Degeneration of dopaminergic neurones in the substantia nigra, pars compacta 1

Transcription

1 Parkinsn s disease Pathphysilgy Degeneratin f dpaminergic neurnes in the substantia nigra, pars cmpacta 1 Balance f dpaminergic and chlinergic activity in the extra-pyramidal system determines activating utflw t mtr crtex Dpamine enhances ACh suppresses In Parkinsn s disease, a relative dpaminergic deficit causes the clinical features f TRAP Tremr ( pill-rlling, absent in 20-30%) Rigidity ( lead pipe, esp. arms) 2 Akinesia/bradykinesia (esp. arms) Pstural reflex lss, gait disturbance Usually asymmetrical (cf. drug-induced: symmetrical) Overview f dpamine metablism Tyrsine tyrsine hydrxylase L-dpa dpa decarbxylase Adrenaline phenlethylamine N-methyl transferase Nradrenaline dpamine β-hydrxylase Dpamine MAO COMT DOPAC 3-methxydpamine COMT MAO HVA Synthesis f further catechlamines Cat abl i sm Receptr activatin Release pathway 1 Nte that Parkinsnism refers t the classical clinical features regardless f aetilgy; Parkinsn s disease is idipathic Parkinsnism. 2 Cgwheeling = rigidity with superimpsed tremr 1/8

2 1 - synt hesi s Synthesis 5 - r e-uptake uptake 1 Dpamine MAO-A 4 - r el ease 3 - agni sm Dpamine uptake met abl ism MAO-B D 1 D 2 Dpamine receptrs At least 5 dpamine receptrs have been clned t date (D 1-5 ), but nly D 1 and D 2 are f significance in Parkinsnism. D 2 receptr is principal target fr anti-parkinsnian drugs. Chrnic D 1 stimulatin als appears t be beneficial paradxically s, since Bth subtypes have ppsite effects n the camp secnd messenger system (D 1 is G s -cupled and stimulates adenylate cyclase, D 2 is G i/ -cupled and inhibits it). Bth subtypes have different spatial lcalizatin. D 1 is mstly fund in the vasculature, whereas D 2 is cncentrated in the areas shwn later. Cnsequent ratinale fr pharmaclgical management Pharmaclgical treatment cannt cure Parkinsn s disease this wuld require replacing lst neurnes. It can, hwever, imprve mtr functin thrugh restring DA/ACh balance by Restring dpaminergic activity 1: replenish neurnal dpamine L-dpa 2: inhibit dpamine metablism MAO-B: selegiline COMT: entacapne 3: stimulate pstsynaptic DA receptrs DA agnists 4: stimulate dpamine release amantadine 5: inhibit dpamine re-uptake amantadine Reducing chlinergic activity Disease mdificatin refers t delaying the prgressin f neurnal degeneratin. Such an effect has been prpsed fr selegiline but has never been prven. Drug classes L-dpa (=levdpa) and dpa-decarbxylase inhibitrs (DDC-Is) Why nt give dpamine itself? Rapid GI/liver/bld metablism by MAO and COMT Dpamine is prly lipid sluble and cannt traverse the bld-brain barrier; L-dpa enters thrugh the neural amin-acid transprter Why give a DDC-I as well? 99% f L-dpa is cnverted t dpamine prematurely by peripheral DDC, causing side-effects f nausea, pstural hyptensin and cardiac arrhythmias Merely 1% enters the brain t be cnverted t dpamine 2/8

3 Wuld have t give huge dses with cnsequently prminent side-effects DDC-Is (carbidpa, benserazide) d nt crss the bld-brain barrier and selectively inhibit the extracerebral metablism f L-dpa. Advantages: Higher efficacy Higher tlerability Smther clinical respnse with a mre rapid nset Bld 1% Brain Dse Gut 70% 29% DDC MAO-A Metablism in GI tract DDC MAO-B Metablism in liver and peripheries Causes peripheral side-effects Dse Gut Bld 10% Brain 40% 50% DDC-I DDC MAO-A Metablism in GI tract DDC MAO-B Metablism in liver and peripheries Less peripheral side-effects 3/8

