RX 517: Exam 3

Urinary Incontinence

Involuntary leakage of urine-inability to experience normal micturition

Urinary Incontinence: Epidemiology

- Peak at the age of menopause for females

- Less common in males, no specific peak

Urinary Incontinence: Risk Factors

- Causative disease states

- Pregnancy and childbirth

- Medications

Urinary Incontinence: Diagnosis

- Neurological exam

- Urinalysis

- Urine culture

- Digital rectal exam (DRE)

Types of incontinence

- Overactive bladder (OAB) or Urge (UUI)

- Stress (SUI)

- Overflow

- Functional

- Mixed

Overactive bladder (OAB) or Urge Urinary Incontinence (UUI)

- Bladder overactivity

- Urgency, frequency, large amount of urinary leakage, sometimes unable to reach toilet, frequent nocturia, nocturnal incontinence

- Often micturition occurs >8 times a day

- Often idiopathic, also caused by neurologic disease or bladder obstruction

Stress Urinary Incontinence (SUI)

- Urethral Underactivity

- Leaking during physical activity, typically small amount of urinary leakage, able to reach toilet, rare nocturia

Stress Urinary Incontinence (SUI) Risk factors

- pregnancy

- childbirth

- menopause

- cognitive impairment

- obesity

- aging

- Men (rare): surgery or injury

Overflow Urinary Incontinence

- Urethral underactivity and/or Bladder underactivity

- Bladder leakage due to disease or medications, increased postvoid residual urine volume, straining to void, interrupted stream

- Often associated with BPH

Functional Urinary Incontinence

Difficult reaching toilet in time due to physical limitations

Mixed Urinary Incontinence

Often stress and urge, but can be any combination

Causes of Urinary Incontinence

- Drugs

- Retention

- Impaction

- Polyuria

- Delirium

- Restricted mobility

- Infection

- Prostatitis

Medications and incontinence

- Diuretics, acetylcholinesterase inhibitors

- α-Receptor antagonists

- α-Receptor agonists

- Calcium channel blockers

- Narcotic analgesics

- Sedative hypnotics

- Antipsychotic agents

- Anticholinergics

- Antidepressants, tricyclic

- Alcohol

- ACEIs

Diuretics, acetylcholinesterase inhibitors: Effect with incontinence

Polyuria resulting in urinary frequency, urgency

α-Receptor antagonists: Effect with incontinence

Urethral muscle relaxation and stress urinary incontinence

α-Receptor agonists: Effect with incontinence

Urethral muscle contraction (increased urethral closure forces) resulting in urinary retention (more common in men)

Calcium channel blockers: Effect with incontinence

Urinary retention due to reduced bladder contractility

Narcotic analgesics: Effect with incontinence

Urinary retention due to reduced bladder contractility

Sedative hypnotics: Effect with incontinence

Functional incontinence caused by delirium, immobility

Antipsychotic agents: Effect with incontinence

Anticholinergic effects resulting in reduced bladder contractility and urinary retention

Anticholinergics: Effect with incontinence

Urinary retention due to reduced bladder contractility

Antidepressants, tricyclic: Effect with incontinence

Anticholinergic effects resulting in reduced bladder contractility (urinary retention), and α-antagonist effects resulting in reduced urethral smooth muscle contraction (stress incontinence)

Alcohol: Effect with incontinence

Polyuria resulting in urinary frequency, urgency

ACEIs: Effect with incontinence

Cough as a result of ACEIs may aggravate stress urinary incontinence

Urinary Incontinence Risk factors: Modifiable

- Obesity

- Diabetes

- Recurrent UTIs

Urinary Incontinence Risk factors: Non-Modifiable

- Advancing age

- Caucasian

- Female sex

- Cognitive impairment

- Neurological disorders

Urinary Incontinence Subjective Information

- Symptoms: Nocturia, urgency, leaking during physical activity, ability to reach toilet on time, amount of leakage

- PMH/FH/SH: Parkinson's disease, Alzheimer's, spinal cord injury, BPH, OA, depression, constipation, pregnancy, DM

- Side effects: diuretics, caffeine, narcotics, antipsychotics, anticholinergics, alcohol, TCAs

Urinary Incontinence Objective Information

- Physical exam: abdominal exam for distended bladder, digital rectal exam, neurologic exam

- Post void residuals

Urinary Incontinence Goals of Therapy

-Decrease symptom burden

--- Incontinence

--- Urgency

--- Frequency

--- Nocturia

- Increased QOL

- Dryness or less use of diapers or pads

- ADL improvement

- Prevent need for surgery

- Lower risk of falls/adverse events from frequent bathroom usage

OAB treatment

Antimuscarinic Agents

Overactive Bladder (OAB) Pathophysiology

Involuntary contractions of the detrusor muscle

Two receptors on detrusor muscle

- Beta-adrenergic (SNS)

