1. Antimuscarinic drugs for overactive bladder
Ilan Z. Kafka MD 2009

2. Overactive Bladder
Defining symptoms of overactive bladder syndrome (OAB) are:
Urinary urgency with or without incontinence
Frequency
Nocturia
1. Abrams P, Cardozo L, Fall M et al., The standardization of terminology of lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society”, Neurourol. Urodyn. (2002);21: pp. 167–178.

3. Overactive Bladder Frequency Urination at night Urgency
8 or more visits to the toilet per 24 hours
Urination at night
• 2 or more visits to toilet during sleeping hours
Urgency
Sudden, strong desire to urinate
Urge Incontinence
Sudden & involuntary loss of urine
OAB

4. Overactive Bladder
Adapted from Tubaro et al

5. Overactive Bladder Local pathology Metabolic factors Medications
infection
bladder stones
bladder tumors
interstitial cystitis
outlet obstruction
Metabolic factors
diabetes
polydipsia
Medications
diuretics
antidepressants
antihypertensives
hypnotics & sedatives
narcotics & analgesics
Other factors
pregnancy
psychological issues

6. Ideal Pharmacologic Treatment for OAB
Safety
Metabolic drug-drug interactions
CNS effects
Cardiovascular safety
Efficacy
Alleviate or significantly improve symptoms
Improve QOL
Tolerability
Fewer AEs

7. Distribution of Muscarinic Receptors in Target Organs of the Parasympathetic Nervous System
Heart
Stomach and esophagus
Dyspepsia
Iris/ciliary body
Lacrimal gland
Blurred vision
Dry eyes
Tachycardia
Dizziness
Somnolence
Impaired memory and cognition
CNS
Salivary glands
Dry mouth
Colon
Constipation
Bladder (detrusor muscle)
This is a “build” slide showing the distribution of peripheral cholinergic (ie, muscarinic) receptors throughout the body
Muscarinic receptors are located in the CNS, iris and ciliary body, lachrymal gland, salivary glands, heart, gallbladder, stomach, colon, and bladder
Agents that are selective for the bladder are preferable over agents that may potentially target other regions of the body
Blockade of muscarinic receptors outside the bladder may result in undesired side effects such as dry mouth (the most common side effect), constipation, and CNS side effects (such as dizziness, somnolence, and cognitive impairment), and effects on the stomach and eyes
Abrams P, Wein AJ. The Overactive Bladder— A Widespread and Treatable Condition

8. Distribution of Muscarinic Receptors in Target Organs of the Parasympathetic Nervous System

9. Distribution of cholinergic and adrenergic receptors in the urinary bladder

10. Antimuscarinic Treatment Options
DRUG DOSE FREQUENCY
Tolterodine LA (Detrusitol)
4 mg
Once-daily
Oxybutynin XL (Lyrinel)
5–15 mg
Oxybutynin (Novitropan)
5–30 mg
BID or TID
Oxybutynin transdermal patch
3.9 mg/d
1 patch BIW
Trospium (Spasmex)
15 mg
TID
Solifenacin (Vesicare)
5–10 mg
Darifenacin (Enablex)
7.5–15 mg
Fesoterodine (Toviaz)
4-8mg
OD-BID

11. Are All Antimuscarinics the Same?
A meta-analysis found:
All antimuscarinics were proven effective for thetreatment of OAB
Individual antimuscarinic profiles are different
There is some evidence of differences among adverse- event (AE) profiles
There are differences in tolerability profiles, which may be clinically significant
A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder.
Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V, Artibani W.
Eur Urol Oct;54(4):

12. Comparative efficacy antimuscarinic medications
Study
Drugs Compared
Efficacy
Side Effects
Pooled data (Cochrane, 2005)
Oxybutinin and tolterodine
Similar in most outcome variables
Slightly less dry mouth and withdrawals with tolterodine
Oxybutinin ER and tolterodine ER
Slightly less dry mouth with tolterodine ER
OPERA (Diokno et al, 2003)
Slightly less dry mouth with tolterodine ER, overall tolerability similar
Trospium and oxybutinin (Halaska et al, 2003)
Oxybutinin and trospium
Slightly less dry mouth with trospium
STAR (Chapple et al, 2005)
Solifenacin and tolterodine ER
Solifenacin had slightly better efficacy than tolterodine ER
Similar rates of side effects
Tolterodine and fesoterodine (Chapple et al, 2008)
Tolterodine and fesoterodine
Fesoterodine had slightly better efficacy than tolterodine ER
A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder.
Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V, Artibani W.
Eur Urol Oct;54(4):

13. Not All Antimuscarinic Agents Are the Same
Structural differences
Molecular size, polarity, permeability
Pharmacokinetics and pharmacodynamics
Metabolism and excretion/Drug-drug interaction
Efficacy : Tolerability : Safety
Receptor specificity, organ selectivity, patient variability (individual, age, race, gender)
Khullar V, et al. Urology. 2006;68(2 suppl):38-48.
Shaya FT, et al. Am J Manag Care. 2005;11(4 suppl):S121-S129.
Staskin DR. Drug Aging. 2005;22:
Wein AJ. Urol. 2003;62(5 suppl 2):20-27.
Pak RW, et al. Curr Urol Rep. 2003;4:

