Updates in LUTS: Treating and Mitchell R. Humphreys, MD Chair and Professor of Mayo Clinic Arizona

28th Perspectives in Urology Thursday November 13th, 2019 Disclosures:

• Advisory Board Member: • Olympus • Boston Scientific • Consultant: • Auris • Ongoing sponsored studies: • UroGen Pharma • Allena Pharmaceuticals • Board of Trustee of Columbia College • Dean of the Mayo Clinic School of Continuous Professional Development Symptoms of BPH/BOO • Contributes to lower urinary tract symptoms (LUTS): • Static component – direct bladder outlet obstruction • Dynamic component – increased smooth muscle tone and resistance • Treatment traditionally focused on alleviating bothersome LUTS from enlargement • Now focus on alteration on disease progression and prevention of complications associated with BPH/LUTS. Consider entire urinary tract, starting with sensory afferent nerves

Oelke M. EAU Guidelines, 2012. Lower Urinary Tract Symptoms (LUTS) • Storage symptoms • • Overactive bladder symptoms • Urgency • frequency • Voiding symptoms • Most common due to BPH • Postmicturition symptoms What is the most bothersome symptom with highest QOL impact? Irwin DE, et al. Results of the EPIC study. Eur Urol 2006; 50(6): 1306. Treatment

Antimuscarinics β-adrenoceptor blocker Medical Therapy Alpha blockers 5-α reductase inhibitors Watchful Waiting PDE5I Increasing EfficacyIncreasing Increasing Invasiveness Filson et al. Urology 2013; 82:1386. 1-adrenergic blockers (1-blockers) • smooth muscle – noradrenergic sympathetic nerves

• Predominantly 1A-adenoceptors • Other subtypes: 1B- or 1D-anenoceptors • Older phenoxybenzamine and prazosin not recommended • Available drugs: Act on the dynamic • Alfuzosin component of BPH, • Doxazosin* counteracting smooth muscle contraction in • prostate • * * Requires dose titration Subtype Selectivity of 1- blockers

Receptor 1A 1B 1D

Tamsulosin 200 16 200

Doxazosin 20 20 16

Alfuzosin 1.2 10 13

Terazosin 1 10 10

Richardson CD, et al. The Prostate 35; 1997. 1-adrenergic blockers • Reduce IPSS by 35-40% • Increase Qmax by 20-25% • Prostate size does not affect efficacy 1 yr • Seem to be more effective in glands < 40 cm3 • Does not prevent acute urinary ret in long term studies • Most frequent SE: • and orthostatic hypotension • Fatigue, nasal congestion, asthenia • Ejaculatory dysfunction less with alfuzosin Uroselective α1-adrenergic blockers • – higher reduction in BOOI than any other α1-antagonist1

• Concurrent action on α1B receptors = orthostatic hypotension, HA, dizziness • Less pronounced than non-selective

• 38X more selective for α1A receptor than tamsulosin • LUTS improvement comparable to tamsulosin • Decrease nocturia in pts > 65yrs (53.4% vs 2 42.8%) 1. Rossi M, et al. Drug Des Devel Ther. 2010; 4: 291. 2. Eisenhardt A, et al. World J Urol 2014; 32:1119.

5-reductase inhibitors (5-ARIs) • Act by inducing apoptosis of prostate epithelial cells. • Prostate size reduction of 18-28% • Circulating PSA reduction of 50% after 6-12 months. • Type I – minor expression in the prostate primarily in skin and liver • Type II – predominant expression in the prostate. • – only inhibits 5-reductase, type II • - inhibits 5-reductase, Type I and II 5-reductase inhibitors (5-ARIs) • Reduce IPSS by 15-30% at 2-4 years • Increase Qmax by 1.5-2.0 mL/s • Equally effective • Reduce the long term risk of AUR and need for • Most frequent SE: • Reduced , erectile dysfunction, ejaculation disorder, gynecomastia occurs in 1-2% Phosphodiesterase (PDE) 5 Inhibitors • Nitric oxide is an important neurotransmitter in signal transmission in the urinary tract. • cGMP is hydrolyzed by PDE isoenzymes • PED 4 and 5 in the prostate, bladder neck • PED5Is prolong cGMP, FDA approved Tadalafil • Several trials have shown a 17-35% improvement in IPSS

• PVR remain unchanged Reduces urgency via • Treat men with ED and LUTS afferent nerve modulation • Increases perfusion of pelvic organs

Oelke et al. Eur Urol 2012; 61:917

Anticholinergic Agents • Anticholineric agents block acetylcholine in the central and peripheral nervous system • 5 muscarinic subclasses of cholinergic receptor in the bladder (M1-M5) • M2 receptors predominate (80%) • M3 receptors are primary responsive for contraction • In RCTs the rate of urinary retention was similar to placebo Antichoinergic agents effective alternative for LUTS secondary to BPH in men with elevated PVR when LUTS are primarily irritative. Use with caution if PVR is > 250-300 mL β-adrenoceptor blocker • In the bladder β3-receptors predominates • Activation associated with • Increased capacity • No change in micturition pressure or PVR • successfully tested in females with OAB and males with OAB and BOO • Benefits shown for urgency, frequency and QOL after 2 months. Nocturia • A symptom not a disease • Considered as voiding two or more times nightly • Prevalence increases with age • Sex ratio reverses after age 60; M > F • 50% adults between 50-79 have nocturia • Consider modifiable causes: • Obesity, poorly controlled , obstructive sleep apnea, BPH, CHF, uncontrolled HTN • yes Prostate & Prostatic Disease 2019; 22(1):77-83. • 7343 men, aged 50-75 yrs • Nocturia was associated with an increased mortality risk ([HR]=1.72; 95%CI 1.15-2.55) • Independent from demographics or medical comorbidities

International Journal of Cardiology 2015; 195:120-2.

Pts that has Nocturia ≥ 2 had a high all-cause mortality even after adjusting for confounding. Treatment • Initial measures: • Reduction in fluid intake, avoiding pm diuretics, tx of edema, double-voiding prior to bedtime • Decrease the impact – bedside urinal, pelvic floor exercises and urge-suppression strategy, treat the BPH or sleep apnea • *Nocturia is the symptom that persists most frequently following surgery for BPH! 78% F 67% M Persistent Nocturia Achieved 33% reduction in voids • The FDA approved w desmopressin analogs in 2018. • Nocdurna™ (Ferring Pharmaceuticals): sublingual tablets • 25 or 50 mcg one hr prior to bed • Noctiva (Avadel Pharmaceuticals): nasal spray • 0.83 or 1.66 mcg on spray either nostril 30 min prior • Can cause severe hyponatremia (3-4%)! • Pts > 65yrs at higher risk • Monitor baseline Na+, 1 week, 1 month, Q 6 months • Contraindications: Hyponatremia, polydipsia, diuretics, GFR<50, SIADH, CHF, uncontrolled HTN • Also a generic fomulation of DDAVP nasal spray NOT approved by FDA for nocturia – 10 mcg per spray