Farmakoterapi inkontinensia urin, enuresis, BPH, disfungsi ereksi

Farmakoterapi inkontinensia urin, enuresis, BPH, disfungsi ereksi

Nerves and Micturition

Alpha Adrenergic DrugsPhenylpropanolamine

Once a first line drug

8 randomized controlled trials

Study duration: 2-6 weeks

% cure: 0-14

% side effects: 5-33%

WITHDRAWN FROM MARKET due to report of hemorrhagic stroke4Drug Treatment of Overactive BladderAnticholinergic Drugs are mainstayOxybutynin IR 2.5-5 mg bid-qid Ditropan XL 5-20 mg dailyOxytrol patch TDS 3.9 mg 2x/wk Tolterodine tartrate IR 1-2 mg bidDetrol LA 2-4 mg daily

New Drugs:Trospium chloride (Sanctura) 20 mg bidDarifenicin (Enablex) 7.5-15 mg dailySolefenicin (Vesicare) 5-10 mg daily

5Muscarinic ReceptorsM1 Brain (cortex, hippocampus), salivary, glands, sympathetic ganglia

M2 Heart, hindbrain, smooth muscle (80% of detrusor)

M3 Smooth muscle (20% of detrusor), salivary glands, brain, eye (lens, iris)

M4 Brain (forebrain, striatum)

M5 Brain (substantia nigra), eye

6OxybutyninBoth anticholinergic and smooth muscle relaxant properties

6/7 RCTs show benefit

15-58% greater reduction in urge UI than placebo

Dose: 2.5 -5 mg qid, 20 mg/d maximum7Oxybutynin Controlled ReleaseOnce daily dosing

RCT showed rate of daytime continence similar to that for immediate release (53 vs 58%)

Lower rate of dry mouth than immediate release form8Tolterodine tartratePure muscarinic receptor antagonist

Dry mouth most common side effect

3 RCT compared tolterodine (2 mg bid) to oxybutynin (5 mg tid): Equally effective and superior to placebo

Decreased urge UI in study of 293 pts:47% tolterodine, 71% oxybutynin, 19% placebo, dry mouth 86% oxybutynin, 50% tolerodine9TrospiumDose 20 mg bid

Renal metabolism

Nonselective for muscarinic receptors

Effective for detrusor overactivity in placebo-controlled double-blind studies:

Trospium 20 mg bid vs tolterodine 2 mg bid in 232 pts reduced voiding frequency and number of UI episodes

Dry mouth 7% and 9% respectively

10DarifenicinDose 7.5 to 15 mg daily

Selective M3 receptor antagonist

Several RCTs

Mundy et al 2001 Randomized double-blind trial compared darifenacin 15 mg and 30 mg to oxybutynin 5 mg tid in 25 pts , similar efficacy

Side effects: Dry mouth, constipation( 40 mL)Side effects include decreased libido, decreased ejaculate volume, and impotence. Serum PSA is reduced by approximately 50% in patients being treated with finasteride, but individual values may vary, thus complicating cancer detection

Medical Treatment 5-Reductase inhibitors Dutasteride: not enough data! In 3 double-blind trials it reduced acute urinary retention (1.8% versus 4.2%- placebo) and need for surgery (2.2% vs 4.1%) but increased impotence ( 7.3% vs 4.0%), ejaculation disorder, and gynecomastia and lowered libido

Medical Treatment 5-Reductase inhibitors Significantly reduced the relative risk for acute urinary retention(AUR) and enlarged prostate-related surgery, slowed the disease progression, and showed greater relief of symptoms compared to placeboDutasteride, improved symptom scores greater after 4 years of therapy compared with 2 years (-6.4 vs -4.3 points, respectively) and flow rates were better (2.6 vs 2.3 mL/sec).Finasteride showed maintenance of the decreased risk for AUR and enlarged prostate-related surgery over 4 year periodGenerally well tolerated, with sexual dysfunction the most frequently reported adverse effect (1%-8%) Medical Treatment Combination therapyShort termVeterans Affairs Cooperative Study, 1229 men with BPH randomly assigned to placebo, finasteride, terazosin or both for one year. Results as follow:Terazosin lowered the symptom score and increased the peak urinary flow rate when compared with placeboFinasteride alone was no better than placeboThe combination of finasteride and terazosin was no better than terazosin alone

Medical Treatment Combination therapy (contd)Short term

PREDICT trial in which 1095 men were randomly assigned to doxazosin, finasterid or both for one year. Resluts as follow:Doxazosin more effective than finasteride or placebo for urinary symptoms and flow rate Combination no more effective than doxazosine alone

