NON SURGICAL THERAPY OF INCONTINENCE

• Overactive bladder (OAB) is defined as a symptom syndrome characterized by urgency, with or without urge incontinence, usually with frequency and nocturia.

• Other descriptors for this symptom complex are the urge syndrome or urgency–frequency syndrome.

• Patients with OAB represent a substantial proportion of patients with urinary symptomatology.

• One-third of them suffer from incontinence.

• Possible peripheral targets for pharmacologic intervention may be:

• (1) afferent neurotransmission,• (2) efferent neurotransmission, and• (3) the smooth muscle itself, including ion

channels and intracellular second messenger systems.

Muscarinic Receptors

• Acetylcholine, acting on muscarinic receptors on the detrusor, is the main contractile transmitter.

• Muscarinic receptors comprise five subtypes.The M3 receptors in the human detrusor are believed to be the most important for detrusor contraction.

The findings are in line with the clinical observations that antimuscarinics at clinically recommended doses have little effect on voiding contractions and may act mainly during the bladder storage phase, increasing bladder capacity.

A basal release of acetylcholine from non-neuronal(urothelial) as well as neuronal sources has been demonstrated in isolated human detrusor muscle and this release,which is increased by stretching the muscle and in the aging bladder, contributes to DO and OAB by eventually increasing bladder afferent activity during storage.

In turn, enhanced myogenic contractions can generate enhanced afferent activity, contributing to urgency and/or initiation of the micturition reflex.

Adrenergic receptors

• Adrenergic receptors• the detrusor smooth muscle• detrusor vasculature• afferent and efferent nerve terminals• intramural ganglia.

In the bladder,the function of the detrusor muscle is dependent on the vasculature and the perfusion.

Hypoxia induced by partial outlet obstruction is believed to play a major role in both the hypertrophic and degenerative effects of partial outlet obstruction.

β-Adrenoceptors

• In the human detrusor, it is now generally accepted that the most important β-AR for bladder relaxation is the β3-AR

• The β3-AR seems to be an interesting target for drugs aimed at treatment of DO/OAB, and selective β3-AR agonists have shown relaxant effects in Do.

Ion channels

• Calcium channels• An increase in Ca is a key process required for

the activation of contraction in the detrusor. Clinically, the use of Ca antagonists in the treatment of DO/OAB has been disappointing,and there is currently no evidence that Ca antagonists represent an effective treatment principle.

• Potassium channels• Activation or increased activity of SK3

channels seemed to result in decreased bladder sensation during filling, which can be assumed to be of benefit for treating DO/OAB.

Botulinum toxin-sensitive mechanisms

BTX is believed to act by inhibiting acetylcholine release from cholinergic nerve terminals interacting with the protein complex necessary for docking acetylcholine vesicles.

BTX injection results in decreased muscle con-tractility and muscle atrophy at the injection site.

The produced chemical denervation is a reversible process, and axons regenerate in about 3–6 months.

PHARMACOLOGIC AGENTS

• Pure anticholinergics

• Atropine/hyoscyamine• Propantheline bromide (Pro-Banthine®)• Tolterodine tartrate (Detrol®)

• Mixed action

• Oxybutynin chloride (Ditropan®)• Dicyclomine hydrochloride (Bentyl®)• Flavoxate hydrochloride (Urispas®)

Not only a potent muscarinic receptor antagonist with slight M3 and M1 selectivity,mixed action drugs has a direct antispasmodic effect on the detrusor muscle and has been identified as a surface anesthetic agent.

The choice of medication depends often on other factors such as the rate of side effects, cost, and long-term patient compliance.

Anticholinergics and the elderly

Medications are often a cause for delirium, dementia, or cognitive impairment in the elderly.

These side effects can often be attributed to an alterationin pharmacokinetics and pharmacodynamics in older patients as well as polypharmacy.

• Starting with the lowest dose is advisable, and the patient’s family needs to be aware of possible changes in cognition and be able to recognize alterations.

Tricyclic antidepressants

• Important in the action of TCAs is their ability to block reuptake of norepinephrine (NE) and serotonin (5-HT) at nerve terminals, increasing the concentration of these neurotransmitters.

• Part of the effect of TCAs has been attributed to a “local anesthetic” effect on nerves of the bladder.

