IP9 Urinary Incontinence.pdf

Urinary Incontinence RHCHP School of Pharmacy Integrated Pharmacotherapy 9 Fall 2024 Facilitators Readings &...

Urinary Incontinence RHCHP School of Pharmacy Integrated Pharmacotherapy 9 Fall 2024 Facilitators Readings & References Peter Cogan, PhD Required [email protected] Integrated Pharmacotherapy 9: Urinary Incontinence Course Notes 303-964-6154 Optional Leticia Shea, PharmD, BCACP Chapter 101: Urinary Incontinence. From DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 11ed. [email protected] Chapter 9: Muscarinic Receptor Agonists and Antagonists. From Goodman & Gilman’s The Pharmacological Basis 303-964-6182 of Therapeutics, 12e d Quality Measures Urinary Incontinence CMS Learning Objectives 1. Describe the anatomy and function of the structures that comprise the lower urinary tract (urinary bladder, urethra, internal and external sphincters). 2. List the three layers of the bladder. 3. Describe the characteristic of compliance as it relates to bladder filling. 4. Identify neural regulatory pathways (parasympathetic, sympathetic, somatic; neurotransmitter; receptor target) of specific lower urinary tract components. 5. Define the guarding reflex of micturition. 6. List the specific neural mechanisms and corresponding muscle activities/inactivities that inhibit micturition. 7. List the specific neural mechanisms and corresponding muscle activities/inactivities that promote micturition. 8. Compare and contrast local (spinal) and higher order central nervous system control of micturition. 9. Describe the different mechanisms of urinary incontinence (UI) including stress urinary incontinence, urge urinary incontinence, mixed incontinence, overflow incontinence, functional incontinence, and other types. 10. Discuss the epidemiology of UI in terms of the entire population and with respect to age- and sex-based trends. 11. Evaluate the impact of UI on current and future healthcare delivery. 12. Compare and contrast the signs, symptoms, and clinical features of the various types of UI. 13. Given a patient’s general presentation, signs, and symptoms of UI, determine the type of UI that is present within the individual. 14. Explain dysuria, enuresis, frequency, nocturia and urgency so that you may explain these terms to a patient in lay terms. 15. Provide examples of the different signs and symptoms a patient may present with or describe to you that will enable you to differentiate between SUI, UUI/OAB, Mixed incontinence, Overflow incontinence and Functional incontinence. 16. Recognize appropriate care based on the treatment guidelines as provided in the packet. 17. Given a patient case, be able to utilize the treatment guidelines & algorithm to determine appropriate care for the patient. 18. Explain the appropriate length of time a patient should initiate behavioral therapy in order to determine if these methods are efficacious. (treatment algorithm) 19. Explain the appropriate length of time a patient should wait to consider if pharmacotherapy is providing sufficient improvement in symptoms. (treatment algorithm) 20. Identify the common medications and medical conditions that impact bladder function, urinary retention, or UI. 21. Describe the role of patient assessment and its implications for initiating treatment. 22. Explain the basic anatomy of parasympathetic bladder innervation. 23. Describe the distribution of the 5 muscarinic receptor subtypes. 24. Describe the organ specific effects of muscarinic antagonism. 25. Explain the difference between orthosteric and allosteric binding sites and how these differences are pertinent in selective muscarinic blockade. 26. Identify which muscarinic receptor subtype is most directly responsible for bladder control. 27. Explain the effect that muscarinic blockade has on bladder function.  Learning Objectives 28. Identify the names and structures of the commonly employed muscarinic antagonists. 29. Explain the reasoning behind the FDA's approval for over-the-counter (OTC) status of the transdermal patch formulation of oxybutynin. 30. Predict populations in which OTC oxybutynin patches might not be advisable based on the side effect profile and assumptions made by the FDA. 31. Identify the important SAR considerations of the muscarinic antagonists. 32. Describe the available formulations of each of the muscarinic antagonists and beta-3 agents employed in the treatment of UI. 33. Identify how fesoterodine is converted to its active metabolite. 34. **Explain the rationale for the extended release formulations of oxybutynin and tolterodine, noting that the rationale is different for each. 35. **Describe the roles of the different CYP450 isozymes in the metabolism of tolterodine and fesoterodine and explain the roles of these enzymes in metabolism of the drugs by extensive and poor metabolizers. 