ApothekersEveraert.ppt [Compatibiliteitsmodus] · Nicturie Verminderen van de blaascontractiliteit...

15-3-2010

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LUTS en incontinentie

Praktische aanpak

11© 2008 Universitair Ziekenhuis Gent

pProf Dr K. Everaert

Functionele urologieContinentiekliniekDienst Urologie

Universitair Ziekenhuis GentGent, Belgium

http://www.kareleveraert.be/

Voorwaarden Continentie

Alle urine komt in de blaasBlaas voldoende groot


gVolledige plas zonder residuUrethra met voldoende weerstandGeen fistels

Blaas

Vullingsfaze:blaasspier ontspantplaskanaal dicht

Ledigingsfaze:bl i t kt

Continentie


Sluitspierurethra

blaasspier trekt samenplaskanaal open

Vanals iets verstoord krijgen we symptomen van de lagere urinewegen (LUTS) zoals:

incontinentieaandrang, nicturietrage straal, nadruppelen

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Vullings en ledigingsfaze van de blaasStoornissen van de ledigingsfaze:

BPH, bekkenbodemhypertonieHypo/acontractiele detrusor (bv diabetes)

symptomen: startproblemen, trage straal, moeizaam plassen,


y p p g pgevoel niet leeg te plassen, nadruppelen

Stoornissen van de vullingsfaze:

OAB (overactieve blaas)symptomen: urge, vele kleine plasjes, nicturie, bedplassen,

drang incontinentie

SI (stress-incontinentie of inspanningsgebonden verlies)symptomen: verliezen bij hoesten, niezen, springen, etc…

EPIC – LUTS are highly prevalent

80

100 Prevalence of LUTS

Men Women n=19,165


Irwin DE et al. Eur Urol 2006;50:1306–15

51.3

25.716.9

66.659.2

19.514.2

62.5

0

20

40

60

LUTS Storage Voiding Post-micturition

%

Wij behandelen dus eerder symptomen dan ziekten:

Vullingsfaze symptomen: Inspanning gebonden urineverlies

“SHIFT from disease oriented towards symptom oriented therapy”


Overactive blaasNicturie

Verminderen van de blaascontractiliteitVerbeteren van de outflow

Ledigingssymptomen: Slechte straal, nadruppelen, overloop incontinentie

Verbeteren van de blaascontractiliteitVerminderen van de outflow

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Symptoms of BPH:

Until eighties:Disease oriented approach of LUTS (BPH)


Voiding difficultiesPostmicturition dribbleStarting problemsUrgencyNocturia

Nocturia/OAB are as frequent in men as women

TURP – does not always decrease nocturia68% did t d t i i d 1

“SHIFT from disease oriented towards symptom oriented therapy”


68% did not decrease nocturia episodes1

OAB is aging disease of the bladder, improves but rarely dissapears after TURp

CONCLUSION: 1) 60% ⇓ need for TURp from 1968 -19982) treat nocturia; OAB instead of prostate

1. Yoshimura et al. Urology 2003;614:786; 2. Asplund. Can J Urol2002;9:1588–1591; 3. Borth et al. Urology 2001;57:1082–1085

Incontinentie prevalentie

Tussen 15 en 64 jaar1,5 – 5 % voor mannen


1,5 5 % voor mannen10 – 25 % voor vrouwen

Boven de 60 jaar prevalentie 15 – 30 %

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Prevalentie naargelang ernst van verlies

Dagelijks verlies: 5 – 9 % van de bevolking


Dagelijks verlies: 5 9 % van de bevolkingMan/vrouw verhouding van ¼Veroudering doet incontinentie toenemen vooral bij slechtere algemene toestand

Incontinentie behandelen ?

Hoeveel gaan raadplegen: 54 % bij erge graad 30 % voor de ganse groep!!!


30 % voor de ganse groep!!!

