Darifenacin hydrobromide
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Darifenacin Hydrobromide. Overactive Bladder. Frequency 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.

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Overactive bladder
Overactive Bladder

  • Frequency

  • 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


Muscarinic receptors


Treatment
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)


----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

Darifenacin hydrobromide

HBr


Manufacturer: antagonist Novartis & Pfizer

Oct.28.2004—European Commission has granted Marketing Authorization Emselex for the treatment of overactive.

Dec.23.2004—FDA has approved darifenacin HBr for the treatment of OAB.


The structure activity relationship
The structure-activity relationship antagonist

  • 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;


The structure activity relationship1
The structure-activity relationship antagonist

  • 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.


The structure activity relationship2
The structure-activity relationship antagonist

  • 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.


Synthesis
Synthesis: antagonist



Darifenacin
Darifenacin antagonist

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


Mechanism of oab

Mechanism of OAB antagonist

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


Receptors in bladder tissue

Receptors in bladder tissue antagonist

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.


M3 receptor

M3 receptor antagonist

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


Mechanism of action

Mechanism of Action antagonist

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


Effect
Effect antagonist

  • 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.


Side effects

side effects antagonist

dry mouth

constipation

blurred vision

heat prostration

others


Pharmacokinetic properties
Pharmacokinetic properties antagonist

Darifenacin is metabolised by CYP3A4 and CYP2D6.


CYP3A4 antagonist

CYP2D6


Absorption
Absorption antagonist


Distribution
Distribution antagonist

  • lipophilic base

  • 98% bound to plasma proteins

  • Vss =163 litres


Metabolism
Metabolism antagonist

Darifenacin metabolism(oral administration)

  • CYP3A4 CYP2D6 in the liver

  • CYP3A4 in the gut wall


Three main metabolic routes
three main metabolic routes antagonist

  • monohydroxylation in the dihydrobenzofuran ring

  • dihydrobenzofuran ring opening

  • N-dealkylation of the pyrrolidine nitrogen


CYP3A4 antagonist


CYP2D6 antagonist


CYP2D6/CYP3A4 antagonist


Excretion
Excretion antagonist

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%).




NICE states that : antagonist

  • there is NO evidence of clinically important efficacy differences among antimuscarinic drugs


Adverse events antagonist




NICE states that : antagonist

  • 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.


Members
MEMBERS antagonist

  • 0440101 Cui Sisi

  • 0440118 Wang Lutai

  • 0441707 Lu Lisha

  • 0440220 Wang Yan

  • 0440211 Gao Wei


THANK YOU! antagonist