This document provides information on drugs used to treat Parkinson's disease. It begins with a brief history of Parkinson's disease and then discusses the pathophysiology involving the loss of dopamine-producing neurons in the substantia nigra. The main classes of antiparkinsonian drugs described are those affecting the brain's dopaminergic and cholinergic systems. Key drugs discussed in depth include levodopa, peripheral decarboxylase inhibitors like carbidopa, dopamine agonists like pramipexole and ropinirole, MAO-B inhibitors like selegiline and rasagiline, and COMT inhibitors like entacapone and tolcapone. Adverse effects and considerations for each drug class are

1. ANTIPARKINSONIAN
DRUGS
1

2. CONTENT
• Introduction
• Pathophysiology
• Classification.
• Description Of Drugs
• Newer Advances
• Non Pharmacological Management Of PD 2

3. HISTORY
• Parkinson's Disease Was First
Described In "An Essay On The
Shaking Palsy," Published In 1817 By
A London Physician Named James
Parkinson.
• The Term “Parkinson’s Disease”
Which Was Earlier Called As Shaking
Palsy Was Coined By French
Neurologist Jean – Martin Charcot.
3

4. FAMOUS PERSONALITIES 4
Michael Richard Clifford:
Parkinson's in Space
Muhammad Ali: A Fighter
for Parkinson's
Awareness
Linda Ronstadt: Parkinson's
Took Her Voice But Not Her
Spirit

5. PARKINSON’S DISEASE
• Parkinson’s disease is a common kind of
parkinsonism .
• It is a progressive neurodegenerative disorder
characterized by the same motor conditions
as parkinsonism.
• The symptoms caused by parkinson’s include
1. An ongoing loss of motor control (resting
tremors, stiffness, slow movement, postural
instability)
2. Wide range of non-motor symptoms (such
as depression, loss of sense of smell,
gastric problems, cognitive changes and
5

6.  Parkinsonism is an
extrapyramidal motor disorder
Rigidity Tremor
Hypokinesia
 Secondary manifestations
defective posture
and gait
Mask-like face
sialorrhoea
6

7. PATHOPHYSIOLOGY
The basal ganglia consists of five large subcortical nuclei that participate in
control of movement.
1. Caudate Nucleus
2. Putamen
3. Globus Pallidus
4. Subthalamic Nucleus
5. Substantia Nigra
Substantia Nigra Pars Compacta Provide Dopamine
Innervation To Striatum.
7

8. Degeneration of neurones in the Substantia Nigra Pars Compacta (SN-PC)
Degeneration of nigrostriatal (dopaminergic) tract
Results in deficiency of Dopamine in Striatum - >80%
Disrupts the balance of • Dopamine (DA)
• Acetylcholine (Ach) in the basal ganglia
An imbalance between dopaminergic (inhibitory) & cholinergic
(excitatory) system in the striatum occurs motor defect. Cholinergic
system is not primarily affected, its suppression tends to restore
balance.
8

9. 1. Ageing
2. Genetic predisposition
3. Oxidative generation of free radicals
4. Environmental toxins like MPTP
5. Excitotoxic neuronal death
6. Drug induced
FACTORS CAUSING PARKINSON’S
DISEASE
9

10. CLASSIFICATION
1. Drugs Affecting Brain Dopaminergic System
a. Dopamine Precursor - Levodopa
b. Peripheral Decarboxylase Inhibitors - Carbidopa,
Benserazide
c. Dopaminergic Agonists - Bromocriptine, Ropinirole,
Pramipexole
d. MAO-B Inhibitors - Selegiline, Rasagiline
e. COMT Inhibitors - Entacapone, Tolcapone
f. Glutamate (NMDA Receptor)
Agonist (Dopamine Facilitator) - Amantadine
10

11. 2. Drugs Affecting Brain Cholinergic System
a. Central Anticholinergics - Trihexyphenidyl, Procyclidine,
Biperiden
b. Antihistaminics - Orphenadrine, Promethazine.
11

12. LEVODOPA
 Levodopa/ L-DOPA/ L- 3,4 – dihydroxyphenylalanine - a prodrug -
is a metabolic precursor of dopamine.
 It is the single most effective agent in the treatment of Parkinson’s
disease.
 It is given because dopamine cannot cross the blood brain barrier by
itself.
12

