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4th ICI Lecture Series: Drug treatment (Committee 8)

Presented by Karl-Erik Andersson, MD, PhD, and Christopher Chapple, MD, et al., at the Fourth International Consultation on Incontinence (ICI) - July 5 - 8, 2008. Palais des Congres, Paris, France.


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Committee Committee 8: 8: Drug Treatment Drug Treatment ommittee 8: 8: Drug Treatment Drug Treatment Chairmen Chairmen: : K-E K-E Andersson (USA), C R Chapple (UK), Andersson (USA), C R Chapple (UK), Members Members: : L L Cardozo (UK), F Cruz (Portugal), Cardozo (UK), F Cruz (Portugal), C Hampel (Germany), H Hashim (UK) C Hampel (Germany), H Hashim (UK) M Michel (Holland), C Tannenbaum (Canada), M Michel (Holland), C Tannenbaum (Canada), A A Wein (USA) Wein (USA) K-E Andersson: K-E Andersson: Astellas, Pfizer, Novartis, Allergan Astellas, Pfizer, Novartis, Allergan, , Xention Xention C R Chapple: C R Chapple: Astellas, Pfizer, Novartis, Allergan, Xention, Recordati Astellas, Pfizer, Novartis, Allergan, Xention, Recordati L Cardozo: L Cardozo: Astellas, Pfizer, Schering Astellas, Pfizer, Schering F Cruz: F Cruz: Allergan, Mt Cook Allergan, Mt Cook C Hampel: C Hampel: Allergan, Astellas, Bayer, Lilly Allergan, Astellas, Bayer, Lilly H Hashim: H Hashim: Ferring Ferring M Michel: M Michel: Astellas, Bayer Boehringer, Lilly, Elbion, Pfizer, Theravance Astellas, Bayer Boehringer, Lilly, Elbion, Pfizer, Theravance C Tannenbaum: C Tannenbaum: None None A Wein (USA): A Wein (USA): Astellas, Pfizer, Novartis, Allergan Astellas, Pfizer, Novartis, Allergan Disclosures Disclosures Lower Urinary Tract Symptoms (LUTS): Lower Urinary Tract Symptoms (LUTS): ICS ICS definition definition Abrams Abrams et al., et al., Neurourol Urodyn Neurourol Urodyn, 21:167, 2002 , 21:167, 2002 “ “Lower urinary tract symptoms are defined from the Lower urinary tract symptoms are defined from the individual´s individual´s perspective, who is usually, but not perspective, who is usually, but not necessarily, a patient within the health care system. necessarily, a patient within the health care system. Symptoms are either volunteered by, or elicited from, Symptoms are either volunteered by, or elicited from, the individual or may be described by the the individual or may be described by the individual´s individual´s caregiver. caregiver. Lower urinary tract symptoms are divided Lower urinary tract symptoms are divided into 3 groups, storage, voiding and post into 3 groups, storage, voiding and post micturition micturition symptoms. symptoms.” ” ” ”Urgency Urgency, with or , with or without urge incontinence without urge incontinence, , usually usually with with frequency frequency and and nocturia nocturia, , can can be be described described as the as the overactive overactive bladder bladder syndrome syndrome, , urgency urgency syndrome syndrome, or , or urgency urgency- - frequency syndrome frequency syndrome” ” Overactive Overactive Bladder Bladder Syndrome (OAB): Syndrome (OAB): ICS ICS definition definition Abrams Abrams et al., et al., Neurourol Urodyn Neurourol Urodyn, , 2002;21:167; 2002;21:167; Abrams et al., Abrams et al., Neurourol Neurourol Urodyn Urodyn, 2006;25:293 , 2006;25:293   Neurogenic Neurogenic detrusor detrusor overactivity overactivity ( (previously hyperreflexia previously hyperreflexia): ): when there when there is a is a relevant relevant neurological condition neurological condition   Idiopathic detrusor overactivity Idiopathic detrusor overactivity: : when there when there is no is no defined cause defined cause ” ”a a urodynamic urodynamic observation observation characterized characterized by by involuntary detrusor contractions during involuntary detrusor contractions during the the filling phase which may filling phase which may be be spontaneous spontaneous or or provoked provoked” ” Detrusor Detrusor Overactivity (DO): Overactivity (DO): ICS ICS definition definition Abrams