4 Mst ptent treatment available, and treatment f chice fr idipathic Parkinsn s disease. Over 75% f patients regain nrmal r near-nrmal physical activity. Usually slw respnse ver 6-18 mnths and then maintained fr up t 2 years fllwed by gradual decline. After 8 years, 50% have chre-athetid dyskinesia and end-dse akinesia. The ELLDOPA (Early vs. Late L-dpa) trial has shwn that disease prgressin is nt influenced by L- dpa therapy. Cnsequently, instigatin f therapy shuld depend n symptmatlgy and quality f life. Less valuable in Elderly patients r thse with lngstanding disease, wh may nt tlerate a dse large enugh t vercme the deficit. Pst-encephalitic Parkinsnism Parkinsnism due t degenerative brain disease (e.g. multiple system atrphy) Neurleptic-induced Parkinsnism. Instead, withdraw the ffending drug and give antimuscarinics. A dudenal gel frmulatin prvides a mre cnstant L-dpa plasma level because it circumvents irregular gastric emptying and unpredictable small bwel absrptin. It is an alternative t IV L-dpa, which is impractical as L-dpa is hydrphbic and requires large liquid vlumes t disslve. The dudenal frmulatin requires a percutaneus tube and prtable pump, and is an advanced treatment fr patients with severe mtr fluctuatins r dyskinesia. Preparatins Oral C-careldpa (Sinemet ) = L-dpa + carbidpa (4:1 r 10:1) C-beneldpa (Madpar ) = L-dpa + benserazide (4:1) Dudenal C-careldpa (Dudpa ) Central Enhanced dpaminergic actin is nt cnfined t the nigr-striatal tract. Mescrtical Meslimbic Excitatin up t psychsis Nigr-striatal Treatment f Parkinsn s disease Tuber-infundibular Treatment f hyperprlactinaemia (dpamine agnists, nt L-dpa) Chemreceptr trigger zne Vmiting Nte that the chemreceptr trigger zne is sensitive t substances utside the bld-brain barrier; vmiting is therefre nt a purely central side-effect. Peripheral Pstural hyptensin thrugh D 1 activity. Thus up-titrate the dse until the best trade-ff between decreasing symptms and increasing side-effects is reached. Interactins Remember the interactin between L-dpa and nn-selective MAO-Is: 4/8

5 Tyrsine tyrsine hydrxylase 2. Diversin f dpamine int further catechlamine synthesis L-dpa dpa decarbxylase 3. Excessive adrenaline causes hypertensive crisis Adrenaline Nradrenaline phenlethylamine N-methyl transferase dpamine β-hydrxylase Dpamine MAO COMT DOPAC 3-methxydpamine COMT MAO HVA Synthesis f further catechlamines Cat abl i sm Receptr activatin 1. Catablic pathway blcked Pharmackinetics t 1/2 = 90min Dpamine agnists Classificatin Ergt-derived (erglinic) Brmcriptine Perglide (D 1 and D 2 ) Cabergline Nn-ergt derived (nn-erglinic) Rpinirle Apmrphine (D 1 and D 2 ) Pramipexle (D 2 and D 3 ) Rtigtine Dpamine dysregulatin syndrme Uncmmn disrder Use f any dpaminergic medicatin, esp. dpamine agnists Behaviural disturbance including hypersexuality, pathlgical gambling and steretypic mtr acts Management: wean drug Brmcriptine Mst cmmnly used ergt-derived agnist Has n advantage ver L-dpa and is used When L-dpa alne is n lnger adequate t cntrl symptms When L-dpa is assciated with intlerable side-effects Useful fr akinetic perids and n-ff phenmena (has a lnger t 1/2 f 5h and hence a smther actin than levdpa) Akin t L-dpa Als a weak α-blcker, hence mre marked pstural hyptensin All ergt derivatives carry a risk f retrperitneal/pulmnary/pericardial/heart valve fibrsis (5-HT 2B verstimulatin; regurgitant valve lesins) 3 Obtain ESR/crea/CXR ± lung functin tests befre starting Mnitr fr abd pain/tenderness, SOB/cugh/CP r features f heart failure Prgressin f fibrsis can be prevented by early diagnsis and cessatin f drug treatment Perglide Very similar, but als stimulates D 1. Cabergline 3 ZANETTI, R. ET AL. (2007): Valvular heart disease and the use f dpamine agnists fr Parkinsn s disease. NEJM 356: SCHADE, R. ET AL. (2007): Dpamine agnists and the risk f cardiac-valve regurgitatin. NEJM 356: /8

6 Extra-lng half-life f 80h, thus suitable fr nce daily r even twice weekly dsing, but clinical experience is still limited. Rpinirle Newer drug with similar side-effect prfile. D 1-3 agnist. As an adjunct t L-dpa As mntherapy in yung patients at risk f develping disabling dyskinesias with lng-term therapy Apmrphine Mrphine derivative that is a full D 1 and D 2 agnist; lacks activity at piid receptrs. Useful fr stabilizing patients with unpredictable ff perids with L-dpa Ptent emetic 4 ; thus need t give dmperidne (DA antagnist that des nt crss the bld-brain barrier) fr 3 days befre initiating therapy, then tailed ff ver weeks Rare but well-described: haemlytic anaemia Needs t be given by SC injectin 5 /infusin under Cnsultant supervisin. This rute allws fr fast nset and abrtin f an ff perid Rtigtine Neupr is a transdermal patch, avids fluctuating dpaminergic stimulatin Mnamine xidase inhibitrs (MAO-Is) The MAO enzyme exists in tw isfrms: Central lcatin Peripheral lcatin Substrate MAO-A Neurns Liver, sympathetic neurns Principally 5HT, als NrAdr/Adr/DA MAO-B Glia Gut Principally phenylethylamine, als NrAdr/Adr/DA In Parkinsn s disease, the nigrstriatal neurns and their MAO-A activity are lst. Therefre DA is predminantly catablised by MAO-B in the glia. MAO-B blckade can thus bst prevailing DA cncentratin. Selegiline Selective irreversible inhibitr f MAO-B Adjunct t L-dpa in severe Parkinsnism t reduce end-f-dse deteriratin Can halve the L-dpa requirement Cntrversies Delayed need fr L-dpa treatment/disease prgressin thrugh early selegiline? untrue Increased mrtality with cmbinatin f selegiline and L-dpa? UKPRG (1995) trial suggests s, but used a flawed methd f data cllectin and analysis Rasagiline Selective irreversible inhibitr f MAO-B Mntherapy (TEMPO) Adjunct t L-dpa (LARGO) 4 Famusly used by a murderer in an Agatha Christie nvel wh drank pisned tea with her victim and then injected herself with apmrphine t vmit up the pisn. 5 Penjet devices available, i.e. like insulin 6/8

