Drugs for parkinsonism

ANTI-PARKINSON DRUGS

2. DRUGS FOR
PARKINSONISM AND
OTHER MOTOR
DISORDERS

3. LEARNINGOBJECTIVES
•List drugsusedinthe managementof
Parkinsonism
•Describe themechanismofaction ,
pharmacologicaleffectsandadverseeffectsof:
–Levodopa,Carbidopa
–Ropinirole,Pramipexole
•Describethedruginteractionsof levodopa
•Explaintherationalebehindcombininglevodopa
withcarbidopa.

4. PARKINSONISM

5. PARKINSONISM
•A disorderwhichimpairstheregulationof
voluntary motor activity without directly
affectingstrength
•UsuallyIdiopathic:Parkinson’sdisease
•Otheretiology

6. THEORIESABOUTTHECAUSE
OFPARKINSON’SDISEASE
•Viralinfection/Brain infection
•Blowstothehead
•Prion disease: Lewy bodies (intracellular
inclusionbodiescontainingα-synuclein)in
dopaminergic cells
•Atherosclerosis
•Exposuretocertaindrugs
•Environmentalfactors
•Geneticpredisposition

7. GENETICFACTORS
Synucleinopathy
•Mutationsoftheα-synucleingeneat4q21or
•Duplication and triplication of the normal
synucleingene
Autosomaldominantparkinsonism
•Mutationsofleucine-richrepeatkinase2
(LRRK2)geneat 12cen&UCHL1gene
Familialparkinsonism/
Sporadicjuvenile-onsetparkinsonism
•Earlyonset,autosomalrecessive
•Mutationsinparkingene(6q25.2–q27)

8. PROGRESSION OF
PARKINSON’SDISEASE
•Rigidity/weakness(RAFT)
•Akinesia/bradykinesia
•Flat/mask-likeexpression
•Tremorsatrest
•Troublemaintainingpositionorposture
•Lackofcoordination
•Problemwalking
•Droolingandaffectedspeech

9. Functionalcircuitrybetweenthe cortex,basalganglia,andthalamus.
In Parkinson’s disease, there is degeneration of the pars compacta of substantia nigra, leading to
overactivityintheindirectpathway(red)&increasedglutamatergicactivitybythesubthalamicnucleus.

10. PATHOPHYSIOLOGY
•Lossofdopaminergic
neuronsinsubstantianigra
•Dopaminergicneurons
normallyinhibitoutputof
GABAergiccellsincorpus
striatum

11. DEGENERATION OF
NEURONSTHATLEADSTO
PARKINSON’SDISEASE
Imbalancebet.Dopaminergic(inhibitory)&cholinergic
(excitatory)

12. Legend:Schematicrepresentationofthesequenceofneuronsinvolvedinparkinsonism.Top:Dopaminergicneurons(red)
originatinginthesubstantianigra normallyinhibittheGABAergicoutputfromthestriatum,whereascholinergic neurons
(green)exertanexcitatory effect.Bottom:Inparkinsonism,thereisaselectivelossofdopaminergicneurons(dashed,
red).

13. PATHOPHYSIOLOGY

14. TREATMENTOFPARKINSON’S
DISEASE

15. ANTIPARKINSONISM DRUGS
Drugsaffectingbrain
dopaminergic
system:
Dopamine
Drugsaffectingbrain
cholinergicsystem:
ACh

16. GOALSOFTHERAPYINTREATING
PARKINSON’SDISEASE
MAO,COMTinhibitors

17. ANTIPARKINSONISM DRUGS
AFFECTINGBRAIN
DOPAMINERGIC SYSTEM

18. 18
EFFECTOR SITES
DOPAMINETYPE1;
D1FAMILY
(D1,D5):Excitatory
D
1-receptor
stimulation may also
be requiredfor
maximalbenefit
StimulateAdenyl
cyclase
cAMP
•Pars
compactaof
substantianigra
•Presynapticallyon
striatalaxons
coming from cortical
neurons & from
dopaminergic cells in
substantia nigra.
DOPAMINETYPE2;
D2,D3,D4:Inhibitory
Inhibit Adenyl
Cyclaseactivity,
??????cAMP
Open K
+
channels
??????calciuminflux
•Postsynapticallyon
striatalneurons
•Presynaptically on
axonsinsubstantia
nigra belonging to
neurons in basal
ganglia
Dopaminergic
antiparkinsonism
drugs:stimulation
ofD2receptors

19. THERAPEUTICACTIONS
OFDOPAMINERGICS
•??????Levelsof dopamineinthe substantia
nigra
•Directlystimulatedopamine
receptors(D2)inthatarea
•Helpingtorestorethebalancebetween
inhibitory (D) and stimulating neurons
(ACh)

