Prof. Dr. K. Everaert, MD, PhD Universitair ziekenhuis Gent MEDICATIE VOOR LUTS Prof. Dr. K. Everaert, MD, PhD Functionele Urologie Universitair ziekenhuis Gent

BLAAS CONTRACTILITEIT TONUS SFINCTERAPPARAAT RPS Everaert K. 1

BLAAS CONTRACTILITEIT BETANECHOL CHLORIDE Muscaran Myocholine Glennwood Ubretid s.c. - p.o. p.o. ZWETEN ROODHEID KRAMPEN DIARREE NAUSEA RPS Everaert K.

BLAAS CONTRACTILITEIT Anticholinergica Oxybutinine: Ditropan, Dridase Tolderodine: Detrusitol, Detrusitol Retard Solufenacine: Vesicare Oxyphencyclimine Imipramine: Tofranyl Spierrelaxantia Flavoxate: Urispas Bijwerkingen: droge mond, constipatie, accomodatie stoornissen, centrale bijwerkingen, glaucoom, carries RPS Everaert K.

Pharmacotherapie: anticholinergica bij de geriatrische patiënt Constipatie fecale impactie Wazig zicht Droge monde carries Cognitieve achteruitgang Aggressie Nevenwerkingen meer frequent, bij lagere dosis, meer uitgesproken en met grotere impact The higher frequency and greater severity of adverse events in this population, even at lower treatment doses, also should carefully be considered when choosing pharmacotherapy The specific considerations that need to be addressed in the elderly are constipation and fecal impaction, particularly in bedridden patients blurred vision, which can lead to falls and other problems social isolation and cognitive impairment, which can lead to acute confusion and could possibly be misdiagnosed as dementia effects on the salivary gland that can cause dry mouth leading to tooth decay Lamy PP. Drugs and Aging. 1991;1:385-404. Mintzer and Burns. J R Soc Med. 2000;93:457-462.

Anticholinergica en potentieel cognitieve achteruitgang Acetylcholine is belangrijke mediator voor korte termijn geheugen Ook andere medicatie kan cognitieve achteruitgang veroorzaken (antihistaminica, antispasmodica, anti-psychotica) Dubbel blind, placebo gecontroleerde crossover studie: placebo, oxybutynine 5 mg en 10 mg (n = 12 gezonde vrijwilligers, leeftijd 65–76) Pleidooi voor tolterodine, solifenacin Drachman DA, et al. Neurobiol Aging. 1980;1:39-43. Katz IR, et al. J Am Geriatr Soc.1998;46:8-13.

Urinaire anticholinergica en cardiaal risico bij patiënten met OAB Retrospectieve cohort analyse 14.638 patiënten met urge incontinentie 65 jaar: mediane leeftijd ~ 79j Resultaten: geen associatie tussen gebruik urinaire anticholinergica en verhoogd risico op ventriculaire arrythmie of plotse dood Wang PS et al. J Am Geriatr Soc. 2002;50:117-124.

Receptor Selectiviteit van anticholinergica Subtype Tolterodine Ki (nM) Oxybutynin Ki (nM) Darifenacin Ki (nM) M1 3.0 2.4 35.0 M2 3.8 6.7 56.0 M3 3.4 0.67 1.2 M4 5.0 2.0 18.0 M5 11.0 9.0 This slide compares receptor selectivity for tolterodine, oxybutynin, and darifenacin, with lower numbers indicating higher selectivity. The non receptor selectivity of tolterodine are clear from these data. Lager cijfer = hogere receptor selectiviteit *fase 3 studies veelbelovend *Adapted from Gillberg et al., 1998; Nilvebrant et al., 1997.

Passieve diffusie over de bloedhersenbarrière Vasculature BBB CNS  Lipofiel,  diffusie  lading/polariteit, binding aan waterstof,  diffusie  Moleculaire afmeting,  diffusie - + Pardridge WM. J Neurochem. 1998;70:1781-92. Habgood MD, et al. Cell Mol Neurobiol. 2000;20:231-52.

Anticholinergica: passage door bloedhersenbarrière Vasculature BBB CNS High lipophilicity, neutral, relatively “small” molecular structure Oxybutynin Low lipophilicity, charged, relatively bulky molecular structure + Tolterodine/active metabolite + + + + + + + + Trospium chloride Highly polar + + + + + + + + + + + + + + + Dimpfel W. J Urol 2000;163(4):226 abstract.

