Sweatman - Overactive Bladder Flashcards
1
Q
Describe the efferent pathways of the lower urinary tract.
A
- 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
2
Q
Describe the urine storage reflexes.
A
- 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
3
Q
Describe the voiding reflexes.
A
- 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
4
Q
Where in the body do conscious bladder sensations and the mechs underlying switch from storage to voiding originate?
A
- These presumably involve cerebral circuits above the PAG (periaqueductal grey)
5
Q
What is the general approach to tx of urinary incontinence?
A
- 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
6
Q
Name some of the common causes or urinary incontinence and their associated txs (chart).
A
- Purpose of this is to underline the fact that incontinence can arise from a # of instigating factors, and these should guide the treatment approach
7
Q
What muscarinic receptors are where? Effects of their blockage (chart)?
A
- 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
8
Q
What are the peripheral and central effects of the anti-cholinergic drugs (chart)?
A
- 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
9
Q
What are the important pharmacologic differences between the anti-muscarinics (chart)?
A
- 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
10
Q
What are the issues with anti-muscarinics?
A
- 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
11
Q
How do you choose which anticholinergic to use?
A
- 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 > Tol: <risk>
<p>3. Feso > 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 -> insufficient data to recommend specific ER prep</p>
</risk></p>
</risk>
12
Q
What is one of the major reasons for pts coming off antimuscarinic drug?
A
Dry mouth
13
Q
When should botox be used to tx urinary incontinence? Efficacy?
A
- 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
14
Q
What are the complex effects of botox?
A
- 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
15
Q
How does the SYM work in bladder control?
A
- 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
16
Q
How is the new sympathomimetic different than the previous ones (chart)?
A
- 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
21
Q
Compare the pharmacology of the two oral drugs used to treat urinary retention (chart).
A
- 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
