Bladder neurogenic- management- medical

The medical management of
Neurogenic bladder.
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

Moderators:
Professors:
• Prof. Dr. G. Sivasankar, M.S., M.Ch.,
• Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
• Dr. J. Sivabalan, M.S., M.Ch.,
• Dr. R. Bhargavi, M.S., M.Ch.,
• Dr. S. Raju, M.S., M.Ch.,
• Dr. K. Muthurathinam, M.S., M.Ch.,
• Dr. D. Tamilselvan, M.S., M.Ch.,
• Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

• PHARMACOLOGIC THERAPY TO FACILITATE
BLADDER FILLING AND URINE STORAGE
• Behavioral and Pelvic Floor Therapy,
• Urethral and Pelvic Devices
• Electrical Stimulation
3
Dept of Urology, GRH and KMC, Chennai.

PHARMACOLOGIC THERAPY TO FACILITATE
BLADDER FILLING AND URINE STORAGE
• Inhibiting Bladder Contractility,
• Decreasing Sensory Input,
• Increasing Bladder Capacity
4

International Consultation on Incontinence
Assessments, 2004: Oxford Guidelines
(modified
Levels of Evidence Grades of Recommendation
Level 1: Systematic reviews, meta-
analyses, good-quality randomized
controlled clinical trials
Level 2: Randomized controlled
clinical trials, good-quality
prospective cohort studies
Level 3: Case-control studies, case
series
Level 4: Expert opinion
Grade A: Based on level 1 evidence
(highly recommended)
Grade B: Consistent level 2 or 3
evidence (recommended)
Grade C: Level 4 studies or “majority
evidence” (optional)
Grade D: Evidence inconsistent or
inconclusive (no recommendation
possible)
5

Drugs Used in the Treatment of
Detrusor Overactivity
• Antimuscarinic Drugs
• Drugs with Mixed Actions
• α Adrenoceptor Antagonists
• β Adrenoceptor Antagonists
• Cyclooxygenase Inhibitors
• Other Drugs
6

Drugs Used in the Treatment of Detrusor
Overactivity (assessments according to the
Oxford system, modified)
Level of Evidence Grade of Recommendation
Antimuscarinic Drugs
Tolterodine 1 A
Trospium 1 A
Solifenacin 1 A
Darifenacin 1 A
Propantheline 2 B
Atropine, hyoscyamine 3 C
7

• Antimuscarinic (Anticholinergic) Agents—Specific Drugs
• Antimuscarinics selectively block muscarinic receptors,
and they are currently the mainstay of treatment of
OAB-DO.
• The drugs act by blocking the muscarinic receptors on
the detrusor muscle that are stimulated by
acetylcholine, released from activated cholinergic
(parasympathetic) nerves.
• They decrease the ability of the bladder to contract
• Antimuscarinic drugs act mainly during the storage
phase, decreasing urgency and increasing bladder
capacity, and
• Normally no parasympathetic input to the lower
urinary tract
8

• Antimuscarinics are usually competitive
antagonists.
• When there is a massive release of
acetylcholine, as during micturition, the
effects of the drugs should be decreased;
• Otherwise, the reduced ability of the detrusor
to contract would eventually lead to urinary
retention.
9

• During the storage phase,
• Acetylcholine may be released from both
neuronal and non-neuronal sources (e.g., the
urothelium-suburothelium) and directly or
indirectly (by increasing detrusor smooth muscle
tone) excite afferent nerves in the suburothelium
and within the detrusor.
• This mechanism may be important in the
pathophysiologic process of overactive bladder
and a possible target for antimuscarinic drugs
10

Antimuscarinics can be divided into
tertiary and quaternary amines
• Tertiary amines
• Atropine, hyoscyamine
• Tolterodine
• Oxybutynin
• propiverin
• Solifenacin
• Darifenacin
• Quaternary amines
• Propantheline
• Trospium
11

• Tertiary amines
• Well absorbed
• High lipophilicity
• Small molecular size
• Less molecular charge
• Increase in passing BBB
• Quarternary amines
• Not well absorbed
• Low lipophilicity
• Large molecular size
• Pass into CNS to a
limited extent
12