36. **Explain the rationale for the required precautions (or lack thereof ) when dosing poor metabolizers with tolterodine and fesoterodine. 37. **Explain why caution is necessary with all patients when coadministering CYP3A4 inhibitors and tolterodine. 38. Explain the rationale for using quaternary ammonium salts in terms of drug distribution, paying particular attention to CNS distribution and absorption from the GI tract. 39. Describe what is meant by the term “uroselective”, both in terms of its common pharmacological definition and the more appropriate clinical definition. 40. Identify the common clinically pertinent adverse effects associated with the antimuscarinic agents and the major differences in antimuscarinic side effects between the agents. 41. Recommend strategies for managing antimuscarinic side effects to increase patient tolerability to these agents. 42. Describe the mechanism of action and significant adverse effects of each medication described in this packet. 43. Compare the adverse effects profiles of the muscarinic antagonists and beta-three agents (mirabegron & vibegron). 44. Summarize the clinical effectiveness of antimuscarinic and beta-3 agents for reducing the symptoms of overactive bladder and UI. 45. Describe the action and effect of botulinum toxin A on the detrusor muscle. 46. Explain the effects of estrogen on bladder control. 47. Explain the effects of adrenergic agonists on bladder control. 48. Describe the common lifestyle changes for treating UI and the nonpharmacologic treatments that are most beneficial for UI. 49. **Formulate a comprehensive, patient-specific therapeutic plan for managing UI that includes both pharmacologic and nonpharmacologic therapies. 50. Select an antimuscarinic agent to treat urge urinary incontinence considering effectiveness and risk of adverse events. 51. **Debate the use of antimuscarinic medications to treat UI in patients with cognitive impairment, with specific consideration of adverse events, blood-brain barrier penetration, and CNS impairment. Integrated Pharmacotherapy 9 2 Urinary Incontinence PHYSIOLOGY The storage and elimination of urine depend on the coordinated activity of both smooth and striated muscles of the urinary bladder, its outlet, the bladder neck, containing the urethra and internal urethral sphincter, as well as the external urethral sphincter. Complex neural circuitry that is widely distributed (brain, spinal cord, and peripheral ganglia) coordinate these anatomical components. Though involuntary urination is normal in infants and young children until the age of 3 to 5, it can re-emerge in adults following disease or injury of the nervous system, and therefore constitutes a major health problem. Lower Urinary Tract Figure 1. Structures of lower urinary tract The anatomy and physiology of the lower urinary tract was introduced in the IP8 Urinary Tract Infections and Prostatitis course notes. Recall that the lower urinary tract is made up of the following structures: bladder, urethra, and the internal and external urethral sphincters (Figure 1). Unlike some other visceral structures (e.g. cardiovascular organs), which are able to maintain a level of function in the absence of extrinsic neural input, the lower urinary tract is dependent on the CNS to control its two modes of operation: storage and elimination. In such, neural circuitry innervating the bladder have switch-like patterns of activity. Furthermore, since micturition is under voluntary control, it is a learned behavior that develops during maturation of the nervous system. Urinary Bladder The bladder is a collapsible, muscular sac that temporarily stores urine. It contains three layers: an innermost layer of transitional cell epithelium, a thick layer of smooth muscle, referred to as the detrusor muscle, and an outer fibrous adventitia that surrounds the bladder. The bladder collapses when empty and, as urine accumulates, expands dramatically to accomodate up to 800-1000 mL. The increasing volume of a filling bladder does not significantly increase bladder pressure, which constitutes a unique property of the bladder (compliance), but rather activates stretch receptors that initiate the micturition reflex, discussed in further detail in "Micturition" section below. Detrusor muscle contraction is mediated by stimulation from autonomic (involuntary) parasympathetic neurons. Acetylcholine released by these neurons binds to muscarinic receptors. In the bladder, the majority of receptors are of the M2 and M3 subtype (of five known