20. COMMONADVERSEEFFECTS
OFDOPAMINERGICS
GIT
•Nausea,vomiting
•StimulateCTZ
CVS
•Posturalhypotension:
•??????Centralsympoutflow
BEHAVIORALEFFECTS
•Anxiety,Depression,Moodchanges,
•Mania,hallucinations,Frankpsychosis

21. DRUGS
AFFECTING
BRAIN
DOPAMINERGIC
SYSTEM
1.Dopamineprecursor Levodopa+Carbidopa
2.Dopaminereceptor
agonists
Ergots:bromocriptine,
pergolide
Pramipexole,Ropinirole
Apomorphine
3.Monoamineoxidase
inhibitors
Selegiline (deprenyl),
rasagiline
4.Catechol-o-
methyltransferase
inhibitors
Tolcapone,entacapone
5.Glutamate(NMDA
Receptor)antagonist
Amantadine

22. 1.DOPAMINE PRECURSOR:
LEVODOPA

24. LEVODOPA
•LevorotatorystereoisomerofDopa
PrecursorofDopamine
CrossesBloodBrainBarrier(BBB)
ConvertedtoDopaminebyenzyme
Dopadecarboxylase
•DopaminenotusedasDopaminecannot
crossBBB + lowbioavailability
•MosteffectiveforsymptomaticRxofPD
•Drugoffirstchoicefortroublesome
bradykinesia
•Doesnotcure
CLINICAL
CORELATION

25. LEVODOPA:PHARMACOKINETICS
•Rapidlyabsorbed
•Bioavailability:??????byfood
(protein)
•Highfirstpass
Metabolism
•Metabolizedin
Liver
•ExcretedinUrine:
Homovanillicacid(HVA);
Dihydroxyphenylacetic
acid(DOPAC)
BRAIN

26. LEVODOPA:PHARMACOKINETICS
•Peaks at1-2hrsafteroraldose
•t
½:1–3Hoursbutdosageinterval:three
timesadayorally
•Levodopaisconvertedintodopamine;
stored in vesicles of nigrostriatal
dopaminergicneuronsandreleased.
CLINICAL
CORELATION

27. LEVODOPA:PHARMACOKINETICS

28. CLINICALUSE
CLINICALRESPONSE
•Symptomatic improvement:Relievesbradykinesia
rigidity, tremor
•Best results obtained infirstfewyearsRx
•Therapeuticwindownarrowsafter severalyearsof
treatment
•DailydoseofLevodopa??????over timetoavoidadverseeffectsat
dosesthatweretoleratedinitially.
•Patients less responsive to Levodopa: loss of dopaminergic
nigrostriatalnerveterminalsorpathologicalinvolvementof
striatalD receptors.
ADVANTAGES
•Earlyinitiationlowersmortalityrate.
DISADVANTAGES
•Does notstopprogressionof parkinsonism
•Long-term therapyleadstoon-offphenomenon
CLINICAL
CORELATION

29. DRUGHOLIDAYOF LEVODOPA
•Discontinuanceofthe drugfor 3–21days
•Temporarynatureofanybenefit,
•Notrecommended.
DEFINITION
ADVANTAGES
•MaytemporarilyimproveresponsivenesstoLevodopa
•Mayalleviatesome of itsadverseeffects
DISADVANTAGES
•Not manage on-offphenomenon.
•Risksofaspirationpneumonia,venousthrombosis,
pulmonaryembolism,anddepressionduetoimmobility
accompanyingsevereparkinsonism
CLINICAL
CORELATION

30. ADVERSE
EFFECTS
I.EARLYADVERSE
EFFECTS
1.GIT
2.CVS
3.EYE
II.CHRONIC
ADVERSEEFFECTS
1.BEHAVIORAL
EFFECTS
2.MOTOREFFECTS

31. I.EARLYADVERSEEFFECTS
•DuetoPeripheraleffects ofdopamine
MECHANISM
1.GIT:Nausea,vomiting
•StimulatesD2inCTZ
•Tolerancedevelops;
•by:Divided doses;Slowlytitrating dose;Takingdrugwithmeals
•RxwithDomperidone&notMetoclopromide
2.CVS
•Posturalhypotension: Esp. withInitialdoses;dueto??????
central sympoutflow;Tolerancedevelops
•Arrhythmias:tachycardia,ventricularextrasystoles;atrial
fibrillation:duetoCatecholaminesperipherally
3.SENSES/EYE:
•Mydriasis(adrenergiceffect):precipitateglaucoma
•Alterationintaste
CLINICAL
CORELATION