- Muscarinic receptors (PNS):

--- M1: CNS, GI tract salivary glands

--- M2: bladder, CNS, GI tract, heart

--- M3: bladder, eye, GI tract, salivary glands

Anti-muscarinics MOA

suppress involuntary bladder contractions by blocking muscarinic M3 receptor activity in the bladder

Anti-muscarinic Medications used in OAB

- Oxybutynin

- Tolterodine

- Fesoterodine

- Trospium

- Darifenacin

- Solifenacin

Oxybutynin M receptor(s)

M1, M2, M3

Tolterodine M receptor(s)

M1, M2, M3

Fesoterodine M receptor(s)

M1, M2, M3

Trospium M receptor(s)

M1, M2, M3

Darifenacin M receptor(s)

M3

Solifenacin M receptor(s)

M3

Oxybutynin Dosage forms

- IR tablet

- syrup

- ER tablet

- transdermal patch

- 10% gel

Oxybutynin IR vs XL vs TDS vs gel: IR

substantial nonurinary antimuscarinic effects

Oxybutynin IR vs XL vs TDS vs gel: XL

- reduced first-pass metabolism.

- lower concentration of active metabolite, N-desethyloxybutynin (associated with dry mouth as a side effect)

- XL was better tolerated than oxybutynin IR, and at least as effective as tolterodine IR or long acting (LA) in managing urinary symptoms

Oxybutynin IR vs XL vs TDS vs gel: Transdermal (TDS)

similar efficacy as oxybutynin IR or tolterodine LA bypasses first-pass hepatic and gut metabolism and is more tolerable (anticholinergic side effects <10%).

Oxybutynin IR vs XL vs TDS vs gel: Gel

less dry mouth than oral oxybutynin

Patient education: Oxybutynin gel instructions

- Wash hands after use

- Cover with clothing after gel has dried to reduce transfer to others

- Do not bathe, shower or swim 1 hour after administration

- Do not apply to recently shaved skin

- Rotate sites

Patient education: Oxybutynin patch

- Rotate sites and avoid same site within 7 days

- Do not expose patch to sunlight

Anti-muscarinic Medications Dosing Adjustments: Renal

- Tolterodine

- Fesoterodine

- Trospium

Anti-muscarinic Medications Dosing Adjustments: Hepatic

- Tolterodine

- Darifenacin

Oxybutynin patch and gel: Side effects

- Anti-SLUDGe ++

- CNS effects ++++

- CV +

- Application site reactions

Trospium: Side effects

- Anti-SLUDGe ++++

- CNS effects ++

- CV +

Darifenacin, Solifenacin: Side effects

- Anti-SLUDGe ++++

- CNS effects ++

- CV +

Oxybutynin, Tolterodine, Fesoterodine: Side effects

- Anti-SLUDGe ++++

- CNS effects ++++

- CV ++

Anti-muscarinic Medication specific pearls: Tolterodine IR and LA (Detrol)

Can cause QT prolongation

Anti-muscarinic Medication specific pearls: Trospium IR (Sancturna)

Taken on an empty stomach (1 hour before or 2 hours after meals) as food decreases the bioavailability by up to 60

Anti-muscarinic Medication specific pearls: Solifenacin (Vesicare)

Prolonged corrected QT intervals have been reported with high-dose solifenacin

Anti-muscarinic Medication specific pearls: Darifenacin ER (Enablex)

Do not crush or chew

Anti-muscarinic Medication specific pearls: Fesoterodine ER

Prodrug of tolterodine

Anti-muscarinic Medication Drug interactions: CYP3A4 and 2D6 substrates

- Both: Tolterodine, Fesoterodine, Darifenacin, Solifenacin

- 3A4 only: Oxybutynin

- Neither: Trospium

Anti-muscarinic Medication Contraindications

- Narrow-angle glaucoma

- Urinary retention

- Severely decreased GI motility

β3-adrenergic receptor agonists MOA

agonism at β3 receptor leads to smooth muscle relaxation of detrusor

β3-adrenergic receptor agonists medications

- Vibegron (Gemtesa)

- Mirabegron (Myrbetriq)

β3-adrenergic receptor agonists Side effects (class effects)

headache, nasal congestion

Mirabegron side effects

Cardiovascular effects

--- Hypertension (10%)

--- Tachycardia (2%) and palpitations (1%)

Vibegron Drug interactions

3A4 substrate (minor)

Mirabegron Drug interactions

CYP2D6 inhibitor (moderate)

Mirabegron should be avoided in what?

