This document provides an overview of pharmacotherapy for Parkinsonism. It discusses the clinical features and etiology of Parkinson's disease and outlines the mechanisms and uses of various drug classes for treatment, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, and other drugs. Side effects and considerations for each class are also reviewed. Non-motor symptoms can be treated with additional drugs like antidepressants, anxiolytics, and atypical antipsychotics as adjunctive therapy.

1. PHARMACOTHERAPY OF PARKINSONISM
DR. JINIA GHOSH
MD PGT (PHARMACOLOGY)
RGKMCH

2. INTRODUCTION
Parkinsonism is a generic term that is used to define a
syndrome manifest as bradykinesia with rigidity and/or
tremor. It has a differential diagnosis that reflects damage
to different components of the basal ganglia.
Among the different forms of parkinsonism, idiopathic
form is the most common known as Parkinson’s Disease
(approximately 75% of cases).

3. PARKINSON’S DISEASE
Second commonest neurodegenerative disease, exceeded
only by Alzheimer's disease.
Affects men and women of all races, all occupations, and
all countries.
Mean age of onset is about 60 years, but cases can be
seen in patients in their 20s, and even younger.
Prevalence will dramatically increase in future decades.

4. CLINICAL
FEATURES

6. ETIOLOGY
Most PD cases occur sporadically (~85–90%) and are of
unknown cause.
Environmental factors :
• Important role in patients >50 years.
• Increased risk with exposure to pesticides, rural living,
and drinking well water.
• Reduced risk with cigarette smoking, caffeine, anti-
inflammatory drug and high serum uric acid levels.

7. Genetic factors :
• Important in younger patients.
• LRRK2 mutation, alpha synuclein, tau, and HLA are risk
factors.
•UCHL1 gene  AD parkinsonism.
•parkin gene early-onset, AR, familial, or sporadic
juvenile-onset parkinsonism.
Others : Excitotoxicity, mitochondrial dysfunction,
oxidative stress, inflammation and apoptosis.

9. PATHOPHYSIOLOGY
The dopaminergic deficit which arises from a loss of the
neurons in the substantia nigra pars compacta that provide
innervation to the striatum.
The disorder affects a wide range of other brain
structures, including the brainstem, hippocampus, and
cerebral cortex. This pathology is likely responsible for
the “non-motor” features of PD.

10. Basal Ganglia in PD

12. MOLECULAR ASPECTS
Associated with the development of intracellular protein
aggregates known as Lewy bodies.
They consist largely of α-synuclein, a synaptic protein.
 α-synuclein may act as a prion-like protein and that PD is
in fact a prion-like disease.
α-helical conformation β-sheet-rich structure
polymerises to form toxic aggregates and amyloid plaques.
Misfolding and aggregation renders the protein resistant to
degradation within cells pile up in Lewy bodies.

13. How PD Medications Work

14. LEVODOPA
Metabolic precursor of DA.
Single most effective agent in the treatment of PD.
About 80% of patients show initial improvement
particularly of rigidity and bradykinesia, and about 20%
are restored virtually to normal motor function.
Does not alter the disease course.
Administered orally.
Absorbed rapidly from the small bowel.
Peak plasma concentration between 0.5 and 2 hours.
The plasma t1/2 is 1-3 hours.

15. The rate and extent of absorption depends on the rate of
gastric emptying, the pH of gastric juice, the degradative
enzymes of the gastric and intestinal mucosa, competition
with dietary amino acids ,co-administration with high-
protein meals.
Entry of the drug into the CNS across the blood-brain
barrier also is mediated by a membrane transporter for
aromatic amino acids.

16. Molecular structure :

17. Metabolism of Levodopa

18. Adverse Effects
A. Gastrointestinal Effects :
Anorexia, nausea and vomiting.
B. Cardiovascular Effects :
• Tachycardia, ventricular extrasystoles and, rarely, atrial
fibrillation.
•Postural hypotension is common, but often asymptomatic.
•Hypertension may also occur, especially in the presence of
nonselective MAO inhibitors or sympathomimetics or massive
doses of levodopa.

19. C. Behavioral Effects :
Depression, anxiety, agitation, insomnia, somnolence,
confusion, delusions, hallucinations, nightmares, euphoria, and
other changes in mood or personality.
D. Dyskinesias and Response Fluctuations :
Dyskinesias occur in up to 80% of patients receiving levodopa
therapy for >10 years.
“

20. “wearing off” phenomenon -
Each dose of levodopa effectively improves mobility for a
period of time, but rigidity and akinesia return rapidly at
the end of the dosing interval. Increasing the dose and
frequency of administration can improve this situation, but
this often is limited by the development of dyskinesias.
on/off phenomenon –
In the later stages of PD, patients may fluctuate rapidly
between being “off,” having no beneficial effects, and
being “on” but with disabling dyskinesias. Dyskinesias are
observed most often when the plasma levodopa
concentration is high, rising or falling.

