DRUGS IN PARKINSONISMDRUGS IN PARKINSONISM ClinicalClinical signssigns • tremor • muscle rigidity • bradykinesis (postural reflex disorders, slow down initiation of movements ) dopaminergic drug anticholinergic drug DA Ach normální parkinsonismus treatment treatment ANTIPARKINSONIC AGENTS Pharmacotherapy in Parkinson's diseasePharmacotherapy in Parkinson's disease central anticholinergics ((benztropinebenztropine,, etoprazineetoprazine,, procyclidinprocyclidin,, trihexyfenidyltrihexyfenidyl,, orfenadrinorfenadrin)); H1 antihistaminergics dopaminergics ((dopamine does not pass blooddopamine does not pass blood--brain barrier):brain barrier): - levodopa - amantadine - bromocriptine, lisuride, pergolide, pramipexol (D2/3 r. agonist) - ropinirol (relatively selective D2-receptor agonist) - MAOB inhibitor (selegilin, reversible - caroxazone) - COMT inhibitors (tolcapone, entakapone) - adenosine A2A receptor antagonist (theophyline) LLEVODOPAEVODOPA LEVODOPA +LEVODOPA + dedeccarboxylarboxylasease InhibitorInhibitor ((CCARBIDOPA; BENSERAZIDARBIDOPA; BENSERAZIDEE)) kidney liver stomach 12%12% 14%14% 12%12% 5%5% 20%20% 45%45% 30%30%62%62% LL--DOPA 4.8 g/DOPA 4.8 g/dayday LL--DOPA 0.8 g/DOPA 0.8 g/ddayay ++ benserazidbenserazidee 0.2 g/0.2 g/ddayay + + ++ + + + ++ + ++ -- AMANTADINAMANTADINEE -- increasesincreases DADA releaserelease -- slows down DAslows down DA rere--uptakeuptake -- NMDANMDA glutamglutamaatergtergicic receptorreceptor antagonistantagonist -- anticholinerganticholinergicic effecteffect AdverseAdverse effeffeectscts:: -- halhalllucinaucinationstions -- fuzzinessfuzziness -- nightnight--maresmares -- sleeplesnesssleeplesness -- sleepinesssleepiness -- dysarthriadysarthria BROMOBROMOCCRRIIPTINPTINEE -- DD22 receptorreceptorss stimulastimulationtion inin striatustriatumm -- prolactineprolactine synthesis and releasesynthesis and release inhibitedinhibited ((for treatment offor treatment of galactorheagalactorhea)) -- decreadecreasses growth hormone secretion ines growth hormone secretion in aaccromegalromegalyy ADVERSE EFFECTSADVERSE EFFECTS:: -- smeary vision,smeary vision, diplopiadiplopia -- dyskinesiadyskinesia -- dizzinessdizziness -- constipationconstipation -- mental disordersmental disorders CENTRCENTRALAL ANTICHOLINERGIANTICHOLINERGICSCS Adverse effectsAdverse effects:: •• periphperipheraleral:: dry mouth,dry mouth, smeary visionsmeary vision,, tachytachyccardiardiaa,, constipation, urine retentionconstipation, urine retention,, mydrimydriasisasis, vomiting, vomiting •• centrcentralal:: sleepinesssleepiness, nervosit, nervosityy,, memory disordersmemory disorders TThheraperapyy ofof musclmusclee rigidityrigidity GABAergiGABAergicscs -- benzodiazepinbenzodiazepineses -- babacclofenlofen !!!! CORTEX / motoric functions CORPUS STRIATUM SUBST. NIGRA V V VV V THALAMUS V V MOVEMENTMOVEMENT DADA GABA glutamate Ach XX XX Parkinson disease Huntington disease (-) (-) XX Pharmacotherapy ofPharmacotherapy of Huntington's diseaseHuntington's disease huntingtinhuntingtinee = protein autosomally coded by dominant gene through interaction with other cell proteins involved in excitotoxicity, apoptosis HUNTINGTON DIS.HUNTINGTON DIS. == geneticalygeneticaly based hyperkinetic disorderbased hyperkinetic disorder with progressive dementiawith progressive dementia • clasical antidopaminergic antipsychotics (neuroleptics) • reserpine, meserpine, tetrabenazine (depletion of DA) • central myorelaxant agents (e.g. baclofen) • drugs decreasing excitotoxicity CC O G N I T I VO G N I T I V E SE S DEMENDEMENTIATIA 1.1. Alzheimer type (50%)Alzheimer type (50%) presenilepresenile (until 65 )(until 65 ) senile (senile (after 65)after 65) 2.2. vasvascculularar typtypee ((in pastin past :: arterioscleroticarteriosclerotic)) 3.3. mixed typemixed type ( ad 1. + ad 2.