L20 Urinary Incontinence, Urinary Flow problems, and ED

Question 1

Subtypes of Urinary Incontinence? (3)

Answer 1

Overflow Incontinence (Hypotonic Bladder):
Urethral Blockage
Bladder Unable to empty properly

Stress Incontinence (Urethral sphincter incompetence)
Relaxed pelvic floor
Increased abdominal pressure
Effects a lot of females post partum (not related to psychological stress)

Urinary Urgency Incontinence (Overactive bladder syndrome):
Bladder oversensitivity from infection
Neurologic disorders

Question 2

Innervation of the Bladder?

Answer 2

Sympathetic nerves, most of which arise from the superior and inferior hypogastric plexuses and nerves (L2-T4). Supplies fibers to detrusor muscle (inhibitory) and internal sphincter.

Parasympathetic innervation (S2-S4), from pelvic splanchnic nerves supplying fibres to detrusor muscle and sphincter (inhibitory).

Question 3

Receptor Targets for Urge Incontinence?

Answer 3

1. Cholinergic/muscarinic receptors (Tolterodine) found in smooth muscle. Stimulation with ACh leads to detrusor contraction
2. Adrenergic receptors α and β types (Mirabegron)

• Norepinephrine stimulation of α receptors leads to contraction of the urethra (α1 ANTAGONISTS bladder outflow obstruction due to postatism)
• Norepinephrine stimulation of β3 receptors leads to inhibition/relaxation of the detrusor (β AGONISTS used to treat Urge Incontinence)

Question 4

Indication/MOA/Side Effects of Muscarinic Receptor Antagonists

Answer 4

Main Drug: Tolterodine

Indication: Urge Incontinence (overactive bladder)

MOA
Cholinergic/muscarinic receptors (M-type) are found in smooth muscle (80% M2, 20% M3). Stimulation of M3 receptors with ACh causes the release of IP3 and calcium => detrusor contraction

Muscarinic receptor antagonist drugs block the receptor => prevent detrusor contraction

Anti-muscarinic side effects can include:
* Sedation, insomnia, confusion, cognitive (M1)
* Dry mouth (M3)
* Due to side effects many patients stop taking, always review after 6 months

Question 5

Muscarinic Receptor Antagonist Drugs?

Answer 5

Non-selective muscarinic antagonists
Tolterodine, Fesoterodine , Trospium
Much less lipophilicity
Reduced cognitive SIEs
Tolterodine better tolerated

More selective for M3 receptors
Solifenacin, Darifenacin
May have fewer CNS effects

Oxybutynin (Lyrinel):
Metabolised to an active metabolite in liver

Some Ca channel blocking effects also in bladder SMCs [only at v. high dose]

Some local anaesthetic-type activity [only at v. high dose]

V Lipophilic and crosses BBB

Question 6

Adrenergic β Receptor Agonists Indication/MOA/SEs?

Answer 6

Main Drug: Mirabegron

Indication: Urge Incontinence (overactive bladder)

MOA
Stimulation of β3 Receptors in the bladder by hypogastric nerve releasing ACh leads to inhibition/relaxation of the detrusor and increased bladder capacity

SEs: hypertension, headache, urinary retention

Seen as an alternative option if tolerance/efficacy a problem with muscarinic antagonists

Question 7

Most common type of urinarry incontinence in women/older
women?

How do we manage it?

Answer 7

Stress (Urethral sphincter incompetence)

Occurs when an activity, such as coughing or sneezing, causes a small amount of urine to leak from the urethra

Management
Pelvic floor exercises (Kegels) essential

Surgical options: slings, colposuspension to provide urethral support

Drug therapy: Duloxetine(Combined serotonin & noradrenaline reuptake inhibitor)

Question 8

Causes of Stress Incontinence?