7 Catechyl-O-methyl transferase inhibitrs (COMT-Is) Inhibit an alternative enzyme invlved in the breakdwn f dpamine. Theretically mre attractive than MAO-Is since COMT als catablises L-dpa. The riginal cmpund, tlcapne, is nly used with extreme cautin due t ptential hepattxicity and NMS. Entacapne (Cmtess ) was subsequently intrduced Adjunct t L-dpa therapy in patients with end-f-dse deteriratin Available as a cmbined frmulatin: Stalev = L-dpa + carbidpa + entacapne Minimises number f tablets Ensures entacapne maximally effective as taken at same time as L-dpa Amantadine Develped as an antiviral agent t treat influenza, amantadine was nticed t imprve Parkinsnian symptmatlgy by chance. Mechanism: increases synthesis and release f dpamine by acting as an NMDA antagnist; reduces re-uptake f dpamine Less effective than L-dpa but mre than antichlinergics Mild imprvement in all 3 majr symptms Relatively free frm side-effects (ankle edema, mild D 2 effects), but Only a small prprtin f patients derive benefit Tlerance ccurs Antimuscarinic agents E.g. benzhexl, prcyclidine, rphenadrine Generally less useful than levdpa Greater effect n tremr and rigidity than n bradykinesia Pssible indicatins Predminant tremr Pst-encephalitic r drug-induced Parkinsnism 6 Drling (sialrrhea) Typically antichlinergic: dry muth, blurred visin, mydriasis, tachycardia, cnstipatin, urinary retentin, erectile imptence Pharmaclgical management in cntext 1. Cnservative measures Speech therapy Physitherapy Occupatinal therapy 2. Pharmaclgical measures Cmmence drug therapy nce symptms impact significantly n quality f life Mainstay f treatment remains L-dpa + DDC inhibitr Rapid, marked imprvement Especially bradykinesia and rigidity; tremr less well cntrlled Use lwest effective dse and titrate up gradually After several years f L-dpa therapy, side-effects usually supervene Dpaminergic side-effects 6 L-dpa is largely ineffective here: it wuld have t act at receptrs which are already blcked. But dn t give antimuscarinics in tardive dyskinesia (see antipsychtics) they make it wrse! 7/8

8 Peak-dse dyskinesia End f dse akinesia with drug-resistant ff perids Randm n-ff phenmena whse timing is unrelated t the dse schedule 7 Pssible appraches Mdified release L-dpa Frequent L-dpa dses Add in selegiline (helps with end f dse deteriratin) Add in dpamine agnists Nt drug hlidays risk f NMS NICE guidelines Optins in early disease: L-dpa, dpamine agnists, MAO-B inhibitrs Optins in later disease: dpamine agnists, MAO-B inhibitrs, COMT inhibitrs 3. Nn-pharmaclgical measures Cnsidered in patients wh (NICE guidelines) Have mtr cmplicatins that are refractry t best medical treatment Are bilgically fit with n clinically significant active c-mrbidity Are levdpa respnsive Have n clinically significant active mental health prblems, fr example, depressin r dementia Steretactic neursurgery In PD, neurnal activity is abnrmally increased in the subthalamic nucleus and the glbus pallidus pars interna Deep brain stimulatin (DBS) invlves the implantatin f electrdes int ne r ther f these areas bilaterally, cnnected t an implantable pulse generatr. High frequency stimulatin f the abve areas induces a functinal lesin. This is preferable t ablative surgery since It is in principle reversible It can be perfrmed bilaterally with relative safety Stimulatin parameters can be adjusted and ptimised after implantatin Benefits On average 60% f dpaminergic drug dses can be replaced with DBS 10% f subjects n lnger require any L-dpa Off-perids and dyskinesias are reduced by 60-70% Drawbacks Invasive Ptential psychiatric sequelae Future perspectives Intraputaminal implantatin f retinal pigment epithelium (RPE) cells, which prduce L- dpa and can be islated frm human eyes pst mrtem Intrastriatal infusin f a viral vectr cntaining the gene fr human L-amin acid decarbxylase 7 One pssible mechanism is receptr dwnregulatin 8/8