Atropine
• Atropine (dl-hyoscyamine) is rarely used for
treatment of OAB-DO because of its systemic
side effects
• In patients with neurogenic DO, intravesical
atropine may be effective for increasing
bladder capacity without causing any systemic
adverse effects
• The pharmacologically active antimuscarinic
moiety of atropine is l-hyoscyamine.
13

Propantheline
• Propantheline bromide is a quaternary ammonium
compound,
• nonselective for muscarinic receptor subtypes
• a low (5% to 10%) and individually varying biologic
availability.
• It is metabolized (metabolites inactive) and
• has a short plasma half-life (less than 2 hours)
• It is usually given in a dose of 15 to 30 mg four times daily
• propantheline 15 mg three times daily, and placebo in a
randomized, double-blind, multicenter trial on the treatment
of frequency, urgency, and incontinence related to DO (154
patients),
• no differences between the placebo and propantheline
groups 14

Trospium
• Trospium chloride is a quaternary ammonium
• a biologic availability of less than 10%
• It is expected to cross the blood-brain barrier to a
limited extent
• no negative cognitive effects
• The drug has a plasma half-life of approximately 20
hours
• 60% of the dose absorbed eliminated unchanged in the
urine by renal tubular secretion.
• It is not metabolized by the cytochrome P-450 enzyme
system
• Trospium has no selectivity for muscarinic receptor
subtypes
15

• patients with neurogenic DO the drug was given
twice daily in a dose of 20 mg during a 3-week
period.
• It increased maximum cystometric capacity,
• decreased maximal detrusor pressure, and
• increased compliance in the treatment group,
• whereas no effects were noted in the placebo
group.
• Side effects were few
16

• In UI
• significant increases were found in volume at
first unstable contraction and in maximum
bladder capacity in the trospium-treated
group.
• Trospium was well tolerated
17

• Zinner and colleagues (2004a) treated 523 patients
with symptoms associated with OAB and urgency
incontinence with 20 mg trospium twice daily or
placebo in a 12-week, multicenter, parallel, double-
blind, placebo-controlled trial.
• Dual primary endpoints were change in average
number of toilet voids and change in urgency
incontinent episodes per 24 hours.
• Secondary efficacy variables were change in average
of volume per void, voiding urgency severity,
urinations during day and night, time to onset of
action, and change in Incontinence Impact
Questionnaire score. 18

• Trospium significantly decreased average frequency of
toilet voids and urgency incontinent episodes
compared with placebo.
• It significantly increased average volume per void and
decreased average urgency severity and daytime
frequency.
• All effects occurred by week 1, and all were sustained
throughout the study.
• Nocturnal frequency decreased significantly by week 4,
and Incontinence Impact Questionnaire scores
improved at week 12.
• Trospium was well tolerated.
• The most common side effects were dry mouth
(21.8%), constipation (9.5%), and headache (6.5%). 19

Tolterodine
• Tolterodine is a tertiary amine, rapidly
absorbed and extensively metabolized by the
cytochrome P-450 system (CYP2D6).
• The major active 5-hydroxymethyl metabolite
has a pharmacologic profile similar to that of
the mother compound
• plasma half-life of both tolterodine and its
metabolite is 2 to 3 hours
20

• The relatively low lipophilicity of tolterodine implies
limited propensity to penetrate into the CNS,
• a low incidence of cognitive side effects
• Tolterodine has no selectivity for muscarinic
receptor subtypes but is claimed to have functional
selectivity for the bladder over the salivary glands
• In healthy volunteers, orally given tolterodine in a
large dose (6.4 mg) had a powerful inhibitory effect
on micturition and also reduced stimulated
salivation 1 hour after administration of the drug
21

• However, 5 hours after administration, the effects
on the urinary bladder were maintained, whereas
no significant effects on salivation could be
demonstrated.
• Tolterodine is available as both an immediate-
release form (1 or 2 mg, twice daily dosing) and an
extended-release form (2 or 4 mg, once daily
dosing).
• The extended-release form seems to have
advantages over the immediate-release form in
terms of both efficacy and tolerability
22

