ANTI-PARKINSON DRUGS

2. DRUGS FOR
PARKINSONISM AND
OTHER MOTOR
DISORDERS

3. LEARNING OBJECTIVES
• List drugs used in the management of
Parkinsonism
• Describe the mechanism of action ,
pharmacological effects and adverse effects of:
– Levodopa, Carbidopa
– Ropinirole, Pramipexole
• Describe the drug interactions of levodopa
• Explain the rationale behind combining levodopa
with carbidopa.

4. PARKINSONISM

5. PARKINSONISM
• A disorder which impairs the regulation of
voluntary motor activity without directly
affecting strength
• Usually Idiopathic: Parkinson’s disease
• Other etiology

6. THEORIES ABOUT THE CAUSE
OF PARKINSON’S DISEASE
• Viral infection/ Brain infection
• Blows to the head
• Prion disease: Lewy bodies (intracellular
inclusion bodies containing α-synuclein) in
dopaminergic cells
• Atherosclerosis
• Exposure to certain drugs
• Environmental factors
• Genetic predisposition

7. GENETIC FACTORS
Synucleinopathy
• Mutations of the α-synuclein gene at 4q21 or
• Duplication and triplication of the normal
synuclein gene
Autosomal dominant parkinsonism
• Mutations of leucine-rich repeat kinase 2
(LRRK2) gene at 12cen & UCHL1 gene
Familial parkinsonism/
Sporadic juvenile-onset parkinsonism
• Early onset, autosomal recessive
• Mutations in parkin gene (6q25.2–q27)

8. PROGRESSION OF
PARKINSON’S DISEASE
• R igidity/weakness (RAFT)
• A kinesia/ bradykinesia
• F lat/mask-like expression
• T remors at rest
• Trouble maintaining position or posture
• Lack of coordination
• Problem walking
• Drooling and affected speech

9. Functional circuitry between the cortex, basal ganglia, and thalamus.
In Parkinson’s disease, there is degeneration of the pars compacta of substantia nigra, leading to
overactivity in the indirect pathway (red) & increased glutamatergic activity by the subthalamic nucleus.

10. PATHOPHYSIOLOGY
• Loss of dopaminergic
neurons in substantia nigra
• Dopaminergic neurons
normally inhibit output of
GABAergic cells in corpus
striatum

11. DEGENERATION OF
NEURONS THAT LEADS TO
PARKINSON’S DISEASE
Imbalance bet. Dopaminergic (inhibitory) & cholinergic
(excitatory)

12. Legend: Schematic representation of the sequence of neurons involved in parkinsonism. Top: Dopaminergic neurons (red)
originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons
(green) exert an excitatory effect. Bottom: In parkinsonism, there is a selective loss of dopaminergic neurons (dashed,
red).

13. PATHOPHYSIOLOGY

14. TREATMENT OF PARKINSON’S
DISEASE

15. ANTIPARKINSONISM DRUGS
Drugs affecting brain
dopaminergic
system:
 Dopamine
Drugs affecting brain
cholinergic system:
ACh

16. GOALS OF THERAPY IN TREATING
PARKINSON’S DISEASE
MAO,COMT inhibitors

17. ANTIPARKINSONISM DRUGS
AFFECTING BRAIN
DOPAMINERGIC SYSTEM

18. 18
EFFECTOR SITES
DOPAMINE TYPE 1;
D 1 FAMILY
(D1,D5): Excitatory
D1- receptor
stimulation may also
be required for
maximal benefit
Stimulate Adenyl
cyclase
 cAMP
• Pars
compacta of
substantia nigra
• Presynaptically on
striatal axons
coming from cortical
neurons & from
dopaminergic cells in
substantia nigra.
DOPAMINE TYPE 2;
D2,D3,D4:Inhibitory
Inhibit Adenyl
Cyclase activity,
🢃 cAMP
Open K+
channels
🢃 calcium influx
• Postsynaptically on
striatal neurons
• Presynaptically on
axons in substantia
nigra belonging to
neurons in basal
ganglia
Dopaminergic
antiparkinsonism
drugs : stimulation
of D2 receptors