Nogal wat wensen niet behandeld te worden vooral vrouwen en ouderen

Vrouw Man

Inspanningsincontinentie 53 % 7 %

Drangincontinentie 14 % 40 %


Drangincontinentie 14 % 40 %

Gemengde 10 % 3%

Overloopsincontinentie, continue incontinentie,nadruppelen,….

23 % 50 %

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2° Prevalence of OAB in Patients Over 65 Years Old

32 3130%

40%MenWomen


23

912

19

0%

10%

20%

Overall Prevalence Prevalence OABWet

Prevalence OABDryData From the National Overactive BLadder Evaluation (NOBLE) Research Program.

NeurophysiologyEFFERENTS

1414© 2008 Universitair Ziekenhuis Gent Yoshimura N 2004

Graduele verwittiging van volheid van de blaasEerste drang (40% van de capaciteit)- 30 min ophouden kan

Sterke drang (70% van de capaciteit) – 15 min ophouden kan

Neurophysiology: Afferents


Volle blaas gevoel (vol is vol) - < 5 min tijd

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AFFERENTS


Steers W 2002

AFFERENTS : interstitial cells (Cajal like cells)Superficial network of IC: the sensing network (valinoied receptors), connect urothelium – nerve fibers – IC-cells off detrusor - detrusorDetrusor network of IC: modulators of autonomous activity, rather then pacemakers


y, p

- Purinergic P2Y receptor- Cholinergic M2-3 receptors- Vallinoied receptors

Van Der Aa Fr, 2007

Stress Urinary Incontinence


Treatment is surgery

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Pelvische reeducatie = een specialisatie in de kinesitherapie


Kine

Aanleren gevoel en bewustwordingElectrostimulatieBiofeedbackOefeningenCoordinatietraining


20

Drugtherapy of SI?


Chancellor M 2004

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Neural regulation of the innervation of the EUsphincter


Chancellor M 2004

NauseaDry MouthFatigueInsomniaConstipation

TEAEa

23.213.412.712.611.0

Discontinuationb

5.0c

0.21.4c

1.7c

0.3


HeadacheDizzinessSomnolenceDiarrhea

9.79.56.85.1

0.72.1c

1.0c

0.2

a Treatment Emergent Adverse Events with >5% incidence with duloxetine and significantly more common with duloxetine than placebo

b Discontinuations due to TEAEsc Significantly more common with duloxetine than placebo

Chirurgie inspanningsincontinentie

Burch, TVT, TOT, kunstsfincter,…)Resultaten korte termijn 80 90 %


Resultaten korte termijn 80 – 90 %Resultaten lange termijn 70 – 80 %

Let op incontinentie behandeling is veel meer dan Let op incontinentie behandeling is veel meer dan operatie alleenoperatie alleen

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TVT


TOT


Het netje voor de man


- lichte tot matige incontinentie

- 50-70% verbetering

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AS 800“Kunstsfincter”

Mechanisch systeem voor weerstandige


y gstressincontinentieDynamisch> 30 jaar bestaande

Stress Urinary Incontinence

Alpha-mimetics (Clarinase, Actifed)Imipramine (tricyclic antidepressant: anticholinergic, alphamimetic?): Tofranyl


alphamimetic?): TofranylDuloxetin (SNRI): Cymbalta, YentrevePhysiotherapy: increase sphincter/pelvic floor tone and strength, improve proprioception and reflexesEstrogens, no evidence-based effectSurgery (restore anatomical defect)


80


Men Women n=19,165



51.3

25.716.9

66.659.2

19.514.2

62.5

0

20

40

60


%

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EPIC – nocturia was the most common LUTS identified

54.548.6

40

50

60Prevalence of storage symptoms

n=19,165

Men Women

3131© 2008 Universitair Ziekenhuis Gent Irwin DE et al. Eur Urol 2006;50:1306–15

5.4

13.110.8

12.86.8 7.4

0

10

20

30

40

NocturiaIncontinenceUrgency Frequency

%

Overactive Bladder Symptoms (OAB)