• Several randomized, double-blind, placebo-
controlled studies of patients with OAB-DO (both
idiopathic and neurogenic DO) have documented a
significant reduction in micturition frequency and
number of incontinence episodes
• Comparative RCTs, such as the OBJECT (Overactive
Bladder: Judging Effective Control and Treatment)
and the OPERA (Overactive Bladder: Performance of
Extended Release Agents) studies, have further
supported its effectiveness.
• It is well tolerated and is currently, together with
oxybutynin, first-line therapy for patients with this
disorder.
23

Darifenacin
• Darifenacin is a tertiary amine with moderate
lipophilicity,
• well absorbed from the gastrointestinal tract after
oral administration and
• extensively metabolized in the liver by the
cytochrome P-450 isoforms CYP3A4 and CYP2D6.
• Darifenacin has been developed as a controlled-
release formulation, which allows once-daily dosing.
Recommended doses are 7.5 and 15 mg/day.
• Darifenacin is a relatively selective muscarinic M3
receptor antagonist 24

• The clinical efficacy and adverse effects of a drug are
dependent
• Darifenacin 7.5 mg and 15 mg had a rapid onset of effect,
• Darifenacin 7.5 mg and 15 mg, superior for improvements in
micturition frequency, bladder capacity, frequency of urgency,
severity of urgency, and number of incontinence episodes
leading to a change in clothing or pads
• The most common adverse events were mild to moderate dry
mouth and constipation, with a CNS and cardiac safety profile
• Darifenacin was well tolerated, the most common adverse
events being mild to moderate dry mouth and constipation
• Darifenacin has a well-documented effect in OAB-DO, and the
adverse event profile seems acceptable.
25

Solifenacin
• Solifenacin (YM905) is a tertiary amine,
• well absorbed from the gastrointestinal tract
(absolute bioavailability of 90%).
• It undergoes significant hepatic metabolism
involving the cytochrome P-450 enzyme
system (CYP3A4).
• The mean terminal half-life is approximately
50 hours
26

• Solifenacin, with a flexible dosing regimen, showed
greater efficacy than tolterodine in decreasing urgency
episodes, incontinence, urge incontinence, and pad use
and increasing the volume voided per micturition.
• More solifenacin-treated patients became continent &
improvements in perception of bladder condition
assessments.
• The majority of side effects were mild to moderate in
nature,
• solifenacin, with a flexible dosing regimen, was superior
to tolterodine ER
• Solifenacin has a well-documented effect in OAB-DO,
and the adverse event profile seems acceptable.
27

Calcium antagonists
• Available information does not suggest that
systemic therapy with calcium antagonists,
blocking L-type Ca2+ channels, is an effective
way to treat OAB-DO.
28

Potassium channel openers
• At present, there is no evidence from RCTs to
suggest that K+ channel openers represent a
treatment alternative.
29

Drugs with Mixed Actions
Oxybutynin 1 A
Propiverine 1 A
Dicyclomine 3 C
Flavoxate 2 D
Antidepressants
Imipramine 3 C
30

Drugs with Mixed Actions
• A more or less pronounced antimuscarinic effect
and,
• an often poorly defined “direct” action on bladder
muscle.
• The antimuscarinic effects can be demonstrated at
much lower drug concentrations which may involve
blockade of voltage-operated Ca2+ channels.
• The clinical effects of these drugs can be explained
mainly by an antimuscarinic action.
31

Oxybutynin.
• Oxybutynin is a tertiary amine
• well absorbed and undergoes extensive upper
gastrointestinal and
• first-pass hepatic metabolism via the cytochrome P-
450 system (CYP3A4) into multiple metabolites.
• The primary metabolite, N-desethyloxybutynin
(DEO), has pharmacologic properties similar to
those of the parent compound
• major cause of the troublesome side effect of dry
mouth
32

• It has both an antimuscarinic and a direct muscle
relaxant effect and,
• in addition, local anesthetic actions.
• The anesthetic effect may be of importance when the
drug is administered intravesically but probably plays
no role when it is given orally.
• In vitro, oxybutynin was 500 times weaker as a smooth
muscle relaxant than as an antimuscarinic agent
• Most probably, when it is given systemically, oxybutynin
acts mainly as an antimuscarinic drug.
• Oxybutynin has a high affinity for muscarinic receptors
in human bladder tissue and effectively blocks
carbachol-induced contractions
33