Abrams et al., et al., Neurourol Urodyn Neurourol Urodyn, 21:167, 2002 , 21:167, 2002 Pathophysiology Pathophysiology of the of the Overactive Overactive Bladder Bladder Myogenic activity and Myogenic activity and increased sensitivity to increased sensitivity to contraction-mediating contraction-mediating transmitters and mediators transmitters and mediators Increased afferent Increased afferent activity activity Decreased capacity Decreased capacity to handle to handle afferent information afferent information Decreased suprapontine Decreased suprapontine inhibition inhibition Andersson Andersson, , Lancet Neurol. Lancet Neurol. 2004 Jan;3(1):46-53 2004 Jan;3(1):46-53   Antimuscarinics Antimuscarinics   Antidepressants Antidepressants   Alpha- Alpha-adrenoceptor adrenoceptor antagonists antagonists   Beta- Beta-adrenoceptor adrenoceptor agonists agonists   Phosphodiesterase Phosphodiesterase inhibitors inhibitors   COX inhibitors COX inhibitors   Vasopressin analogues Vasopressin analogues   Toxins Toxins ( (Botulinum Botulinum, , Vanilloids Vanilloids) )   Estrogens Estrogens   Other Drugs Other Drugs (Baclofen, Opioids, Gabapentin, (Baclofen, Opioids, Gabapentin, NK-1 receptor antagonists NK-1 receptor antagonists) ) Drugs for Treatment of Overactive Bladder (OAB) Drugs for Treatment of Overactive Bladder (OAB) and Detrusor Overactivity (DO) and Detrusor Overactivity (DO) Lamina Lamina propria propria Muscularis Muscularis mucosae mucosae Detrusor Detrusor Basal Basal membrane membrane Urothelium Urothelium A Aδ δ fiber fiber C-fiber C-fiber C-fiber C-fiber IC = IC = interstitial interstitial cells cells IC IC IC IC M M 3 3 M M 3 3 M M 3 3 M M 2 2 M M 2 2 M M 2 2 M M 2 2 M M 3 3 Muscarinic Receptor Subtypes Muscarinic Receptor Subtypes in Human Urothelium in Human Urothelium Bschleipfer et al., Life Sci, Febr 2007 Bschleipfer et al., Life Sci, Febr 2007 Efferent nerve (no activity) Enhanced spontaneous contractions C-fibres? Detrusor Overactivity: Myocyte Activity during Filling Enhanced Enhanced afferent afferent activity activity Nerve damage + ACh ACh ACh ACh + Local Factors + Detrusor Overactivity: Initiation of Micturition Reflex Efferent nerve (no activity) Afferent activity Aδ−fibres Distension Afferent activity C-fibres Spontaneous (”myogenic”) contractions Nerve damage ACh ACh + Local Factors ACh ACh + + K-E Andersson, 2007 K-E Andersson, 2007 C: saline C: saline D: oxybutynin D: oxybutynin C fibre-activity C fibre-activity De Laet et al., Neurourol Urodyn, 2006;25156-161 De Laet et al., Neurourol Urodyn, 2006;25156-161 Effect of Systemic Oxybutynin on Bladder Afferent Activity Effect of Systemic Oxybutynin on Bladder Afferent Activity Effect of Systemic Oxybutynin on Bladder Afferent Activity Effect of Systemic Oxybutynin on Bladder Afferent Activity A: saline A: saline B: oxybutynin B: oxybutynin A Aδ δ-fibre activity -fibre activity De Laet et al., Neurourol Urodyn, 2006;25156-161 De Laet et al., Neurourol Urodyn, 2006;25156-161  Antimuscarinics Antimuscarinics are active during the filling phase are active during the filling phase when there is no activity in the cholinergic nerves when there is no activity in the cholinergic nerves  ACh ACh can be generated and released from the can be generated and released from the urothelium urothelium and may also and may also “ “leak leak” ” from cholinergic from cholinergic nerves during filling of the bladder nerves during filling of the bladder Antimuscarinics Antimuscarinics for OAB Treatment for OAB Treatment Urothelium – derived ATP Release of ACh from nerves and urothelium (?) Filling-induced stretch of detrusor cells Activation of intramural afferent nerves Enhancement of myogenic activity Activation of suburothelial afferent nerves Increased afferent nerve activity Initiation of micturition Antimuscarinics Bladder Bladder Effects Effects of Antimuscarinics of Antimuscarinics Rationale for Use of Rationale for Use of Antimuscarinics Antimuscarinics in OAB in