19. THERAPEUTIC ACTIONS
OF DOPAMINERGICS
• 🢃 Levels of dopamine in the substantia
nigra
• Directly stimulate dopamine
receptors (D2)in that area
• Helping to restore the balance between
inhibitory (D) and stimulating neurons
(ACh)

20. COMMON ADVERSE EFFECTS
OF DOPAMINERGICS
GIT
• Nausea, vomiting
• Stimulate CTZ
CVS
• Postural hypotension:
• 🢃 Central symp outflow
BEHAVIORAL EFFECTS
• Anxiety, Depression, Mood changes,
• Mania, hallucinations, Frank psychosis

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

22. 1.DOPAMINE PRECURSOR:
LEVODOPA

24. LEVODOPA
•Levorotatory stereoisomer of Dopa
Precursor of Dopamine
Crosses Blood Brain Barrier(BBB)
Converted to Dopamine by enzyme
Dopa decarboxylase
•Dopamine not used as Dopamine cannot
cross BBB + low bioavailability
•Most effective for symptomatic Rx of PD
•Drug of first choice for troublesome
bradykinesia
•Does not cure
CLINICAL
CORELA
TION

25. LEVODOPA:PHARMACOKINETICS
•Rapidly absorbed
•Bioavailability: 🢃 by food
(protein)
•High first pass
Metabolism
•Metabolized in
Liver
•Excreted in Urine :
Homovanillic acid(HVA);
Dihydroxyphenylacetic
acid (DOPAC)
BRAIN

26. LEVODOPA:PHARMACOKINETICS
• Peaks at 1-2 hrs after oral dose
• t½: 1–3 Hours but dosage interval : three
times a day orally
• Levodopa is converted into dopamine;
stored in vesicles of nigrostriatal
dopaminergic neurons and released.
CLINICAL
CORELA
TION

27. LEVODOPA:PHARMACOKINETICS

28. CLINICAL USE
CLINICAL RESPONSE
• Symptomatic improvement: Relieves bradykinesia
rigidity, tremor
•Best results obtained in first few years Rx
• Therapeutic window narrows after several years of
treatment
•Daily dose of Levodopa 🢃 over time to avoid adverse effects at
doses that were tolerated initially.
•Patients less responsive to Levodopa: loss of dopaminergic
nigrostriatal nerve terminals or pathological involvement of
striatal D receptors.
ADVANTAGES
• Early initiation lowers mortality rate.
DISADVANTAGES
• Does not stop progression of parkinsonism
• Long-term therapy leads to on-off phenomenon
CLINICAL
CORELA
TION

29. DRUG HOLIDAY OF LEVODOPA
• Discontinuance of the drug for 3–21 days
• Temporary nature of any benefit,
• Not recommended.
DEFINITION
ADVANTAGES
• May temporarily improve responsiveness to Levodopa
• May alleviate some of its adverse effects
DISADVANTAGES
• Not manage on-off phenomenon.
• Risks of aspiration pneumonia, venous thrombosis,
pulmonary embolism,and depression due to immobility
accompanying severe parkinsonism
CLINICAL
CORELA
TION

30. ADVERSE
EFFECTS
I.EARLY ADVERSE
EFFECTS
1.GIT
2.CVS
3.EYE
II.CHRONIC
ADVERSE EFFECTS
1.BEHAVIORAL
EFFECTS
2.MOTOR EFFECTS

31. I.EARLY ADVERSE EFFECTS
• Due to Peripheral effects of dopamine
MECHANISM
1.GIT : Nausea, vomiting
• Stimulates D2 in CTZ
• Tolerance develops;
•  by: Divided doses; Slowly titrating dose; Taking drug with meals
• Rx with Domperidone & not Metoclopromide
2.CVS
• Postural hypotension: Esp. with Initial doses ;due to 🢃
central symp outflow; Tolerance develops
• Arrhythmias: tachycardia, ventricular extrasystoles;atrial
fibrillation: due to  Catecholamines peripherally
3.SENSES/ EYE:
• Mydriasis (adrenergic effect):precipitate glaucoma
• Alteration in taste
CLINICAL
CORELA
TION

