Diagnosis and Treatment of Overactive Bladder

Transcription

1 Diagnosis and Treatment of Overactive Bladder

2 Case study: Mr. Lin I I have started to rush out of meetings to go to the toilet I I need to void every one hour I I used to be quite active. This is becoming more difficult I I no longer plan activities, unless I know I will have access to a restroom (toilet mapping) Occupation Age Medical history Current medication Bank manager 63 years Healthy None

3 ICS Terminology: Overactive Bladder Urgency, with or without urge incontinence, usually with frequency and nocturia In the absence of pathologic or metabolic conditions that might explain these symptoms OAB is defined based on symptoms Abrams P et al. Urology. 2003;61: Abrams P et al. Neurourol Urodyn. 1988;7:

4 Majority of Patients are Continent 12.2 million (6.1% of the population) 37% Incontinent OAB 63% Continent 21.2 million (10.5% of the adult population) Stewart WF et al. World J Urol. 2003;20:

5 OAB Can Lead to Other Disabling Conditions OAB is significantly associated with the risk of hospitalization (30% increased risk in women; 50% increased risk in men) or admission to nursing homes 1 Frequent occurrence of urinary tract infections and skin irritation 1 Increased risk for falls (by 35%) and fractures (by 45%) 1 50% increased risk for femoral neck fractures in postmenopausal women 1 60% of OAB patients suffer from depression 2 1. Adapted from Brown J, et al. Am J Managed Care ; 6 ( s u ppl 11) : S Z orn BH, et al. J U ro l ; 16 2 :

6 Overactive Bladder Is Highly Prevalent in the USA and Europe Overall, 16.6% of the population aged >40 years in 6 European countries have symptoms of OAB Prevalence of OAB increases with age Overall, 16.5% of the US population aged >18 years (~33 million people) have symptoms of OAB Prevalence of OAB increases with age Stewart WF et al. World J Urol. 2003;20: Milsom I et al. BJU Int. 2001;87:760-6.

7 53% of Asian Women Have Symptoms of OAB Percent of Women with OAB Symptoms Questionnaire survey of 5,502 women from 11 countries in Asia Urgency and frequency are the most common LUTS OAB is undertreated Urgency Frequency Incontinence Percent Seeking Treatment Lapitan MC, Chye PL. Int Urogynecol J Pelvic Floor Dysfunct. 2001;12:

8 OAB prevalence with increasing age Prevalence (%) Men Women Age (years) Milsom I, et al. BJU Int 2001;87:760 6

9 Quality of Life Scores: OAB Syndrome vsv Other Chronic Conditions (SF-36) Physical functioning Normal Hypertension Diabetes Overactive Bladder Syndrome Depression Role functioning Physical Bodily pain General health perception Vitality Social functioning Role functioning Emotional Mental health Reprinted by permission of The American Journal of Managed Care. Copyright All rights reserved.

10 Components of patient bother Physical symptoms Gradual increase in frequency Increase in urgency Loss of sleep Wetting accidents (for some) Rational Women s concern: Am I sick do I have cancer? I want information Men s concern: Do I have a prostate problem? Emotional Embarrassment Fear Frustration Anger Behavioural Job performance Relationship stress Social activities Drinking behaviour

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12 Clinical Evaluation Symptoms A thorough history, physical examination Urinalysis Postvoid residual urine Urodynamic study or cystoscopy for patients with complicating factors or fail initial therapy

13 Differential Diagnosis of OAB Pathologic conditions UTI Bladder cancer Bladder stone Interstitial cystitis Bladder outlet obstruction Atrophic urethritis, vaginitis Metabolic condition Metabolic Diabetes Neurologic disease Psychiatric illness Constipation Medications- diuretics, antihistamine, narcotics

14 Time Course of OAB A chronic rather than an acute condition Symptoms may wax and wane Likely to require long term or even lifelong therapy to control their symptoms

15 Neurogenic Causes of DO Decreased central or peripheral inhibitory control Increased afferent activity Combination of these factors

16 Myogenic causes of DO Detrusor change- widened intercellular spaces, cellular junction abnormality Degeneration of muscle cells and axons Abnormal spontaneous activity Supersensitivity to acetylcholine or direct electrical stimulation

17 OAB Shifting Focus Motor Muscle Incontinence Sensory Nerve Urgency

18 Treatment of OAB Behavioral therapy Pharmacotherapy Surgical therapy A combination of behavior and pharmacotherapy offers the greatest chance for success

19 Drug Therapy The mainstay in the treatment of OAB Effective in relief of symptoms May produce some side effects and limits their use

20 Neurophysiology of the Detrusor Muscle M 1 NA Ach M 2/4 M 1 M 2/4 β M 2 M 3 camp + IP3/DAG + Relaxation Contraction DETRUSOR MUSCLE TONE

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22 Storage Phase Effects of Antimuscarinic Agents Reduce bladder tone during storage Increase bladder capacity The release of ACh A h (non-neuronal, neuronal, urothelial) ) during filling increases bladder afferent activity and may be the contributor to OAB (Andersson,, Lancet, 2004)

