Prof. Dr. K. Everaert, MD, PhD Universitair ziekenhuis Gent

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

2 BLAAS CONTRACTILITEIT
TONUS SFINCTERAPPARAAT RPS Everaert K. 1

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

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

5 Receptor Selectivity of Antimuscarinic Agents
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. Lower number = greater receptor selectivity *Phase 3 studies promising in humans *Adapted from Gillberg et al., 1998; Nilvebrant et al., 1997.

6 Receptor/organ Selectivity of Antimuscarinic Agents
Solifenacin (Vesicare): 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 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.

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

8 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 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.

9 Publications neurogenic
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): Trial with non-neurogenic patients under study

10 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

11 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

12 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

13 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

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

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

16 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.

17 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

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

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

20 NOCTURIA – desmopressin meta-analysis
Proven in elderly to decrease nocturia, nocturnal polyuria and improve Qol Risk hyponatremia: 7.6% (3-20%) - only shortime studies! - cardiac, renal co-morbidity excluded - drugs that can cause hyponatremia excluded Considerable caution and monitoring needed!!!: 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:

21 Reduction in Nocturia Episodes During Treatment With 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

22 Complete Remission* of Nocturia During Treatment With Solifenacin
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