• Immediate-Release Oxybutynin
• Extended-Release Oxybutynin
• Transdermal Oxybutynin
• Rectal administration
34

• Dose titrations began at 5 mg, and the dose was
increased every 4 to 7 days until one of three endpoints
was achieved:
• (1) the patient reported no urgency incontinence
during the final 2 days of the dosing period;
• (2) the maximum tolerable dose was reached; or
• (3) the maximum allowable dose (30 mg for
oxybutynin ER or 20 mg for oxybutynin IR) was reached.
• The mean percentage reduction in weekly urgency and
total incontinence episodes was statistically similar
between oxybutynin ER and oxybutynin IR, but dry
mouth was reported statistically more often with
oxybutynin IR. 35

Dicyclomine
• a direct relaxant effect on smooth muscle and an
antimuscarinic action
• An oral dose of 20 mg three times a day in adults
was reported to increase bladder capacity in
patients with neurogenic DO
• The effect of dicyclomine on DO are favorable, the
drug is not widely used, and controlled clinical trials
documenting its efficacy and side effects are scarce.
36

Propioverine
• drug is rapidly absorbed
• high first-pass metabolism
• biologic availability is about 50%.
• Propiverine is an inducer of hepatic
cytochrome P-450 enzymes
• Propiverine has been shown to have
combined antimuscarinic and calcium
antagonistic actions
37

Flavoxate
• Flavoxate is well absorbed, and
• oral bioavailability appeared to be close to 100%
• The drug is extensively metabolized, and
• its plasma half-life was found to be 3.5 hours
• The main metabolite of flavoxate (3-methylflavone-8-
carboxylic acid, MFCA) has been shown to have low
pharmacologic activity
• The drug has been found to possess a moderate
calcium antagonistic activity,
• to have the ability to inhibit phosphodiesterase, and
• to have local anesthetic properties;
• no antimuscarinic effect was found
38

Imipramine
• imipramine, are useful agents for facilitating urine
storage, both by decreasing bladder contractility and by
increasing outlet resistance
• three major pharmacologic actions:
• (1) they have central and peripheral antimuscarinic
effects at some but not all sites;
• (2) they block the active transport system in the
presynaptic nerve ending that is responsible for the
reuptake of the released amine neurotransmitters
norepinephrine and serotonin; and
• (3) they are sedatives, an action that occurs
presumably on a central basis but is perhaps related to
antihistaminic properties
39

α Adrenoceptor Antagonists
Alfuzosin 3 C
Doxazosin 3 C
Prazosin 3 C
Terazosin 3 C
Tamsulosin 3 C
40

• α adrenoceptor antagonists may be effective
in selected cases of DO, convincing effects
documented in RCTs are lacking.
41

Treatment of OAB-DO with selective β2
adrenoceptor agonists has not been successful.
Whether β3 adrenoceptor stimulation will be a
more effective way of treating OAB-DO has yet
to be shown in controlled clinical trials.
β Adrenoceptor Antagonists
Terbutaline 3 C
Salbutamol 3 C
42

Cyclooxygenase Inhibitors
Indomethacin 2
Flurbiprofen 2 C
Desmopressin[§] 1 A
43

Cyclooxygenase Inhibitors
• Prostanoids (prostaglandins and thromboxanes) are
generated locally in both detrusor muscle and mucosa
• Synthesis is initiated by various physiologic stimuli, such as
stretch of the detrusor muscle, but also by injuries of the
vesical mucosa, nerve stimulation, and agents such as ATP
and mediators of inflammation (e.g., bradykinin and the
chemotactic peptide)
• Prostanoids are synthesized by cyclooxygenase in the bladder
• This enzyme exists in two isoforms, one constitutive
(cyclooxygenase 1) and one inducible (cyclooxygenase 2).
• It has been suggested that in the bladder, the constitutive
form is responsible for the normal physiologic biosynthesis,
whereas the inducible form is activated during inflammation
• difficult to evaluate their therapeutic value.
44