14. Comparison of antimuscarinic Drugs
Hepatic Impairment
Renal Impairment
Half-Life (h)
SELECTIVITY
DRUG
Caution
13–19
Selective, predominantly M3
Darifenacin
Mild/moderate: start with 4 mg, increase dose cautiously to 8mg Severe: 4mg 7
Non-Selective
Fesoterodine
2–3
Selective, predominantly M1/M3
Oxybutynin
Max dose 30mg
14-22
Propiverine
Mild/moderate: no adjustment Severe: max 5mg
45–68
Solifenacin
Mild/moderate: no data Severe: max 2_1mg IR or 2mg ER
Tolterodine 2–3, 5-HMT 3-4
Tolterodine
Mild/moderate: caution
Severe: max 20mg
10–20
Trospium

15. Antimuscarinic drug Receptor affinity
How do medications used to treat urinary incontinence affect the cerebral function of the elderly? Urologe 2007 · 46:387–392

16. Anticholinergic drugs used for OABS and drugs that can potentiate their adverse effects
Drugs that can potentiate AE’s
Anti-arrythmics
Anti- depressants
Anti-Diarrheal
Antihstamines
Antipsychotics
Muscle Relaxants
Anticholinergic Agents
Anti- emetics
Drugs to treat Parkinson’s
Antispasmodics
Mydriatics/Cyclopegics

17. Cognitive Function in Patient Receiving Antimuscarinic Therapy
Antimuscarinics used in the treatment of overactive bladder differ in their potential to affect cognitive function.
In particular, treatment with agents that block
M1/M3 receptors in the brain are known to cause cognitive impairment.
Darifenacin and tolterodine stand out as having been shown to not cause impairment of memory or other cognitive functions in randomized clinical trials.
Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin.
Kay GG, Ebinger U. Int J Clin Pract Nov;62(11):

18. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
FES 4 or 8mg od vs.placebo (PL)
n = 1135
FES 4 or 8mg od vs.placebo (PL)
Active control arm of tolterodine extended
release (TOL ER) 4mg od
Two randomized, double blind, phase III, 12-week studies
Primary endpoints (a) the reduction from baseline (BL) in the mean number of voids per
24-hour period
(b) the reduction in the mean number of episodes of urge incontinence
per 24-hour period both assessed over a 3-day period at study end,
(c) treatment response derived from a 4-category pt-assessed
treatment benefit scale.

19. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
* p < 0.01, ** p < vs PL
Mean Change in Baseline in No. of Voids/24 hrs
Kate McKeage , Gillian M. Keating
Fesoterodine;Drugs 2009; 69 (6):

20. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
* p < 0.01, ** p < vs PL
Mean Change in Baseline in No. episodes in Urge Incontinence/ 24h
Kate McKeage , Gillian M. Keating
Fesoterodine;Drugs 2009; 69 (6):

21. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
* p < 0.01, ** p < vs PL
Patient Responding to Treatment (%)
Kate McKeage , Gillian M. Keating
Fesoterodine;Drugs 2009; 69 (6):

22. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
y = incidence <1%.
Kate McKeage , Gillian M. Keating
Fesoterodine;Drugs 2009; 69 (6):

23. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
2008 Nov;102(9):
-Post hoc analysis
-n=1135
-HrQol- Incontinent vs. All
-Max Dose Fesoterodine (8mg) vs Max Dose Tolterodine (4mg)

24. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
Comparison of fesoterodine and tolterodine in patients with overactive bladder.Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. BJU Int Nov;102(9):

25. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
Comparison of fesoterodine and tolterodine in patients with overactive bladder.Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. BJU Int Nov;102(9):

26. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
Comparison of fesoterodine and tolterodine in patients with overactive bladder.Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. BJU Int Nov;102(9):

27. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
BJU Int. 2010; Vol 105( 1):p58-56
n= week follow-up - double-blind, double dummy, placebo-controlled, RCT
Endpoints - Changes from baseline to week 12 in UUI episodes (primary endpoint),
-Total and nocturnal voids, urgency episodes, severe urgency episodes, and
frequency-urgency sum per 24 h; mean voided volume per void (MVV); OAB
questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC), and
Urgency Perception Scale (UPS).
- Safety and tolerability

28. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
*P < 0.05 vs placebo; †P < 0.05 fesoterodine vs tolterodine ER.

29. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
*P < 0.05 vs placebo; †P < 0.05 fesoterodine vs
tolterodine ER.
*P < 0.001
fesoterodine vs placebo; †P = fesoterodine
vs tolterodine ER (post hoc comparison). The
tolterodine ER vs placebo comparison was not
significant (P = 0.167).
Patient Perception of Bladder Condition
Urgency Perception Scale
†P < fesoterodine vs
tolterodine ER (post hoc comparison); ‡P < 0.001
tolterodine vs placebo (post hoc comparison).

30. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
Comparison of fesoterodine and tolterodine in patients with overactive bladder BJU International Volume 102, Issue 9, Date: November 2008, Pages:  Christopher R. Chapple, Philip E. Van Kerrebroeck, Klaus-Peter Jünemann, Joseph T. Wang, Marina Brodsky

31. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
Urology ARTICLE IN PRESS Nov 13
N= 358 men fesoterodine 4 mg- n =120
fesoterodine 8 mg, n = 114
placebo, n =124
subanalysis of pooled data

32. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER
* P .05 vs placebo; † P .05 vs fesoterodine 4 mg.

33. ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER

34. Conclusions OAB is a highly prevalent condition
As our population ages, rates will increase
OAB has a large impact on our patient’s quality of life
Patients perceive benefit with therapy and improvements in quality of life have been demonstrated
Pharmacotherapy is better in combination with other non pharmacological therapies!!

35. Conclusions Multiple OAB agents are available
Many are well proven over years of use and
research
New choices do not necessarily mean better choices
Clinical effectiveness is key
Range of side effects and incidences
M1/M3 selectivity may lead to additional unwanted AEs

36. THANK YOU…