the Prostate Physiology Relevant to BPH: Prostatic Smooth Muscle The most common adrenoceptor subtype present in prostate tissue is the α1A receptor , which in turn mediates active tension in human prostatic smooth muscle. Stimulation of these receptors results in a dynamic increase in prostatic urethral resistance causing symptoms of outflow obstruction. Previous studies have demonstrated that the density of stromal α1A -adrenoceptors is increased in BPH tissues. The nitric oxide–cyclic GMP (cGMP) pathway is another pathway involved in smooth muscle contractility. Phosphodiesterase type 5 (PDE5) negatively impacts BPH by hydrolyzing c-GMP to inactive GMP (c-GMP is responsible for activation of Protein Kinase G, a critical mediator of smooth muscle relaxation via its ability to reduce “free” intracellular Ca2+ levels, and by activation of the the myosin light-chain phosphatase). Accordingly, inhibition of PDE5 elevates/maintains c-GMP levels, thus enhancing relaxation of smooth muscle in the detrusor musculature, bladder neck, urethra and prostate. Additionally, PDE5 inhibition possibly increases tissue perfusion, modulates autonomic nervous system activity and inhibits the prostatic inflammatory process, all of which lead to an improvement in voiding symptoms Location of the Phosphodiesterase 5 Enzyme in the Urinary Tract Detrusor smooth muscle layers Bladder neck (internal urinary sphincter) Prostatic stromal smooth muscle cell layers Vascular smooth muscle layers External urinary sphincter ? Important Enzymes and Receptor Sites of the Bladder and Prostate Pharmacologic Treatment Options for BPH Muscarinic Receptor Antagonists Treatment of BPH: α-1 Receptor Antagonists BPH has been attributed to both static (prostatic tissue) and dynamic (smooth muscle) factors. As the α1A-adrenoceptor is the predominate receptor in prostate stromal smooth muscle, medical therapies target this and other adrenergic receptor subtypes (namely, the α1B-adrenoceptor and the α1D-adrenoceptor). Blockade of α1Aadrenoceptors (which are also expressed in the bladder neck) results in smooth muscle relaxation and subsequent improvement in the passage of urine. Uro-“selective” α1A -adrenergic antagonists, including tamsulosin and silodosin, are often regarded as first-line medical therapy for men with lower urinary tract symptoms. Tamsulosin exhibits a modest degree of selectivity for the α1A-adrenoceptor versus the α1B-adrenoceptor, whereas it shows no selectivity for the α1A-adrenoceptor versus the α1D-adrenoceptor. Silodosin shows 162/1 selectivity for α1A-adrenoceptors versus α1B-adrenoceptors. Both drugs can produce rapid and considerable improvement in symptoms within 3–4 days of treatment initiation and this benefit is durable for >12 months Alpha-1 Receptors: Localization in Bladder Neck, Prostate, and Elsewhere FYI Alpha-adrenergic receptors are located in the bladder neck/ prostate gland/ urethra In locations where you do find α-2 receptors they are more common in women than men Alpha receptors are rare in the detrusor muscle. Alpha-1-receptors are classified into three subtypes (α1A, α1B, and α1D) In the urinary bladder neck lies the urethral internal sphincter; α1A-receptors prevail. Adrenergic stimulation of α1A-receptors leads to an increase of bladder neck closure. The inhibition of α1A-receptors lead to a reduction of closure. α1AARs predominate in human prostate; blockade relaxes prostate smooth muscle and increases urine flow α1DARs predominate in spinal cord, and afferent nerves; blockade decreases LUTS symptoms Bladder outlet obstruction shows α1DARs increase with bladder hypertrophy α1AR subtypes vary in human vascular bed. Aging increases vascular α1AR density two-fold → α1B increasingly predominates over α1A; no change in α1D subtype Receptor Sites in the Urinary Tract of the Male Bladder neck (internal urethral sphincter) (α1) Mohammad A. Rattu, US Pharmacist 40 (8) p. 35-38 (2015) Subtype Selectivity of α1 Adrenergic Receptor Antagonists FYI FYI: Subtype Selectivity of α1 Adrenergic Receptor Antagonists FYI FYI: Treatment of Overflow Incontinence Associated with BPH: Alpha-Adrenergic Receptor Antagonists Alpha blockers: In men with urge or overflow incontinence, α1Areceptor antagonists relax bladder neck muscles and muscle fibers in the prostate, thereby facilitating emptying of the bladder: Tamsulosin (Flomax®) → “Uroselective” Alfuzosin (Uroxatral®) → “Uroselective” Silodosin (Rapaflo®) → “Uroselective” Doxazosin (Cardura®) Terazosin Side Effects of α1 Receptor Antagonists The most common side effects of α1-adrenergic receptors antagonists are: Postural hypotension (less with “uroselective” agents) Dizziness Rhinitis Impaired or retrograde ejaculation hypotension Adverse Effects of Select α1 Receptor Antagonists The hypotensive effects of Terazosin and Doxazosin can be potentiated by sildenafil or vardenafil (tadalafil?). Use