( ad 1. + ad 2. –– 1010--20% )20% ) 4.4. variousvarious –– alcoholicalcoholic intoxicantintoxicant 1010--20%20% postraumaticpostraumatic better treatablebetter treatable rainrain tumourstumours encephalitis (e.g. in AIDS)encephalitis (e.g. in AIDS) metabolic (Bmetabolic (B1212 carencycarency,, hepatocerebralhepatocerebral sysy.).) hypothyreosishypothyreosis Parkinson's diseaseParkinson's disease Huntington's diseaseHuntington's disease betabeta--amyloidamyloid gene mutation (fragment of neuron membrane protein precursor) extracellularextracellular plaquesplaques neurofibrillaryneurofibrillary tanglestangles of abnormally phosphorylated tautau--proteinprotein ++ deficit of Ach-ergic activity ++ excitotoxicity Alzheimer's diseaseAlzheimer's disease excitotoxicityexcitotoxicity III (III (neurodegenerationneurodegeneration, stroke), stroke) excitotoxicityexcitotoxicity II (II (neurodegenerationneurodegeneration, Alzheimer's dis.), Alzheimer's dis.) excitotoxicityexcitotoxicity I (slightI (slight demagedemage of dendrites)of dendrites) overexcitationoverexcitation (mania, panic attacks)(mania, panic attacks) normalnormal glutamatergicglutamatergic excitationexcitation EXCITOTOXICITEXCITOTOXICITYY excessiveexcessive CaCa2+2+ channel openingchannel opening CaCa2+2+ →→→→→→→→ aacctivtivationation of proteasesof proteases,, free radical productionfree radical production,, lipidlipid peroxidperoxidationation damage of further compoundsdamage of further compounds aandnd cell componentscell components gradually resulting in cell deathgradually resulting in cell death glutamate release inhibitors free radical scavangers protease inhibitors NO synthesis inhibitors antagonisti mGluR NMDA r. antagonists Ca2+channel inhibitors CaCa2+2+ proteases free radicals glutamate glutamate Ca2+ depolarization NMDANMDA PHPHARMAARMACCOTOTHHERAPERAPYY in pastin past:: -- cerebralcerebral vasodilatvasodilatorsors -- cell metaboliccell metabolic enhacersenhacers ((hyderginhyderginee –– mixture of ergotmixture of ergot alcaloidsalcaloids changingchanging ““secondsecond messengermessenger systemsystem““ -- cAMPcAMP)) -- vitaminvitaminss,, hormonhormoneses,, chelachelationtion (B(B66, B, B1212, estrogen,, estrogen, desferdesferrrioxaminioxaminee –– to removeto remove AlAluminiumuminium )) currently:currently: -- cholinergic enhancers (cholinergic enhancers (donepezildonepezil,, rivastigminrivastigmin)) -- nootropicsnootropics -- scavangersscavangers of free radicalsof free radicals ((vitvit. E,. E, selegilinselegilin, Ginkgo, Ginkgo bilobabiloba ..)..) -- calcium channel blockerscalcium channel blockers -- NMDA r. antagonistsNMDA r. antagonists ((memantinememantine)) PHPHARMAARMACCOTOTHHERAPERAPYY in the futurein the future:: -- betterbetter cholinergicholinergicscs -- blokblokadeade ofof amyloidamyloid constructionconstruction onon DNADNA levellevel -- growth factorsgrowth factors// implanimplantatationtion of healthy neuronal tissueof healthy neuronal tissue CHOLINERGICHOLINERGICSCS acetylcholinesteracetylcholinesterasease inhibitorinhibitorss donepezildonepezil (! 