Antikolinerjik Tedavi

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Antikolinerjik Tedavi

• Dr. Ruhan Düsünsel
• Erciyes Üniversitesi Tip Fakültesi
• Çocuk Nefroloji Bilim Dali, Kayseri

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Neden antikolinerjik tedavi ?
Beyin
Beyin
Dolum
Bosalma
P
P
Sempatik sistem ()
Parasempatik sistem (-)
Sempatik sistem (-)
Parasempatik sistem ()
Pudental sinir ()
Pudental sinir (-)
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Neden antikolinerjik tedavi ?
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Antikolinerjiklerin etki mekanizmasi
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Antikolinerjiklerin etki mekanizmasi
Figure . Schematic showing the role of muscarinic
receptor subtypes in modulation of detrusor
contractility. The micturition reflex is
dependent on the operation of the
spinalbulbospinal reflex. Detrusor contractile
tone is dependent on the phosphorylation state of
myosin filaments. The lumbosacral parasympathetic
outflow provides the major excitatory efferent
input to the detrusor. ACh release from
post-ganglionic parasympathetic nerves is
regulatedby prejunctional inhibitory M4
andfacilitatory M1 receptors.
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Muskarinik reseptörlerin dagilimi

• M1 Beyin (korteks, hipokampus), bezler,
  sempatik ganglionlar
• M2 Kalp, arka beyin, düz adale
• M3 Düz adale, bezler, beyin
• M4 Beyin (ön beyin, striatum)
• M5 Beyin (substansiya nigra), göz

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Disfonksiyonel iseme patofizyolojisinde
muskarinik reseptörlerin etkileri

• M1 Mesanede Ach salinimi
• M2 Muskarinik reseptör iliskili detrüsör
  kontraksiyonu
• M3 Muskarinik reseptör iliskili detrüsör
  kontraksiyonu
• M4 Rolü bilinmiyor
• M5 Rolü bilinmiyor

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Kullanilan Antikolinerjikler

• Oxybutynin (1972, 1975)
• Tolterodine (1997)
• Trospium Chloride
• Propiverine
• Solifenacin Succinate
• Darifenacin

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Oxybutynin

• 1975de FDA onayi
• Tersiyer amin, lipofilik
• Hepatik yolla metabolize olur
• Antimuskarinik
• Direk adale gevsetici
• Lokal anestetik

Oral, intravezikal, transdermal IR 2,5-3-5 mg
tab. ER 5-10-15 mg tab. (1999) Susp 5 mg / 5ml
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• Int J Clin Pract 62 167170 , 2008
• Evolution of transdermal oxybutynin in the
• treatment of overactive bladder
• A. Sahai, R. Mallina, C. Dowson, T. Larner, M. S.
  Khan