21. E. Miscellaneous Adverse Effects :
•Mydriasis may occur and may precipitate an attack of acute
glaucoma.
• Various blood dyscrasias; a positive Coombs’ test
with evidence of hemolysis, hot flushes.
•Aggravation or precipitation of gout.
•Abnormalities of smell or taste.
•Brownish discoloration of saliva, urine, or vaginal secretions.
•Priapism
•Mild elevations of blood urea nitrogen, serum transaminases,
alkaline phosphatase, and bilirubin.

22. Drug Interactions
Pyridoxine (vitamin B 6 ) enhance the extracerebral
metabolism of levodopa and may therefore prevent its
therapeutic effect.
Levodopa should not be given to patients taking
MAO-A inhibitors or within 2 weeks of their
discontinuance because such a combination can lead to
hypertensive crises.

23. Contraindications
•Psychotic patients.
•Angle-closure glaucoma
•Should be used cautiously in patients with cardiac disease,
active peptic ulcer.
•Should be used with particular care in patients with a
history of melanoma or with suspicious undiagnosed skin
lesions.

24. PERIPHERAL DECARBOXYLASE
INHIBITOR
Carbidopa & benserazide.
Peripherally acting inhibitor of aromatic L-amino acid
decarboxylase.
Do not penetrate well into the CNS.
Markedly increases the fraction of administered
levodopa that remains unmetabolized and available to
cross the blood-brain barrier and reduces the incidence of
GI side effects.
In clinical practice, levodopa is almost always
administered in combination with this drug.

25. Fate of orally administered levodopa with or
without carbidopa

26. Dosage & Formulation
Total daily dose should be increased very slowly.
The most commonly prescribed form of carbidopa/levodopa
is the 25/100 form, three or more tablets daily.
A controlled-release formulation is available.
A formulation of carbidopa-levodopa (10/100, 25/100,
25/250) that disintegrates in the mouth is available and is best
taken about 1 hour before meals.
Finally, therapy by intraduodenal infusion appears to be safe
and is superior to a number of oral combination therapies in
patients with response fluctuations.

27. DOPAMINE RECEPTOR AGONISTS
Older dopamine agonists - Bromocriptine and Pergolide
are ergot derivatives, and are rarely used to treat
parkinsonism.
Newer agents – Pramipexole, Ropinirole and Rotigotine .
Better tolerated.
Mechanism of action - Direct agonists of striatal DA
receptors. Selective activity at D2 class sites(specifically at
the D2 and D3 receptor) and little or no activity at D1 class
sites.

28. Advantages -
•Do not require enzymatic conversion to an active
Metabolite
•Have no potentially toxic metabolites
•Do not compete with other substances for active transport
into the blood and across the BBB.
•Selectively affecting certain DA receptors. May have
more limited adverse effects.
•Do not depend on the functional capacities of the
nigrostriatal neurons.
•Longer durations of action.
•May have the potential to modify the course of PD.

29. Uses –
• Lower incidence of the response fluctuations and
dyskinesias.
• May be first-line therapy.
• Alternatively, a low dose of carbidopa+levodopa is
introduced, and a dopamine agonist is then added.
•May also be given to patients who are becoming resistant
to treatment with levodopa.
•The response is generally disappointing in patients who
have never responded to levodopa.

30. Dose –
•The dose is built up gradually depending on response and
tolerance.
•Initial dose of pramipexole – 0.125 mg orally 3 times daily
•Initial dose of ropinirole – 0.25 mg orally 3 times daily
•Both are available in once-daily sustained release
formulation, which is more convenient and may reduce
adverse effects.
• Rotigotine is delivered daily through a skin patch in early
PD.

31. Adverse effects –
A. Gastrointestinal Effects -
•Anorexia and nausea and vomiting.
•Constipation, dyspepsia, and symptoms of reflux
esophagitis.
•Bleeding from peptic ulceration has been reported.
B. Cardiovascular Effects -
•Postural hypotension
•Cardiac arrhythmias
•Peripheral edema

32. C. Dyskinesias -
Abnormal movements.
D. Mental Disturbances -
•Confusion, hallucinations, delusions, and other psychiatric
reactions. More common & severe than with levodopa.
•Disorders of impulse control.
Contraindications –
contraindicated in patients with a history of psychotic illness
or recent myocardial infarction, or with active peptic
ulceration.