Yoshimura N 2004

Overactive Bladder Symptoms (OAB)

3333© 2008 Universitair Ziekenhuis Gent Yoshimura N 2004

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Pharmacotherapy and OAB:

Antimuscarinic therapy:

T ti i t i b ti i t lt di


Tertiary amines: atropine, oxybutinine, tolterodine, darifenacine, fesoterodine, propiverine, solifenacineWell absorbed in GIT, diffusion in CNS depending on charge, size, etc…

Quaternary amines: probantheline, trospium chlorideLittle absorption in GIT, little diffusion in CNS

Passive Diffusion Across the BBB

↑ Lipophilicity,↑ diffusion

↑ Charge/polarity,

Vasculature CNSBBB

++


g p y,hydrogen bonding, ↓ diffusion

↓ Molecular size,↑ diffusion

Pardridge WM. J Neurochem. 1998;70:1781-92. Habgood MD, et al. Cell Mol Neurobiol. 2000;20:231-52.

-+ --

---++

+

+

Receptor Selectivity of Antimuscarinic Agents

SubtypeTolterodine

Ki (nM)Oxybutynin

Ki (nM)Darifenacin

Ki (nM)

M1 3.0 2.4 35.0


M2 3.8 6.7 56.0M3 3.4 0.67 1.2M4 5.0 2.0 18.0M5 3.4 11.0 9.0

*Adapted from Gillberg et al., 1998; Nilvebrant et al., 1997.

Lower number = greater receptor selectivity

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Oxybutinine TDSKentera (UCB)Minder bijwerkingen door minder N-deoxymetabolietenKlinische studies minder spectaculairOp de markt in België, geen terubetaling NDOHuidirritatie


Huidirritatie

DarifenacineEmselex (Ipsen), uitgesproken receptorspecifiekBest bestudeerd anticholinergicum bij de bejaarde

Regurin (Madaus), orgaanspecifiek, goedkoop!!!!Niet beschikbaar in België

Trospium chloride

Organ Selectivity of Antimuscarinic AgentsTolterodine:

Detrusitol 2mg 2/d


- Detrusitol 2mg, 2/dgeen terugbetalingduidelijk minder bijwerkingen en betere

compliance dan oxybutinineideaal voor kinderen, « indien-nodig indicatie »

- Detrusitol Retard (4mg), 1/dterugbetaling bij neurogeen blaaslijdenefficiënter en minder bijwerkingen dan

Detrusitol IR

Receptor/organ Selectivity of Antimuscarinic AgentsSolifenacin (Vesicare):

5 10 mg once daily


- 5-10 mg, once daily- M 2-3 selectivity (x 2 vs oxy, x 4 vs tolter, << darif)- bladder versus salivary glands (3 x higher vs all others)

selectivity in animals and humans (phase 2-3)- in animals no CNS symptoms up to 3 mg/kg- some more constipation- More efficaceous then tolterodine

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Fesoterodine5-HMTEsterases

Ubiquitous

Fesoterodine Conversion to 5-HMT Is Simple and Predictable

What Links Fesoterodine (ToviazR, Phizer) to Tolterodine?


CYP2D6

Liver, gut Tolterodine

PoorMetabolisers7%

Tolt

ExtensiveMetabolisers78%

Tolt

5-HMT

+

Tolt

Intermediate Metabolisers15%

5-HMT

+

Tolterodine Metabolism Is More Complex and Less Predictable

“Organ Selectivity”:5-HM Tolt is Less Lipophilic than Tolterodine

Tolterodine is a tertiary amine with minimal BBB penetration

The hyroxylation of tolterodine makes the molecule even less


The hyroxylation of tolterodine makes the molecule even less lipophilic, i.e., less able to enter the CNS

LogD value 0.74 for 5-HM tolterodine, vs. 1.83 for tolterodine

In the in vitro model of porcine brain endothelial cells, representative of human BBB, the permeability was found to be approximately 3-fold lower for 5-HM tolterodine compared to tolterodine

Pharmacotherapy and OAB: Considerations in the Elderly

Adverse events may occur more frequently, are present at lower doses, are more pronounced, and have a greater impact in the elderly:


Constipationfecal impaction

Blurred visionDry mouth

tooth decayCognitive impairment

Antimuscarinic therapy:

Lamy PP. Drugs and Aging. 1991;1:385-404.Mintzer and Burns. J R Soc Med. 2000;93:457-462.

