Alpha1adrenoceptors and BPH.ppt

Alpha1-adrenoceptors and BPHA.G.Ramage D.Sc.Department of PharmacologyUniversity College LondonRoyal Free CampusUrinary Symptoms in Men80706050403020100-4950-5960-6970-7980-84Weak StreamUrgencyFrequencyNocturiaPrevalence(%)Urinary Symptoms in Women60503020100-4950-5960-6970-7980-84Weak StreamUrgencyFrequencyNocturia Prevalence(%)40Innervation of Lower Urinary TractSympathetic Nerves from T10 to L2Hypogastric NervePelvicNervePudentalNerveT10T11T12L1L2L3L4L5Parasympathetic and Somatic Nerves from the 2nd,3rd and 4th Sacral SegmentsProstateGlandExternal Urethral SphincterRole of the Sympathetic Not essential-for either storage or release-role in the control of bladder capacity and outlet resistance during storageSympathetic input to the bladder is tonically active during fillingSurgical or pharmacological blockade of sympathetic pathways to the bladderurethral resistance bladder capacity bladder wall compliance frequency and amplitude of bladder contractionsmediate by alpha adrenoceptors Distribution of Alpha1-AdrenoceptorsPelvic FloorExternal SphincterInternal SphincterTrigoneDetrusorProstate GlandPhysiological Consequence of a a-adrenoceptor blockadeFALL IN BLOOD PRESSURE POSTURAL HYPOTENSIONNASAL STUFFINESSFAILURE OF EJACTULATIONMIOSISUrinary incontinence?Reflex to BP Fall -Tachycardia -Sodium&Water retention(Renin)b b1-adrenoceptor antagonistsAlpha Adrenoceptor Classification a-a1 and a2 adrenoceptorsObservation-phenoxybenzamine caused an increase in the releaseof noradrenaline from sympathetic nervesPhenoxybenzamineSelective a a1-adrenoceptor antagonist -less postural hypotension -less tachycardiaCause Central sympathoinhibitionAvailable a1adrenoceptor antagonists:-Prazosin;Doxazosin;Terazosin Terazosin;Alfuzosin;Tamsulosin;Indoramin!a a1-adrenoceptor receptors and the lower urinary tractTrigone&Sphincter muscles -contractiona a1-adrenoceptor can be divided into :-1A,1B and 1Da a1LRole 1B unknown really 1A and 1D Reduces Severity and Bothersomeness of SymptomsImprovement in Key Urinary Symptoms of BPH with Doxazosin Correlation PlotsHuman Prostate&a a1 Subtypes109876109876109876678910678910678910pKipKipKiPrazosinTerazosinIndoraminSNAP-10695-methylurapidilSK&F104856Prostate pA2 Forray et al 1995 Ford et al 1996Doxazosin7.09.08.58.07.5In Vivo ProfileDoxTerAlfTam5-MUProstate PressureBlood PressurePseudo pA2Subtype Selectivity9.59.08.58.07.57.0DoxTerAlfTam5-MUalpha 1Aalpha 1Balpha 1DpKiLowAffinityHighChon JK et al 1999 J Urol 161(6):2002-8doxazosin does the sameEffect of Terazosin on Prostate Apoptosis in Clinical BiopsiesTreatment period in monthsThe Sympathetic Cascade and the Pathophysiology of Disease Urethral Resistance De-Tumescence Tissue Proliferation Blood PressureTreatment of the Whole PatientA Balancing ActADBADBDBABPLipid Profile1A?1B?1D?HDL to LDL RatioTissue Proliferation1A?1B?1D?Anti-proliferative1A1B1DBlood Pressure Control1A1B?1D?Balance Is BeneficialADADBDBABAAA