Receptor/orgaan Selectiviteit van anticholinergica Solufenacin (Vesicare): M 2-3 selectiviteit (x 2 vs oxy, x 4 vs tolter, << darif) blaas versus speekselklieren (3 x hoger vs alle andere) selectiviteit bij dier en mens (phase 2-3) - Bij dieren geen centrale symptomen tot 3 mg/kg This slide compares receptor selectivity for tolterodine, oxybutynin, and darifenacin, with lower numbers indicating higher selectivity. The non receptor selectivity of tolterodine are clear from these data.

Oxybutinine TDS Darifenacine Trospium chloride Kentera (UCB) Minder bijwerkingen door minder N-deoxymetabolieten Klinische studies minder spectaculair Sinds kort op de markt in België Darifenacine Emselex (Novartis), uitgesproken receptorspecifiek Trospium chloride Regurin (Madaus), orgaanspecifiek, goedkoop!!!!

Biologische neuromodulatie Vanilloieden: Capsaicine, Resiniferatoxine (RTX) Via vanilloied receptoren op C-vezels neurogene OAB en Blaaspijn blokkeren, werkt niet voor idiopatische OAB. Via vanilloied recepto Conotoxine (uit slakken) Blokkeert nicotine receptoren = sfincter paralyse Botuline toxine: Botox, Disport Blokkeert niet enkel Ac Col maar ook norepinephrine, ATP, sub P, CGRP, ATP, NO, glutamaat release Vandaar effect bij idiop OAB, hyperreflexie en IC RPS Everaert K.

Publicaties bij neurogene blaas BT-A for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. Schurch B, Stöhrer M, Kramer G, Schmid D, Gaul G, Hauri D. J Urol 2000;164:692-7. BT is a safe and effective treatment for neurogenic urinary incontinence: results from a randomised, placebo controlled study. Schurch b, de Sèze M, Denys P, Chartier Kastler E, Haab F, Everaert K, Plante P, Perrouin-Verbe B, Kumar C, Fraczek S, Brin M. J Urol 2005; 174(1):196-200. Trial with non-neurogenic patients under study

Reduction in number of UI episodes compared to baseline (%) Results: UI Episodes * † *† *† † † † Reduction in number of UI episodes compared to baseline (%) † *p<0.05 for differences between BTX (BOTOX®) group and placebo †p<0.05 for difference within-group changes from baseline

Results: Urodynamics – MCC 300 U BTX 200 U BTX Placebo *† *† *† *† *† Mean increase in MCC from baseline (ml) * *p<0.05 for within-group changes from baseline †p<0.05 for pairwise contrasts between BTX (BOTOX®) groups versus placebo

Results: Urodynamics – MDP 300 U BTX 200 U BTX Placebo *† *† *† *† *† Mean reduction in MDP (cmH2O) *† *p<0.05 for within-group changes from baseline †p<0.05 for pairwise contrasts between BTX (BOTOX®) groups versus placebo

Results: Quality of Life 300 U BTX 200 U BTX Placebo *† *† *† *† *† *† *† *† *† Increase in Total I-QoL Score from baseline (%) *† Week 2 Week 6 Week 12 Week 18 Week 24 *p<0.05 for pairwise contrasts between BTX (BOTOX®) groups and placebo †p≤0.002 for within-group differences from baseline

Solifenacin Effect on Incontinence, Urgency and Volume Voided Incontinence/24 hr Urgency/24 hr Volume voided/micturition 50 4 40 *** *** 3 *** *** 30 Mean decrease in numbers 2 *** Mean increase (ml) ** ** 20 1 10 Baseline 2.7 2.7 2.6 2.3 5.3 5.8 5.8 5.4 144 150 147 147 This slide shows results for the other efficacy parameters. Placebo Solifenacin 5 mg Solifenacin 10 mg Tolterodine 2 mg bd P Values: * <0.05 ** <0.01 *** < 0.001 Chapple et al BJU 2004 93;303-310

Publicaties niet neurogeen? 10-tal rapporten geen duidelijkheid over dosis (wellicht 50-150 units Botox of 250 units Disport), injectieplaats, aantal injecties, veiligheid geen bewijs van veiligheid: risico op urine retentie is reëel, cave: bejaarden antidepressiva Parkinson, hernia, latente MS BPH, prolaps kan onder lokale anesthesie en poliklinisch maakt van een niet neurogene blaas een neurogene blaas

TONUS SFINCTERAPPARAAT  EPHEDRINE, PSEUDO EPHEDRINE, NOREPHIDRINE, … PHENYLPROPANOLAMINE : IMIPRAMINE : DULOXETINE  Clarinase Cirrus ...  Tofranyl Yentreve RPS Everaert K.

