Download NON SURGICAL THERAPY OF INCONTINENCE Overactive bladder

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 nonneuronal(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
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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 contractility 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 alphablockers 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 produces 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 improvement in bladder wall contractility during volitional 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.