23 Antimuscarinics Helping OAB by Acting on: Conventional Wisdom: Efferent nerve-smooth muscle neurally evoked contraction (M3 receptors) New Local Effect Theory: Urothelial-afferent afferent nerve sensory mechanisms (M2 receptors)

24 Muscarinic Receptor Distribution Dizziness Somnolence Cognitive impairment, especially memory CNS Iris/ciliary body Lacrimal gland Salivary glands Heart Blurred vision Dry eyes Dry mouth Tachycardia Stomach and esophagus Colon Constipation Dyspepsia Bladder (detrusor muscle) Abrams P, Wein AJ. The Overactive Bladder A Widespread and Treatable Condition

25 The Concept of Organ (Bladder) Selectivity Desired effects on the bladder with minimal effects on muscarinic receptors in other organs No true bladder selective antimuscarinic so far Local treatment can limit the antimuscarinic effects on the bladder

26 Oxybutynin Tertiary amine,, potent p muscarinic receptor antagonist with some degree of selectivity for M 3, M 4, and M 1 receptors Local anesthetic as well as smooth muscle relaxant effects at doses higher than those used in clinical practice Broadley, Kelly. Molecules. 2001;6:

27 Plasma Concentrations After a Single Dose of Oxybutynin* Mean Plasma R-oxybutynin Concentration (ng/ml) Oxybutynin ER 10 mg QD Oxybutynin 5 mg tid Time (hours) * Ditropan XL (oxybutynin chloride) Prescribing Information.

28 Oxybutynin Transdermal Delivery System (TDS) Translucent matrix-type type patch Twice-weekly weekly application

29 Tolterodine Developed specifically for OAB Largest clinical development program ever conducted for an OAB compound 32 registration studies conducted in 16 countries (17 phase 1; 4 phase 2; 11 phase 3) Not selective for any muscarinic receptor subtype Organ selective for bladder over salivary glands More than 4,000 patients treated with tolterodine in clinical trials Studies showed significant reductions in urinary frequency, urgency, and urge incontinence Nilvebrant L et al. Life Sci. 1997;60:

30 Tolterodine Has the Ability to Block Both the Sensory and Motor Arms K i (nm)* Antagonist M 1 M 2 M 3 M 4 M 5 Tolterodine Oxybutynin Lower number = greater affinity for receptor Chapple C. Urology 2000;55 (Suppl. 5A). Gillberg PG et al. Eur J Pharmacol. 1998;349: *CHO cells expressing human muscarinic receptors. Nilvebrant L et al. Eur J Pharmacol. 1997;327:

31 Tolterodine vs Oxybutynin Tolterodine: anticholinergic Effective Bladder selective 8 times selectivity for the bladder over salivary glands Higher cost Oxybutynin: anticholinergic,, smooth muscle relaxant, local anesthetic Effective Non-bladder selective 80% dry mouth 25% drop out due to side effect

32 Perception of Urgency Tolterodine ER: Percent Able to Finish Task Before Toileting 35 * 33 Baseline 12 weeks 30 Patients (%) *P < vs placebo Tolterodine ER 4 mg Placebo Freeman R. Obstet Gynecol. 2003;102:605.

33 Tolterodine ER: Patient Perception of Treatment Benefit at 12 Weeks Patients (%) * Much benefit Little benefit No benefit 10 0 Tolterodine ER 4 mg Placebo *P < vs placebo. Freeman R. Obstet Gynecol. 2003;102:605.

34 Adverse Events: Nighttime Dosing vs Daytime Dosing 25 23* % Reporting AEs * *Daytime dose (n=507) Nighttime dose (n=848) 3 3* 1 0 Dry mouth Constipation Blurred vision *Van Kerrebroeck P et al. Urology. 2001;57: Mattiasson A et al. ICS 2004.

35 The Ideal OAB Treatment: Finding the Optimal Profile Dry mouth Constipation Visual effects CNS effects PK/PD Other Tolterodine ER + + Oxybutynin ER Oxybutynin TD + + +? - Solifenacin Darifenacin? - + Trospium + + Beneficial effect Nonspecific effect Adverse effect (Andersson KE, Lancet, 2004)

36 Poison the Bladder with Neurotoxin Capsaicin: initial excitation, then desensitization of C-fibersC Resiniferatoxin (RTX): desensitize C-C afferent fibers with initial weaker excitation Botulinum toxin (BoNT( BoNT): inhibit various neurotransmitters release, including acetylcholine, CGRP, ATP; treat OAB in sensory and motor arm

37 Noxious stimulation Bladder Aδ -fiber C-fiber glutamate SP CGRP Spinal cord

38 Silent (Sleeping) C-FibersC Normally do not respond to mechanical stimulation (bladder distension). Respond to cold and to noxious stimuli (chemical irritation, inflammation). Do respond to bladder distension after inflammation or spinal cord injury.