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Anticholinergics and Potential Cognitive Impairment

Acetylcholine is a pivotal mediator of short-term memory Drugs from several therapeutic classes (eg, antihistamines antispasmodics antips chotics)


antihistamines, antispasmodics, antipsychotics) may cause cognitive impairmentOxybutinin, highly lipophyllic, tertiary amineA plead for darifenacine, fesoteridine, tolterodine, solifenacin or quaternary amines (trospium)combined use of donepezil, a central acetylcholinesterase inhibitor, and propiverine, a peripheral muscarine receptor antagonist

Drachman DA, et al. Neurobiol Aging. 1980;1:39-43. Sakakibara R. J Am Geriatr Soc. 2009, Katz IR, et al. J Am Geriatr Soc.1998;46:8-13.

Anticholinergics and Potential Cognitive Impairment

Antimuscarinics and Alzheimer: can we associate with cholinesterase inhibitors (donezepil – Aricept)

Does it decrease efficacy of donezepil?


y pIt seems feasable in certain patients with mild Alzheimer, but is not proven to be safe

Does donezepil increase incontinence? Yes, probably but not in all patients

Could adding donezepil to antimuscarinics prevent CNS side-effects? No information

Pharmacotherapy and OAB: Considerations in the Elderly

Antimuscarinic therapy:- Glaucoma: rarely an absolute contraindication, even not in narrow angle type!


not in narrow angle type!- Cytochrome P450 metabolisation in the liver- Secretion by renal tubules: trospium (not metabolised by P450 in liver)- Prolongation QT interval: not with available drugs in normal dosage- Increase hearth rate: tolterodine

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Therapie nicturie, bedplassen


1. Nachtelijke polyurie

2. Nicturie en OAB

3. Slaapstoornissen

Reduction in Nocturia Episodes During Treatment With Solifenacin: nocturia & OAB

00 10 20 30 40 50 60

Solifenacin Exposure Time (weeks)

Median baseline = 1.7 episodes/day


-60

-50

-40

-30

-20

-10

Med

ian

Cha

nge

(%)

-50%

Yamanouchi Data on File

LEVEL 2 evidence

Idem Toviaz

Als patiënten met nycturie en nachtelijke polyurie worden behandeld met desmopressine:

D i F i 0 5 1 l

Desmopressine en nycturie en bedplassen


• Desmopressine Ferring 0,5 -1 compr voor slapengaan

• verbeteren de symptomen in 75-80% van de gevallen• duurt de eerste periode van onverstoorde slaap langer• kan > 1 patiënt op de 3 weer normaal slapen• ontwikkelt slechts 5% van de patiënten een significante

hyponatriëmie1

1. Middelkoop H et al. J Gerontol 1996;51A:108–115 2. Cardozo L et al. J Urol 2004;172:1919–1924

3. Rudy D et al. Urology 2006;67:275–280

ICI, International Consultation on Incontinence*Nadien is aangetoond dat ook muscarineantagonisten een significant effect hebben2,3

LEVEL 1 evidence

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AnobotulinetoxineA of Botox® injecties

Met naald door een cystoscoop in de blaasspier inspuiten


blaasspier inspuiten(100-300 units)

Botuline Toxine in detrusor te herhalen na gem. 5-10 m

The Emerging Role of Botox:

- LE 1b, Graad A advies voor NDO door ICI

- LE 1b, graad B advies voor IDO door ICI


- Herinjecties om de 5-10 maand

- Lokale of algemene narcose

- maar off-label

- cave retentie en veralgemeende spierzwakte

Implantation

6-48 h hospitallocal-spinal-general A2 small incisions


2 small incisions

Lead site

Pocket site

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Future drugs


Chancellor M 2004

Beta-3 agonists actually in phase 3 trialsNO (Phosphodiesterase inhibitors), phase 2 trials

Purinergic system (ATP), Tachykinine, TRPV1 (capsaicin, RTX)?