Vasopressin Analogs: Desmopressin
• Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is a
synthetic vasopressin analog with a pronounced antidiuretic
effect
• It is widely used for treatment of primary nocturnal enuresis
• dose used in most studies has been 20 μg intranasally at
bedtime.
• the drug is orally active, even if the bioavailability is low (less
than 1% compared with 2% to 10% after intranasal
administration),
• side effects are uncommon during desmopressin treatment,
there is a risk of water retention and hyponatremia
• In elderly patients, it was recommended that serum sodium
concentration be measured before and after a few days of
treatment
• Desmopressin is a well-documented therapeutic alternative in
pediatric nocturnal enuresis and is effective also in adults with
nocturia with polyuric origin. 45

Other Drugs
Baclofen[*] C
Capsaicin[†] 2 C
Resiniferatoxin[†] 2 C
Botulinum toxin[‡] 2 B
Estrogen 2 C
46

Dimethyl Sulfoxide
• Dimethyl sulfoxide has not been shown to be
useful in the treatment of neurogenic or
idiopathic DO or in any patients with urgency-
frequency but without interstitial cystitis.
47

Polysynaptic Inhibitors
• Baclofen (Lioresal) is discussed primarily along
with agents that decrease outlet resistance
secondary to striated sphincter dyssynergia.
• Baclofen is a GABAB receptor agonist that
depresses monosynaptic and polysynaptic
motoneurons and interneurons in the spinal cord
• It has also been shown to be capable of
depressing neurogenic DO secondary to a spinal
cord lesion
48

Botulinum Toxin
• The toxin blocks the release of acetylcholine and other
transmitters from presynaptic nerve endings by
interacting with the protein complex necessary for
docking vesicles
• This results in decreased muscle contractility and
muscle atrophy at the injection site.
• The produced chemical denervation is a reversible
process, and axons are regenerated in about 3 to 6
months.
• The botulinum toxin molecule cannot cross the blood-
brain barrier and therefore has no CNS effects.
49

Capsaisin & resineferatoxin
• capsaicin exerts its effects by acting on specific, “vanilloid”
receptors on these nerves
• Capsaicin exerts a biphasic effect:
• initial excitation is followed by a long-lasting blockade, which
renders sensitive primary afferents (C fibers) resistant to
activation by natural stimuli.
• In sufficiently high concentrations, capsaicin is believed to
cause “desensitization” initially by releasing and emptying the
stores of neuropeptides, then by blocking further release
• Resiniferatoxin (RTX) is an analog of capsaicin, approximately
1000 times more potent for desensitization than capsaicin
• The intravesical use of such agents has the potential to
significantly contribute to the treatment of DO in patients
with neurogenic and other types of lower urinary tract
dysfunction.
50

Estrogens
• The use of estrogens alone to treat urinary
incontinence has given disappointing results.
51

Increasing Outlet Resistance
• total intraurethral pressure of the striated muscle
component in
• (1) urethra and pelvic floor,
• (2) urethral vascular bed, and
• (3) smooth musculature and connective tissues in urethra
and periurethral tissues
• size of the urethral striated muscle and the thickness of the
urethropelvic ligaments decreased with increasing degrees
of SUI
• mainly in elderly women with lack of estrogen, may be insufficient
mucosal “sealing” function
• The aims of most treatments are to increase intraurethral pressure
by effects on the urethral smooth muscle or on the striated
muscles in the urethra and pelvic floor
52

Drugs Used in the Treatment of Overflow
Incontinence (assessments according to the Oxford
system)
Drug Level of Evidence Grade of Recommendation
Alfuzosin 4 C
Doxazosin 4 C
Prazosin 4 C
Terazosin 4 C
Tamsulosin 4 C
(Phenoxybenzamine) 4 NR
53

Muscarinic Receptor Antagonists
Bethanechol 4 D
Carbachol 4 D
Cholinesterase Inhibitors
Distigmine 4 D
Other Drugs
Baclofen 4 C
Benzodiazepines 4 C
Dantrolene 4 C
54

Drugs Used in the Treatment of Stress Incontinence
(assessments according to the Oxford system,
modified)
Drug Level of Evidence Grade of Recommendation
Duloxetine 1 A
Imipramine 3 D
Clenbuterol
Methoxamine 2 D
Midodrine 2 C
Ephedrine 3 D
Norephedrine
(phenylpropanolamine)
3 D
Estrogen 2 D 55

