Mediator of involuntary & volitional bladder contractions

Acetylcholine

Causes of Acute Urinary Incontinence

D Drugs, Delirium

R    Retention, Restricted mobility

I Impaction, Infection, Inflammation

P Polyuria, Prostatitis

Medications That Cause Urinary Incontinence

Diuretics
alpha-adrenergic antagonists
Opiod analgesics
Sedative Hypnotics

Anticholinergics

TCAs

Ethanol

ACEIs

Urinary effects of alpha-adrenergic antagonists

Urethral relaxation

May relieve obstruction in males

Induces/worsens stress urinary incontinence in females

Urinary effects of opiod analgesics

Impaired bladder contractility

Urinary effects of sedative hypnotics

• Cause functional urinary incontinence due to sedation & immobility

Urinary effects of Anticholinergics

May cause urinary retention

Potential to help with urge incontinence

Urinary effects of TCAs

• Combination of anticholinergic effects & alpha-blocking activities lead to unpredictable effects on urinary incontinence

Urinary effects of Ethanol

Polyuria & frequency

Functional urinary incontinence

Urinary effects of ACEIs

• May worsen stress incontinence due to adverse effect of cough

Treatment of urge incontinence

Anticholinergics/Antispasmotics are 1st line treatment

• Most effective agents to suppress premature detrusor contractions, enhance bladder storage, and overall relief of symptoms

Drugs to treat Urge Incontinence

Oxybutynin (Ditropan®), Tolterodine (Detrol®)

Solifenacin (Vesicare®), Trospium (Sanctura®), Darifenacin (Enablex®), Fesoterodine (Toviaz®)

Adverse effects for Anticholinergics/Antispasmotics

• Lack selectivity for bladder
• Systemic adverse effects: dry mouth, constipation, blurred vision, confusion tachycardia

Use of Anticholinergic for Urinary Incontinence

Oxybutynin (Ditropan®)

• Dosage: IR tablets, solution SR, XL tablets, TD patch
• Caution with CYP 450 3A4 Inhibitors

Use of anticholinergics for Urinary Incontinence

Tolterodine (Detrol®)

• Dosage: IR tablets, SR, LA capsules
• Caution with CYP 450 3A4 inhibitors, severe liver or renal impairment

Use of Anticholinergics to treat Urinary Incontinence

Trospium (Sanctura®)

• Dosage: IR tablets
• Give on empty stomach, caution with renal impairment

Use of anticholinergics for Urinary Incontinence

Solifenacin (Vesicare®)

• Dosage: IR tablets
• Caution with CYP 450 3A4 inhibitors & severe liver or renal impairment

Use of anticholinergics to treat Urinary Incontinence

Darifenacin (Enablex®)

• Dosage: ER tablets
• Caution with CYP 450 3A4 inhibitors/substrates & 2D6 substrates

Actions of Oxybutynin (Ditropan®)

Also has alpha-blockade & antihistaminic activity - orthostatic hypotension, sedation, & weight gain

Treatment considerations with Oxybutynin (Ditropan®)

• Careful dosage titration is necessary to minimize AEs
• Titrate to maximum tolerated dose & maintain maximum dose for 4 weeks for an adequate trial
• If therapeutic goals are not reached, change to another medication
• Women with mixed urinary incontinence plus atrophic vaginitis may also benefit from the addition of vaginal estrogen to anticholinergic therapy

Goals of therapy in treatment of stress incontinence

• Stimulation of alpha-adrenergic receptors in smooth neck muscle of the proximal urethra & bladder neck
• Enhancing supportive structures underlying the urethral mucosa
• Enhancing the positive effects of serotonin & norepinephrine in the afferent & efferent pathways of the micturition reflex

Nonpharmacologic Treatment of Stress Incontinence

Rehabilitation of pelvic floor muscles

Pelvic muscle exercises

Pessaries

Surgical repair

Treatment of stress incontinence using estrogen

Only used in conjunction with other symptoms of estrogen deficiency (vaginal atrophy/dryness)

Treatment of Stress Incontinence w/ α-adrenergic agonists

• Pseudoephedrine: ↑ resting urethral tone
• AEs: hypertension, headache, dry mouth, nausea, insomnia, restlessness

Treatment of Stress Incontinence with Duloxetine (Cymbalta®)

• Selective serotonin & norephinephrine reuptake inhibitor (off-label use)
• Enhanced central serotonergic & adrenergic tone which is involved in control of urethral smooth muscle & internal urinary sphincter

Treatment of Overflow Incontinence with Atonic Bladder

Trial of bethanecol (if no contraindications exist)

• Cholinomimetic effects are not urospecific - systemic AEs
• AEs: muscle & abdominal cramping, hypersalivation, diarrhea, bradycardia, & bronchospasm