32. II.CHRONIC ADVERSE EFFECTS
1.BEHAVIORAL ADVERSE EFFECTS
•  dopamine In basal ganglia
MECHANISM
SYMPTOMS
• Depression, anxiety, agitation, insomnia, somnolence,
confusion,delusions, halucinations, nightmares,
euphoria, changes in mood or personality.
• More with Levodopa+ Carbidopa
🢃 higher levelsreaching brain
MANAGEMENT
• Reduce or withdraw drug;
• Atypical antipsychotic agents(clozapine, olanzapine,
quetiapine, risperidone)
• PIMAVANSERIN: Selective 5HT2A inverse agonist
CLINICAL
CORELA
TION

33. 2. CHRONIC MOTOR
ADVERSE EFFECTS
A. WEARING-OFF
REACTIONS/
END OF DOSE AKINESIA
B. DYSKINESIA
C. ON-OFF PHENOMENON
More than half of patients
develop motor ADR after 5
years of treatment with
levodopa-Carbidopa

34. CHRONIC MOTOR ADVERSE
EFFECTS

35. FACTORS UNDERLYING
APPEARANCE OF CHRONIC
MOTOR ADVERSE EFFECTS

36. 2.CHRONIC MOTOR ADR:
A.WEARING-OFF REACTIONS/END OF DOSE AKINESIA
• Fluctuations related to the timing of doses
SYMPTOMS
• Each dose of levodopa improves mobility for 1–2 hours
• Rigidity and akinesia return rapidly at end of dosing
interval.
MECHANISM
• With low plasma conc. at end of dose interval
• As disease progress:
• 🢃 Loss of substantia nigra neurons
• 🢃 Loss of buffering (dopamine not stored in vesicles)
• 🢃 t½ of levodopa 🢃
• 🢃 Loss of continuous stimulation of postsynaptic
dopamine receptors
MANAGEMENT
• Increasing dose & frequency but dyskinesias develops
with high dose
CLINICAL
CORELA
TION

37. 2.CHRONIC MOTOR ADR:
• Fluctuations related to the timing of doses
• Occurs in 80% patients on Ldopa >10 years
• Excessive & abnormal involuntary movements
• Choreoathetosis of face & limbs(commonly)
B. DYSKINESIA
SYMPTOMS
• Unequal distribution of striatal dopamine
• Dopaminergic denervation due to disease progress +
Chronic pulsatile stimulation of dopamine receptors with Levodopa
MECHANISM
MANAGEMENT
• Reducing doses
• Lower incidence of dyskinesias with Levodopa given continuously
(intraduodenally / intrajejunally/ intravenous infusion) OR Sustained-
release formulation
• Amantadaine
CLINICAL
CORELATION

38. 2.CHRONIC MOTOR ADR:
C.ON-OFF PHENOMENON
SYMPTOMS
• Fluctuations unrelated to the timing of doses
• Alternating on and off periods within few hours
• Off periods :Marked Akinesia
• On periods :Marked Dyskinesia
• Most likely in patients who responded well initially.
MECHANISM OF DYSKINESIA
• Unknown
MANAGEMENT
• In patients with severe off-periods unresponsive to other measures,
Apomorphine SC inj
CLINICAL
CORELATION

39. MANAGING MOTOR
FLUCTUATIONS
smaller doses more often

40. INTERACTIONS
Pyridoxine (vit.B6)
• Cofactor for Dopa decarboxylase
• 🢃 extra-cerebral metabolism ∴ 🢃 effect
Nonselective Monoamine Oxidase A
inhibitors
• Hypertensive crisis due to 🢃 catecholamines
Anti-hypertensives
• Postural hypotension
Anti-dopaminergics
• Phenothiazine, Metoclopromide:Block
effect by blocking DA receptors
• Domperidone : blocks nausea vomiting,
but not effect as not cross BBB
CLINICAL
CORELATION

41. CONTRA-
INDICATIONS
REASON
Psychotic patients ↑ Mental disturbance
Angle-closure
glaucoma
Cause mydriasis
Active peptic ulcer Occasional G.I. Bleeding
H/o melanoma or
undiagnosed skin
lesions:
levodopa is precursor of
skin melanin