subtypes, M1-M5). The ratio of receptor numbers is approximately 3:1, M2:M3. Despite being outnumbered by the M2 subtype, the M3 subtype exerts greater physiological action on the bladder, as it primarily controls both the contraction of normal voiding as well as involuntary bladder contractions. Most pharmacological interventions in the treatment of urinary incontinence are focused on the M3 receptor subtype, though none are perfectly specific for the M3 receptor and all are associated with side effects resulting from binding to the other muscarinic subtypes. Table 1. Overview of Lower Urinary Tract Innvervation Detrusor muscle relaxation is mediated by autonomic sympathetic Characteristic Detrusor Internal External neurons that release norepinephrine (NE) onto β3- and β2- Sphincter Sphincter adrenoceptors, the former being the most prominent. Type of muscle Smooth Smooth Skeletal Nature of Sympathetic Urethra Innervation Parasympathetic Sympathetic Somatic The urethra is a thin-walled muscular tube that drains the bladder of urine during urination/micturition/voiding. It is ~3-4 cm long Figure 2. Neural Control of Lower Urinary Tract in females, and ~20 cm long in males. Contraction of urethral smooth muscle is mediated by sympathetic neurons that release norepinephrine (NE) onto α1-adrenoceptors. Internal and External Urethral Sphincters The internal urethral sphincter is composed of smooth muscle at the bladder-urethra junction and is autonomically controlled by sympathetic neurons. Sympathetic stimulation results in smooth muscle contraction in the bladder neck (and urethra) via norepinephrine (NE)-activated α1-adrenoceptor signaling (see Figure 2). Integrated Pharmacotherapy 9 3 Urinary Incontinence The external urethral sphincter is composed of skeletal muscle, is under somatic (voluntary) control, and serves as the primary urinary continence mechanism. Somatic stimulation and contraction of the external urethral sphincter is mediated by acetylcholine (ACh) activated nicotinic acetylcholine receptors (N). Collectively, the sphincters prevent the flow of urine when it is not being passed and prevents leaking between urinations. To do so, urethral closure pressure (force) must be greater than bladder pressure, both at rest and during times of increased abdominal pressure (e.g. coughing), in order to retain urine in the bladder and maintain continence. Micturition Micturition, or urination, is a coordinated effort between the functional units of the lower urinary tract and the complex neural control system. Before learning the processes of micturition regulation below, it helps to relate the functional branches of the nervous system to the anatomical components of the lower urinary tract in which they innervate (i.e. Figure 2 on page 3). In short, recall that the parasympathetic branch of the autonomic nervous system is active during times of "rest and digest" (increased urine formation, bladder filling and voiding), whereas the sympathetic branch is active during times of "fight or flight" (decreased urine formation, less bladder filling, and guarding--no voiding). Of course, we know it is not this simple, since micturition is also voluntarily controlled despite autonomic stimuli. Bladder Filling and The Guarding Reflex As urine accumulates in the bladder, stretch receptors located in the bladder wall are activated. When ~150-200 ml of urine has accumulated in the bladder, afferent signals are sent via the spinal cord to the brain, indicating there is urine in the bladder. This is when one first senses the urge for voluntary bladder emptying. Until a socially acceptable time to void presents itself, impulses from the brain, in a learned reflex, inhibit the excitatory parasympathetic innervation of the detrusor muscle (i.e. inhibit detrusor contraction). Additionally, in what is known as the guarding reflex, somatic neurons progressively increase stimulation of the external urethral sphincter in an effort to increase external urethral sphincter pressure over bladder pressure. Hence, the micturition reflex is effectively inhibited within a minute or so, and urine continues to accumulate. Specific mechanisms include (Two S's and no Pee!): Sympathetic neuron stimulation of ӽ detrusor muscle that keeps it relaxed (norepinephrine-β3-adrenoceptor signaling), ӽ internal sphincter smooth muscle that keeps it contracted (norepinephrine-α1-adrenoceptor signaling), Somatic stimulation of the external sphincter (acetylcholine-nicotinic acetylcholine receptor signaling) that keeps it contracted, and Somatic inhibition of Parasympathetic signaling (at ganglia) during the filling phase. After another 200 ml of urine has accumulated in