13. Levodopa
About 1–2% of administered levodopa -
crosses - brain - taken up by -
dopaminergic neurones, converted to
DA - stored and released as a
transmitter.
More than 95% of an oral dose -
decarboxylated to DA in the
peripheral tissues (mainly gut and
liver).
DA formed is further metabolized, and the remaining acts on heart, blood
vessels, other peripheral organs and on CTZ (though located in the brain,
i.e. floor of IV ventricle, it is not bound by blood brain barrier). 13

14. 14

15. ACTIONS OF LEVODOPA
15

16. CNS
• Hypokinesia and rigidity resolve first, later tremor as well.
• Secondary symptoms of posture, gait, handwriting, speech, facial
expression, mood, self care and interest in life are gradually
normalized.
• ‘General alerting response’.
• Excitement - Frank psychosis may occur.
• Increase in sexual activity.
• Dementia, does not improve; rather it predisposes to emergence of
psychiatric symptoms.
• Found to ameliorate idiopathic dystonia in children and adolescents
16

17. CVS
• Peripherally formed DA cause Tachycardia by acting on β
adrenergic receptors.
• Postural hypotension is quite common.
• Gradual tolerance develops to both cardiac stimulant and
hypotensive actions.
• Excess DA & NA - Decrease sympathetic outflow.
• DA formed in autonomic ganglia can impede ganglionic
transmission.
17

18. CTZ
• DA acts as an excitatory transmitter.
• The DA formed peripherally gains access to the CTZ without
hindrance—elicits nausea and vomiting.
• Tolerance develops gradually to this action.
• DA acts on
• Pituitary mammotropes to inhibit prolactin level
• Somatotropes to increase GH release
ENDOCRINE
18

19. PHARMACOKINETICS
• Bioavailability of levodopa is affected by:
(i) Gastric emptying
(Ii) Amino acids present in food compete for the same carrier for
absorption
19

20. ABSORPTION
Absorbed rapidly from small
intestine.
DISTRIBUTION
Plasma levels peak in 1 to 2 hrs
METABOLISM
Undergoes high first pass
metabolism in G.I. mucosa and
liver.
EXCRETION
Metabolites are excreted in urine
after conjugation.
LEVODOPA
20

21. ADVERSE EFFECTS
21

22. AT THE INITIATION OF THERAPY
1. Nausea and vomiting
2. Postural hypotension: It is more common in patients
receiving antihypertensives.
3. Cardiac arrhythmias
4. Exacerbation of angina
5. Alteration in taste sensation
These side effects can be minimized by starting with a low
dose.
22

23. APROLONGED THERAPY
1. Abnormal movements (dyskinesias):
• Facial tics, grimacing, tongue
thrusting, choreoathetoid movements
of limbs.
• These dyskinesias worsen with time.
• No tolerance develops to these side
effects, but dose reduction decreases
severity.
23

24. 2. Behavioural effects:
• Range from mild anxiety,
nightmares, etc. to severe
depression, mania, hallucinations,
mental confusion or frank
psychosis.
• Levodopa is contraindicated in
patients with psychotic illness.
24

25. 3. Fluctuation in motor performance: After 2–5 years of therapy, the level
of control of parkinsonian symptomatology starts showing fluctuation.
25

26. Cautious use of levodopa is needed in the
• Elderly
• Patients with ischaemic heart disease; cerebrovascular,
psychiatric, hepatic and renal disease; peptic ulcer; glaucoma
and gout.
26

27. INTERACTIONS
1. Pyridoxine: Abolishes the therapeutic effect of levodopa.
2. Antipsychotic drugs: Phenothiazines, butyrophenones, metoclopramide
reverse the therapeutic effect of levodopa by blocking DA receptors.
3. Nonselective MAO inhibitors: Prevent degradation of DA and NA. This
may cause hypertensive crisis.
4. Antihypertensive drugs: Postural hypotension.
5. Anticholinergic drugs : Therapeutic action with low doses of levodopa
but retard its absorption—more time is available for peripheral
degradation—efficacy of levodopa may be reduced. 27

28. PERIPHERAL DECARBOXYLASE INHIBITORS
Carbidopa
Extracerebral Dopa Decarboxylase Inhibitors
Benserazide
• They do not penetrate blood-brain barrier and do not inhibit
conversion of levodopa to DA in the brain.
28

