Sweatman - Overactive Bladder

Question 1

Describe the efferent pathways of the lower urinary tract.

Answer 1

• PARA: post-gang axons in pelvic N release Ach, producing bladder contraction via M3 in smooth m
  1. Post-gang NN also release ATP, exciting bladder sm m, and NO, relaxing urethral sm m
• SYM: post-gang neurons release NE, activating B3 adrenergic receptors to relax bladder sm m, and alpha-1 receptors to contract urethral smooth m
• SOMATIC: pudendal N axons release Ach, causing contraction of external sphincter striated muscle by activating nicotinic cholinergic receptors

Question 2

Describe the urine storage reflexes.

Answer 2

• Storage: distention of bladder produces low-level vesical afferent firing -> stimulates SYM outflow in hypogastric N to bladder outlet (bladder base and urethra) AND pudendal outflow to external urethral sphincter
• Spinal reflex pathways (guarding reflexes) promote continence
• SYM firing also INH contraction of detrusor m and modulates neurotransmission in bladder ganglia
• Region in the rostral pons (pontine storage center) may INC striated urethral sphincter activity

Question 3

Describe the voiding reflexes.

Answer 3

• Elim of urine: intense bladder-afferent firing in pelvic N activates bulbospinal reflex pathways that pass through pontine micturition center
• Stimulates PARA outflow to bladder and urethral sm m, and INH SYM and pudendal outflow to urethral outlet
• Ascending afferent input from spinal cord may pass through relay neurons in periaqueductal grey (PAG) before reaching pontine micturition center

Question 4

Where in the body do conscious bladder sensations and the mechs underlying switch from storage to voiding originate?

Answer 4

• These presumably involve cerebral circuits above the PAG (periaqueductal grey)

Question 5

What is the general approach to tx of urinary incontinence?

Answer 5

• Begin with noninvasive approaches: behavioral tx, incl pt education, fluid mgmt, bladder retaining, pelvic floor exercises, biofeedback, timed bladder emptying -> pts need to be cognitively intact
  1. Sx procedures, catheterization appropriate for some pts
• Add pharmacotherapy when behavioral mods fail: anti-muscarinic meds (Tolterodine and Oxybutynin) most commonly prescribed drugs
• Reluctance in nursing home use due to lack of efficacy data: often severe cognitive impairment, and risk of drug-drug interactions

Question 6

Name some of the common causes or urinary incontinence and their associated txs (chart).

Answer 6

• Purpose of this is to underline the fact that incontinence can arise from a # of instigating factors, and these should guide the treatment approach

Question 7

What muscarinic receptors are where? Effects of their blockage (chart)?

Answer 7

• M2 and M3 receptor subfamilies in the bladder
• M2 opposes the beta adrenergic receptor, an indirect effect
• M3 has a direct effect in contracting the smooth muscle of the urinary bladder

Question 8

What are the peripheral and central effects of the anti-cholinergic drugs (chart)?

Answer 8

• Diverse distribution of muscarinic receptors in the body means that therapeutic intent in one organ usually gives rise to AE’s elsewhere
• Degree of discomfort with these AE’s is often the limiting factor in the drugs’ clinical applicability

Question 9

What are the important pharmacologic differences between the anti-muscarinics (chart)?

Answer 9

• STRUCTURE: Trospium is a quaternary amine, so it does NOT cross the BBB, so central AE’s should be lower than with the others (also should be taken on empty stomach)
• SELECTIVITY: Darifenacin has >M3 selectivity, but NO clinical significance
• ORAL MEDS: hepatic metabolism to inactive products (except Trospium; only one with NO CYP metabolism)
• HALF-LIVES: vary from short to long -> Oxybutynin and Tolterodine are available in extended release (ER) formats to counter their otherwise short duration of clinical effect
  1. Solifenacin has longest half-life and greatest bioavailability
• NOTE: Fesoterodine rapidly hydrolyzed and parental drug not detectable in systemic circulation

Question 10

What are the issues with anti-muscarinics?

Answer 10

• Elderly pts may be taking many anticholinergics
• Monitor for AE’s: urinary retention, esp. with BPH
  1. CV effects may incl palpitations, tachy, and prolonged QT interval
  2. GI effects: mild constipation to severe obstructions -> alters absorption of concurrent oral drugs
• Contraindications: angle closure or narrow-angle glaucoma
  1. Urinary and gastric obstruction
  2. Need for mental alertness
  3. Alzheimer’s type dementia: worsen already existing cholinergic deficit

Question 11

How do you choose which anticholinergic to use?

Answer 11

• Try a couple of these agents in your pts to see which one best balances outcome and adversity
  1. Oxy = Tol (both immediate release oral): Tol has <risk></risk>

<p>2. Sol &gt; Tol: <risk>

<p>3. Feso &gt; Tol (ER): fewer withdrawals with Tol </p>

<p>4. <u>ER delivery DEC risk of dry mouth</u> w/o any apparent loss of efficacy -&gt; insufficient data to recommend specific ER prep</p>
</risk></p>

</risk>

Question 12

What is one of the major reasons for pts coming off antimuscarinic drug?