the bladder, the micturition reflex occurs again. Eventually the urge to void becomes irresistible. Figure 3. Local (Spinal) and Central Control of Micturition Bladder Voiding When a person is ready and able to void, the micturition reflex stimulates both the central nervous system (pontine micturition center in the brainstem to thalamus to cerebral cortex) as well as spinal parasympathetic neurons which together coordinate a sustained contraction of the detrusor muscle and relaxation of the internal sphincter smooth muscle (see Figure 3). The parasympathetic neurons also inhibit somatic efferent signaling which relaxes the external sphincter. Sympathetic outflow is inhibited. Collectively, these processes allow urine to flow out through the urethra. Only about 10 ml of urine remain in the bladder after micturition. Specific mechanisms include (No S's and all Pee!): inhibition of sympathetic neurons at level of spinal cord ӽ removes relaxation signaling to detrusor muscle ӽ removes contraction signaling to internal sphincter muscle inhibition of somatic neurons at level of spinal cord ӽ removes contraction signaling to external sphincter parasympathetic stimulation of detrusor muscle contraction Integrated Pharmacotherapy 9 4 Urinary Incontinence PATHOPHYSIOLOGY The International Continence Society defines urinary incontinence (UI) as the involuntary loss of urine. There are several different mechanisms or types of UI Definitions which will be covered in these notes. Dysuria: difficult/painful urination Enuresis: involuntary loss of urine Urethral Underactivity (Stress Urinary Incontinence) Frequency: micturition more than eight (8) times Stress urinary incontinence (SUI) typically results when exertional stress during the day; may also refer to a patient com- (including exercise, running, lifting, coughing, and sneezing) increases intra- plaint that he/she voids too often during the day abdominal pressure to the point where a compromised urethral sphincter Nocturia: awakening at night one or more times to can no longer resist the flow of urine. The exact etiology that compromises void the integrity of the sphincter is likely multifactorial and may include normal Urgency: a sudden compelling desire to pass urine aging, hypoestrogenic state post menopause, impairment of pelvic musculature that is difficult to delay and urethral support after childbirth, or pelvic surgery and/or trauma. Thus, risk factors in women include pregnancy, childbirth, menopause, cognitive impairment, obesity, and age. In men, risk factors include lower urinary tract surgery, neurologic illness, or injury. Bladder Overactivity, aka Urge Urinary Incontinence or overactive bladder (OAB) Bladder overactivity occurs when the detrusor muscle is overactive and causes involuntary bladder contractions during bladder filling or storage. The International Continence Society defines overactive bladder (OAB) as a syndrome characterized by urinary urgency, with frequency and nocturia, with or without associated UI in the absence of a known pathologic condition that may result in similar symptoms (e.g., urinary tract infection, bladder cancer). When actual urine loss occurs in the setting of OAB symptoms (especially urgency), it is called urge urinary incontinence (UUI). The mechanism for bladder overactivity is hypothesized to be either neurogenic or myogenic. The neurogenic mechanism may involve either the central or peripheral nervous system. One example is bladder outlet obstruction where partial denervation of smooth muscle can lead to decreased responsiveness to neural input but hyperresponsiveness to contractile agents and direct electrical activation. The myogenic mechanism includes dysfunctional smooth muscle activity in the bladder wall. Mixed Incontinence Mixed incontinence includes a combination of urethral underactivity and bladder overactivity. Urethral Overactivity and/or Bladder Underactivity (Overflow Incontinence) Urethral overactivity and/or bladder underactivity are responsible for overflow incontinence. In the case of urethral overactivity, the bladder fills to capacity, but an urethral obstruction prevents the bladder from emptying. Eventually, however, urine leaks past the sphincters. In men, urethral overactivity typically involves BPH and prostate cancer. Urethral overactivity is rare in women, but may result from a kinking of the urethra or surgical overcorrection. Neurological dysfunction or disease may also cause overflow incontinence. Bladder underactivity may result from a weakened detrusor muscle that can no longer contract forcefully. When the bladder is unable to empty completely, large volumes of residual urine are left after