1. PPS 946 Dr Piascik 1/21/16

2. At the end of this session, students should be able to:  Describe the types of urinary incontinence  Describe the non-pharmacologic treatments of UI  Describe drug therapies that are effective for SUI and UUI, respectively  Apply principles of drug therapy to solving patient- specific UI problems

3.  UI = the involuntary loss of urine  11 of 13 million U.S. patients are women  Biggest risk factor is age  >2X as many women affected  50-70% don’t seek treatment  Under-reported by about 50%  A leading cause of admission to nursing homes  Report by age:  7% in women 20-39yrs  17% in women 40-59yrs  23% in women 60-79yrs  32% in women >80yrs NHANES 2005-2006.

4.  Stress incontinence (SUI) – involuntary loss of urine associated with sneezing, coughing, laughing, lifting, or exercising  Urge incontinence (UUI)–involuntary leakage accompanied by or immediately preceded by urgency  Mixed incontinence – both stress and urge factors  Overflow incontinence - uncommon; overfillled, hypotonic bladder  Functional incontinence - occurs when patient cannot get to the toilet in a timely fashion

5. Estimated Prevalence of Stress, Urge, and Mixed UI Symptoms in Women

6. Coordinated neuromuscular response called the "guarding reflex“ maintains urinary continence.  increase in nerve activity → contraction of the urethral sphincter →  loss of urine  NE and 5-HT play a role in this process  Pelvic floor muscles contract → support bladder → maintain continence  SUI may result from insufficient urethral closure and/or intrinsic sphincter deficiency

7.  Leak urine during physical activity  Coughing, sneezing, laughing, lifting  Anxiety about wetting accidents  Feeling of urgency or frequency is rare  Lack of nocturia  Patient can reach bathroom in time when needed

8. Detrusor muscle in bladder wall normally remains relaxed until bladder is full; nerve signals tell patient it is time to urinate Nerve innervation to the detrusor muscle is cholinergic, primarily muscarinic 3 receptors In UUI, involuntary bladder contractions occur as the bladder fills.

9.  frequent urination  8 or more times over a 24-hour period  Nocturia  2 or more times a night  Feel overwhelming and uncontrollable urge to urinate (urge incontinence)  Little warning time between feeling the bladder is full and needing to urinate  Leak urine due to inability to make it to the bathroom in time  Anxiety about wetting accidents

10.  Aging  Pregnancy, childbirth and menopause  Obesity  Smoking  UTI  Alcohol, excess fluid intake  Drug-induced  Neurologic causes  Stroke  Multiple sclerosis  Neurologic injury  Parkinson’s disease  Pelvic surgery

11.  History – assess severity of the incontinence and its effect on the patient's life  Bladder diary  Physical exam - evaluate the degree of incontinence and possible neurologic disorders  Mental assessment – impact on patient’s QOL  Functional/Environmental assessment – lifestyle issues

12.  Embarrassment  A belief that it is a normal part of aging  The availability of absorbent products  Poor knowledge of management options  Low expectations for treatment UUI and male patients experience the same feelings and avoid seeking therapy

13.  ↓ ability to cope with routine activities  Afraid to venture far from a bathroom  Frequent changes of clothing  Anxiety due to odor, toilet access, appearance  Wearing sanitary napkins or protective undergarments  Shame and lack of self-confidence  Increase in skin disorders from persistent wetness on skin  Falls when trying to get to the bathroom quickly  Institutionalization for elderly

14.  Contract pelvic floor muscles - “draw vagina up and in”  Hold contraction for 3-5 sec; relax for 10 sec  Depending on ability, repeat 10 times/session, at least 2 sessions/day  Gradually increase the number of exercises per set and the number of sets per day  Improvement in 4-6 wks, major change by 6 months Pelvic (Kegel) Exercises

15.  Weight loss  Dietary changes –   caffeine, alcohol, and tea  Electrical stimulation to lower pelvic muscles  Biofeedback/Bladder training

16. Pessary, Urethral inserts, Urine seals Collagen and fat implants Catheterization Dryness aids Surgery

17.  Mechanism of Action:  Dual reuptake inhibitor of NE + 5HT  ↑ s tone and contraction of urethral sphincter  Approved in Europe as Yentreve  Investigational in U.S.  40mg po twice daily  ADRs  Nausea, headache, insomnia, constipation, dry mouth, dizziness, fatigue, somnolence, vomiting, diarrhea  Small  in BP and withdrawal symptoms (sleep disturbances) Duloxetine for Treatment of SUI

18.  Alpha agonists  Pseudoephedrine, phenylpropanolamine, ephedrine, norfenefrine, midodrine  Modest efficacy  ADRs ▪ ↑ BP, headache, dry mouth, nausea, insomnia  CIs ▪ HTN, CAD, tachyarrhythmias, MI, hyperthyroidism, glaucoma  Improved efficacy when combined with estrogen?