Tonus sfincter apparaat Alfa receptor blokkers: Omic, Hytrin, Xatral Bijwerkingen: hypotensie, sufheid, orthostatisme Baclofen (Lioresal), benzodiazepines (Valium) Bijwerkingen: veralgemeende spierzwakte, sufheid Botuline toxine in de sfincter: 3-4 maand effect zelden SI effect op mictie en pijn klachten    RPS Everaert K.

OESTROGENEN OESTROGENEN EBM: geen effect! P.O. TRANSDERMAAL VAGINAAL RPS Everaert K. OESTROGENEN OESTROGENEN EBM: geen effect! P.O. TRANSDERMAAL VAGINAAL P.O. TRANSDERMAAL VAGINAAL Aacifemine, Premazin Extraderm, Systen, Oestrogel Aacifemine, Premazin Extraderm, Systen, Oestrogel TONUS BEKKENBODEM SLIJMVLIES VAGINA EN BLAAS BLAASPRIKKELING TONUS BEKKENBODEM SLIJMVLIES VAGINA EN BLAAS BLAASPRIKKELING

Antidepressiva  TRICYCLISCHE ANTIDEPRESSIVA: imipramine anticholinerg betamimetisch alfamimetisch centraal effect? antidiuretisch? Bijw: droge mond, constipatie, orthostatisme, cardiotoxicicteit SSRI: duloxetine verhoogt sfinctertonus (centraal) bewezen effect op OAB (centraal) Bijw: nausea, seksuele dysfunctie  RPS Everaert K.

Urgency, pijn, inflammatie bij interstitiële cystitis DMSO (25-50%): lokaal anti-inflammatoir pijnlijk vergt instillatie stinkt vreselijk berust op empirie Redomex (diffucaps 25-75 mg/d) RPS Everaert K.

NOCTURIE – desmopressine meta-analyse Bewezen vermindering nocturie, nachtelijke polyurie en verbetering QOL Risico hyponatriëmie: 7.6% (3-20%) - korte follow-up! - cardiale, renale co-morbiditeit exclusie - geen andere medicatie die hyponatriëmie kan veroorzaken Voorzichtigheid en monitoring aangewezen monitoring!!: bloedanalyse dag 3 en 7 Minirin (1-4 puffs bij slapengaan), Desmopressine Ferring (1-2 pillen 1 uur voor slapengaan) The elderly adult takes an average of 5 medications (not including vitamins) One study found that 10 of the top 25 prescribed drugs in the elderly had some anticholinergic properties Possible drug effects to consider are those that may cause symptoms that mimic those of OAB, from medications including diuretics and the antihypertensives. Treatment schedules can be manipulated to minimize possible complications between OAB therapies and these medications that also effect filling and voiding Other considerations include: effects from the acetylcholinesterase inhibitors, that primarily act on M1 receptors within the brain, but their effects on the micturition axis are unknown. anticholinergic adverse effects of medications, eg, the antidepressants, antihistamines, antipsychotics, and over‑the‑counter sleep aids like Tylenol PM® (acetaminophen and diphenhydramine). These effects may be augmented by the addition of an antimuscarinic agent. Thus, regimen’s must be scrutinized for potential interactions. Weatherall M. J Neurourol Urodyn 2004;23:302-305.

Reductie in nocturie episodes bij behandeling met solifenacin Solifenacin Exposure Time (weeks) Median baseline = 1.7 episodes/day Median Change (%) -50% This slide shows the median change in nocturia episodes over 52 weeks for all patients on solifenacin. It shows that the effect of solifenacin on nocturia is maintained during long term therapy. Yamanouchi Data on File

Complete Remissie* van nocturie bij behandeling met solifenacine 23.5% Percent This slide shows those who were defined as having complete remission of their nocturia symptoms at 52 weeks For nocturia, a subject in remission is defined as one who had at least one episode of nocturia at baseline but no episodes of nocturia during the specified on-treatment diary period. Solifenacin Exposure Time (weeks) *For nocturia, a subject in remission is defined as one who had at least one episode of nocturia at baseline but no episodes of nocturia during the specified on-treatment diary period. Yamanouchi Data on File