Pharm 343.17 Lower Urinary Tract Symptoms - Pharmacologic Management PDF

LUTS – Pharmacologic Therapy Cheryl Sadowski, Pharm.D. October 16, 2024 1  OAB/UUI Antimuscarinics Beta-adrenergic agonists Botulinum Toxin Stress UI Alpha-a...

LUTS – Pharmacologic Therapy Cheryl Sadowski, Pharm.D. October 16, 2024 1  OAB/UUI Antimuscarinics Beta-adrenergic agonists Botulinum Toxin Stress UI Alpha-agonists Hormone therapy Duloxetine Outline Overflow UI BPH treatments Alpha-antagonists 5-alpha reductase inhibitors Phosphodiesterase 5 inhibitors Neurogenic treatments Cholinergic agonists Nocturia Desmopressin Diuretics 2 Types of Intervention Education Lifestyle Behavioural Mechanical Pharmacologic Surgical 3  Overactive Bladder Urge Urinary Incontinence 4  OAB Treatment Anticholinergic Surgical – None Pharmacologic - Anticholinergics 5 Antimuscarinics Clinical expectations Contraindications Safety Comparisons Improvement in uncontrolled narrow- M2/M3 receptors on All appear to have symptoms, sometimes angle glaucoma, smooth muscles benefit a cure urinary or gastric including bladder, M1 Oxybutynin most Improvement within 4 retention, and M4 in the brain frequently weeks, maximum tachyarrhythmias, Extended-release discontinued due to effect at 12 weeks myasthenia gravis forms have fewer AE Benefit: adverse effects than approximately 1-2 less immediate-release incontinence forms episodes/day and 1-2 General AE : Dry fewer voids/day mouth, constipation, urinary retention Possible AE: blurred vision, tachycardia, drowsiness, confusion 6  Drug Selectivity Dosing Metabolism Oxybutynin M non- BID - QID 3A4, renal (Ditropan, Oxytrol, selective Tablets or OAB Uromax) syrup Treatment Tolterodine M3>M2 BID 2D6, renal (Detrol) LA – daily Grade A, Fesoterodine M3>M2 ER - daily 2D6, 3A4, renal International (Toviaz) Consultation on Incontinence Trospium M3>M2 BID – daily Renal, heptic (Trosec) (non-P450) Darifenacin M3 Daily 2D6, renal (Enablex) Solifenacin M3>M2, Daily 3A4, renal (Vesicare) M1 Propiverine M non- Daily 3A4 (Mictoryl) selective 7 Antimuscarinics - Interactions Pharmacokinetic interactions Pharmacodynamic interactions Monitor for P450 interactions Anticholinergics 3A4 E.g. antihistamines, TCA 2D6 Cholinergics E.g. cholinesterase inhibitors for dementia 8  Halls Shall Ditropan ? 9  Antimuscarinic – Reduction in Micturition Buser N, et al Eur Urol 2012 10 Antimuscarinic – Reduction in Leakage episodes Buser N, et al. Eur Urol 2012 11 Antimuscarinics – UUI episodes in 24h Stoniute A, et al. Cochrane Database Syst Rev 2023 12 Antimuscarinics – QoL Stoniute A, et al. Cochrane Database Syst Rev 2023 13 Antimuscarinics – Patient Perception of Cure Stoniute A, et al. Cochrane Database Syst Rev 2023 14 OAB Treatment - Anticholinergic Comparative Effectiveness Reynolds, et al. Obstetrics & Gynecology 2015 15 Anticholinergics Reduction in events per day Placebo on treatment ↓urgency incontinence ↓urgency incontinence 1.73 (CI95 1.37-2.09) vs episodes 2.79 (CI95 0.70– 4.88) at 1.06 (CI95 0.7–1.42) baseline ↓voids by 2.06 per day ↓voids (CI95 1.66–2.46) 1.2 (CI95 0.72– 1.67) per 11.28 (CI95 7.77–14.80) day at baseline Reynolds et al. Obstetrics & Gynecology 2015 16  They decrease: The number of urinations The number of incontinence episodes They increase: Antimuscarinics Patient perception of QoL – Evidence Patient perception of UUI cure Summary Debate: The differences are statistically significant Are they clinically meaningful? Do these benefits outweigh the risks? 