42. PERIPHERAL DECARBOXYLASE
INHIBITORS

43. PERIPHERAL DECARBOXYLASE
INHIBITORS
• Carbidopa; Benserazide
• Rationale behind combining levodopa with
carbidopa:
• Carbidopa is an Extracerebral dopa-
decarboxylase inhibitor
• Not cross BBB
• Always given with levodopa as fixed dose
combination
• No effect when given alone
CLINICAL
CORELATION

44. PERIPHERAL DOPA
DECARBOXYLASE INHIBITORS

45. PERIPHERAL DOPA
DECARBOXYLASE INHIBITORS
ADVANTAGES
•🢃 Plasma t½,
•🢃 L-dopa dose to ¼
•🢃 degree of
improvement
•🢃 Systemic
toxicity as 🢃
peripheral
dopamine levels
🢃 Nausea, vomiting
🢃 Cardiac complications
DISADVANTAGES
• CNS toxicity
enhanced or appear
earlier as 🢃
Central dopamine
levels
• Dyskinesia
• Behavioral abnormalities
• Postural hypotension
CLINICAL
CORELATION

46. Width of each
pathway indicates
absolute amount of
drug at each site,
whereas percentages
shown denote the
relative proportion of
the administered
dose.
The benefits of co-
administration of
carbidopa include:
Reduction of amount of
levodopa required for
benefit
Reduction in absolute
amount diverted to
peripheral tissues
Increase in fraction of
dose that reaches brain.

47. DOSAGE FORMS: Carbidopa / Levodopa
COMMON FIXED DRUG COMBINATIONS
• Combination treatment started with small
dose(carbidopa 25 mg, Levodopa 100 mg TDS &
gradually increased)
• Co- Careldopa: Levodopa 100 mg + Carbidopa 25mg
• Co – Beneldopa: Levodopa100mg + Benserazide25mg
OTHER FORMULATIONS OF CARBIDOPA-LEVODOPA
• Controlled-release formulations
• Parcopa: Disintegrates in the mouth; swallowed with
saliva
• Stalevo: Levodopa+ Carbidopa+ Entacapone
• Infusion of Levodopa-carbidopa into duodenum or
upper jejunum

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

49. 2. DOPAMINE RECEPTOR
AGONISTS

50. DOPAMINE RECEPTORS
D1 FAMILY
• D1;D5
• Excitatory
• D1- receptor stimulation may also be required
for maximal benefit
D2 FAMILY
• D2;D3;D4
• Inhibitory
• Benefits of dopaminergic anti-parkinsonism
drugs appear to depend mostly on stimulation
of D2 receptors

51. BROMOCRIPTINE
PERGOLIDE

52. CLINICAL USE DOPAMINE AGONISTS
• Monotherapy in early PD(First line):
• Symptomatic relief = Levodopa-Carbidopa;
• Lower incidences of dyskinesia & motor
fluctuation vs. Levodopa-Carbidopa
AS FIRST LINE THERAPY
• Low dose Carbidopa-Levodopa + Dopamine
agonist
AS ADD ON THERAPY
• More advanced disease :Add-on in Patients
with end-of-dose akinesia/ on-off
phenomenon/ resistant to treatment with
Levodopa.
• Use lower doses of Levodopa + Carbidopa
• Ineffective in patients who show no response
to levodopa
CLINICAL
CORELA
TION

53. CLINICAL USE DOPAMINE AGONISTS
ADVANTAGES
DISADVANTAGES
• Impulse control disorders enhanced by activation of
D2 or D3 receptors in mesocorticolimbic system
CLINICAL
CORELATION
• Do not require enzymatic conversion to active
metablt
• Act directly on postsynaptic D receptor
• No potentially toxic metabolites
• Do not compete with other substances for active
transport into blood & across BBB.
• Less adverse effects : more selective on D
receptors
• +Levodopa:↓Fluctuations with long-term levodopa
therapy

54. OLDER ERGOT DERIVATIVES
BROMOCRIPTINE
• Add –on in late cases
PERGOLIDE
• More effective than bromocriptine
ERGOT RELATED ADVERSE
EFFECTS
• Pulmonary infiltrates,
• Erythromelalgia (red, painful, tender feet)
• Painless digital vasospasm: dose related