32. II.CHRONIC ADVERSE EFFECTS
1.BEHAVIORALADVERSEEFFECTS
•dopamine Inbasalganglia
MECHANISM
SYMPTOMS
•Depression,anxiety,agitation,insomnia,somnolence,
confusion,delusions,halucinations,nightmares,
euphoria,changesinmood orpersonality.
•MorewithLevodopa+Carbidopa
??????higherlevelsreachingbrain
MANAGEMENT
•Reduceorwithdrawdrug;
•Atypicalantipsychoticagents(clozapine,olanzapine,
quetiapine,risperidone)
•PIMAVANSERIN:Selective5HT
2Ainverseagonist
CLINICAL
CORELATION

33. 2.CHRONICMOTOR
ADVERSEEFFECTS
A.WEARING-OFF
REACTIONS/
ENDOFDOSEAKINESIA
B.DYSKINESIA
C.ON-OFFPHENOMENON
More than half of patients
develop motor ADR after 5
yearsof treatment with
levodopa-Carbidopa

34. CHRONICMOTOR ADVERSE
EFFECTS

35. FACTORSUNDERLYING
APPEARANCE OFCHRONIC
MOTORADVERSEEFFECTS

36. 2.CHRONICMOTORADR:
A.WEARING-OFFREACTIONS/END OFDOSEAKINESIA
•Fluctuationsrelatedtothetimingofdoses
SYMPTOMS
•Eachdoseoflevodopaimprovesmobilityfor1–2hours
•Rigidityandakinesiareturnrapidlyat endofdosing
interval.
MECHANISM
•Withlowplasmaconc.atendofdoseinterval
•Asdisease progress:
•??????Lossofsubstantianigraneurons
•??????Lossofbuffering(dopaminenot storedin vesicles)
•??????t½of levodopa??????
•??????Lossofcontinuousstimulationofpostsynaptic
dopaminereceptors
MANAGEMENT
•Increasingdose&frequencybutdyskinesiasdevelops
withhighdose
CLINICAL
CORELATION

37. 2.CHRONICMOTORADR:
•Fluctuationsrelatedtothetimingofdoses
•Occursin80%patientsonLdopa>10 years
•Excessive&abnormalinvoluntarymovements
•Choreoathetosisofface& limbs(commonly)
B.DYSKINESIA
SYMPTOMS
•Unequaldistributionofstriataldopamine
•Dopaminergicdenervationduetodiseaseprogress+
ChronicpulsatilestimulationofdopaminereceptorswithLevodopa
MECHANISM
MANAGEMENT
•Reducingdoses
•LowerincidenceofdyskinesiaswithLevodopagivencontinuously
(intraduodenally/ intrajejunally/intravenousinfusion)OR Sustained-
releaseformulation
•Amantadaine
CLINICAL
CORELATION

38. 2.CHRONIC MOTOR ADR:
C.ON-OFFPHENOMENON
SYMPTOMS
•Fluctuationsunrelatedtothetimingofdoses
•Alternatingonandoffperiodswithinfewhours
•Offperiods:MarkedAkinesia
•Onperiods:MarkedDyskinesia
•Mostlikelyin patientswhorespondedwellinitially.
MECHANISMOFDYSKINESIA
•Unknown
MANAGEMENT
•Inpatientswithsevereoff-periodsunresponsivetoothermeasures,
ApomorphineSCinj
CLINICAL
CORELATION

39. MANAGINGMOTOR
FLUCTUATIONS
smallerdosesmoreoften

40. INTERACTIONS
Pyridoxine(vit.B6)
•CofactorforDopadecarboxylase
•??????extra-cerebralmetabolism∴??????effect
NonselectiveMonoamineOxidaseA
inhibitors
•Hypertensivecrisisdueto??????catecholamines
Anti-hypertensives
•Posturalhypotension
Anti-dopaminergics
•Phenothiazine,Metoclopromide:Block
effectbyblockingDAreceptors
•Domperidone:blocksnauseavomiting,
butnoteffectasnotcrossBBB
CLINICAL
CORELATION

41. CONTRA-
INDICATIONS
REASON
Psychoticpatients↑ Mentaldisturbance
Angle-closure
glaucoma
Causemydriasis
ActivepepticulcerOccasionalG.I.Bleeding
H/omelanomaor
undiagnosedskin
lesions:
levodopaisprecursorof
skinmelanin