SUMMARY Overactive bladder (OAB) syndrome affects
millions of people worldwide. In addi- tion to
adversely affecting quality of life, the direct
and indirect costs in managing patients with OAB
incur a substantial ?nancial burden on health
services. Among the approved anticholinergics for
treating OAB, oxybutynin is the most
extensively studied drug in clinical trials. The
principle metabolite of oxybutynin has a
higher af?nity for muscarinic receptors in
salivary glands which lead to signi?cantly
high dry mouth rates. This prompted the
development of alternative formulations
of oxybutynin aiming to achieve better
tolerability whilst sustaining ef?cacy. This
edi- torial examines the ef?cacy and tolerability
of transdermal oxybutynin (OXY-TD) in treating
OAB. Articles were retrieved from PubMed between
2000 to the present day relating to OXY-TD. Data
is presented from phase IIV trials. The results
from placebo-controlled trials indicate that
OXY-TD is ef?cacious in treating patients with
OAB associated with urge urinary or mixed
incontinence. Systemic side effects most notably
dry mouth, appear to be less with this
formulation compared with oral anticholinergics.
However, further study is required in different
OAB popula- tions. The main limitation appears to
be related to application site adverse
events such as pruritis and erythema. OXY-TD is
likely to ?nd its place as ?rst-line
phar- macotherapy in the clinicians
armamentarium in treating OAB
Review Criteria The PubMed search engine was used
for article relating to transdermal oxybutynin
from 2000 to the present day. Only fully
published articles were considered. The keywords
searched included transdermal, oxybutynin,
overactive bladder and detrusor. Message for the
Clinic Transdermal oxybutynin appears to be
effective in treating patients with overactive
bladder associated with urge urinary or mixed
incontinence. Its delivery system allows for
ef?cacious treatment with a reduction in systemic
side effects associated with oral
anticholinergics, most notably dry mouth.
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• J Urol 141(6)1350-2, 1989
• Topical oxybutynin chloride for relaxation of
  dysfunctional bladders
• Brendler CB, Radebaugh LC, Mohler JL.
• Department of Urology, Johns Hopkins University
  School of Medicine, Baltimore, Maryland.
• Eleven patients with persistent urge incontinence
  and frequent side effects on oral anticholinergic
  agents were treated with oxybutynin chloride
  administered intravesically. Five mg. tablets
  were dissolved in saline, and the solution was
  instilled twice daily and retained for 30
  minutes. One patient was unable to retain the
  medication because of severe detrusor
  hyperreflexia and was eliminated from the study.
  The remaining 10 patients all reported subjective
  improvement following treatment and all became
  totally continent. No side effects were observed.
  In these 10 patients mean bladder capacity
  increased from 224 to 360 ml. (p less than 0.01)
  and mean maximum filling pressure decreased from
  33 to 24 cm. water (p equals 0.17). Two
  additional patients with continent ileocecal
  urinary diversions were treated with topical
  oxybutynin chloride instilled directly into the
  intestinal reservoir. Both patients reported
  improved comfort with filling and 1 demonstrated
  a decrease in uninhibited contractions. These
  encouraging results suggest that treatment with
  topical oxybutynin chloride is an effective
  alternative in patients with voiding dysfunction
  who either are unresponsive to or have
  intolerable side effects on oral medications.

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Tolterodine

• 1997de FDA onayi
• Tersiyer amin, lipofilik
• IR 1 mg, 2 mg (2x2)
• ER 2 mg, 4 mg (1x4)

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• INDIAN PEDIATRICS 43(17)980-983, 2006
• Effectiveness of Tolterodine in Non-Neurogenic
  Voiding Dysfunction
• Ramesh Babu
• From the Pediatric Urology Unit, Sri Ramachandra
  Medical College and Research Institute, Chennai,
  India.
• The efficacy of tolterodine was analysed in
  children with non-neurogenic voiding dysfunction,
  using dysfunctional voiding symptom score (DVSS).
  Of 44 patients (mean age 9.3 yrs MF 2519),
  36 received long acting tolterodine tartrate at a
  dose of 2mg OD and 8 at a dose of 4mg OD. The
  mean (SD) DVSS before and after the treatment was
  17.1 (2.8) and 12.0 (2.4). There was a
  significant improvement in the mean DVSS score at
  the end of the treatment (Students t test P lt
  0.01). The dysfunctional symptoms were cured in
  28(63.6), improved in 14(31.8) and failed to
  show improvement in 2 (4.6). Over all 95 were
  compliant with the single daily medication. Our
  results demonstrate that long acting tolterodine
  is effective in children with voiding
  dysfunction. The single daily dose has good
  compliance and minimal side effect profile.
• Key words Bladder instability, Dysfunctional
  voiding, Overactive bladder.