29. BENEFITS OF
COMBINATIO
N
1. The plasma t½ of levodopa is prolonged and its dose is
reduced to approximately 1/4th.
2. Systemic concentration of DA is reduced; nausea and
vomiting are not prominent— therapeutic doses of
levodopa can be attained quickly.
3. Cardiac complications are minimized.
4. Pyridoxine reversal of levodopa effect does not occur.
5. ‘On-off’ effect is minimized since cerebral DA levels
are more sustained.
6. Degree of improvement may be higher; some patients,
not responding adequately to levodopa alone, also
improve.
29

30. PROBLEMS NOT RESOLVED OR
ACCENTUATED
Problems not resolved or accentuated are—
1. Involuntary movements
2. Behavioural abnormalities
3. Excessive day time sleepiness in some patients.
4. Postural hypotension.
• Levodopa is practically always used along with a decarboxylase
inhibitor, except in patients who develop marked involuntary
movements with the combination.
• ‘Co-careldopa’ levodopa + carbidopa 30

31. DOPAMINERGIC AGONISTS
• The DA agonists act on striatal DA receptors in patients who have largely
lost the capacity to synthesize, store and release DA from the
administered levodopa.
• They are longer acting, can exert subtype selective activation of DA
receptors involved in parkinsonism and not share the concern expressed
about levodopa of contributing to dopaminergic neuronal damage by
oxidative metabolism.
• Bromocriptine and pergolide - older dopamine agonists - rarely used.
• Pramipexole and Ropinirole - newer agents.
• Apomorphine - potent dopamine agonist, used primarily as a rescue drug
for patients with disabling response fluctuations to levodopa.
31

32. Pharmacological action
• Decrease prolactin
release and is a strong
antigalactopoietic.
• Increase GH release, but
decrease from pituitary
tumors causing
acromegaly
Adverse effect
• Vomiting,
hallucinations,
hypotension, nasal
stuffiness, conjunctival
injection.
• Marked fall in BP with
the ‘first dose’ patients
Pharmacokinetics
Improvement in
parkinsonian symptoms
occurs within ½–1 hr of an
oral dose and lasts for 6–
10 hours.
Mechanism of action
It has greater action on
D2 receptors, at certain
dopamine sites in the
brain it acts as a partial
agonist or antagonist of
D1 receptors.
BROMOCRIPTINE
32

33. ROPINIROLE AND
PRAMIPEXOLE
These are non ergoline, selective D2/D3 receptor agonists with
negligible affinity for D1 and nondopaminergic receptors.
Used as monotherapy for early pd.
Side-effects - nausea, dizziness, hallucinations, and postural
hypotension, episodes of day sleep.
Behavioral side effects - impulsive shopping, gambling, betting and
inappropriate sexual overactivity. 33

34. PRAMIPEXOLE
 Pramipexole has relatively greater affinity for D3 receptors.
 It permits the dose of levodopa to be reduced and smoothing out
response fluctuations.
 Pramipexole is rapidly absorbed after oral administration.
 Peak plasma concentrations in 2 hours
 Excreted largely unchanged in the urine.
34

35. ROPINIROLE
• It is a relatively pure D2 receptor agonist
• It is thus longer acting than levodopa,
useful in the management of motor
fluctuations and reducing frequency of
on-off effect.
• Ropinirole is FDA approved for use in
‘restless leg syndrome’.
Absorbed - orally -
rapidly
Plasma protein bound -
40%
Metabolized - by
hepatic CYP1A2
Eliminated - with a
terminal t½ of 6 hrs.
35

36. ROTIGOTINE
• The dopamine (D2 & D3) agonist - skin patch.
• It supposedly provides more continuous dopaminergic stimulation
than oral medication in early disease.
• The product was recalled in the united states in 2008 because of
crystal formation on the patches, affecting the availability and
efficacy of the agonist. It is still available in europe.
36

37. APOMORPHINE
• Dopaminergic agonist - subcutaneous injection
high affinity for D4 receptors.
• Pretreatment with the antiemetic trimethobenzamide - 3 days and
then continued for at least 2 months of therapy.
• Nausea is often troublesome at the initiation of apomorphine
treatment.
• Other adverse effects include dyskinesias, drowsiness, chest pain,
sweating, hypotension, and bruising at the injection site.
37

38. MAO – B INHIBITORS
• Two isoenzyme forms of MAO : MAO-A and MAO-B
• They are present in peripheral adrenergic structures and intestinal
mucosa.
• Monoamine oxidase A metabolizes norepinephrine, serotonin and
dopamine.
• Monoamine oxidase B metabolizes dopamine predominates in the
38