17 Antimuscarinic Side Effects 18 https://images.app.goo.gl/kJhzgrwYSk9TPgcq7 Antimuscarinic Side Effects vs Placebo Effect RR CI95% Dry mouth 3.50 3.26-3.75 Urinary retention 3.52 2.04-6.08 Withdraw due to AE 1.37 1.21-1.56 Stoniute A, et al. Cochrane Database Syt Rev 2023 19 Side Effects – QT prolongation Female Electrolyte imbalance Bradycardia Heart disease, heart failure, ischemia, history of syncope, AF with recent cardioversion Genetic predisposition Kidney or liver impairment Precautions with solifenacin, tolterodine and mirabegron 20 Side Effects - Cognition Cognitive impairment Individuals with dementia excluded from clinical trials Evidence of cognitive impairment with long-term anticholinergic burden Khastgir J. Expert Opinion Pharmacotherapy 2018 Callegari E, et al. Br J Clin Pharmacol 2011 21 Chancellor MB, et al. Drugs Aging 2012 Dengler KL, et al. Urogynecology 2023 Antimuscarinics - Contraindications Glaucoma Myasthenia Gravis GI: Obstruction, inflammatory bowel disease, atony Urogenital: Obstruction 22 OAB Treatment - Antimuscarinics The bottom line: Antimuscarinics are better than placebo They reduce the number of micturitions and leakage (incontinence) episodes, but do not ‘cure’ the incontinence Side effects can be serious, but discontinuations are often due to the ‘nuisance’ side effect of xerostomia 23  Beta-3 Adrenergic Agonist Beta-3 receptors Mirabegron Relaxes bladder smooth muscle Dosed daily Change in Change in Change in urgency incontinence/24h micturitions (grade 3-4) Mirabegron 50mg -1.5 -1.8 -1.9 Mirabegron Baseline (2.7) (11.7) (5.8) Placebo -1.1 -1.2 -1.3 Placebo Baseline (2.7) (11.6) (5.6) Deeks ED, Drugs 2018 24 Mirabegron – Safety Safety – clinical trials Treatment Mirabegron Placebo Tolterodine Any AE 18.6% 16.8% 26.5% Hypertension 4.7% 4.6% 6.1% Headache 2.0% 1.3% 2.2% Dry Mouth 0.9% 1.6% 9.5% Constipation 0.8% 1.2% 1.4% Safety – product monograph AE: nausea, headache, diarrhea, constipation, dizziness CV safety: tachycardia, increased BP, prolonged QTc 25 Mirabegron vs Antimuscarinic Therapy Athanasiou S, et al. Eur J Obstet Gynecol Reproduc Biol 2020 26 Mirabegron vs Antimuscarinics - Persistence Athanasiou S, et al. Eur J Obstet Gynecol Reproduc Biol 2020 27 FORTA Classification 28 Oelke M., et al. Age and Ageing. 2015 FORTA Classification 29 Oelke M., et al. Age and Ageing. 2015 OAB - Alternatives Not labelled for use for OAB Anticholinergic effect Tricyclic antidepressants Dicyclomine Flavoxate Botulinum toxin 30  OAB/UUI Antimuscarinics Beta-adrenergic agonists Botulinum Toxin Stress UI Alpha-agonists Hormone therapy Duloxetine Outline Overflow UI BPH treatments Alpha-antagonists 5-alpha reductase inhibitors Phosphodiesterase 5 inhibitors Neurogenic treatments Cholinergic agonists Nocturia Desmopressin Diuretics 31 Stress Urinary Incontinence 32 Stress Urinary Incontinence 33 Alpha- Agonists - Evidence Cochrane Review (Alhasso, et al. 2010) 11 studies (n=1099 women) Phenylpropanolamine, midodrine, norepinephrine, clenbuterol, terbutaline, eskornade “There was weak evidence to suggest that use of an adrenergic agonist was better than placebo treatment.” No evidence these medications are superior to PFMT Shamliyan et al, Annals Intern Med 2008 Alhasso A, et al. Cochrane Database of Systematic Reviews 2010 34 Alpha Agonists Patients may self treat Pseudoephedrine 15-30 mg tid Side Effects: Increased BP, anxiety, insomnia, cardiac arrhythmias 35 Hormone Therapy Rationale: Minimize atrophy Sensitize alpha receptors Evidence is inconsistent Landmark trials (WHI, HERS) showed a consistently higher risk of self-reported incident UI at all time points in women who took combined E+P orally vs placebo. WHI trial at 1 y combined E+P, RR for urinary incontinence = 1.39 [95% CI, 1.27 - 1.52] WHI at 3 y RR = 1.81 [95% CI, 1.16 - 2.84] HER trial E+P x 4,2y OR = 1.6 [95% CI, 1.