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Trospium Chloride

• Kuarterner amin
• Hidrofilik, kan-beyin bariyerini geçmez
• 2x20 mg tab / gün
• Avrupada 20 yil
• Amerikada 5 yil

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Propiverine

• Tersiyer amin
• 2 x 15 mg, 3 x 15 mg

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Solifenacin Succinate

• Selektif M3 antagonisti
• Hepatik yolla metabolize olur
• 1 x 5 mg, 1 x 10 mg
• Darifenacin
• 7,5 mg
• 15 mg

oral
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• International Journal of Urology (2006) 13,
  105108
• Comparison of the effectiveness and side-effects
  of tolterodine and oxybutynin in children with
  detrusor instability
• NIZAMETTIN KILIC, EMIN BALKAN, SEMRA AKGOZ, NURI
  SEN AND HASAN DOGRUYOL
• The Medical Faculty of Uludag University,
  Departments of Paediatric Surgery, Paediatric
  Urology and Biostatistics, Bursa, Turkey
• Background Treatment with anticholinergic
  agents is the mainstay of therapy for detrusor
  instability (DI), a chronic and morbid condition
  characterized by urge urinary incontinence. The
  aim of this study is to assess the effectiveness
  and tolerability of tolterodine and oxybutynin in
  children with DI.
• Methods A total of 60 children with DI were
  enrolled, 30 (14 male, 16 female, mean age 7.97
  2.71 years) in the tolterodine group and 30 (12
  male, 18 female, mean age 7.33 2.23 years) in
  the oxybutynin group. In this prospective study
  we reviewed data from 60 children followed for at
  least 6 months. All of the patients in the study
  population had a history of dysfunctional
  voiding. Urodynamic investigations were conducted
  in all of the patients before and after
  anticholinergic treatment. Episodes of urge
  urinary incontinence and adverse events were also
  evaluated.
• Results Improvements in urge incontinence
  episodes were similar for the children who
  received tolterodine or oxybutynin. Improvements
  in the urodynamic parameters were also the same
  in the two groups. Adverse events were
  signi?cantly lower in the tolterodine group (13
  events in 13 patients) compared to the oxybutynin
  group (27 events in 20 patients P 0.027).
• Conclusion Reductions in urge urinary
  incontinence episodes were similar with
  tolterodine and oxybutynin in children with DI.
  Side-effects were more common with oxybutynin.
  Treatment of children with DI with tolterodine
  shows signi?cantly better tolerability and this
  may enhance childrens compliance during
  long-term treatment.
• Key words anticholinergics, detrusor
  instability, oxybutynin, tolterodine.