micturition. Incontinence may occur when the bladder is overdistended and intrabladder pressure exceeds the resting urethral closure pressure, resulting in urine overflow. The etiology for bladder underactivity include both neurogenic and myogenic factors. Other types of Urinary Incontinence Functional incontinence is caused by factors independent of the lower urinary tract, and typically is a result of a separate primary disorder. In most cases of functional incontinence, the underlying condition causes a physical or mental inability to access toileting facilities. Dementia/delirium is a common cause of functional incontinence, whereby the patient lacks normal urinary awareness and/ or cues to reach a toilet. Functional incontinence can also result from a physical inability to reach a toilet, such as the case with acute or chronic mobility impairment. Reduced mobility may render a patient unable to access toileting facilities in a reasonable amount of time and he/she may become incontinent as a result. Consider a postoperative orthopedic surgery patient, following extensive orthopedic reconstructions such as total hip arthroplasty; patients are often immobile secondary to pain or traction. UI can also result from detrusor hyperreactivity with impaired contractility, which is when the bladder is overactive but empties ineffectively because of impaired contractile function. Many diseases and medications may lead to UI, and these are presented in the “Patient Assessment & Clinical Presentation” section on page 6. Integrated Pharmacotherapy 9 5 Urinary Incontinence EPIDEMIOLOGY Age- and Sex-related Patterns Age is the single largest risk factor for UI, with prevalence of the condition increasing with advancing age. Also, in noninstitutionalized populations (i.e. not in a long-term care facility) UI appears to be more common in females than in males, across all ages. Urinary Incontinence Type Some studies have found that mixed UI (SUI plus OAB) is the most common type of UI. However, the proportions of SUI versus OAB versus mixed UI vary considerably with age group and sex of patients studied, study methodology, and a variety of other factors. Studies have shown that SUI tends to be more common in women younger than 65 years, while OAB and mixed UI are more common in women older than 65 years. SUI affects 15-60% of women- both young and older individuals. More than 25% of nulliparous young college athletes have reported SUI when participating in sports. SUI in men is uncommon. Underdiagnosis UI is often underdiagnosed and underreported, and it is likely that the actual prevalence is underestimated. An estimated 50-70% of women with UI fail to seek medical evaluation and treatment because of social stigma. A 2009 survey of women in a managed care population found that the prevalence of undiagnosed UI was 53% in the preceding year. Finally, many of the UI estimates have been derived from a non-institutionalized population, but the prevalence of UI among residents of long-term care facilities is known to be higher, with estimates of 50-80%. KEY CONCEPT Regardless of the current estimates and numbers, UI will continue to present a significant disease burden based on the confirmed correlation with advancing age, the overall aging of the U.S. population, and the projected increase in the percentage of geriatric patients. Quality measures in determining "Value-based care" now require that UI be evaluated at least once a year in those > 65. PATIENT ASSESSMENT & CLINICAL PRESENTATION One of the most important elements of UI evaluation is obtaining a thorough patient history and clinical presentation of urinary complaints. Patients may be reluctant to initiate discussions about incontinence due to embarrassment or the belief that these issues are normal. Approximately 40% of patients with OAB fail to mention their OAB symptoms to their health care provider. Therefore, patients with UI or suspected UI, especially those older than 65 years, should be asked focused questions about voiding problems. Table 5 on page 9 lists many of the elements that should be investigated when taking a patient history. There are several validated questionnaires (ICIQ) to gather appropriate information in a patient presenting with possible UI. One of the major goals of assessing a patient’s presentation and history are to determine the type of UI. A patient’s symptoms and history can provide clues to whether UI is related to activity or movement, a physiologic disorder/impairment, and/or medications. A complete medical history, including an assessment of symptoms and a physical examination, is essential for correctly classifying the type of incontinence and thereby