39. SELEGILINE (DEPRENYL)
• Inhibits irreversibly enzyme that breaks down dopamine, which
increases dopaminergic effect.
• Higher doses - hypertensive interactions with levodopa and
indirectly acting sympathomimetic amines.
• Selegiline + levodopa attenuates motor fluctuations and decreases
‘wearing off’ effect.
39

40. • It is beneficial in 50–70% patients and permits 20–30% reduction in
levodopa dose.
• The peak dose levodopa side effects - dyskinesias, mental
confusion or hallucinations - worsened. ‘On-off’ effect - not
improved.
• Based on the hypothesis that oxidation of DA and environmental
toxins (MPTP-like) in the striatum by MAO to free radicals was
causative in parkinsonism, it was proposed that early therapy with
selegiline might delay progression of the disorder. 40

41. hypotension,
nausea, confusion,
accentuation of
levodopa induced
involuntary
movements and
psychosis.
Partly metabolized
by liver into
amphetamine
which causes
insomnia and
agitation.
Contraindicated
in patients with
convulsive
disorders.
Interacts with
Pethidine gets
metabolised to
norpethidine -
causes excitement,
rigidity,
hyperthermia,
respiratory
depression.
41

42. RASAGILINE
• More potent than selegiline in preventing MPTP- induced
parkinsonism
• Longer acting and not metabolized to amphetamine.
• It is given once a day in the morning and does not
produce excitatory side effects or insomnia.
42

43. COMT INHIBITORS
COMT Inhibitors
43
COMT Inhibitors
Dopa Decarboxylase (DDC)
DDC

44. SAFINAMIDE
• A third monoamine oxidase B inhibitor, approved by FDA.
• It is used to reduce response fluctuations in patients taking
carbidopa-levodopa, diminishing off-periods in patients with
wearing off effect or on – off phenomenon.
• Safinamide - both dopaminergic and non-dopaminergic effects.
• It works through multiple mechanisms, namely as a reversible
selective monoamine oxidase-B inhibitor and through modulation
of glutamate release. 44

45. Features:
 Both rapidly absorbed.
 Bound to plasma proteins.
 Metabolized before excretion.
 Enhance and prolong the
action of levodopa by
diminishing its peripheral
metabolism.
Difference :
 Entacapone is preferred
because it is not associated
with hepatotoxicity & No
other toxicity has been
reported.
 Tolcapone - both central and
peripheral effects, whereas
the effect of entacapone is
peripheral.
 The half-life ~ 2 hours, but
tolcapone is slightly more
potent and has a longer
duration of action.
COMT INHIBITORS:
Entacapone and Tolcapone
45

46. ADVERSE EFFECTS
• COMT inhibitor + levodopa adverse effects such as nausea,
vomiting, dyskinesia, postural hypotension, hallucinations, etc
• Other prominent side effect - diarrhoea (less with entacapone)
- yellow orange discolouration of urine.
• Reports of acute fatal hepatitis and rhabdomyolysis.
46

47. GLUTAMATE (NMDA RECEPTORS)
ANTAGONIST (DOPAMINE
FACILITATOR)
• Amantadine
• Antiviral drug for prophylaxis of influenza A2.
• Amantadine promotes presynaptic synthesis and release of DA in
the brain and has an antagonistic action on NMDA type of
glutamate receptors, through which the striatal dopaminergic
system exerts its influence.
• It serves to suppress motor fluctuations and abnormal movements.
• The effect of a single dose lasts 8–12 hours.
47

48. SIDE EFFECTS
• Insomnia, restlessness, confusion, nightmares,
anticholinergic effects and rarely hallucinations.
• A characteristic side effect due to local release of
cas resulting in postcapillary vasoconstriction is
livedo reticularis (bluish discolouration) and
edema of ankles.
• Side effects are accentuated when it is combined
with anticholinergics.
48

49. CENTRAL ANTICHOLINERGICS
• Have a higher central : peripheral anticholinergic action
• They act by reducing the unbalanced cholinergic activity in the striatum
of parkinsonian patients.
• Produce 10–25% improvement in parkinsonian symptoms lasting 4–8
hours after a single dose.
• Tremor is benefited more than rigidity; hypokinesia is affected the
least.
• Sialorrhoea is controlled by their peripheral action.
• Anticholinergics are the only drugs effective in drug (phenothiazine)
induced parkinsonism.
49