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International Journal of Urology (2006) 13,
105108 Comparison of the effectiveness and
side-effects of tolterodine and oxybutynin in
children with detrusor instability NIZAMETTIN
KILIC, EMIN BALKAN, SEMRA AKGOZ, NURI SEN AND
HASAN DOGRUYOL The Medical Faculty of Uludag
University, Departments of Paediatric Surgery,
Paediatric Urology and Biostatistics, Bursa,
Turkey
Conclusion Reductions in urge urinary
incontinence episodes were similar with
tolterodine and oxybutynin in children with DI.
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Efficacy of tolterodine as a first-line treatment
for non-neurogenic voiding dysfunction in
children SEMIH AYAN, KEMAL KAYA, KAHRAMAN
TOPSAKAL, HAKAN KILICARSLAN, GOKHAN GOKCE and
YENER GULTEKINDepartment of Urology, Medical
Faculty, Cumhuriyet University, Sivas, Turkey
BJU Int 96 (3) 411-4, 2005
OBJECTIVE To assess the effect of
antimuscarinic treatment with tolterodine
combined with behavioural modification as a
first-line treatment, before invasive
investigation, in children with non-neurogenic
voiding dysfunction but no obvious anatomical or
neurogenic cause. PATIENTS AND METHODS The
study comprised 44 children presenting with
voiding dysfunction (30 girls and 14 boys, mean
age 7 years, range 514) all had a noninvasive
evaluation consisting of a history, urine
analysis, renal and bladder ultrasonography and
physical examination,
with specific emphasis on the voiding pattern.
Anticholinergic treatment with tolterodine (1
mg twice daily) was started in all patients
they were also informed about conservative
management, including timed voiding, double
voiding and relaxation of the pelvic floor during
voiding. At the start and after 3 months, the
dysfunctional voiding symptom score (DVSS) was
completed twice by all patients. RESULTS For
all patients the mean (SD) DVSS was 14.0 (2.67)
and 6.68 (3.67) before and after treatment,
respectively the difference was statistically
significant (Plt 0.001). The mean scores for
girls and boys, respectively, were
13.8 (2.79) and 14.5 (2.44) before and 6.43
(3.79) and 7.50 (3.34) after treatment.
CONCLUSION Tolterodine combined with
behavioural modification for dysfunctional
voiding in children with no neurological or
anatomical abnormality can be recommended as a
first- line treatment before invasive evaluation.
Additionally, the DVSS appears to provide
accurate and objective data for monitoring the
effect of treatment in such children. KEYWORDS
voiding dysfunction, tolterodine, dysfunctional
voiding symptom score
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• Eur Urol 48 464-70, 2005
• A Comparison of the Efficacy and Tolerability of
  Solifenacin Succinate and Extended Release
  Tolterodine at Treating Overactive Bladder
  Syndrome Results of the STAR Trial
• Chapple CR, Martinez-Garcia R, Selvaggi L,
  Toozs-Hobson P, Warnack W, Drogendijk T, Wright
  DM, Bolodeoku J.
• Objective To compare two new generation
  antimuscarinics at their recommended doses for
  treatment of overactive bladder syndrome (OAB).
• Methods A prospective, double blind,
  double-dummy, two-arm, parallel-group, 12-week
  study was conducted to compare the efficacy and
  safety of solifenacin 5 or 10 mg and tolterodine
  extended release (ER) 4 mg once daily in OAB
  patients. After 4 weeks of treatment patients had
  the option to request a dose increase but were
  dummied throughout as approved product labelling
  only allowed an increase for those on
  solifenacin.
• Conclusions Solifenacin, with a flexible dosing
  regimen, was found to be superior to tolterodine
  ER with respect to the majority of the efficacy
  variables.

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Yan etkileri nelerdir ?
International Journal of Urology (2006) 13,
105108 Comparison of the effectiveness and
side-effects of tolterodine and oxybutynin in
children with detrusor instability NIZAMETTIN
KILIC, EMIN BALKAN, SEMRA AKGOZ, NURI SEN AND
HASAN DOGRUYOL The Medical Faculty of Uludag
University, Departments of Paediatric Surgery,
Paediatric Urology and Biostatistics, Bursa,
Turkey

• Conclusion Side-effects were more common with
  oxybutynin. Treatment of children with DI with
  tolterodine shows signi?cantly
• better tolerability and this
  may enhance childrens compliance during
  long-term treatment.

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J Urol 177(6)2325-2329, 2007Efficacy of
Combined Anticholinergic Treatment and Behavioral
Modification as a First Line Treatment for
Nonneurogenic and Nonanatomical Voiding
Dysfunction in Children A Randomized Controlled
Trial.Ayan, S., Topsakal, K., Gokce, G.,
Gultekin, E.
Kombine tedaviler

• Materials and Methods A total of 72 children
  meeting inclusion criteria were randomly
  allocated to 1 of 3 groups. One group received
  tolterodine (1 mg twice daily) along with
  behavioral modification, 1 received behavioral
  modification only and 1 received placebo with
  behavioral modification. A dysfunctional voiding
  scoring system questionnaire was completed for
  all patients at the beginning of the study, and
  at 1 and 3 months of treatment.Conclusions
  Tolterodine combined with behavioral modification
  for voiding dysfunction in children without
  neurological or anatomical abnormality can be
  recommended as a first line treatment before
  invasive evaluation.

