1. Darifenacin Hydrobromide

2. Overactive Bladder OAB 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
Among the symptoms of OAB, frequency is defined as eight or more visits to the toilet per 24-hour period, two or more of which may be during the night.
Urgency is defined as a sudden, strong desire to urinate.
Urge incontinence is defined as the sudden, involuntary loss of urine.
OAB 2

4. Muscarinic receptors

5. Treatment Antimuscarinic drugs First-generation----e.g Oxybutynin
(primarily selective)
Second-generation---- e.g Tolterodine
(balanced selective M2/M3)
New drugs----e.g Darifenacin
(M3 selective receptor antagonis)

6. Darifenacin hydrobromide
----A potent and competitive M3 selective receptor antagonist
a white to almost white, crystalline powder.
Brand name : Emselex
Synonyms: (S)-2-{1-[2-(2,3-Dihydrobenzofuran-5-yl)Ethyl]-3-Pyrrolidinyl}-2,2-Diphenylacetamide Hydrobromide
HBr

7. Manufacturer: Novartis & Pfizer
Oct —European Commission has granted Marketing Authorization Emselex for the treatment of overactive.
Dec —FDA has approved darifenacin HBr for the treatment of OAB.

8. The structure-activity relationship
Part A imidazole ring being replaced by alkyl will significantly affect anti-cholinergic receptor activity and selectivity;
Part B for the connecting part, usually two carbon anticholinergic activity at best. carbon chain growes, activity will decrease;

9. The structure-activity relationship
Part C of the amide or H atom, anticholinergic activity and M3 receptor selectivity better, N-monosubstituted, N, N-disubstituted or ester is anticholinergic activity decreases even without anticholinergic activity.

10. The structure-activity relationship
Part D benzene generally no replaced if heterocyclic or alkyl replace it activity decreases, one of benzene may be replaced by six atom ring : Oxybutynin.

11. Synthesis:

12. Pharmacodynamics of darifenacin

13. Darifenacin
Darifenacin is a competitive muscarinic receptor antagonist labeled for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

14. Mechanism of OAB
The symptoms of OAB are thought to result from involuntary contractions of the detrusor muscle during the bladder filling phase.

15. Receptors in bladder tissue
M2，M3 muscarinic receptors with a ratio of 3:1 exist in human bladder tissue. Although the density of M2 receptors is much greater than that of the M3 subtype, M3 receptor subtype is predominant in the mediation of bladder contraction.

16. M3 receptor
M3 are responsible for urinary bladder contraction,gastrointestinal smooth muscle contraction, saliva production, and iris sphincter regulation.

17. Mechanism of Action
Darifenacin has been shown to have high affinity and selectivity for the muscarinic M3 receptor, with low selectivity for the other muscarinic receptor subtypes.

19. Effect Help to reduce the incidence of urinary incontinence .
Increase urinary bladder reserves .
Reduce the frequency of urination.
Reduce the oppressive sense of eager to urinate and urinary urgency sense.

20. dry mouth constipation blurred vision heat prostration others
side effects
dry mouth
constipation
blurred vision
heat prostration
others

21. Pharmacokinetic properties
Darifenacin is metabolised by CYP3A4 and CYP2D6.

22. CYP3A4
CYP2D6

23. Absorption

25. ENABLEX® 7.5 mg (N = 68 EM, 5 PM)
ENABLEX®15 mg (N = 102 EM, 17 PM)
AUC24 (ng.h/mL)
Cmax (ng/mL)
Cavg (ng/mL)
Tmax (h)
t1/2 (h) EM
29.24 (15.47)
2.01 (1.04)
1.22 (0.64)
6.49 (4.19)
12.43 (5.64) a
88.90 (67.87)
5.76 (4.24)
3.70 (2.83)
7.61 (5.06)
12.05 (12.37) b PM
67.56 (13.13)
4.27 (0.98)
2.81 (0.55)
5.20 (1.79)
19.95 c
(77.08)
9.99 (5.09)
6.58 (3.22)
6.71 (3.58)
7.40 d

27. Distribution lipophilic base 98% bound to plasma proteins
Vss =163 litres

28. Metabolism Darifenacin metabolism (oral administration)
CYP3A4 CYP2D6 in the liver
CYP3A4 in the gut wall

29. three main metabolic routes
monohydroxylation in the dihydrobenzofuran ring
dihydrobenzofuran ring opening
N-dealkylation of the pyrrolidine nitrogen

30. CYP3A4

31. CYP2D6

32. CYP2D6/CYP3A4

33. Excretion
Following administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the faeces. Only a small percentage of the excreted dose was unchanged darifenacin (3%).

34. Comparison of Darifenacin with Other Antimuscarinics

36. Efficacy against urinary frequency

37. NICE states that :
there is NO evidence of clinically important efficacy differences among antimuscarinic drugs

38. Adverse events

39. Selected adverse events

40. Selection of antimuscarinic drug for treatment of OAB

42. NICE states that :
Non-proprietary, immediate-release oxybutynin, which is the most cost-effective of the available options, should be offered as first-line antimuscarinic if bladder training is ineffective.
If not tolerated, darifenacin, solifenacin, tolterodine, trospium or an extended-release or transdermal formulations of oxybutynin should be considered.

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Wang Yan
Gao Wei

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