42. PERIPHERALDECARBOXYLASE
INHIBITORS

43. PERIPHERALDECARBOXYLASE
INHIBITORS
•Carbidopa;Benserazide
•Rationalebehindcombininglevodopawith
carbidopa:
•CarbidopaisanExtracerebraldopa-
decarboxylaseinhibitor
•NotcrossBBB
•Alwaysgivenwithlevodopaasfixed dose
combination
•Noeffect whengivenalone
CLINICAL
CORELATION

44. PERIPHERAL DOPA
DECARBOXYLASE INHIBITORS

45. PERIPHERAL DOPA
DECARBOXYLASE INHIBITORS
ADVANTAGES
•??????Plasmat½,
•??????L-dopadose to¼
•??????degreeof
improvement
•??????Systemic
toxicity as??????
peripheral
dopaminelevels
??????Nausea, vomiting
??????Cardiaccomplications
??????On-offeffect
DISADVANTAGES
•CNS toxicity
enhanced or appear
earlier as??????
Central dopamine
levels
•Dyskinesia
•Behavioralabnormalities
•Posturalhypotension
CLINICAL
CORELATION

46. Width of each
pathway indicates
absolute amount of
drug at each site,
whereaspercentages
shown denote the
relative proportion of
the administered
dose.
The benefits of co-
administration of
carbidopa include:
Reductionofamountof
levodoparequiredfor
benefit
Reductioninabsolute
amountdivertedto
peripheral tissues
Increaseinfractionof
dosethatreachesbrain.

47. DOSAGEFORMS:Carbidopa/ Levodopa
COMMONFIXED DRUGCOMBINATIONS
•Combinationtreatmentstartedwithsmall
dose(carbidopa 25 mg, Levodopa 100 mg TDS &
graduallyincreased)
•Co-Careldopa:Levodopa100mg+ Carbidopa25mg
•Co–Beneldopa:Levodopa100mg+ Benserazide25mg
OTHERFORMULATIONS OFCARBIDOPA-LEVODOPA
•Controlled-releaseformulations
•Parcopa:Disintegratesinthemouth;swallowedwith
saliva
•Stalevo:Levodopa+Carbidopa+Entacapone
•InfusionofLevodopa-carbidopaintoduodenumor
upper jejunum

48. DRUGS
AFFECTING
BRAIN
DOPAMINERGIC
SYSTEM
1.Dopamineprecursor Levodopa+Carbidopa
2.Dopaminereceptor
agonists
Ergots:bromocriptine,
pergolide
Pramipexole,Ropinirole
Apomorphine
3.Monoamineoxidase
inhibitors
Selegiline (deprenyl),
rasagiline
4.Catechol-o-
methyltransferase
inhibitors
Tolcapone,entacapone
5.Glutamate(NMDA
Receptor)antagonist
Amantadine

49. 2.DOPAMINERECEPTOR
AGONISTS

50. DOPAMINERECEPTORS
D1FAMILY
•D1;D5
•Excitatory
•D
1-receptorstimulationmayalsoberequired
for maximalbenefit
D2FAMILY
•D2;D3;D4
•Inhibitory
•Benefits of dopaminergic anti-parkinsonism
drugs appeartodependmostly onstimulation
of D
2receptors

51. BROMOCRIPTINE
PERGOLIDE

52. CLINICALUSEDOPAMINEAGONISTS
•MonotherapyinearlyPD(First line):
•Symptomaticrelief=Levodopa-Carbidopa;
•Lowerincidences ofdyskinesia&motor
fluctuationvs. Levodopa-Carbidopa
ASFIRSTLINETHERAPY
•LowdoseCarbidopa-Levodopa+Dopamine
agonist
ASADD ONTHERAPY
•More advanced disease:Add-oninPatients
with end-of-dose akinesia/ on-off
phenomenon/ resistant to treatment with
Levodopa.
•UselowerdosesofLevodopa+Carbidopa
•Ineffective in patients who show no response
tolevodopa
CLINICAL
CORELATION

53. CLINICALUSEDOPAMINEAGONISTS
ADVANTAGES
DISADVANTAGES
•Impulse controldisordersenhancedbyactivationof
D2orD3receptorsinmesocorticolimbicsystem
CLINICAL
CORELATION
•Donot requireenzymaticconversiontoactive
metablt
•ActdirectlyonpostsynapticDreceptor
•Nopotentiallytoxicmetabolites
•Do notcompetewithothersubstancesforactive
transportintoblood& acrossBBB.
•Less adverseeffects:moreselectiveon D
receptors
•+Levodopa:↓Fluctuationswith long-termlevodopa
therapy