33. APOMORPHINE
Dopaminergic agonist. It has high affinity for D4
receptors, moderate affinity for D2, D3, D5, and
adrenergic α1D, α2B, and α2C receptors.
Administered by SC injection.
“rescue therapy” for the acute intermittent treatment of
“off” episodes.
Highly emetogenic. Oral trimethobenzamide should be
started 3 days prior and continued at least during the first
2 months of therapy.

34. QT prolongation, injection-site reactions, and abuse
potential.
Used only when other measures, such as oral DA
agonists or COMT inhibitors, have failed.
Initiated with a 2-mg test dose. If tolerated, it can be
titrated slowly up to a maximum dosage of 6 mg three or
more injections daily.
The concomitant use with 5-HT3 antagonist class is
contraindicated.

35. CATECHOL-O-METHYLTRANSFERASE
(COMT) INHIBITORS
Tolcapone and Entacapone
Significantly reduce the “wearing off” symptoms.
Mechanism of action - Addition of carbidopa reduces the
formation of DA but increases the fraction of levodopa that is
methylated by COMT. COMT inhibitors block this peripheral
conversion of levodopa to 3-O-methyl DOPA.
Tolcapone -Relatively long duration of action, administered
two to three times a day.
Both central and peripheral inhibition of
COMT.

36. Entacapone - Short duration of action and administered
simultaneously with each dose of levodopa/carbidopa.
Peripheral inhibition of COMT.
Adverse effects - Nausea, orthostatic hypotension, vivid
dreams, confusion, and hallucinations.
An important adverse effect associated
with tolcapone is hepatotoxicity. Up to 2% of the patients
treated have increased serum ALT and AST.
Entacapone has not been associated
with hepatotoxicity and requires no special monitoring.

37. MAO-B INHIBITORS
MAO-B is the predominant form in the striatum and is
responsible for most of the oxidative metabolism of DA in
the brain.
Two selective MAO-B inhibitors are used for the
treatment of PD: selegiline and rasagiline.
Selectively inactivate MAO-B through irreversible
inhibition of the enzyme.
selective MAO-B inhibitors do not substantially
inhibit the peripheral metabolism of catecholamines and
can be taken safely with levodopa.
Do not exhibit the “cheese effect”

38. Selegiline –
• Well tolerated in younger patients with early or mild PD.
• In patients with more advanced PD or underlying
cognitive impairment, selegiline may accentuate the
adverse motor and cognitive effects.
•Metabolites of selegiline include amphetamine and
methamphetamine  anxiety, insomnia, and other
adverse symptoms.
•Available in an orally disintegrating tablet and a
transdermal patch  reduce hepatic first-pass metabolism
 decreased formation of the amphetamine metabolites.

39. Rasagiline -
•Does not give rise to undesirable metabolites.
•Monotherapy was effective in early PD. Adjunctive
therapy significantly reduced “wearing off” symptoms in
advanced PD.
•Inhibition of MAO-B in the brain  reduction in the
overall catabolism of DA  reduced formation of
potentially toxic free radicals.
•No conclusive evidence suggesting a neuroprotective
effect of rasagiline.

40. MUSCARINIC RECEPTOR
ANTAGONISTS
Trihexyphenidyl (2-4 mg 3 times/day), Benztropine
mesylate (1-4 mg 2 times/day), and Diphenhydramine
hydrochloride (25-50 mg 3 or 4 times/day).
Only used in the treatment of early PD or as an adjunct
to dopamimetic therapy.
May act within the neostriatum which has intrinsic
cholinergic innervation arises primarily from cholinergic
striatal interneurons
Adverse effects - sedation and mental confusion. Other
side effects are constipation, urinary retention, and
blurred vision. All anticholinergic drugs must be used
with caution in patients with narrow-angle glaucoma.

41. AMANTADINE
An antiviral agent.
Appears to alter DA release in the striatum, has
anticholinergic properties, and blocks NMDA glutamate
receptors.
The effects are modest.
Initial therapy of mild PD. It also may be helpful as an
adjunct in patients on levodopa with dose-related
fluctuations and dyskinesias.
Dose - 100 mg twice a day. well tolerated.
Adverse effects – Mild. Dizziness, lethargy,
anticholinergic effects, and sleep disturbance, as well as
nausea and vomiting.

42. MANAGEMENT OF THE NONMOTOR AND
NONDOPAMINERGIC FEATURES
Dopaminergic drugs - anxiety, panic attacks,
depression, sweating, sensory problems, freezing,
and constipation all tend to be worse during “off” periods
and may improve with better dopaminergic control.
Antidepressants - Approximately 50% of PD patients
suffer depression during the course of the disease.
Antidepressants should not be withheld, particularly for
patients with major depression. Pramipexole may have
antidepressant effects.