α Adrenoceptor Agonists
• Nonselective α Adrenoceptor Agonists.
• Ephedrine is a noncatecholamine sympathomimetic
agent that enhances release of norepinephrine from
sympathetic neurons and directly stimulates both α and
β adrenoceptors.
• The oral adult dosage is 25 to 50 mg four times a day
• Some tachyphylaxis develops to its peripheral actions,
probably as a result of depletion of norepinephrine
stores
• Pseudoephedrine, a stereoisomer of ephedrine, is used
for similar indications with similar precautions. The
adult dosage is 30 to 60 mg four times a day, and the
30-mg dose form is available 56

• Norephedrine (phenylpropanolamine, PPA)
• share the pharmacologic properties of ephedrine
and to be approximately equal in peripheral
potency while causing less central stimulation.
• A dose of 75 to 100 mg of PPA (norephedrine
chloride) has been shown to increase maximum
urethral pressure and maximum urethral closure
pressure in women with SUI
• cough-induced leak point pressure be adopted as
a standard measure of the effects of treatment in
patients with SUI.
• PPA in a dose of 100 mg significantly increased
the cough-induced leak point pressure 57

• Selective α1 Adrenoceptor Agonists.
• Midodrine is a relatively selective α1-adrenergic agonist
effective in alleviating SUI in doses ranging from 5 to 22.5
mg/day
• no urodynamic improvement
• Methoxamine evoked nonsignificant increases in maximum
urethral pressure and diastolic blood pressure
• Systemic side effects, including piloerection, headache, and
cold extremities, were experienced in all subjects.
• the clinical usefulness of direct, peripherally acting subtype-
selective α1 adrenoceptor agonists in the medical treatment
of SUI may be limited by side effects.
58

• β Adrenoceptor Antagonists
• No RCTs
• Antidepressants
• Imipramine
• enhance the contractile effects of norepinephrine
on urethral smooth muscle.
• Theoretically, such an action may also influence
the striated muscles in the urethra and pelvic
floor by effects at the spinal cord level
• NO RCTs
59

• Duloxetine hydrochloride, a combined
norepinephrine and serotonin reuptake inhibitor,
has been shown to significantly increase urethral
sphincteric muscle activity during the filling-storage
phase of micturition
• Duloxetine is lipophilic, well absorbed, and
extensively metabolized (CYP2D6). Its plasma half-
life is approximately 12 hours
• The effectiveness of duloxetine for treatment of SUI
is documented. Adverse effects occur but seem
tolerable
• Duloxetine is available in Europe
60

• β Adrenoceptor Agonists.
• β Adrenoceptor stimulation is generally conceded to decrease
urethral prssure
• but β2 adrenoceptor agonists increase the contractility of some
fastcontracting striated muscle fibers and to suppress that of
slow-contracting fibers from others
• β adrenoceptor agonists also stimulate skeletal muscle
hypertrophy—in fast-twitch more so than in slow-twitch fibers
• Clenbuterol has been reported to potentiate the field
stimulation–induced contraction in rabbit isolated periurethral
muscle preparations,
• an increase in urethral pressure with clinical use of clenbuterol
and to speculate on its potential for the treatment of SUI.
• well-designed RCTs documenting the effects of clenbuterol are
needed to adequately assess its potential for treatment of SUI; it
is possible that this agent may have a novel as yet undefined
mechanism of action.
61

Estrogen
• combination of pelvic floor exercise and estriol
(1 mg/day) with postmenopausal SUI. Efficacy
was evaluated every 3 months on the basis of
stress scores obtained from a questionnaire.
• They found a significant decrease in stress score
in patients with mild and moderate SUI in both
groups 3 months after the start of therapy
• combination therapy with estriol plus pelvic
floor exercise was effective and capable of
serving as first-line treatment of mild SUI.
62

PHARMACOLOGIC THERAPY TO
FACILITATE BLADDER EMPTYING
• Increasing Intravesical Pressure and Bladder
Contractility
• Decreasing Outlet Resistance
63

Increasing Intravesical Pressure and Bladder
Contractility
• Parasympathomimetic agents
• Prostoglandins
• Opioid receptor antagonists
64