55. PRAMIPEXOLE
MECHANISM OF ACTION & PK
• Preferential affinity for D3 family of receptors
• Extended release :more convenient for
patients & avoids swings in blood levels of
drug over day.
USES
• Mild parkinsonism: Monotherapy
• Advanced disease: reduce dose of levodopa &
smooth out response fluctuations
• May ameliorate affective symptoms.
• Neuroprotective effect: Scavenge hydrogen
peroxide; 🢃 neurotrophic activity in
mesencephalic dopaminergic cell cultures

56. ROPINIROLE
• Pure D2 receptor agonist
• Extended release :more convenient for patients &
avoids swings in blood levels of drug over day.
• Metabolized by CYP1A2: Drug interactions
MECHANISM OF ACTION & PK
USES
• Mild parkinsonism: Monotherapy
• Advanced disease: reduce dose of levodopa & smooth
out response fluctuations

57. ROTIGOTINE
MECHANISM OF ACTION & PK
• Transdermal patch
USES
• Early parkinsonism: provides more continuous
dopaminergic stimulation than oral medication in early
disease

58. APOMORPHINE
MECHANISM OF ACTION
• Postsynaptic D2 receptor agonist in caudate nucleus and
putamen
USES
• SC: temporary relief (“rescue”) of off-periods of akinesia in
patients on optimized dopaminergic therapy
ADVERSE EFFECTS
• Nausea on initiation
• Dyskinesias, drowsiness, insomnia, chest pain,
• Sweating, hypotension, syncope, constipation, diarrhea,
mental or behavioral disturbances, bruising at injection site.

59. ADVERSE EFFECTS OF DOPAMINE
RECEPTOR AGONISTS
GIT:
• Nausea, Vomiting, Anorexia
• Take with meals
V. S:
• Postural hypotension,
• Arrhythmias (not for post M.I. patients)
CNS:
• Behavioral effects (lack of impulse control,
confusion, hallucination) more than levodopa,
• Tendency to fall asleep at inappropriate times
:Ropinirole & pramipexole
• Dyskinesia less than levodopa

60. SUMMARY
• Levodopa
• Carbidopa
• Dopamine agonists

61. MECHANISM EFFECTS USES ADR &DI
LEVODOPA
Precursor of
dopamine
Symptomatc
improvemnt
Relieves
rigidity,
tremor
bradykinesia
Most effective
for
symptomatic
Rx of PD
Drug of first
choice for
bradykinesia
Early: GIT; CVS;Eye;
Therapeutic window
narrows after
several years of Rx
Late: Behavioral
ADR;Motor ADR:
Wearing off;
Dyskinesia;
On-off effect
DI: Vit B6;MAO In
CARBIDOPA
Peripheral
dopa-
decarboxylas
inhibitor
Systemic
Toxicity🢃
GIT;CVS ;
On-off effect
Fixed dose
combination
with
Levodopa
Enhanced or appear
earlier: Dyskinesia
Behavioral
abnormalities
Postural
hypotension

62. MECHANISM EFFECTS USES ADR
DOPAMINE
AGONISTS
ERGOTS
BROMOCRYPTINE
PERGOLIDE
Pergolide
more
effective than
bromocriptine
Add-on in late
cases
Pulmonary
infiltrates,
Erythromelalgia
Painless digital
vasospasm
DOPAMINE
AGONISTS
PRAMIPEXOLE
ROPINIROLE
ROTIGOTINE
Direct agonist
at D3
Symptomatic
relief =
Ldopa;
Less ADR vs
Levodopa;
+ Levodopa:
Smoothens
fluctuations
of Levodopa;
Less
dyskinesia
Initial therapy
(Monotherapy);
Add-on with
Levodopa in
advanced
disease: 🢃 on-
off effect
N; V, postural
hypotension,
More Behavioral
effects (lack of
impulse control)
Sleepiness:
Ropinirole &
pramipexole

63. PREVIOUS QUESTIONS
• Explain the rationale / lack of rationale for
the use of : Levodopa for drug induced
parkinsonism
• Name a drug that causes the following
adverse effect. Explain the mechanism of
causation and treatment for the adverse
effect :On-off phenomenon