43. Benzodiazepines - Anxiety can be treated with short-
acting BZD.
Atypical neuroleptics - Psychosis can be a problem.
Clozapine is the most effective drug, but it can be
associated with agranulocytosis. For this reason, many
physicians start with quetiapine. Anticholinesterase may
have anti-psychotic effects.
Measures for dementia - Dementia is common, affecting
as many as 80% of patients. Drugs are usually discontinued
in the following sequence:
anticholinergicsamantadinedopamine agonists
COMT inhibitorsMAO-B inhibitors.
Patients should be managed with the lowest dose of
levodopa. Rivastigmine and donepezil can be tried.

44. Sleep Disorders - Modafinil may be considered for
daytime hypersomnolence .
Autonomic dysfunction -
• General measures for treating urinary urgency and
incontinence.
• Add peripherally acting anticholinergic drugs.
Constipation -
• Apply general measures for treating constipation.
• Reduce or discontinue drugs with anticholinergics
activity.
• Add domperidone.

45. Orthostatic hypotension –
1. Non-pharmacological: ↑ fluid intake, ↑ dietary salt,
avoid alcohol / large meals (frequent small meals instead)
/ excessive warmth, elevate head of bed. Patients should
be advised to rise slowly, especially in morning or after
sitting/lying for a period of time
2. Discontinue unnecessary medications, e.g.,
antihypertensives
3. Fludrocortisone
4. Domperidone
5. Midodrin
6. Consider pyridostigmine

47. DRUG-INDUCED PARKINSONISM
Predictable
Neuroleptic Drugs (Both Typical And Atypical)
Hidden Neuroleptics – Metoclopromide
Prochlorperazine
Combination With Antidepressants (Fluphenazine )
Calcium Antagonist
Idiosyncratic
Lithium
Sodium Valproate
Amiodarone
Mainly Tremor But Parkinsonism Reported.

48. Causative drugs –
•Reserpine and tetrabenazine deplete biogenic
monoamines from their storage sites.
• Haloperidol, metoclopramide, and the phenothiazines
block dopamine receptors.
These drugs may therefore produce a parkinsonian
syndrome, usually within 3 months after introduction.
Treatment - It is related to high dosage and clears over
several weeks or months after withdrawal.
If treatment is necessary, antimuscarinic agents are
preferred.
Levodopa is of no help and may in fact aggravate the
mental disorder.

49. RECENT
ADVANCES

50. NEUROPROTECTIVE AGENTS
MAO inhibitors: selegiline & rasagiline
Antiexcitotoxicity drugs: Riluzole
Bioenergetic antioxidant agent: coenzyme Q10, creatine
GDNF
Anti apoptotic kinase inhibitors(eg omigapil,CEP-1347)
Antiglutamatergics
Calcium channel blocker : Isradipine
Vaccine : PD01A (to destroy α-synuclein)
Deacetylase inhibitors -target the transport system
and reverse the defects caused by the faulty LRRK2
within nerve cells.

51. GENE THERAPY
•Adeno-associated virus (AAV) type 2 used as vector.
•Gene for aromatic L-amino acid decarboxylase (AADC)
into putamen to increase metabolism of levodopa.
•Gene for glutamic acid decarboxylase to STN to facilitate
synthesis of GABA.
•Gene for neurturin to putamen to enhance the survival of
dopaminergic neurons.

52. Intraduodenal gel formation in development is a
combination of levodopa and carbidopa, which helps
prevent levodopa from being degraded before it reaches the
brain. This mechanism of delivery helps prevent levodopa
degradation and promotes faster absorp-tion, and
maintenance of more constant levels of levodopa.

53. Adenosine A2A receptor antagonists (eg, istradefylline) :
A2A receptor regulates glutamate and dopamine release.
Antagonist reduces dyskinesia.
Nicotine
Intake of nicotine has shown to slow the degeneration of
neurons. Acts similar to levodopa.
Melatonin
Serotonin derivative that helps insomnia. Also shown to
cause a reduction in production of neurodegenerative radicals.

54. STEM CELL THERAPY
Transplant strategies are based on the concept of
implanting dopaminergic cells into the striatum to replace
degenerating SNc dopamine neurons. Fetal nigral
mesencephalic cells have been demonstrated to survive
implantation, re-innervate the striatum in an organotypic
manner, and restore motor function in PD models.

55. THANK YOU