50. SIDE EFFECTS
• Impairment of memory, organic confusional states and blurred vision
are more common in the elderly.
• Urinary retention is possible in elderly males.
• The antihistaminics are less efficacious than anticholinergics but are
better tolerated by older patients.
• Their sedative action also helps.
• Orphenadrine has mild euphoriant action.
50

51. TRIHEXYPHENIDYL
• It is the most commonly used drug.
• Start with the lowest dose in 2–3 divided portions per day and
gradually increase till side effects are tolerated.
51

52. SOME GENERAL POINTS
1. None of the drugs alter the basic pathology of PD—the disease continues
to progress.
Drugs only provide symptomatic relief and give most patients an additional
3–6 years of happier and productive life.
2. When disease is mild, only anticholinergics or selegiline may be sufficient.
3. Combination of levodopa with a decarboxylase inhibitor increases efficacy
and reduces early complications.
4. Subsequently the duration of benefit from a levodopa dose progressively
shortens—end of dose ‘wearing off’ effect is seen.
52

53. 5. Levodopa alone is now used only in those patients who develop
intolerable dyskinesias with a levodopa-decarboxylase inhibitor
combination.
6. A MAO-B inhibitor (rasagiline) relief symptoms in early/mild cases
and may retard disease progression. The MAO-B inhibitor serves to
prolong and smoothen levodopa- carbidopa effect.
7. The direct DA agonists (ropinirole/ pramipexole) are commonly
used to supplement levodopa in late cases to smoothen ‘on off’
phenomenon, to reduce levodopa dose and possibly limit
dyskinesias.
53

54. 8. The COMT inhibitor entacapone may be added to levodopa-carbidopa
to prolong its action and subdue ‘on off’ fluctuation. It can be given to
patients receiving selegiline or DA agonists as well.
9. ‘Drug holiday’ (withdrawal of levodopa for 4–21 days) to reestablish
striatal sensitivity to DA by increasing dopaminergic receptor population
is no longer practiced.
54

55. NEWER DRUGS
• ISTRADEFYLLINE
• APOMORPHINE OPICAPNE
55

56. MANAGEMENT
Pharmacologic
• Dopamine precursor
• Peripheral
decarboxylase
inhibitors
• Dopaminergic agonists
• MAO-B inhibitors
• COMT inhibitors
• Central
anticholinergics
• Antihistaminics
Non – pharmacologic
• Education
• Nutrition
• Psychiatric counselling
• Exercise
• Speech therapy
• Occupational therapy
• Neurohabilitation
Surgery
• Deep brain stimulation
56

57. • Helps to relieve some of the motor symptoms.
• Aid in the management of postural instability and non- motor
symptoms.
• Education: Provide patient & family information and control over the
disorder.
• Nutrition: Elderly patients with chronic illness are at risk of poor
nutrition and weight. A high fiber diet & adequate hydration therapy is
beneficial. Protein restriction.
• Support: Exercise, physiotherapy, speech therapy & occupational
therapy are essential to help patients to cope up with their progressive
disability.
NON PHARMACOLOGICAL MANAGEMENT OF PARKINSONS
DISEASE
57

58. SURGERY
• Plays a role in people who can’t achieve a satisfactory response to
available medications.
• Deep brain stimulation: brain pacemaker sends impulses to brain to
stimulate sub thalamic nucleus.
• Stem cell transplantation: transplanting foetal dopaminergic neurons
directly into dopamine depleted regions of basal ganglia.
58

59. REFERENCE
1. Goodman L, Gilman A. The Pharmacological Basis Of Therapeutics. 13th Ed. New
York : Mcgraw-hill; 2018. Chapter 18,treatment Of Central Nervous System
Degenerative Disorder; Erik D Roberson; P.327-333.
2. Bertram G. Katzung. Basic & Clinical Pharmacology 14th Ed: Mcgraw-hill; 2018.
Chapter 28,pharmacologic Management Of Parkinsonism & Other Movement
Disorder; P.492-503
3. Tripathi KD. Essentials Of Medical Pharmacology. 8th Edition, New Delhi : Jaypee
Brothers Medical Publications (P) Ltd; 2019. Chapter 31,antiparkinsonian Drugs;
P.453-461.
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