Parasympathomimetic agents
• Acetylcholine, which is a quaternary amine, cannot be
used for therapeutic purposes because of its action at
both muscarinic and nicotinic receptors;
• it is rapidly hydrolyzed by acetylcholinesterase and by
butyrylcholinesterase
• Many acetylcholine-like drugs exist, but only
bethanechol chloride exhibits a relatively selective in
vitro action on the urinary bladder and gut with little
or no nicotinic action.
• Bethanechol is cholinesterase resistant and causes an
in vitro contraction of smooth muscle from all areas
of the bladder
65

• Bethanechol, or agents similar to it, has historically been
recommended for the treatment of postoperative or
postpartum urinary retention, but only if the patient is
awake and alert and if there is no outlet obstruction.
• The recommended dose has been 5 to 10 mg
subcutaneously.
• For more than 50 years, bethanechol has been
recommended for the treatment of the atonic or hypotonic
bladder and has been reported as effective in achieving
“rehabilitation” of the chronically atonic or hypotonic
detrusor
• Bethanechol has also been reported to stimulate or to
facilitate the development of reflex bladder contractions in
patients in spinal shock secondary to suprasacral spinal cord
injury 66

• combination therapy with a cholinergic drug and an α-
adrenergic receptor antagonist appeared to be more useful
than monotherapy for the treatment of underactive
detrusor.
• The potential side effects of cholinomimetic drugs include
flushing, nausea, vomiting, diarrhea, gastrointestinal
cramps, bronchospasm, headache, salivation, sweating, and
difficulty with visual accommodation
• Intramuscular or intravenous administration can precipitate
acute and severe side effects resulting in acute circulatory
failure and cardiac arrest and is therefore prohibited.
• Contraindications to the use of this general category of drug
include bronchial asthma, peptic ulcer, bowel obstruction,
enteritis, recent gastrointestinal surgery, cardiac arrhythmia,
hyperthyroidism, and any type of bladder outlet
obstruction.
67

Opioid Receptor Antagonists
• an intravenous injection of 0.4 mg of
naloxone enhanced detrusor reflex activity in
five of seven patients with neuropathic
bladder dysfunction caused by incomplete
suprasacral spinal cord lesions.
• little practical use at present.
68

Decreasing Outlet Resistance
• α Adrenoceptor Antagonists
• Nitic oxide donors
• Benzodiazepines, Baclofen, and Dantrolene
• Botulinum Toxin
• Other Agents
69

• The smooth muscle of the bladder base and proximal
urethra contains predominantly α adrenoceptors,
although β adrenoceptors are present. The bladder
body contains both varieties of adrenergic receptors,
with β adrenoceptors (β3 subtype) being more
common
• usefulness of α adrenoceptor blockade in the
treatment of what is now usually referred to as
smooth sphincter or bladder neck dyssynergia or
dysfunction. Successful results, usually defined as an
increase in flow rate, a decrease in residual urine, and
an improvement in upper tract appearance (where
pathologic), could often be correlated with an
objective decrease in urethral profile closure pressure.
70

• Phenoxybenzamine was the α adrenoceptor antagonist
originally used for the treatment of voiding dysfunction
• Phenoxybenzamine has blocking properties at both α1 and
α2 adrenoceptor sites.
• The initial adult dosage of this agent is 10 mg/day, and the
usual daily dose for voiding dysfunction is 10 to 20 mg.
• Side effects affect approximately 30% of Patients and
include orthostatic hypotension, reflex tachycardia, nasal
congestion, diarrhea, miosis, sedation, nausea, and vomiting
(secondary to local irritation).
• It has mutagenic activity in the Ames test, and repeated
administration to animals can cause peritoneal sarcomas
and lung tumors 71

• Prazosin was the first potent selective α1 adrenoceptor
antagonist used to lower outlet resistance.
• The duration of action is 4 to 6 hours;
• therapy is generally begun in daily divided doses of 2 to 3 mg.
The dose may be gradually increased to a maximum of 20 mg
daily.
• The potential side effects of prazosin are consequent to its α1
adrenoceptor blockade.
• On occasion, there occurs a “first-dose phenomenon,” a
symptom complex of faintness, dizziness, palpitation, and,
infrequently, syncope, thought to be caused by acute postural
hypotension.
• The incidence of this can be minimized by restricting the initial
dose of the drug to 1 mg and administering this at bedtime.
• Other side effects associated with chronic prazosin therapy are
generally mild and rarely necessitate withdrawal of the drug.
72