tamsulosin, alfuzosin, or silodosin in men who are also using PDE 5 Inhibitors Terazosin and Doxazosin generally need to be initiated at bedtime to reduce postural lightheadedness soon after starting the medication Tamsulosin and Silodosin in particular can affect ejaculation: - Tamsulosin decreased mean ejaculate volume in > 90% of patients with 35% having no ejaculate - Silosodin produced retrograde ejaculation in 25% of patients α-1 Receptor Antagonists: Tamsulosin Chemically, a benzene sulfonamide: contraindicated in patients with a sulfa allergy Treats BPH with little effect on blood pressure Well absorbed orally; T1/2 = 5 -10 hours Extensively metabolized by CYPs; contraindicated in patients taking CYP inhibitors Side effect: decreased/absent ejaculate volume, intraoperative floppy syndrome (during cataract surgery) Intraoperative floppy syndrome syndrome is characterized by a flaccid iris which billows in response to ordinary intraocular fluid currents, with a propensity for this floppy iris to prolapse towards the area of cataract extraction α-1 Receptor Antagonists: Silodosin Selective antagonist of α1A receptors T1/2 = 13-14 hours Metabolized by glucuronidation Side effect: retrograde ejaculation Contraindicated in patients with renal impairment, severe hepatic impairment α-1 Receptor Antagonists: Alfuzosin Oral bioavailability: 64% T1/2 = 3-5 hours Substrate for CYP3A4 Contraindicated in patients with moderate to severe hepatic impairment, known hypersensitivity, in patients taking CYP3A4inhibiting drugs Avoid in patients with prolonged QT syndrome α-1 Receptor Antagonists: Terazosin FYI Structural analog of prazosin; more water soluble than prazosin More effective than finasteride, dultaseride in treatment of BPH Bioavailability is 90%; highly protein bound T1/2 = 12 hours, duration of action more than 18 hours, once daily dosing Metabolized by demethylation, dealkylation in liver 40% excreted in urine Contraindicated in patients with known sensitivity to quinazolines Side effects: first-dose hypotension, dizziness, fatigue Use with caution in patients taking diuretics, other hypertensive agent PDE5 inhibitors α-1 Receptor Antagonists: Doxazosin FYI Structural analog of prazosin Bioavailability 65%; highly protein bound T1/2 = 20 hours, duration of action around 36 hours Metabolized by demethylation, dealkylation in liver; most of the metabolites are excreted in the feces Contraindicated in patients with known sensitivity to quinazolines Use with caution in patients taking diuretics, other antihypertensive agents PDE5 inhibitors, in hepatic dysfunction Side effects: first dose hypotension, dizziness, fatigue, headache Dihydrotestosterone (DHT) Dihydrotestosterone (DHT), 5α-dihydrotestosterone is an endogenous androgen sex steroid and hormone. DHT signals mainly in an autocrine and paracrine manner in the tissues in which it is produced, playing only a minor role as a circulating endocrine hormone. The enzyme steroid 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues including the prostate gland, seminal vesicles, epididymides, skin, hair follicles, liver, and brain. This enzyme mediates reduction of the C4-5 double bond of testosterone. Relative to testosterone, DHT is considerably more potent as an agonist of the androgen receptor (AR). DHT is biologically important for sexual differentiation of the male genitalia during embryogenesis, maturation of the penis and scrotum at puberty, growth of facial, body, and pubic hair, and development and maintenance of the prostate gland and seminal vesicles Dihydrotestosterone (DHT) In tissues with high 5α-reductase expression such as the prostate gland, local (intracellular) DHT levels may be up to 10 times those of testosterone. Unlike other androgens such as testosterone, DHT cannot be converted by the enzyme aromatase into an estrogen In addition to normal biological functions, DHT also plays an important causative role in a number of androgen-dependent conditions including hair conditions like hirsutism (excessive facial/body hair growth), pattern hair loss (androgenic alopecia or pattern baldness) and prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer Testosterone versus DHT: Physiological Effects Testosterone DHT Spermatogenesis and fertility Prostate enlargement and prostate cancer risk Male musculoskeletal development Facial, axillary, pubic, and body hair growth Voice deepening Scalp temporal recession and pattern hair loss Increased sebum production and acne Increased sex drive and erections 5-Alpha Reductase 5-α reductase catalyzes the conversion of testosterone into DHT The reduction is that of a double bond in the “A-ring” of testosterone There are actually three isoenzymes of 5-α reductase, but the major forms are Type I and Type II Importantly, these two isoenzymes have different tissue distributions (see next slide) Type II is