Avoid in pregnancy or breastfeeding

β3-adrenergic receptor agonists Cannot be...

crushed (ER tablet)

OAB Treatment algorithm

- All pharmacotherapy is second line treatment per guidelines

- Consider after 4-6 weeks of non-pharmacologic behavior therapies

Stress Incontinence: Treatment algorithm

- Non Pharm

- Surgery

Urge (OAB) Incontinence: Treatment algorithm

- Non Pharm

- Anti-Muscarinics

- B3 agonist

Overflow (BPH) Incontinence: Treatment algorithm

- Watchful Waiting

- Alpha Blockers

- 5-alpha reductase inhibitors

- PDE5 inhibitors

Mixed Incontinence: Treatment algorithm

- Stress + OAB

- BPH + OAB

OAB Non-pharmacologic measures

- Voiding diary

- Bladder control strategies

- Kegel exercise

- Avoiding diet triggers

OAB Pharmacologic options

1. B3-receptor agonist

2. Muscarinic antagonist

- Selective agent

- ER non-selective

- IR non-selective

- Topical

3. Combination therapy

Urinary Incontinence Non Pharmacologic Interventions: Lifestyle modifications

Smoking cessation, weight reduction, limiting bladder irritants, fluid modification

Urinary Incontinence Non Pharmacologic Interventions: Scheduling regimens

Timed voiding, habit training, prompted voiding, bladder training

Urinary Incontinence Non Pharmacologic Interventions: Pelvic floor rehabilitation

Pelvic floor exercises, vaginal weight training

Urinary Incontinence Non Pharmacologic Interventions: Incontinence devices

Alarms, pessaries, urethral insert, penile clamp, catheters

Urinary Incontinence Non Pharmacologic Interventions: Supportive interventions

Absorbent products, urinals, bedside commodes, elevated toilet seats

Urinary Incontinence Nonpharm treatment

- Timed voiding-for functional incontinence

- Bladder training-for stress, urgency, and mixed

- Kegel exercise-for stress, urgency, and mixed

- Biofeedback-for stress, urgency, and mixed

- Acupuncture-for stress, urgency, and mixed

LUTS

Lower urinary tract symptoms

Lower urinary tract symptoms (LUTS): Dynamic symptoms

increased smooth muscle tone and resistance

Lower urinary tract symptoms (LUTS): Static symptoms

direct, mechanical obstruction of the bladder

Lower urinary tract symptoms (LUTS): Irritative/Storage

- Urinary frequency

- Nocturia

- Urgency

- Incontinence

- Bladder pain

- Dysuria

Lower urinary tract symptoms (LUTS): Obstructive/Voiding

- Urinary hesitancy

- Delay in initiating micturition

- Intermittency

- Involuntary interruption of voiding

- Weak urinary stream

- Straining to void

- Sensation of incomplete emptying

- Terminal dribbling

LUTS Risk factors

- Advancing age

- Levels of endogenous testosterone and dihydrotestosterone

- Black race

- Obesity

- Diabetes

- High levels of ETOH consumption

- Physical inactivity

- Medications

LUTS Diagnosis

- Digital rectal exam: to evaluate the size and contour of the prostate

- Prostate specific antigen (PSA)

- International Prostate Symptom Score (I-PSS)

--- Self administered to determine the severity of LUTS

--- Provides a guide for therapy response

--- Assesses 7 items

- Incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia

AUA Symptom Score <= 7 Disease Severity

Mild

AUA Symptom Score 8-19 Disease Severity

Moderate

AUA Symptom Score >=20 Disease Severity

Severe

LUTS Pharmacologic therapy: Initiate treatment when one or more of the following

- I-PSS ≥ 8

- Bothersome symptoms

LUTS Pharmacologic therapy: Options

- α-adrenergic receptor antagonists

- 5 α reductase inhibitors

- Phosphodiesterase type 5 (PDE5) inhibitors

α-adrenergic receptor antagonists: Mechanism of action

- Antagonism of α-adrenergic receptors

- Causes smooth muscle relaxation

α-adrenergic receptor antagonists: Agents

- Doxazosin

- Terazosin

- Alfuzosin

- Tamsulosin

- Silodosin

α-adrenergic receptor antagonists: Uroselective agents

- Alfuzosin

- Tamsulosin

- Silodosin

α-adrenergic receptor antagonists: Dosing pearls for Doxazosin, Terazosin

Titration to target dose needed for non-selective agents

α-adrenergic receptor antagonists: Dosing pearls for Tamsulosin

increase after 2-4 weeks in patients who fail to respond

α-adrenergic receptor antagonists: Dosing pearls for Silodosin

Renal adjustment:

- CrCl30-50 ml/min: max 4 mg/day

- CrCl<30: not recommended

α-adrenergic receptor antagonists: Class side effects

- Dizziness

- Syncope

- Hypotension

- Floppy Iris

- Headache