Pharm of Overactive Bladder: Sweatman

Question 1

Describe neuronal connections to the urinary bladder, including receptor sub-types, and explain the storage and voiding reflexes.

Answer 1

PSNS—> ACh—> M3 muscarinic receptors on bladder–> bladder contraction —> voluntary micturition “urination”
PSNS—> ATP (excites bladder SM) + NO (relaxes urethral SM)—> voluntary micturition

SNS—> norepinephrine (NE) —> B3 adrenergic receptors —> relaxes bladder SM (no micturition)
SNS—> NE —> a1 adrenergic receptors—> urethral SM contraction (no micturition)

Somatic NS–> ACh —> contraction of external urethral sphincter striated muscle (no micturition)

Receptor subtypes:
SNS: B3- detrusor relaxation 
PSNS:
M2 in bladder- opposes B3 (SNS effect)
M3 in bladder- direct effect to increase contraction of detrusor

Question 2

Recall the types of incontinence for which antimuscarinics and alpha-agonists are indicated and the rationale for cholinomimetic drugs.

Answer 2

Indicated for urge (detrusor over-activity) - antimuscarinics (relaxation of detrusor)
Outlet incompetence- a-agonists (contraction of urethral SM)

Rationale for cholinomimetics:
Bethanechol and neostigmine are given to treat bladder tone insufficiency (can’t empty bladder).
Also used to treat opiate induced bladder insufficiency.
Beth- muscarinic agonist
Neo- AChEsterase antagonist

Question 3

Comparatively evaluate the mechanism of action, central vs. peripheral actions and the adverse effects of the alpha-agonists and anticholinergic drugs.

Answer 3

MOA of a- agonists —> urethral SM contraction —I urine flow

MOA of anticholinergics—I M2/M3 PSNS activity —I bladder contraction
Peripheral effects: (all anti PSNS effects) dry mouth, myadriasis, constipation, urinary retention, tachycardia
Central effects:
Sedation, confusion/delirium, hallucinations, slowed cognitive fxn, sleep disruption. (can’t relax)

Question 4

Explain the contraindications to use of antimuscarinic drugs in the setting of overactive bladder.

Answer 4

Glaucoma, Urinary/GI obstruction (gotta get that shit moving), need for mental alertness, Alzheimer’s type dementia (worsen existing cholinergic deficit)

Question 5

Describe the patient profile most likely to respond to botox to treat overactive bladder.

Answer 5

Pts who responded to anticholinergic drugs but could not tolerate the AEs. Botox injected into the urothelial wall.
Botox MOA: inhibits vesicular release of excitatory neurotransmitters thought to cause detrusor overactivity.

Question 6

Discuss the clinical utility of methionine and collagen injection for treatment of overactive bladder.

Answer 6

Methionine reduces odor associated with leaked urine. (ancillary effect) - creates ammonia-free urine by acidifying pH

Collagen injections “bulk up” the tissues at the sphincters and urethra to help w/ incontinence by creating a mass effect to block flow.

Question 7

Explain opiate-induced urinary retention and how it is treated.

Answer 7

Mediated by mu and delta receptors in sacral cord inhibiting PSNS outflow —I detrusor activation.

Cholinomimetics- Bethanechol

Question 8

List the anticholinergic drugs and something special about each.
What are the benefits of extended release (ER) drugs?

Answer 8

::Oxybutinin and tolterodine have a 2 hr half-life. Fast acting.
::Trospium does not cross BBB, so will not have central effects comparable to those that do (good thing)
::Solifenacin- good oral bioavailability (90%). Lowest r/o dry mouth.
::Fesoterodine- least withdrawal symptoms

Extended release efficacy:
ER admin. reduces r/o dry mouth w/o any apparent loss of efficacy.