assuring appropriate therapy. Urethral Underactivity (Stress Urinary Incontinence, SUI) General presentation: Patients with SUI usually notes UI during activities such as exercise, running, lifting, coughing and sneezing. Occurs more in women. (Seen only in men with lower urinary tract surgery or injury compromising the sphincter). Symptoms: Urine leakage with physical activity (volume proportional to activity level). No UI with physical inactivity, especially when supine (no nocturia). May develop urgency and frequency as a compensatory mechanism (or as a separate component of bladder overactivity). Additional information: Urgency and frequency may develop as a compensatory mechanism wherein the patient with SUI learns to toilet frequently to prevent large-volume urine loss during physical activity. However, urgency and frequency may also be present because the patient has mixed IU, which is the combination of SUI and OAB. As stated above, stress UI is more common in women. If a male presents with symptoms of stress UI, he has likely experienced a lower urinary tract surgery or injury that compromised the sphincter mechanism of the urethra. Transurethral resection of the prostate for BPH or radical prostatectomy for treatment of prostate adenocarcinoma are the most common surgical manipulations that lead to SUI in men. Integrated Pharmacotherapy 9 6 Urinary Incontinence Overactive Bladder , OAB (Urge Urinary Incontinence) One can have bladder overactivity and UI without urgency if sensory input from the lower urinary tract is absent. Thus "overactive bladder" (OAB) provides a better definition of this condition than "urge UI" as in some individuals they are not feeling the "urge" component. General presentation: Because urine leakage is unpredictable, and the volume loss may be large, some patients may wear protection (e.g. panty liners, pads, or briefs) both day and night. Symptoms: Urinary frequency (> 8 micturations per day), urgency with or without urge incontinence; nocturia (> 1 micturation per night) and enuresis may be present. (Enuresis is involuntary or unintentional release of urine.) Additional information: Urinary urgency requires intact sensory input from the lower urinary tract. In patients with spinal cord injury, sensory neuropathies, and other neurologic diseases, OAB may manifest as UI without awareness or sense of urinary urgency due to a diminished ability to perceive or process sensory input from the lower urinary tract. When bladder contraction occurs without warning and sensation is absent, the condition is referred to as reflex incontinence. Urinary frequency can be affected by a number of factors unrelated to bladder overactivity, including excessive fluid intake (polydipsia). Interstitial cystitis and urinary tract infections (UTIs) cause bladder hypersensitivity and should be ruled out before OAB is diagnosed. These conditions can be excluded by collecting a urinalysis and urine culture. The symptoms of OAB may be triggered by certain factors or events, most likely as a result of a psychological conditioning. For example, patients may experience urgency when they hear the sound of running water, walk by the freezer section in the supermarket. Some patients experience urgency when they enter their driveway or insert a key into the door of their home. Urethral Overactivity and/or Bladder Underactivity (Overflow Incontinence) General presentation: Patients with overflow UI typically have an identifiable factor in their medical history that is responsible their symptoms, such as prostatic enlargement in males or surgical overcorrection following stress incontinence surgery in women. Symptoms: Lower abdominal fullness, hesitency, straining to void, decreased force of stream, interrupted stream, sense of incomplete bladder emptying. May have urinary frequency and urgency. Abdominal pain if acute urinary retention is present Signs: Increased postvoid residual urine volume. Additional information: A patient’s history may identify a possible neurologic cause of a nonfunctioning detrusor, such as diabetic neuropathy. The medication history may suggest a pharmacologic cause, especially when the onset of symptoms associated with new or prolonged use of an anticholinergic or antispasmodic drug. Men with overflow incontinence symptoms should be assessed for prostatic enlargement via digital rectal examination or transrectal ultrasound. Renal function tests can assess for renal failure due to acute urinary retention. Mixed Incontinence Patients with mixed incontinence exhibit symptoms of both stress incontinence and overactive bladder. Urinary frequency, urgency, and nocturia may all be present. Most of the