primarily active in reproductive tissues (prostate, seminal vesicles, epididymis) and in the hair follicle and scalp Type I is mostly active in liver, bone, and non-genital skin Tissue Distribution of Type I and Type II Forms of Steroid 5-α Reductase 5-α Reductase Inhibitors FYI Offer a 5-α reductase inhibitor to men with lower urinary tract symptoms (LUTS) and prostate > 30 grams or a PSA > 1.4 ng/ml, and who appear to be at risk of progression (e.g., older men). Review after 3-6 months treatment Reduces prostatic volume Reduces PSA by 50% after 6 months treatment Reverses BPH processes Reduces risk of requiring surgical intervention. Potential reversal of male-pattern balding (or, at least, may prevent further balding) Mechanism of a 5-alpha reductase inhibitor (finasteride) in treating BPH 5-Alpha Reductase Inhibitors Used In the Treatment of BPH: Finasteride and Dutasteride Finasteride Relatively selective inhibitor of the Type II isoenzyme Usual daily oral dose for treatment of BPH = 5 mg A 1 mg tablet (Propecia®) is available for oral treatment of male-pattern baldness Produces a decrease in DHT levels within 8 hours after administration that lasts for 24 hours Dutasteride An inhibitor of both the Type I and Type II isoenzymes More potent than finasteride, and produces a greater reduction of DHT Dutasteride decreases DHT concentrations by as much as 90% after 2 weeks, and 93% after two years Usual daily oral dose for treatment of BPH = 0.5 mg Treatment for 3-6 months is generally needed before prostate size is sufficiently reduced to improve urine flow (either agent) Pharmacokinetics of 5-Alpha Reductase Inhibitors Finasteride (Proscar®, Propecia®) Oral Bioavailabilty Absorption Half-live 65% Not affected by food 5-8 hours Dutasteride (Avodart®) 60% Not affected by food 4-5 weeks Metabolism Extensive metabolism by CYP3A4 followed by aldehyde oxidase to form two active metabolites with approx. 20% of the inhibitory effect of finasteride on 5-alpha reductase Extensive metabolism by CYP3A4 to three active metabolites, one of which has similar inhibitory potency to dutasteride on 5-alpha reductase Elimination Feces (57%, primarily as metabolites) Urine (40%), primarily as metabolites) Feces (40%, primarily as metabolites) Side effects: Dutasteride vs Finasteride Side effects of dutasteride and finasteride that are similar include impotence and decreased sex drive, testicle swelling or pain. Dutasteride may also cause ejaculation disorder, breast enlargement, and breast tenderness. Side Effects of 5-α Reductase Inhibitors Caution: 5-α Reductase Inhibitors Product information for finasteride and dutasteride warns that the active ingredient can be absorbed through the skin. In animal studies, these drugs have been shown to interfere with normal development of male external genitalia and internal sex organs by inhibiting conversion of testosterone to dihydrotestosterone. Pregnant females should avoid touching crushed or broken tablets (finasteride), or capsules (dutasteride). For finasteride unbroken tablets are coated, which prevents contact with the active ingredient during normal handling. Dutasteride is administered in a capsule; women should always use caution whenever handling. Pregnant women or women trying to conceive should not handle the product; if contact with a leaking capsule occurs, wash area immediately with soap and water. There are no reports in humans of abnormal development of external genitalia related to men using finasteride or dutasteride. Perhaps the safest way to prevent a fetal effect from these medications is for men also to avoid finasteride and dutasteride while trying to conceive and during a partner’s pregnancy because it is likely that these drugs are present in the seminal fluid in men who take them. Importance of 5-alpha Reductase for in utero Sexual Development of the Male Fetus FYI Many people with 5-alpha reductase deficiency are born with external genitalia that appear female. In other cases, the external genitalia do not look clearly male or clearly female (sometimes called ambiguous genitalia). Still other affected infants have genitalia that appear predominantly male, often with an unusually small penis (micropenis) and the urethra opening on the underside of the penis (hypospadias). Clinical Efficacy of 5-Alpha Reductase Inhibitors IPPS = International Prostate Symptom Score Qmax = Maximum Urinary Flow Rate AUR = Acute Urinary Retention Agents Used to Treat Overactive Bladder in Men With BPH Muscarinic Antagonists Prevent contraction of the detrusor muscle of the urinary bladder wall Tolterodine (Detrol®) Fesoterodine (Toviaz®) Selective β3 adrenergic receptor agonists Relaxes the detrusor muscle of the urinary bladder → increases bladder capacity Safe and effective for overactive bladder (OAB) induced by BPH in men receiving tamsulosin Mirabegron (Myrbetriq®) Vibegron (Gemtesa®) 0 0