39 Afferent Blockade Intravesical Peppers

40 Vanilloid Effect on C-fiber Neurons Initially activates VR1 receptor (Excitation): Influx of Na + and Ca +2 => nerves fire Release peptides (Sub-P, CGRP) Long-term (Desensitization): Inhibits release of peptides Neuronal terminal degeneration

41 Vanilloid Rational C-fibers exist in bladder C-fibers mediate bladder pain and involuntary contractions Vanilloid blocks c-fibers Vanilloid pretreatment desensitizes irritating stimuli

42 Pepper Scoville Value Bell 1 Habanero 200,000 Capsaicin 16,000,000 RTX 16,000,000,000

43 Intravesical BTX Injection

44 Bladder Botulinum Toxin Botox can suppress ACh release from cholinergic terminals Botox can inhibit aberrant sensory neurotransmitter Botox can treat OAB in both sensory and motor pathway

45 Botulinum Toxin Presynaptic Nerve Terminal ACh ACh Muscle ACh Vesicles BT SNAP-25 BT Blocks Ach Fusion & Release

46 Botulinum Toxin Afferent Effect? Purkiss (1998) botulinum toxin A inhibited glutamate release from rat dorsal root ganglia Welch (2000) botulinum toxins inhibit substance P release from rat dorsal root ganglia Effect lasted at least 15 days Chuang (2004)- botulinum toxin inhibits CGRP release from rat bladder

47 Fig 3. CGRP staining in representative section from experimental rat bladder 7 days after instillation of PS/saline (A), and 3 days (B) and 7 days (C) after instillation of PS/BTX-A. CGRP was detected at the mucosal layer of bladder 7 days after instillation of PS/BTX-A, which was not detected at the other groups. (Chuang et al., 2004, J Urol)

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49 Targets for OAB: Afferent Receptors Vanilloid receptors-capsaicin, capsaicin, RTX Purinergic receptors (P2X 3 receptors) 5HT receptors (5HT 1A?) Neurokinin receptors (NK1-3) Cannabinoid receptors (CB1, CB2) Voltage-gated gated ion channels Sodium channels (Nav1.8) Potassium channels

50 Targets for Therapy of OAB (bladder afferent pathways)-cont cont d Growth factors Neurotrophic factors (NGF,, BDNF, GDNF) Angiogenic factors (PD-ECGF) Second messengers (PKG, PKA, PKC) Nitric oxide donor (PKG)- Calcium channels Phosphodiesterase inhibitors Gene therapy Enkephalin precursor gene (Franks et al, 2001; Chuang 2005) Preopioidmelanocortin gene (Chuang et al, 2003)

51 Nerve Growth Factor (NGF) and bladder disorders NGF involved in regulation of neural function, inflammation and pain NGF produced by bladder urothelium and smooth muscle NGF levels elevated in the bladder of BPH, IC, and idiopathic OAB

52 Intravesical application of NGF induces bladder hyperactivity Control Post NGF-treatment cm H2O 50 cm H2O min min Chuang et al., J. Urol 2001

53 Effects of Chronic NGF Application on Intercontraction Interval (ICI) in CMG ICI (min) sham 1W 2W 0 sham 1W 2W

54 NGF Results Acute and chronic application induced bladder hyperactivity Acute and chronic application induced hyperexcitability of bladder afferent neurons Suppression of NGF expression in bladder afferent pathways was effective to inhibit bladder hyperactivity induced by C-fiber hyperexcitability

55 POMC or PPE plasmid DNA gene gun injection CNS PMC POMC or PPE plasmid DNA (gold particles) injection Bladder Afferents Urinary Bladder Local expression of endorphin/enkephalin & suppression of pain responses Efferent Output L6-S1 Spinal Cord (Chuang et al., J Urol 2003; Urology 2005)

56 Targeting The Future S t C l P o g i c Gene Therapy em el harm ac enet

57 OAB Conclusions Treatment is high priority Affects >40 million Americans >80% unaware of treatment Treatment of OAB Efficacy and tolerability of antimuscarinics are increased Various targets for future OAB treatments

58 DM Cystopathy Prevalence 45% in DM patients Prevalence increased with duration of DM (25%, DM> 10years; greater than 50%, DM> 45 years) 75% to 100% with DM neuropathy developed cystopathy Develop insidiously, symptoms appear at the advanced stage

59 Characteristic of DM Cystopathy Onset- decreased sensation Increased capacity Decreased contractility Increased residual urine Chief complication- UTI, can develop UVR and hydronephrosis,, uremia Related to DMneuropathy Sensory as well as autonomic nerve dysfunction NGF level decreased in bladder and DRG associated with DM cystopathy in rats

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64 Treatment of DM Cystopathy Control of blood sugar does not mean the prevention of diabetic cystopathy Careful survey of voiding symptoms and residual urine to prevent late complications rhngf equivacal effects Targeting the future may rely on NGF gene therapy

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