time, patients are not able to distinguish these 2 different symptom complexes. The symptoms of urge incontinence may unwittingly be confused with the symptoms of stress incontinence and vice versa. In this situation, the symptom complex most unbearable to the patient is treated first. Table 2. Differentiating Bladder Overactivity from Urethral Underactivity-Related UI Symptoms Bladder Overactivity (OAB) Urethral Underactivity (SUI) Urgency Yes Sometimes Frequency with urgency Yes Rarely Leaking during physical activity (coughing, No Yes sneezing, lifting, etc.) Amount of urinary leakage with each episode of Large if present Usually small incontinence Ability to reach the toilet in time following an urge No or just barely Yes to void Nocturnal incontinence Yes Rare Nocturia Usually Seldom Integrated Pharmacotherapy 9 7 Urinary Incontinence Urinary Incontinence Caused by Medication or Medical Conditions Many medications contribute to UI either directly or indirectly. Some medications are responsible for UI via urinary tract instability and reduced muscle tone, while others contribute to urinary retention. Medications must always be considered as the cause of new- onset UI, especially in elderly persons, in whom polypharmacy is common. Some of the more common agents and their associated effects are listed in Table 3. Table 3. Medications Impacting Bladder Function Medication/Drug Impact on Bladder and/or UI Diuretics, acetylcholinesterase inhibitors Polyuria, frequency, urgency α-Receptor antagonists Urethral relaxation and stress urinary incontinence in women α-Receptor agonists Urethral constriction and urinary retention in men Calcium channel blockers Urinary retention Narcotic analgesics Urinary retention from impaired contractility Sedative hypnotics Functional incontinence caused by delirium, immobility Antipsychotic agents Anticholinergic effects and urinary retention Anticholinergics (or drugs w/ these side effects) Urinary retention Antidepressants, tricyclic Anticholinergic effects, α-antagonist effects Alcohol Polyuria, frequency, urgency, sedation, delirium Angiotensin-converting enzyme inhibitors (ACEIs) Cough as a result of ACEIs may aggravate stress urinary incontinence by increasing intraabdominal pressure Medical conditions that may contribute to UI are listed in Table 4. These conditions Table 4. may result in UI because of their effects on the lower urinary tract or the surrounding Medical Conditions Associated with UI structures. As part of the patient assessment, these conditions should be ruled-out as Benign prostatic hyperplasia the underlying cause of a patient’s UI symptoms. Conditions associated w/ chronic cough (e.g. Aside from identifying the conditions listed in Table 4, the patient should be assessed COPD, asthma) for a condition causing functional incontinence. Congenital malformations Constipation Another unique circumstance in which UI may arise is the postoperative setting. Depression Acute UI manifesting in the immediate postoperative setting may be secondary Diabetes mellitus to a number of factors, including surgical manipulation, mechanical immobility, Neurologic disease (e.g., stroke, Parkinson’s immobility due to pain, and side effects from medications, especially opioid disease, multiple sclerosis, spinal cord or CNS analgesics. In this setting, acute urinary retention and overflow incontinence are injury) Pelvic organ malignancy commonly related to the administration of anesthetic agents and/or opioid analgesics Postmenopausal atrophic urethritis or vaginitis in the perioperative period. These agents may have profound effects on bladder Urinary tract infection (cystitis) contractility that are completely reversible once the agents are metabolized and Urinary tract stones excreted. When evaluating UI in women, gynecologic factors may reveal an underlying cause of the patient’s symptoms. In particular, UI may be related to recent childbirth, hormonal status, and prior gynecologic surgery. Pregnancy and childbirth, particularly vaginal delivery, are associated with stress UI and pelvic prolapsed, whereas stress UI in the nulliparous woman is less likely. In older women, UI that has developed progressively at or around menopause suggests a hormonal component and may suggest specific pharmacotherapy (i.e. estrogen or hormone replacement therapy). THE ASSESSMENT OF SYMPTOMS AND PRESENTATION HAS MANY FACTORS, BUT IT IS A VITAL STEP IN PROVIDING PATIENT CARE Determining the type of incontinence (SUI, OAB/UUI, overflow incontinence, mixed incontinence, functional incontinence) is a crucial step in selecting appropriate therapy The various types of UI require different treatment strategies. A