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Antikolinerjik tedavi yetersizliginin
farmakolojik nedenleri

• Uygunsuz doz
• Yan etkilere bagli yetersiz doz
• Atropin-rezistan kontraksiyon
• Selektif M3 blokajinda non-M3 kontraksiyon
• M2 ve M3 reseptörlerin upregülasyonu
• Myojenik etyolojik (nörojenik yerine)
• Farmakogenomiks

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BJU INTERNATIONAL 91 398401, 2003The use of
tolterodine in children after oxybutynin failure
S. BOLDUC, J. UPADHYAY, J. PAYTON, D.J. BÄGLI,
G.A. MCLORIE, A.E. KHOURY and W. FARHAT
Division of Urology, The Hospital for Sick
Children, University of Toronto, Toronto,
Ontario, Canada
because of side-effects after a median (range)
of 5 (111) months. The ef?cacy of tolterodine
was comparable with that of oxybutynin, as
reported by the questionnaire and voiding
diaries. The reduction in wetting episodes at 1
year was gt90 in 23 (68), more than half in ?ve
and less than half (or failure) in six
patients. CONCLUSION Tolterodine is tolerated
well in children. In this subgroup of patients
who could not tolerate oxybutynin, 77 were able
to continue tolterodine treatment with no
signi?cant side-effects. KEYWORDS anticholinergi
c, overactive bladder, tolterodine, oxybutynin,
children
empirically started on antimuscarinic or
anticholinergic agents. The 34 patients were
treated with oxybutynin for a median (range) of
6 (284) months. When signi?cant side- effects
were reported, they were crossed over to
tolterodine. The ef?cacy of tolterodine was
assessed as de?ned by the International
Children's Continence Society, with
tolerability assessed and side-effects
documented using a questionnaire. RESULTS The
mean age at the ?rst dose of tolterodine was 8.9
years the dose was 1 mg twice daily for 12
patients and 2 mg twice daily for 22. The median
treatment with tolterodine was 11.5 months, with
20 (59) patients reporting no side-effects six
described the same but tolerable side-effects as
with oxybutynin. Eight patients discontinued
tolterodine
OBJECTIVE To assess the safety and ef?cacy of
tolterodine tartrate prescribed to children who
previously failed to tolerate oxybutynin
chloride. PATIENTS AND METHODS We reviewed 34
children, followed for gt1 year, who were
prospectively crossed-over from oxybutynin to
tolterodine because of side-effects. The initial
diagnosis was dysfunctional voiding in 31
patients. All patients were placed on a
behavioural modi?cation protocol. When their
symptoms did not improve after 6 months,
treatment with an anticholinergic agent was
considered. Urodynamic studies were conducted in
20 patients, con?rming uninhibited
contractions in 19. The remaining 14 patients
were
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• Eur Urol 48(1) 5-26. 2005
• The effects of antimuscarinic treatments in
  overactive bladder a systematic review and
  meta-analysis.
• Chapple C, Khullar V, Gabriel Z, Dooley JA.
• Sheffield Teaching Hospitals NHS Trust, Royal
  Hallamshire Hospital, Urology Research, J Floor
  Office, Glossop Road, Sheffield, S102JF, UK.
  c.r.chapple_at_sheffield.ac.uk
• OBJECTIVES To evaluate the tolerability,
  safety and efficacy of antimuscarinic drugs used
  to treat overactive bladder and to identify any
  differences between individual antimuscarinics.
• METHODS Medline, Embase, CCTR and Cinahl
  databases were searched for published RCTs
  including an antimuscarinic agent from 1966 to
  August 2004. Data from included trials were
  extracted and meta-analysed where possible.
• RESULTS Fifty-six trials were included. The
  antimuscarinics were found to be safe and
  efficacious. All antimuscarinics apart from
  oxybutynin IR were found to be well tolerated.
  Dry mouth was the most commonly reported adverse
  event and no drug was associated with an increase
  in any serious adverse event. There were
  significant differences between the
  antimuscarinics in rates of withdrawal and rates
  and range of adverse events and efficacy
  outcomes.
• CONCLUSIONS The antimuscarinics have different
  tolerability and safety profiles, which are
  clinically significant.
•  

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Gelecekteki tedavi

• Üroselektif
• Mesane selektif
• Farmakolojik tedavi disinda
• Doku mühendisligi
• Gen tedavisi

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Dikkatiniz Için Tesekkürler
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