OAB Blockade of muscarinic receptors at both detrusor and non- detrusor sites may prevent OAB symptoms and detrusor overactivity without depressing the contraction during voiding Effects on afferent activity (myocyte + urothelium) Effects on voiding contraction Concentration of antimuscarinic ”Therapeutic window” for OAB Key Issues Key Issues   Pharmacology Pharmacology - - Subtype selectivity Subtype selectivity - Pharmacokinetics - Pharmacokinetics - Dosing frequency - Dosing frequency   Dose Flexibility Dose Flexibility   Efficacy Efficacy   Tolerability Tolerability   Safety Safety Target population Target population   Most data is based on female patients Most data is based on female patients   Male patients need to be considered Male patients need to be considered based on symptoms: based on symptoms: - - Storage LUTS Storage LUTS - Voiding and Storage LUTS - Voiding and Storage LUTS   Age is an important factor Age is an important factor   Limited data on the frail elderly Limited data on the frail elderly   Consequences of Consequences of polypharmacy polypharmacy   Other populations are poorly documented Other populations are poorly documented - - Neuropaths Neuropaths - Children - Children Achieving Clinical Satisfaction Achieving Clinical Satisfaction Diagnosis Diagnosis Relieving symptoms of Relieving symptoms of OAB relevant to the patient OAB relevant to the patient Minimisation of side effects Minimisation of side effects that are most bothersome for that are most bothersome for the patient the patient Achieving Balance Achieving Balance Efficacy Efficacy Successful Successful Outcome Outcome Tolerability Tolerability Clinical and QOL assessment Clinical and QOL assessment of patient of patient OAB Syndrome: A symptomatic sequence OAB Syndrome: A symptomatic sequence Chapple Chapple CR, et al. BJU CR, et al. BJU Int Int 2005;95:335 2005;95:335– –40 40 Nocturia Nocturia Urgency Urgency Incontinence Incontinence Reduced Reduced Volume Voided/ Volume Voided/Micturition Micturition Reduced Reduced Intervoid Intervoid Interval Interval ( (Increased Frequency) Increased Frequency) 1/3 1/3 Antimuscarinics Antimuscarinics Non- Non-subtype selective subtype selective   Atropine Atropine, , hyoscyamine hyoscyamine   Propantheline Propantheline   Tolterodine Tolterodine   Fesoterodine Fesoterodine   Trospium Trospium   Solifenacin Solifenacin Subtype Subtype selective selective (M (M 3 3) )   Darifenacin Darifenacin Atropa Atropa belladonna belladonna Antimuscarinics: Level Grade Tolterodine Tolterodine 1 1 A A Fesoterodine Fesoterodine 1 1 A A Trospium Trospium 1 1 A A Darifenacin Darifenacin 1 1 A A Solifenacin Solifenacin 1 1 A A Propantheline Propantheline 2 2 B B Atropine Atropine, , hyoscyamine hyoscyamine 3 3 C C ICI assessments ICI assessments Antimuscarinic + other actions (”mixed actions”)   Oxybutynin Oxybutynin   Propiverine Propiverine   (Dicyclomine) (Dicyclomine)   (Flavoxate) (Flavoxate) Ca2+ channels Atropa belladonna Drugs with mixed actions Drugs with mixed actions Drugs Drugs with with mixed Level mixed Level Grade Grade actions actions Oxybutynin Oxybutynin 1 1 A A Propiverine Propiverine 1 1 A A (Dicyclomine (Dicyclomine 3 3 C) C) (Flavoxate (Flavoxate 2 2 D) D) ICI assessments ICI assessments Imipramine  Antidepressant; complex pharmacological profile, including non-subtype selective antimuscarinic effect  Possible effects on AVP release and renal proximal tubular Na+ and water reabsorption Antidepressants Antidepressants ” ”Imipramine prolonged Imipramine prolonged the PR (p<0.001), QRS (p<0.001) and the PR (p<0.001), QRS (p<0.001) and QTc QTc (p<0.001) intervals, (p<0.001) intervals, increased increased the heart the heart rate rate (p<0.001) (p<0.001) and and lowered lowered T- T-wave amplitude wave amplitude (p<0.05) (p<0.05)” ” Drug Drug Level Grade Imipramine Imipramine 3 3 C* C* Duloxetine Duloxetine 2 2 B* B* ICI assessment ICI assessment * * Should Should be be used used with with caution. Not