《药理学》课程PPT教学课件（Central Nervous Sys）17 Antiparkin

Pharmacologic Management ofParkinsonismand Other Movement DisordersThe Movement disorders include(1) Tremor(2) Parkinson's disease(4) Chorea(3)Huntington'sdisease(5) Ballismus(6)Athetosis and Dystonia(7) Tics(8)Dyskinesias(9)Wilson'sDisease

Pharmacologic Management of Parkinsonism and Other Movement Disorders The Movement disorders include (1) Tremor (2) Parkinson’s disease (3) Huntington’s disease (4) Chorea (5) Ballismus (6) Athetosis and Dystonia (7) Tics (8)Dyskinesias (9)Wilson’s Disease

PARKINSONISM(ParalysisAgitansThe most prominent features of parkinsonismare tremor,rigidity, bradykinesia, and posturalinstability

PARKINSONISM (Paralysis Agitans) The most prominent features of parkinsonism are tremor,rigidity, bradykinesia, and postural instability

Etiology: the loss of striatal dopamine produces an imbalangeAchDAInhibitoryExcitatoryNormalneurotransmitterneurotransmitter(balance)DAParkinsonismAchInhibitory(imbalance)neurotransmitterExcitatoryneurotransmitter

Etiology: the loss of striatal dopamine produces an imbalance Normal (balance) Parkinsonism (imbalance) Inhibitory neurotransmitter DA Ach Excitatory neurotransmitter Inhibitory neurotransmitter Excitatory neurotransmitter Ach DA

Therapy of ParkinsonismSince there is no cure for parkinsonism, the aim ofpharmacological therapy is to relieve symptomaticThese drugs includea:Increases brain dopamine levelslevodopab:Dopamine agonistsdirectly stimulate DA receptors

Therapy of Parkinsonism Since there is no cure for parkinsonism, the aim of pharmacological therapy is to relieve symptomatic These drugs include a:Increases brain dopamine levels levodopa b:Dopamine agonists directly stimulate DA receptors

c: Monoamine oxidase (MAO) inhibitorsprevent dopaminemetabolismrasagilined: Anticholinergic agentswhich reduce the excitatory activity within thestriatumPergolide andPramipexolee: catechol-O-methyl transferase (COMT) inhibitorsprevent dopamine metabolismtolcapone and entacapone

c: Monoamine oxidase (MAO) inhibitors prevent dopamine metabolism rasagiline d: Anticholinergic agents which reduce the excitatory activity within the striatum Pergolide and Pramipexole e: catechol-O-methyl transferase (COMT) inhibitors prevent dopamine metabolism tolcapone and entacapone

CaudateNucleusPresynapticPostsynaptic0DA receptorsDOPADADAAChDOPACSubstantia NigraOther CircuitryPharmacological action ofantiparkinsonian drugs.(1)Levodopa,astheimmediateprecursor ofdopamine, increases dopamine production within the basal ganglia. (2)MAO-B inhibitors(selegiline) block a major pathway in dopamine metabolism and thus increase the duration ofactionofdopamine.(3)Dopaminereceptoragonists(pramipexole,pergolide,bromocriptine)directly activate dopaminereceptors onpostsynaptic neurons.(4)Anticholinergic drugs block theincreased excitatoryactivity ofcholinergic interneurons onoutflowpathways fromthe basalganglia, which is secondary to a loss of inhibitor actions of dopamine on these cholinergicinterneurons.(5)COMT inhibitors (with central actions)block an alternate pathway inthemetabolism ofdopamine

Pharmacological action of antiparkinsonian drugs. (1) Levodopa, as the immediate precursor of dopamine, increases dopamine production within the basal ganglia. (2) MAO-B inhibitors (selegiline) block a major pathway in dopamine metabolism and thus increase the duration of action of dopamine. (3) Dopamine receptor agonists (pramipexole, pergolide, bromocriptine) directly activate dopamine receptors on postsynaptic neurons. (4) Anticholinergic drugs block the increased excitatory activity of cholinergic interneurons on outflow pathways from the basal ganglia, which is secondary to a loss of inhibitor actions of dopamine on these cholinergic interneurons. (5) COMT inhibitors (with central actions) block an alternate pathway in the metabolism of dopamine

II.SPECIFIC AGENTSLevodopaPharmacokineticsSynthesis of norepinephrine:1.Synthesis of norepinephrine:DopaTyrosinehydroxylasedecarboxylaseVDopamineTyrosineDopaN-methyltransferasedopamine β-hydroxylasenorepinephrineepinephrine

1.Synthesis of norepinephrine: Tyrosine Dopa hydroxylase decarboxylase Tyrosine Dopa Dopamine dopamine β- hydroxylase N-methyltransferase norepinephrine epinephrine II. SPECIFIC AGENTS -Levodopa Pharmacokinetics Synthesis of norepinephrine:

PresynapticneuronendingActionTyrosinepotentialsCa++DopaInactivatedDopaminebyMAONorepinephrineReuptake(most)CirculationC.NorepinephrineaSGeEReceptorD6InactivatedPostsynapticbyCOMTcellInactiveproducts

Levodopa(L-DOPA)the most effective drug used in thetreatment of parkinsonism, Levodopa is thebiochemical precursor of dopamine.It isused to elevatedopaminelevels in theneostriatum of parkinsonian patientsDopamine itself does not cross the blood-brain barrier and therefore has no CNSeffects.However,levodopamaycross theblood-brain barrier, where it is converted todopamine by Dopa decarboxylase

Levodopa (L-DOPA) the most effective drug used in the treatment of parkinsonism, Levodopa is the biochemical precursor of dopamine. It is used to elevate dopamine levels in the neostriatum of parkinsonian patients. Dopamine itself does not cross the blood￾brain barrier and therefore has no CNS effects. However,levodopa may cross the blood-brain barrier, where it is converted to dopamine by Dopa decarboxylase

Fate of administered L-dopaL-dopaoralLiver,kidney,90%levodopaismetabolizedgastrointestinal tract1-3%Remain 10%L-dopaIntolevodopaCNSDopa decarboxylase在外周细胞DopaDopamine（胞浆)decarboxylasetherapeutical effectDopamineUndesirableside effect

L-dopa oral 90% levodopa is metabolized Liver,kidney, gastrointestinal tract Dopa decarboxylase Dopamine Dopa decarboxylase 1-3% Dopamine therapeutical effect L-dopa Undesirable side effect Into CNS Fate of administered L-dopa Remain 10% levodopa 在外周细胞 （胞浆）