Goal of Treatment of overflow incontinence

due to obstruction

Goal of treatment: remove obstruction

BPH mechanism

Enlargement of the prostate gland due to ↑ α-adrenergic tone & constriction of smooth muscles

Drugs that can cause BPH

Testosterone

α-adrenergic agonists (decongestants)

anticholinergics

Type of receptors in the stomal/smooth muscle

of the prostate

α-1 adrenergic receptors

Type of receptors in the

capsule of the prostate

α-1 adrenergic receptors

Nonpharmacologic Treatment of BPH

• Watchful waiting & behavioral modifications - for mild disease (if symptoms are not too disruptive)
• ↓ fluid intake near bedtime, avoid caffeine, alcohol, & meds that may worsen symptoms

• Surgical treatment

Action of 5α-reductase inhibitors for BPH

• Interference with stimulatory effect of testosterone (on prostate gland enlargement)
• Slow progression & ↓ risk of complications
• Reduce serum PSA levels by 50%
• Pregnancy category X
• Relaxes prostatic smooth muscle

Actions of α-adrenergic antagonists in BPH treatment

• Interference with stimulatory effect of testosterone (on prostate gland enlargement)
• Relax smooth muscle in prostate gland & bladder neck, ↓ post-void volumes
• Do not decrease prostate volume or PSA levels

Action of 5α-Reductase on Prostate

• 5α-reductase (prostatic conversion of testosterone to dihydrotestosterone)
• Dihydrotestosterone is the active androgen which stimulates prostate growth; induces apoptosis of prostatic epithelial cells

MoA of 5α-Reductase Inhibitors

• Prevents conversion of testosterone to dihydrotesosterone, which would stimulate prostate growth
• SLOW onset of action - 6 months to get full effect

Adverse effects of 5α-reductase inhibitors

↓ Libido

Erectile dysfunction

Ejaculation disorders

Gynecomastia

Breast tenderness

Pregnancy category X

Characteristics of Finasteride (Proscar®)

Selective type II 5α-reductase inhibitor

Characteristics of Dutasteride (Avodart®)

Nonselective (type I & II) 5α-reductase inhibitor

MoA & onset of α-adrenergic antagonists

• Antagonize α-adrenergic receptors

• Causes relaxation of the bladder neck, prostatic urethra, & prostate smooth muscle

• Onset in days to weeks (at least 2 weeks for adequate trial of medication)

Adverse Effects of α-adrenergic antagonists

Hypotension

Syncope

Rhinitis

Malaise

Ejaculation disorders (dose-dependent)

Drug interactions with α-adrenergic antagonists

Additive BP lowering effects with antihypertensives, diuretics or phosphodiesterase inhibitors

(Allow at least 4 hours between α-antagonists & PDE)

Choosing best drug of α-adrenergic antagonists

• All are considered equally efficacious for the treatment of BPH symptoms

Dosage of α-adrenergic antagonists

Titration of dosing should be considered to minimize AEs associated with hypotension (esp. with IR dosage forms)

Tamulosin doesn't have to be titrated

First dose should be given at bedtime (1st dose effect)

1st generation α-adrenergic antagonists

• Typically aren't used due to AEs
• Block presynaptic & postsynaptic receptors
• Postsynaptic blockade - beneficial for BPH Sx
• Presynaptic blockade causes more AEs
• (Release of catecholamines & tachycardia)

Drug example(s) of 1st generation 

α-adrenergic antagonists

Phenoxybenzamine

Action of 2nd Generation α-Adrenergic Antagonists

Selectively block postsynaptic receptors (less AEs)

Drug example(s) of 2nd Generation 

α-Adrenergic Antagonists

Terazosin (Hytrin®)

Doxazosin (Cardura®)

Alfuzosin (Uroxatral®)

Prazosin (Minipress®)

Action of 3rd Generation α-Adrenergic Antagonists

Selectively block postsynaptic αA1 Receptors

Less potential to cause hypotension

Drug example(s) of 3rd generation 

α-Adrenergic Antagonists

Tamulosin (Flomax®)

*Doesn't require dosage titration

Dosage form & other info for Terazosin (Hytrin®)

Taken QHS

Not uroselective

Requires titration

Most common AE: CV

Dosage forms & other info for Doxazosin (Cardura®)

Taken QHS (IR) or QDay (ER)

Not uroselective

IR - requires titration

Most common AE: CV

Dosage form & other info for Alfuzosin (Uroxatral®)

Take after meal for best absorption

Uroselective

ER form requires no titration

Dosage form & other info for Tamulosin (Flomax®)

Taken QDay

Uroselective

Modified release - no titration

Most common AE: ejaculation disorders

Least likely to cause CV AEs