19.  Traditional view – HRT is beneficial (1940’s)  WHI trial - UI symptoms (n=23296)  CEE alone and CEE + MPA ▪ ↑ ed the risk of UI among continent women ▪ Worsened the UI symptoms among women after 1 year  Conclusion: CEE with or without progestin should not be prescribed for the prevention or relief of UI  Recommendations  Use topical forms of estrogen for UI  Most useful for SUI associated with estrogen deficiency (urethritis, vaginitis)

20.  Mainstay of therapy is anticholinergic agents cause the detrusor muscle to relax and  frequency and intensity of bladder contractions can also increase bladder capacity

21. Muscarinic Receptor Location Effects of Antagonism M1Brain, salivary glands, Impairment of memory sympathetic ganglia cognition, dry mouth, impaired gastric acid secretion M2Smooth muscle, Tachycardia, increased gastric hindbrain, cardiac sphincter tone M3Smooth muscle, Decreased bladder and bowel salivary gland, eye contractility, dry eyes and mouth, abnormal vision M4Brain, salivary glands Unknown central effects, ↓ oxotremorine-induced salivation M5Substantia nigra, eye Unknown central effects, reduction in pilocarpine-induced salivation, abnormal vision

22.  Anticholinergics are ~75% effective in treatment of UUI  Most common ADRs  Dry mouth, constipation, urinary retention, and blurry vision  Potency and lipophilicity of anticholinergic agent affects ADR profile  As lipophilicity increases, the ability of the drug to cross blood-brain barrier increases. This produces CNS effects such as memory and cognition impairment

23.  Oxybutynin (Ditropan) (primarily M 3 specific)  2.5 and 5mg taken 2-4 times daily ▪ Generic available: considerably cheaper than other agents  High incidence of ADRs: anticholinergic ▪ Weight gain and orthostatic hypotension ▪ Gradually ↑ dose to manage ADRs ▪ Start with 2.5mg twice daily, then increase monthly  Long-acting dosage forms: ↓ ADRs ▪ Extended-release form (XL): 5, 10, or 20mg daily ▪ Transdermal patch – 3.9mg delivered daily ▪ Low incidence of dry mouth ▪ Gel (10%)

24.  Oxytrol for Women  Patch applied every 4 days  Delivers 3.9mg/day  Based on 9 studies of >5000 women  Common ADRs – dry mouth, constipation and skin irritation  available fall of 2013  $16.99 for 4 patches

25.  Tolterodine (Detrol) (M 2 and M 3 specific)  2 and 4 mg doses for immediate release  Extended-release (LA) dosage given once daily  Undergoes hepatic metabolism ▪ Higher serum levels and t1/2 in patients with impaired renal function or poor metabolizers due to absence of CYP2D6  Use of antacids or PPIs with Detrol LA resulted in increased peak plasma levels - clinical significance is not known

26.  Trospium chloride (Sanctura) (M 2 + M 3 specific)  20mg 2X daily on empty stomach or 1hr ac; XR 60mg once daily  ↓dose by 50% if cc 75yo  Generic now available!  Darifenacin (Enablex) M 3 specific  7.5 or 15mg once daily (extended-release tablets)  Solifenacin (Vesicare) (primarily M 3 specific)  5 or 10mg once daily  With renal or hepatic impairment, do not exceed 5mg daily  Don’t use in severe hepatic impairment  Fesoterodine (Toviaz) – prodrug, analog of tolterodine; extended release, 4 and 8 mg

27.  Newest agent is mirabegron (Myrbetriq)  Beta 3 agonist – relaxes detrusor muscle  Once daily 25-100mg  ADRs -  BP, tachycardia, UTI, constipation, fatigue  Avoids dry mouth in elderly and confusion in Alzheimer;s patients

28.  Diuretics  Alpha antagonists  Calcium channel blockers  Decrease smooth muscle contractility  Sedatives and hypnotics  Functional incontinence  Antipsychotics  dopamine or serotonin antagonists  Alcohol  ACEIs   detrusor overactivity and urethral sphincter tone Drug-Induced Urinary Incontinence. US Pharmacist. 2014;39(8):24-29. 2014

29. Date of download: 3/8/2015 Nonsurgical Management of Urinary Incontinence in Women: A Clinical Practice Guideline From the American College of Physicians Nonsurgical Management of Urinary Incontinence in Women. Ann Intern Med. 2014;161(6):429-440. doi:10.7326/M13-2410 PFMT = pelvic floor muscle training; UI = urinary incontinence. Copyright © American College of Physicians. All rights reserved.American College of Physicians

30.  UI is a common disorder in women  SUI is most common, although UUI and mixed incontinence also occur frequently  Non-drug therapy, in particular PFMT, is the first choice  Quite effective for most patients  Anticholinergics are the mainstay of UUI therapy