caution. Not approved for the approved for the indication indication Vasopressin Desmopressin (DDAVP) Vasopressin analogues Vasopressin analogues  Antidiuretic Antidiuretic, no direct bladder effect , no direct bladder effect  No direct cardiovascular actions No direct cardiovascular actions Desmopressin Desmopressin Drug Drug Level Level Grade Grade Desmopressin Desmopressin 1 1 A* A* * Beware * Beware hyponatremia hyponatremia and and water water retention retention ICI assessment - nocturia ICI assessment - nocturia Drug Drug Level Level Grade Grade Desmopressin Desmopressin 2 2 C* C* * Beware * Beware hyponatremia hyponatremia and and water water retention retention ICI assessment - OAB ICI assessment - OAB Drug Drug Level Level Grade Grade α α1 1-AR -AR antagonists antagonists 1 1 D D ( (alfuzosin alfuzosin, , doxazosin doxazosin, , terazosin terazosin, , tamsulosin) tamsulosin) ICI assessments ICI assessments Drug Drug Level Level Grade Grade β β2 2-AR -AR agonists agonists 3 3 C C ( (terbutaline terbutaline, , salbutamol salbutamol, , clenbuterol) clenbuterol) β β3 3-AR agonists -AR agonists 2 2 B B ICI assessments ICI assessments Drug Drug Level Level Grade Grade Phosphodiesterase Phosphodiesterase 1 1 B B type 5 inhibitors type 5 inhibitors (sildenafil, tadalafil (sildenafil, tadalafil vardenafil) vardenafil) ICI assessments ICI assessments Drug Drug Level Level Grade Grade Indomethacin Indomethacin 2 2 C C Flurbiprofen Flurbiprofen 2 2 C C ICI assessments ICI assessments Cox inhibitors Cox inhibitors Vanilloids Vanilloids ( (intravesical intravesical) )   Capsaicin Capsaicin   Resiniferatoxin Resiniferatoxin Botulinum toxin (bladder wall) Botulinum toxin (bladder wall) Toxins Toxins Drugs for OAB/DO Drugs for OAB/DO Drug Drug Level Level Grade Grade Capsaicin* Capsaicin* 2 2 C C Resiniferatoxin Resiniferatoxin* * 2 2 C C Botulinum Botulinum toxin A** toxin A** 2 2 A A Botulinum Botulinum toxin B** toxin B** 3 3 C C * *Intravesical Intravesical; ; ** **Bladder Bladder wall wall ICI assessments ICI assessments Neurogenic DO Neurogenic DO Drug Drug Level Level Grade Grade Resiniferatoxin Resiniferatoxin* * 3 3 C C Botulinum Botulinum toxin A** toxin A** 2 2 B B Botulinum Botulinum toxin B** toxin B** 3 3 C C * *Intravesical Intravesical; ; ** **Bladder Bladder wall wall ICI assessments ICI assessments Idiopathic DO Idiopathic DO Drug Drug Level Level Grade Grade Estrogens Estrogens 2 2 C C ICI ICI assessments assessments Drugs used Drugs used for for Treatment Treatment of Stress of Stress Urinary Incontinence Urinary Incontinence   Duloxetine Duloxetine   Imipramine Imipramine   Clenbuterol Clenbuterol   Alpha-AR Agonists Alpha-AR Agonists   Ephedrine Ephedrine   Norephedrine Norephedrine ( (phenylpropanolamine phenylpropanolamine, PPA) , PPA)   Estrogens Estrogens Drug Drug Level Level Grade Grade Duloxetine Duloxetine 1 1 A* A* Imipramine Imipramine 3 3 D D Clenbuterol Clenbuterol 2 2 C C ICI ICI assessments assessments * Not approved in the US * Not approved in the US Efficacy/side effect ratio? Efficacy/side effect ratio? Drug Drug Level Level Grade Grade Methoxamine Methoxamine 2 2 D D Midodrine Midodrine 2 2 C C Ephedrine Ephedrine 3 3 D D Norephedrine Norephedrine ( (phenylpropanolamine phenylpropanolamine, PPA) , PPA) 2 2 D D ICI assessments ICI assessments Level Level Grade Grade Estrogens Estrogens 2 2 D D ICI ICI assessments assessments Further Research Directions Further Research Directions  Sites Sites of action, of action, optimum optimum dosage dosage, and , and pharmacokinetic interactions pharmacokinetic interactions, , need need further further investigation investigation  New targets (afferent nerves, CNS control New targets (afferent nerves, CNS control mechanisms) should be further explored mechanisms) should be further explored  Combinations of drugs should be Combinations of drugs should be systematically studiedsystematically studied

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