• Amitriptylline• Imipramine• Duloxetine Duloxetine, has been demonstrated in

large,well-designed studies to decrease stress urinary incontinence, and it may hold promise for use in patients with mixed incontinence.

Propiverine hydrochloride

• Propiverine, a benzylic acid derivative,and antimuscarinic agent is acompound with multiple effects on the urinary bladder smooth muscle and its innervation.

• All studies consistently demonstrated that propiverine is effective in neurogenic detrusor overactivity by increasing functional bladder capacity and decreasing detrusor pressure.

Pharmacotherapy of overactive bladder in bladder outlet obstruction

Pharmacotherapy for LUTS in older men has centered on treatments whose primary aim is to reduce the severity of bladder outlet obstruction (BOO), with the intention of relieving all symptoms, regardless of whether storage or voiding symptoms predominate.

Combined therapy with alpha-blockers and anticholinergics

While there is now good evidence for both safety and efficacy in patients with LUTS suggestive of BOO, the precise place of antimuscarinics amongst the various drug treatment options remains to be defined.

Botulinum toxin (Botox®)

BTX’s mechanism of action has been traditionally described as inhibiting acetylcholine release at the presynaptic cholinergic junction.

• BTX-A treatment is a durable, yet reversible,treatment option as nerves eventually recover their original function.

• BTX-A’s beneficial effects in patients with refractory overactive bladder symptoms are probably multifactorial and may account, in part, for the slow onset and prolonged duration of action of bladder BTX-A injections compared to skeletal muscle injections.

Mixed neurogenic and idiopathic detrusor overactivity

The benefits of treatment in both patient populations included significant increases in maximal cystometric capacity and significant reductions in incontinence episodes and urinary urgency.

Impressively,60.3% of all patients achieved complete continence.

Neuromodulation

Percutaneous sacral neuromodulation

• Sacral neuromodulation is currently the most widely used technique for the treatment of voiding dysfunction.

• A multipolar electrode is placed percutaneously into the foramen of the third sacral nerve root (S3)

• Electrical stimulation of this nerve causes a reflex contraction of the levator ani, coccygeus, and external anal sphincter muscles via the pudendal nerve. This pro-duces a “bellows” response which is elicited during the implantation procedure.

Bladder contractions can be supressed by external sphincter and pelvic floor contractions,so,electrical sacral nerve stimulations cause bladder inhibition.

• Therapeutic neuromodulation is the result of direct activation of sensory nerves ,or indirectly by activation of the striated external sphincter and pelvic floor muscles leading to reflex detrusor relaxation.

Indications

• Detrusor overactivity• Female urinary retension (non obsructive)• Voiding disorders of neurological origine: M.S

and incomplete spinal cord lesions• Painful bladder disorders: IC

• Every patient considered for this technique should undergo a trial period of temporary stimulation known as percutaneous nerve evaluation (PNE).

• Only those patients who gain significant benefit from the PNE proceed to neuromodulator implantation.

Stimulation of the perineal branch of the pudendal nerve and the posterior femoral cutaneous nerve leads to a vibratory sensation in the urethra, penis, and scrotum in men, and in the labia majora and vagina in women. Stimulation of the inferior rectal nerve leads to a vibratory sensation in the rectum.

• In the case of non-obstructive urinary retention,neuromodulation most likely causes an inhibition of the guarding reflex.

• This leads to a reduction in sphincteric overactivity which reduces functional outlet resistance at the bladder neck and urethra.

• Sacral nerve root stimulation may also improve relaxation of the pelvic floor musculature, which could in turn decrease outlet resistance.

“Rebound” Phenomenon

Prolonged stimulation induces bladder inhibition and hypocontractility.

Cessation of this stimulation, modulated by the sacral nerve stimulator, results in an improve-ment in bladder wall contractility during voli-tional voiding attempts.

Results and Complications

• About 70% of the patients who received sacral neuromodulation for urge/frequency and urge incontinence became dry or showed improvement in their main incontinence symptoms.

In patients with non-obstructive urinary retention the data shows that 69% eliminated catheterisation at six month and 14% had a 50% in catheter volume per catheterisation.

• There is a group of patients whose symptoms return within the first few months after implantation.

• This picture represents CNS adaptation to the stimulus.