Answer 12

Dry mouth

Question 13

When should botox be used to tx urinary incontinence? Efficacy?

Answer 13

• Pts intolerant to muscarinic antagonists and their AE’s as opposed to those pts who were unresponsive to them
• Delivered by carefully placed injections into urothelial wall: effective in significant portion of pts, and the benefit lasts for several months

Question 14

What are the complex effects of botox?

Answer 14

• INH vesicular release of excitatory neuro-transmitters and axonal expression of other SNARE-complex-dependent proteins in urothelium and suburothelium mediating intrinsic or spinal reflexes thought to cause detrusor overactivity -> INH afferent cholinergic impulses
• Immediate effect is peripheral afferent desensitization
• Changes phenotype of suburothelial myofibros (integrating stretch receptors): INH of expression of purinergic and proposed SP receptors -> ablates excitatory effect of local chemical mediators that signal via the cholinergic system to make the bladder hyper-responsive
• Blocks proposed excitatory effect on suburothelial afferent and detrusor PARA nerve endings during urine storage

Question 15

How does the SYM work in bladder control?

Answer 15

• SYM postganglionic neurons release NE
• Activates beta-3 adrenergic receptors to relax bladder smooth muscle
• Activates alpha-1 adrenergic receptors to contract urethral smooth muscle

Question 16

How is the new sympathomimetic different than the previous ones (chart)?

Answer 16

• They differ in their receptor specificity and metabolic fate
• Mirabegron: long-acting, and undergoes extensive hepatic metab (CYP3A4) w/little recovery of parent drug in urine; beta-3 agonist
  1. Low oral bioavailability, and DEC by food
• Other two: minimally broken down, and elim is accelerated in presence of acidic urine; shorter duration of action

Question 17

What are the issues with the 3 sympathomimetics?

Answer 17

• MIRABEGRON: INC BP (monitoring recommended, esp. in hypertensives), tachycardia
• PSEUDOEPHEDRINE: HTN, tachyarrhythmia, A-fib, insomnia, anxiety, nervousness, restlessness
• EPHEDRA: HTN, tachyarrhythmia, CHF, MI, insomnia, symptoms of CNS stimulation
• MAOI interaction -> check pt drug history

Question 18

Methionine MOA, use, AE’s

Answer 18

• Creates ammonia-free urine by acidifying urine pH
• Controls odor, dermatitis, and ulceration in incontinent adults; adjunctive agent in tx of urinary incontinence
• Take with food, milk, or other liquid (oral)
• Most common AE’s: drowsiness, N/V

Question 19

Bovine collagen use, admin, MOA, AE’s

Answer 19

• Sterile, highly purified dermal collagen for incontinence due to sphincter deficiency
• Injected into submucosal tissue of urethra and/or bladder neck -> forms soft, cohesive network of fibers INC tissue bulk around urethral lumen
• For pts failing other therapies for >12 mos
• Interactions: immunosuppressive tx, corticosteroids
• AE’s: urinary retention, hematuria, injection site rxn, worsening incontinence, erythema, urticaria, abscess formation

Question 20

How is urinary retention assessed? Managed?

Answer 20

• Assessment of post-void residual urine volume an important part of pt assessment (one reason for high bladder volumes would be poor bladder emptying)
• Strengthening of cholinergic-mediated detrusor muscle contraction is a tx option

Question 21

Compare the pharmacology of the two oral drugs used to treat urinary retention (chart).

Answer 21

• Bethanechol: direct muscarinic agonist
• Neostigmine: acetylcholinesterase inhibitor, so augments action of Ach at muscarinic AND nicotinic receptors
• Both need to be administered several times daily due to short half-lives
• Both also have poor bioavailability

Question 22

What are the issues with Bethanecol?

Answer 22

• CV: lightheadedness, syncope
• GI: diarrhea, stomach cramps
• Neuro: dizziness
• Opthalmic: excessive tear production, miosis
• Renal: urgent desire to urinate

Question 23

What are the issues with Neostigmine?

Answer 23

• AV block, brady-arrhythmia
• Cardiac arrest, cardiac dysrhythmia
• Hypotension, syncope
• Tachycardia

Question 24

How can opiates affect the bladder? Tx?

Answer 24

• May cause urinary retention: oral <5%, epidural or intrathecal <=70% (central effect -> CNS)
• Mediated by mu/delta receptors in sacral cord, INH PARA outflow and detrusor activation -> not seen with intraventricular drug (spinal mechanism)
• Detrusor relaxation readily reversed with opiate antagonists, although reversal of analgesia also likely
• Cholinomimetic agents like Bethanechol may be helpful to tx this retention