54. OLDERERGOTDERIVATIVES
BROMOCRIPTINE
•Add–oninlatecases
PERGOLIDE
•Moreeffectivethanbromocriptine
ERGOTRELATEDADVERSE
EFFECTS
•Pulmonaryinfiltrates,
•Erythromelalgia(red,painful, tenderfeet)
•Painlessdigital vasospasm:doserelated

55. PRAMIPEXOLE
MECHANISMOFACTION&PK
•Preferentialaffinityfor D3 family of receptors
•Extended release :more convenient for
patients & avoids swings in blood levels of
drugoverday.
USES
•Mildparkinsonism:Monotherapy
•Advanceddisease:reducedoseoflevodopa&
smoothoutresponsefluctuations
•Mayameliorateaffectivesymptoms.
•Neuroprotective effect: Scavenge hydrogen
peroxide; ??????neurotrophicactivityin
mesencephalicdopaminergiccellcultures

56. ROPINIROLE
•PureD2 receptor agonist
•Extendedrelease:moreconvenientforpatients&
avoidsswingsinbloodlevelsofdrugoverday.
•MetabolizedbyCYP1A2:Druginteractions
MECHANISMOFACTION&PK
USES
•Mildparkinsonism:Monotherapy
•Advanced disease:reduce doseoflevodopa&smooth
out responsefluctuations

57. ROTIGOTINE
MECHANISMOFACTION&PK
•Transdermalpatch
USES
•Earlyparkinsonism:providesmore continuous
dopaminergicstimulationthanoralmedicationinearly
disease

58. APOMORPHINE
MECHANISMOFACTION
•PostsynapticD2receptoragonistincaudatenucleusand
putamen
USES
•SC:temporaryrelief (“rescue”) of off-periodsofakinesiain
patients onoptimizeddopaminergictherapy
ADVERSEEFFECTS
•Nauseaon initiation
•Dyskinesias,drowsiness,insomnia, chestpain,
•Sweating,hypotension,syncope,constipation,diarrhea,
mentalorbehavioraldisturbances,bruisingatinjectionsite.

59. ADVERSEEFFECTSOFDOPAMINE
RECEPTOR AGONISTS
GIT:
•Nausea,Vomiting,Anorexia
•Takewithmeals
V.S:
•Posturalhypotension,
•Arrhythmias(notfor postM.I. patients)
CNS:
•Behavioral effects (lack of impulse control,
confusion,hallucination)morethanlevodopa,
•Tendencyto fall asleepatinappropriatetimes
:Ropinirole&pramipexole
•Dyskinesialess thanlevodopa

60. SUMMARY
•Levodopa
•Carbidopa
•Dopamineagonists

61. MECHANISM EFFECTS USES ADR&DI
LEVODOPA
Precursorof
dopamine
Symptomatc
improvemnt
Relieves
rigidity,
tremor
bradykinesia
Mosteffective
for
symptomatic
Rx of PD
Drug of first
choice for
bradykinesia
Early: GIT; CVS;Eye;
Therapeuticwindow
narrows after
severalyearsofRx
Late: Behavioral
ADR;Motor ADR:
Wearingoff;
Dyskinesia;
On-offeffect
DI:VitB6;MAOIn
CARBIDOPA
Peripheral
dopa-
decarboxylas
inhibitor
Systemic
Toxicity??????
GIT;CVS;
On-offeffect
Fixeddose
combination
with
Levodopa
Enhanced orappear
earlier:Dyskinesia
Behavioral
abnormalities
Postural
hypotension

62. MECHANISM EFFECTS USES ADR
DOPAMINE
AGONISTS
ERGOTS
BROMOCRYPTINE
PERGOLIDE
Pergolide
more
effective than
bromocriptine
Add-oninlate
cases
Pulmonary
infiltrates,
Erythromelalgia
Painless digital
vasospasm
DOPAMINE
AGONISTS
PRAMIPEXOLE
ROPINIROLE
ROTIGOTINE
Directagonist
atD3
Symptomatic
relief =
Ldopa;
LessADRvs
Levodopa;
+ Levodopa:
Smoothens
fluctuations
ofLevodopa;
Less
dyskinesia
Initial therapy
(Monotherapy);
Add-onwith
Levodopain
advanced
disease:??????on-
off effect
N;V,postural
hypotension,
More Behavioral
effects(lackof
impulsecontrol)
Sleepiness:
Ropinirole&
pramipexole

63. PREVIOUSQUESTIONS
•Explain the rationale / lack of rationale for
the use of : Levodopa for drug induced
parkinsonism
•Name a drug that causes the following
adverseeffect.Explainthemechanismof
causation and treatment for the adverse
effect:On-offphenomenon