therapy intended for one type of UI can actually make other types of UI worse Integrated Pharmacotherapy 9 8 Urinary Incontinence  Table 5. Patient Assessment Questions for UI Severity or quantity of urine lost Frequency of incontinence episodes Duration of the complaint and whether problems have been worsening Constant versus intermittent urine loss Triggering factors or events (eg, cough, sneeze, lifting, bending, feeling of urgency, sound of running water, sexual activity/orgasm) Coexistent complicating or exacerbating medical problems Presense of spinal or CNS injury or surgery Concomitant symptoms of fecal incontinence or pelvic organ prolapse History of pelvic surgery, incontinence procedures, or other urologic procedures (including hysterectomy or pelvic floor reconstructive procedures Specific to women when applicable- Obstetrical history (including difficult deliveries, grand multiparity, obstetrical lacerations, and large babies) Lifestyle issues: smoking, alcohol or caffeine abuse, and occupational and recreational factors that cause severe or repetitive increases in intra-abdominal pressure Current medications Diagnosis & Treatment Algorithm: AUA/SUFU Guideline on Non-Neurogenic Overactive Bladder in Adults Consider urine culture, post-void Diagnosis unclear or additional information needed Not OAB or Complicated History and Physical; Urinalysis residual, bladder diary, and/or OAB; treat or refer symptom questionnaires Signs/symptoms of OAB, (-) urine microscopy Signs/symptoms of OAB Patient Education: - Normal urinary tract function - Benefits/risks of treatment alternatives - Agree on treatment goals Follow-up for efficacy and adverse events Patient desires treatment, is willing to engage in treatment, and/or treatment is in patient’s best interests In extremely rare cases, Treatment goals met consider augmentation cystoplasty or urinary Behavioral Treatments Standard diversion (consider adding pharmacologic management if partially effective) Treatment goals not met after appropriate duration*; Patient desires further treatment, is willing to engage in treatment, and/or further treatment in patient’s best interests Pharmacologic Management Standard With active management of adverse events; consider dose modification or Consider in carefully-selected and thoroughly-counseled alternate medication if initial treatment is effective but adverse patients with moderate to severe symptoms events or other considerations preclude continuation Intradetrusor onabotulinumtoxinA Standard (patients must be willing to perform CISC) Treatment goals not met after appropriate duration*; OR Patient desires further treatment, is willing to Signs/symptoms consistent with OAB diagnosis; Treatment Peripheral tibial nerve stimulation (PTNS) Recommendation engage in treatment, and/or further treatment in goals not met after appropriate duration*; Patient desires (patients must be willing and able to make frequent office visits) patient’s best interests further treatment, is willing to engage in treatment, and/or OR further treatment in patient’s best interests Sacral neuromodulation (SNS) Recommendation Reassess and/or Refer to Specialist Consider urine culture, post-void residual, bladder diary, symptom questionnaires, other diagnostic procedures as necessary for differentiation Integrated Pharmacotherapy 9 9 Urinary Incontinence  Dosing of Medications Approved for UUI (OAB) Drug Brand Name Initial Dose Usual Range Special Population Doses Comments Anticholinergics/Antimuscarinics 2.5-5mg two to four Titrate in increments of 2.5mg/day every Oxybutynin IR Ditropan 2.5mg twice daily times daily 1-2 months; available in oral solution 5-10mg once Adjust dose in 5mg increments at weekly Oxybutynin XL Ditropan XL 5-30mg once daily daily interval; swallow whole 3.9mg/day apply Apply every 3 to 4 days; rotate application Oxybutynin TDS Oxytrol one patch twice site. weekly Apply to clean and dry, intact skin on Oxybutynin gel One sachet (100mg) Gelnique abdomen, thighs or upper arms/shoulder; 10% topically daily contains alcohol 1mg twice daily if patient is Tolterodine tartrate taking CYP3A4 inhibitors, Detrol 1-2mg twice daily IR or in patients with renal/ hepatic impairment 2mg once daily in those who are taking CYP Tolterodine tartrate Swallow whole; avoid in patients with CrCl Detrol LA 2-4mg once daily 3A4inhibitors, or in LA < 10ml/min patients with renal/hepatic impairment 20mg once daily in Take 1 hour before meals or on an empty Trospium chloride Sanctura 20mg twice daily patients > 75 years or CrCl stomach; patients >75 years should take at IR 75 Take 1 hour before meals or on an empty Sanctura XR 60mg once daily ER years or CrCl