Conclusion: Combination treatment with an alpha-blocker and a 5ARI is beneficial for immediate relief of symptoms ( with discontinuation of the alpha-blocker after several months of therapy)

Medical Treatment Combination therapy (contd)Long term

Medical Therapy of Prostatic Symptoms (MTOPS) trial-3047 men with BPH randomly assign to doxazosin, finasteride, combination therapy or placebo were evaluated for symptomatic improvement and overall clinical progression of the BPH. Follow up 4.5 years. Results as follow:Risk of overall progression- reduced to a similar degree by doxazosin and finasteride (39% and 34% when compared to placebo)Combination therapy reduced the risk of clinical progression by 66 %Symptom scores improved with all therapies, but to a greater degree with combined therapyCombination Therapy for BPH ( MTOPS Study )

Medical Treatment Combination therapy(contd)Combination therapy or finasteride alone (but not doxazosin alone), reduced the risk of acute urinary retention and the need for invasive therapyNNT(# needed to treat) to prevent one instance of overall clinical progression was 8.4 for combination therapy, 13.7 for doxazosin, and 15.0 for finasterideAE -similar with combination therapy and monotherapy, with the exception of abnormal ejaculation, peripheral edema, and dyspnea, which were more common with combination therapyConclusion: long-term combination therapy lowered the risk of overall clinical progression of BPH significantly more than treatment with either drug alone. In addition, combination therapy or finasteride alone (but not doxazosin alone), reduced the risk of acute urinary retention and the need for invasive therapy

BPH SummaryAlpha-adrenergic antagonists provide immediate therapeutic benefits and are first line treatment for smaller prostates 40 mL mild to moderate symptomsCombined alpha adrenergic antagonist and 5-alpha-reductase inhibitor therapy appears to be superior to either agent alone for long-term Trx

The choice of medical treatment may be made on the basis of cost and side-effect profile of the drug

Anatomy and Physiology of erection

Reproduced from Carson C, Holmes S, Kirby R. Fast Facts- Erectile Dysfunction. Oxford: Health Press Limited; 2002: 8Anatomy and Physiology of erectionParasympathetic nerves S2-4 mediate erectionSympathetic nerves T11-L2 control ejaculation and detumescenceSmooth muscle relaxationNitric oxide diffuses into cavernosal smooth muscle cells, activates Guanylate cyclase converts guanosine triphosphate to cGMP resulting in smooth muscle relaxation. Effect of cGMP stopped by Phosphodiesterase type 5 which exists primarily in corpora cavernosa.Drugs for EDOral agentsCentrally acting dopamine-receptor agonist Apomorphine (discontinued in UK)Phosphodiesterase type 5 inhibitorsIntra-cavernosalProstaglandin E1 AlprostadilIntra-urethralAlprostadilPDE5 inhibitorsSildenafil (Viagra) 25mg, 50mg, 100mg1 hour before sexual activityAbsorption delayed by fatty mealTadalafil (Cialis) 10mg, 20mg30 minutes before sexual activity36 hour windowAbsorption not affected by foodTadalafil (Cialis) 5mgdailyVardenafil (Levitra) 5mg, 10mg, 20mg30-60 minutes before sexual activity4-6 hour windowAbsorption delayed by fatty mealPDE5 Physiology

Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 : 40PDE5 Inhibitors Side EffectsFacial flushingHeadacheNasal congestionDizzinessDyspepsiaVisual disturbance (blue halo)PriapismNon-arteritic anterior ischaemic optic neuropathy PDE5 ContraindicationsRecent cardiovascular eventNitratesHypotensionAnatomical deformityAngulation, cavernosal fibrosis, Peyronies Predisposition to prolonged erectionSickle cell diseaseMultiple myelomaLeukaemiaIntracavernosal InjectionsAlprostadil (Caverject, Viridal) 5-40 mcgIndependent of intact nervous systemManual dexterity, adequate vision, trainingContraindicated: bleeding disorders, sickle cell anaemia, multiple myeloma, leukaemiaSide effects: penoscrotal pain, haematoma, fibrosis at injection sites, priapismPapaverine, Phentolamine, Aviptadil (vaso-intestinal peptide) been used sole or with AlprostadilIntracavernosal Injections

Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 : 53IntraurethralAlprostadil (Muse) 125mg, 250mg, 500mg,1gPellet inserted with applicatorMassage penis to aid absorptionSide effects: Penile pain, dizziness, priapism rareIntraurethral Alprostadil

Reproduced from Carson C,Holmes S,Kirby R. Fast Facts-Erectile Dysfunction. Oxford: Health Press Limited; 2002 : 55