1x(! 1x perper ddayay , 5, 5--10 mg !)10 mg !) reversible, but noncompetitive (butyrylcholinesterase is not inhibited) ? release of growth factors? ? inhibition of amyloid deposition ? unset of effects primarily after 6 week Adverse effects:Adverse effects: -- nausea, vomiting,nausea, vomiting, diarheadiarhea,, hyperacidity, weight losthyperacidity, weight lost -- sleeplessness, extraordinary dreams, sleepinesssleeplessness, extraordinary dreams, sleepiness -- convulsionsconvulsions -- depressiondepression rivastigminrivastigminee cholinesterase+pseudocholinesterase reversible inhibition ? release of growth factors, inhibition of amyloid deposit ? galantamingalantaminee cholinesterase inhibitor + allosteric modulator of nicotinic receptors NMDANMDA glutamatergicglutamatergic receptor INHIBITORreceptor INHIBITOR memantinmemantinee memory is not improved,memory is not improved, slowingslowing downdown progressionprogression ofof neurodegenerativeneurodegenerative changeschanges possiblepossible coco--administrationadministration withwith cholinesterasecholinesterase inhibitorsinhibitors N O O T R O P IN O O T R O P I C SC S (( N E U R O D Y N A M IN E U R O D Y N A M I C S )C S ) GreekGreek -- noosnoos = mind= mind tropeintropein = towards= towards 19721972 -- NOOTROPIL, UCB /NOOTROPIL, UCB / piracetampiracetam MAIN EFFECTMAIN EFFECT improvement of the CNS mechanisms associatedimprovement of the CNS mechanisms associated with cognitive functionswith cognitive functions MECHANISMS OF ACTIONMECHANISMS OF ACTION •• improvement of the metabolism in the nervous cellimprovement of the metabolism in the nervous cell (the utilization of glucose and oxygen)(the utilization of glucose and oxygen) •• improvement of blood microcirculation in the brainimprovement of blood microcirculation in the brain •• other pharmacological activities as e.g.other pharmacological activities as e.g. glutamatergicglutamatergic effects, cholinergic effects . . .effects, cholinergic effects . . . USE OF NOOTROPICSUSE OF NOOTROPICS •• unconsiousnessunconsiousness of different etiologyof different etiology •• brain injurybrain injury •• mental retardation, dyslexiamental retardation, dyslexia •• brain function disorders in the elderlybrain function disorders in the elderly •• Alzheimer's diseaseAlzheimer's disease •• organicorganic psychosyndromepsychosyndrome •• amnesiaamnesia •• vertigovertigo •• aphasiaaphasia •• after the electroafter the electro--convulsive treatmentconvulsive treatment •• delirium tremensdelirium tremens •• Parkinson's diseaseParkinson's disease piracetampiracetam –– cyclic derivate of GABAcyclic derivate of GABA pyritinolpyritinol ((pyrithioxinepyrithioxine)) –– vitaminevitamine BB66 derivatederivate meclophenoxatemeclophenoxate ((centrophenoxinecentrophenoxine)) –– part of the molecule ispart of the molecule is a synthetica synthetic auxinauxin, which is similar, which is similar to the growth factor of plantsto the growth factor of plants -- auxinauxin BRAIN VASODILATORSBRAIN VASODILATORS papaverinepapaverine (500(500--600 mg/day)600 mg/day) dihydroergotoxinedihydroergotoxine clomethiazolclomethiazol naphtydrophurylnaphtydrophuryl cinnarizinecinnarizine . . .. . .