-to 1.9]) (USPSTF, JAMA 2017) Topical therapy improved LUTS “Topical oestrogen administration is effective for the treatment of vaginal atrophy and seems to decrease complaints of OAB and UI. The potential for local oestrogens in the prevention as well as treatment of pelvic organ prolapse needs further research. “ (Weber MA, et al, Plos One 2015) In some cases topical estrogen is used prior to pessary placement Testosterone therapy in men is avoided 36 Duloxetine Labeled for treatment of depression, neuropathy Mechanism: selective 5-HT and NE reuptake inhibitor Increases sphincter contractility Doses studied: 80 mg qd or 40 mg bid Availability: 30 mg, 60 mg 37 Duloxetine - Efficacy Benefits of duloxetine (80-mg dose), in terms of change in weekly incontinence episodes. Emma Maund et al. CMAJ 2017;189:E194-E203 38 Duloxetine – Quality of Life Benefits of duloxetine (80-mg dose), in terms of the Incontinence Quality of Life total score. Emma Maund et al. CMAJ 2017;189:E194-E203 39 Duloxetine - Safety Primary AE: nausea 40 Additional Options Surgical Bladder suspension Bulking agents Autologous fat Silicone Wu J. NEJM 2021 41  OAB/UUI Antimuscarinics Beta-adrenergic agonists Botulinum Toxin Outline Stress UI Alpha-agonists Hormone therapy Duloxetine Overflow UI BPH treatments Alpha-antagonists 5-alpha reductase inhibitors Phosphodiesterase 5 inhibitors Neurogenic treatments Cholinergic agonists Nocturia Desmopressin Diuretics 42 Benign Prostatic Hyperplasia 43 BPH Guidelines 2022 44  “Are your symptoms bad enough that it would justify taking a medication each day or having a surgical procedure?” BPH Surgery Treatment Catheterization Pharmacotherapy 45 BPH Treatment Algorithm – CUA Guidelines 46 BPH Approach to Treatment 47 48 Surgical Intervention – Gold Standard Forms of intervention TURP (transurethral resection of the prostate) Simple prostatectomy Photovaporization of the prostate Laser enucleation Water vapour thermal therapy Transurethral incision of the prostate Transurethral microwave therapy Transurethral needle ablation Dornbier R, et al. Curr Urol Rep 2020 49 BPH – Approach to Treatment Decisions based on IPSS (AUA) 50 5-Alpha Reductase Inhibitors Abbreviation: 5ARI Finasteride, Dutasteride Mechanism: Prevent formation of DHT Efficacy: Larger prostates Time to benefit: 3-6 months Dose: finasteride 5 mg qd dutasteride 0.5 mg qd 51  5-Alpha Reductase Inhibitors Evidence Improves IPSS significantly improved (4 point) Studies support efficacy for over 1y Lower risk of BPH progression Finasteride vs Dutasteride Dutasteride found to work faster (3 vs 6 months) Dutasteride found to reduce size of prostate more than finasteride (27% vs 20%) Fenter 2008 Ravish 2007 52 Tacklind J, et al. Cochrane Database of Systematic Reviews 2010 5-Alpha Reductase Inhibitors - Safety Tacklind, et al. Cochrane 2010 53 5-Alpha Reductase Inhibitors - Safety Contra-indications: hypersensitivity Side effects: impotence (3.7%) decreased libido (3.3%) decreased volume of ejaculate (2.8%) infertility Warnings: breast cancer, suicide risk https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect- canada/health-product-infowatch/january-2024.html#a3.1.3 Interactions: None known 54 Alpha Antagonists Doxazosin (Cardura) Terazosin (Hytrin) Tamsulosin (Flomax) Alfuzosin (Xatral) Silodosin (Rapaflo) 55 Alpha Antagonists Mechanism: Alpha-1 receptors on prostate, relaxation of muscle Efficacy: Within 1 week will improve symptoms Dosing: Once daily AM versus HS – monitor for nocturia AM – may experience dizziness and other AE throughout the day HS – may sleep through the AE; if patient is rising to urinate then he may experience dizziness while ambulating (note risk for falls) 56  Alpha Antagonists Change in IPSS score Change in QoL Mansbart F, et al. BMC Geriatrics 2022 57 Alpha Antagonists >15 studies to date Studies range from 4-52 weeks No differences found between antagonists Results: Flow rates improved 22% AUA symptom score improved 38% Wilt 2008 58  Alpha- antagonists Adverse events Traditional (non-selective) ↑ dizziness (up to 80%) Selective agents (