AnticholinergicsAntidepressants (decrease detrusor contractility, increase outflow resistance)

Overactive Bladder Symptoms (OAB)Therapy:


Physiotherapy: increase sphincter/pelvic floor tone and strength, improve proprioception and reflexesEstrogens, no evidence-based effectBotulinumtoxin injections in detrusor (cystoscopy)Blocks most neurotransmitters, afferent and efferent!Most efficacious drug treatment availableReinjection's every 5-10 monthsSurgery: - Sacral Nerve Stimulation (see later)

- Bladderaugmentation, derivation


80


Men Women n=19,165



51.3

25.716.9

66.659.2

19.514.2

62.5

0

20

40

60


%

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Functional Voiding DifficultiesNormal uroflow


Dysfunctional Obstructive orHypo-Acontractile detrusor

Incontinence in children, a symptom complex

Daytime incontinence (OAB), enuresisDyschezia, incontinence for stoolsPain


Pain

15% of the 6 year old children suffer from enuresis1% of the young adults have enuresis30-35% of these children have pelvic floor dysfunction

> 40% overlap in symptoms:

Pelvic Floor Dysfunction in adults


OAB wetOAB dry

dysuria/retentionpelvic/perineal pain

constipation/dyscheziafaecal incontinence

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Therapy Functional Voiding DifficultiesDecrease outflow resistance:

1) Bladderneck/urethra: alpha-blockers, NO-releasers2) EUS: tetrazepam, baclofen3) Both: botulinum toxin injected in sphincter,

bladderneck and/or prostate (blocks synaptic release of


most neurotransmittors)Increase contractility: betanecholchlorideMyocholine GlenwoodPhysiotherapySacral nerve stimulation (see later)

Implantation

6-48 h hospitallocal-spinal-general A2 small incisions


2 small incisions

Lead site

Pocket site

Farmaca die incontinentie kunnen VEROORZAKEN

DiureticaAnticholinergica


gPsychofarmacaMorfine analgeticaAlfa adrenergicaAlfa lyticaBeta adrenergica-bronchospasmolytica

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CONCLUSIE:Niet – Medicamenteus: “holistische aanpak”

1) Pelvische reëducatiea. stoornissen van ledigings en vullingsfaze


a. stoornissen van ledigings en vullingsfazeb. pijnklachtenc. stoelgangsincontinentie en dyschezied. naast kiné ook blaastraining

2) Sacrale neuromodulatiea. stoornissen van ledigings en vullingsfazeb. pijnklachtenc. stoelgangsincontinentie en dyschezie

CONCLUSIE:Medicamenteus: Symptoom georiënteerde therapie:

1) Stoornissen van de vullingsfazea. overactieve blaas: anticholinergica, botulinetoxine


a. overactieve blaas: anticholinergica, botulinetoxineb. inspanning gebonden urineverlies: epinefrine, duloxetinec. nicturie-bedplassen: desmopressine, anticholinergica

2) Stoornissen van de ledigingsfazea. benigne prostaathypertrofie: alfa-blokkers en

5-alfa reductase remmersb. hypocontractiele blaas, sfincterhypertonie: alfa-blolkkers,

Myocholine Glenwood, botulinetoxine

ApothekersEveraert.ppt [Compatibiliteitsmodus] · Nicturie Verminderen van de blaascontractiliteit...

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Transcript of ApothekersEveraert.ppt [Compatibiliteitsmodus] · Nicturie Verminderen van de blaascontractiliteit...