Pharmacological Treatment and MOA

Answer 8

Casues
Usually due to collagen loss in the pelvic floor/ perineum

Sometimes trauma (pelvic/prostatectomy)

Treatment
Duloxetine is a combined serotonin noradrenaline reuptake inhibitor

Only ~50 patients respond

MOA
1. blocks norepinephrine/serotonin reuptake

2. Causes accumulation of neurotransmitters in the intersynaptic clefts of Onuf’s nucleus of the sacral spinal cord
3. Stimulates an increase in pudendal nerve activity and urethral skeletal muscle sphincter/pelvic floor contraction

Question 9

Incontinence due to:
Urethral Blockage
Bladder unable to empty properly

Answer 9

Overflow Incontinence (Hypotonic Bladder):

Question 10

Incontinence due to:
Relaxed pelvic floor
Increased abdominal pressure
Effects a lot of females postpartum (not related to psychological stress)

Answer 10

Stress Incontinence (Urethral sphincter incompetence)

Question 11

Incontinence due to:
Bladder oversensitivity from infection
Neurologic disorders

Answer 11

Urinary Urgency Incontinence (Overactive bladder syndrome)

Question 12

Pharmacological treatment options for Urinary flow problems (Prostatism)

Drugs/MOA/SIEs

Answer 12

Alpha-1 blockers (Tamsulosin, -osins)
Norepinephrine stimulation of α leads to contraction of the urethra

MOA: Inhibits smooth muscle cells of
prostate and bladder neck (No effect on the detrusor muscle (α receptors on urethra, β3 on bladder))

SIEs: first dose hypotension (venous
pooling)

5 alpha-reductase inhibitors (5 ARIs)

MOA: Reduce enzymatic conversion of testosterone to Dihydrotestosterone (DHT involved in prostate growth. DHT can also bind receptors in hair follicles causing them to shrink, weaken and eventually die)

Finasteride (Propecia): specific for 5α Reductase 2. (short t½: 6 hr)

Dutasteride: targets 5α Reductase 1/2 => greater prostate reduction (long t½: 4 wk)

SIEs: Reduced libido, Erectile dysfunction, Breast enlargement

Question 13

Scoring of Prostate Symptoms?

Answer 13

The international prostate symptoms score system quantifies the severity of symptoms from benign prostatic
hyperplasia.

Scores range from 0 to 35:
1-7 mild symptoms
8-19 moderate symptoms
>20 severe symptoms

Question 14

Treatment of enlarged prostate & scalp hair loss?

Answer 14

5α Reductase inhibitors (5 ARI): Propecia (Finasteride)

MOA: Reduce enzymatic conversion of testosterone to Dihydrotestosterone
(DHT involved in prostate growth. DHT can also bind receptors in hair follicles causing them to shrink, weaken and eventually die)

Question 15

Sildenafil (Viagra) MOA/Side Effects

Answer 15

MOA
Sildenafil is a PDE5 inhibitor similar in structure to cGMP

Competitively binds PDE5 and inhibits cGMP hydrolysis to inactive 5 ’GMP by PDE5 thus enhancing the effects of NO. This increase in cGMP in the smooth muscle cells is responsible for prolonging an erection

Only pharmacologically active when cGMP synthesis is activated:requires sexual arousal

SEs:
Headache, flushing, nasal congestion, dyspepsia, priapism

Cyanopsia Transient blue coloration in vision due to PDE 6 inhibition at high doses (Makes rod cells in the eye ultrasensitive)

Other Drugs
Taladafil has a v long T ½
Effects last up to 36 h

Patient preference trials have reported preference for tadalafil over sildenafil

Absorption not influenced by food whereas sildenafil/vardenafil is reduced

Question 16

Interplay of NO and PDE 5 for errection

Answer 16

Question 17

Synthetic prostaglandin E 1 (PGE 1) Indication/MOA?

Answer 17

Useful in Treating Erectile Dysfunction for patients for whom oral therapies (PDE5 Inhibitors) are contraindicated (Nitrates, recent stroke/MI, BP< 90/50)

Injection into penis or Intraurethral suppository ‘ stick’ (Muse)

Can induce erection without arousal/desire