• Terazosin and doxazosin are two highly selective
postsynaptic α1 adrenoceptor antagonists.
• They are readily absorbed with high
bioavailability and long plasma half-life,
enabling their activity to be maintained for 24
hours after a single oral dose.
• Both of these agents have been evaluated with
respect to their efficacy in patients with lower
urinary tract symptoms and decreased flow
rates presumed secondary to benign prostatic
hyperplasia
73

• alfuzosin and tamsulosin, both highly selective
α1 adrenoceptor blockers, have appeared and
are marketed solely for the treatment of benign
prostatic hyperplasia
• Tamsulosin and alfuzosin have the advantage of
being able to be administered once daily and
without titration.
• retrograde ejaculation and rhinitis are more
common with tamsulosin,
• dizziness and asthenia are more common with
terazosin and doxazosin
74

Nitic oxide donors
• Nitric oxide is a neurotransmitter capable of producing
smooth muscle relaxation, at least in the female rabbit
urethra, pig urethra, and human bladder neck
• Sublingual administration of isosorbide dinitrate (10 mg)
could significantly reduce the resting pressure of the
external urethral sphincter for at least 1 hour
• nitric oxide donors could offer a new pharmacologic
approach to treat urinary retention due to overactive or
nonrelaxing external urethral sphincter
• nitric oxide donors could offer a potential pharmacologic
option to treat detrusor-sphincter dyssynergia in spinal
cord–injured patients.
75

Benzodiazepines, Baclofen, and
Dantrolene
• The rationale for use is either relaxation of the
pelvic floor striated musculature during bladder
contraction or that such relaxation removes an
inhibitory stimulus to reflex bladder activity.
• Improvement under such circumstances may
simply be caused, by the antianxiety effect of
the drug or by the intensive explanation,
encouragement, and modified biofeedback
therapy that usually accompany such treatment
in these patients
76

• Baclofen has been found useful in the treatment of
skeletal spasticity from a variety of causes (especially
multiple sclerosis and traumatic spinal cord lesions) (
Cedarbaum and Schleifer, 1990 ). Determination of the
optimal dose in an individual patient requires careful
titration. Treatment is started at an initial dose of 5 mg
twice daily, and the dose is increased every 3 days up to a
maximum daily dose of 20 mg four times a day.
• insidious development of autonomic dysreflexia and
hydronephrosis due to dyssynergic voiding after
discontinuation of intrathecal baclofen therapy. They
recommended that in spinal cord–injured patients in
whom intrathecal baclofen therapy is terminated, close
monitoring of the urologic status is needed.
77

• Dantrolene (Dantrium) exerts its effects by a
direct peripheral action on skeletal muscle (
Cedarbaum and Schleifer, 1990 ). It is thought to
inhibit the excitation-induced release of calcium
ions from the sarcoplasmic reticulum of striated
muscle fibers, thereby inhibiting
excitationcontraction coupling and diminishing
the mechanical force of contraction.
• no one currently uses dantrolene for the
treatment of voiding dysfunction.
78

• Botulinum Toxin
• Botulinum A toxin (Botox) is an inhibitor of the release of
acetylcholine and other transmitters at the neuromuscular
junction of somatic nerves in striated muscle and of autonomic
nerves in smooth muscle
• Its urologic use for the treatment of detrusor–striated sphincter
dyssynergia was first reported by Dykstra and colleagues ( Dykstra
and Sidi, 1990 ; Dykstra et al, 1998 ). Injections were carried out
weekly for 3 weeks, achieving a duration of effect averaging 2
months. The only side effects reported in the Dykstra articles were
transitory limb paresis and transitory exacerbation of autonomic
hyperreflexia.
• Botox is a promising treatment for striated sphincter dyssynergia
in certain patients refractory to clean intermittent catheterization
or surgery.
79

80

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