1. Parkinsonism is a progressive neurodegenerative disorder caused by loss of dopamine-producing neurons in the substantia nigra, leading to motor symptoms like bradykinesia, rigidity, resting tremor, and impaired balance. 2. Treatment aims to restore dopamine levels through levodopa or dopamine agonists to improve motor symptoms, and anticholinergics to reduce acetylcholine activity in the striatum. 3. Levodopa is most effective but side effects emerge with long term use, so combinations with carbidopa are used to sustain dopamine levels and minimize side effects.

1. Pharmacological management
of Parkinsonism
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2. Dopaminergic tracts

3. Dopaminergic Neural Pathway
• Niagrostriatal Tract:
– Cell bodies in substantia nigra project to
striatum where they release dopamine which
inhibit GABAergic neuron
– In Parkinson disease, the loss of DA
neurons in this tract leads to excessive
Acetylcholine activity leading to
EXTRAPYRAMIDAL dysfunctions

4. – Dopamine is critical for the initiation of
movement. So lack of dopamine is going to
cause difficulty in initiation of movement called
bradykinesia
– DA agonists are used in parkinsonism and their
excess may cause dyskinesias, which are
hyperkinetic
– DA antagonists –(used in psychosis) pseudo-
parkinsonism

5. Dopaminergic Neural Pathway
• Mesolimbic – mesocortical tracts
– Regulation of affect, postitive reinforcement,
cognitive functions and sensory perception
– Psychotic disorders and addiction are partly
explained by  Dopamine in these pathways
– Drugs that increase Dopamine functions increase
reinforcement (may be drugs of abuse) and at
high doses may cause psychosis
– DA antagonists dec. cognitive functions
– Dopamine along with serotonin plays role in this
tract

6. Dopaminergic Neural Pathway
• Tuberoinfundibular
 DA  decrease in prolactin
 DA agonists e.g pergolide are used in
hyperprolactinemiac states
 DA antagonists may cause endocrine
dysfunctions including gynecomastia
amenorrhea / galactorrhea
 Dopamine also decrease growth hormone
level hence used in acromegaly

7. • Chemoreceptor trigger zone
 Activation of DA receptors causes emesis
 DA agonists (e.g Apomorphine) are emetics
 DA antagonists are antiemetics

8. Two more functions
• Thermoregulatory (role of dopamine in
hypothalamus)
• Another effect of dopamine is shared by nor
epinephrine and serotonin. i.e. anorexia
• Drugs that are dopamine agonist may cause
weight loss and dopamine antagonist cause
weight gain

9. So dopamine is known for its
effect on
• Movement initiation
• Re-enforcement
• Euphoria, pleasure and repeating
movement
• Endocrine function with inhibition of
prolactin and GH
• Control of temperature
• Food intake or appetite control
• CTZ with effect on vomiting

10. What is parkinsonism

11. • Parkinson's disease develops when the
neurons connecting the substantia
nigra to striatum progressively
degenerate

12. Parkinsonism is a
• Progressive degenerative disorder
• Extrapyramidal disorder of muscle
movement
• Due to dysfunction in basal ganglia

13. • Progressive loss of dopaminergic neurons is a
feature of normal aging; however, symptoms
of Parkinsons coincide with excessive loss
(70–80%) of these neurons in substantia
nigra.
• Without treatment, PD progresses over 5–10
years to a rigid, akinetic state, patients are
incapable of caring for themselves.

14. • Death frequently results from
complications of immobility, including
aspiration pneumonia or pulmonary
embolism

15. Four cardinal features
1. Bradykinesia or hypokinesia.
2. Muscle rigidity.
3. Resting tremor.
4. Impairment of postural balance leading to
disturbances of gait, and falling.

16. • The secondary manifestations are
• mask-like face (hypomimia)
• Siallorrhoea,
• Difficulty in speech
• Slowing of mental process
• Dementia

17. Was described in 1817 by
Dr. James Parkinson
Paralysis agitans or
Shaking palsy

18. BRADYKINESIA
• Bradykinesia refers to slowness of
movement and is the most characteristic
clinical feature of Parkinson's disease
• It is hard to start walking, and once in
progress, the patient can not stop quickly

19. RIGIDITY
• Rigidity is due to increased muscle tone.
• Cog wheel rigidity

20. RESTING TREMORS
• Tremors of Parkinsonism are slow.
• pill rolling tremor which tend to diminish
during voluntary activity.
• The “resting tremors” are present at rest
and disappear during voluntary
movements.

22. Pharmacological strategy
• Restore normal dopamine
• Decrease acetylcholine at
muscarinic receptors in the striatum

23. Normal subjects
ACh Dopamine
Parkinson’s disease
Dopamine
ACh

24. Treatment
Levodopa
Amantidine
Bromocriptine
Deprenyl
ACh
Dopamine

25. Anticholinergic drugs
ACh Dopamine
Treatment
Benzhexole,
Procyclidine
Biperiden
Benztropine

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Drugs which increase dopaminergic
activity.
• Drugs that replace dopamine (Dopamine
precursor):
– Levodopa
• Dopa-decarboxylase inhibitors (Drugs which increase
the central availability of Levodopa)
– Carbidopa, Benserazide. They act in the periphery
as they do not enter brain
• Dopamine receptor agonists:
Bromocriptine, Pergolide, Lisuride, pramipexole.
• Drugs which increase release or inhibit
reuptake of dopamine (also called dopamine
facilitator)
– Amantadine.

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Drugs which increase dopaminergic
activity.
• Inhibitors of COMT:
– Entacapone, Tolcapone. They inhibit Catechol-
O-methyl transferase which inactivates
dopamine. They prolong the action of dopamine.
• MAO-B inhibitors:
– Selegiline. They prolong the action of dopamine.

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Drugs affecting brain cholinergic
system
• Central anticholinergics:
– Trihexyphenidyl (Benzhexole),
– Procyclidine
– Biperiden
• Antihistamines:
– Orphenadrine
– Promethazine

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LEVODOPA
• Levodopa crosses blood brain barrier.
• It is the immediate precursor of dopamine.
• It is taken up by the surviving dopaminergic neurons
• It is decarboxylated to dopamine, which is stored
and released as a transmitter.

30. • The effect of levodopa is due to an
increased release of dopamine from
surviving dopaminergic neurons
because the effectiveness of levodopa
decreases as the diseases advances.

33. • Therefore, levodopa must be given in large amounts
when used alone.
• However, when given in combination with a dopa
decarboxylase inhibitor (carbidopa) that does not
penetrate the blood-brain barrier, the peripheral
metabolism of levodopa is reduced
• plasma levels of levodopa are higher, plasma half-
life is longer, and more dopa is available for entry
into the brain

35. Advantages of combination
• Levodopa alone
– Plasma half life is 50 minutes
– 1% crosses BBB b/c of extracerebral metabolism
– High dose required i.e. 4000 mg / day
– Dopmine mediated side effects ( nausea anorexia
and cofusion
• Levodopa + carbidopa: SINEMET
– Plasma half life is 1.5 hours
– 5 to 10% crosses BBB
– Dose reduced to 700 mg/day
– Reduced peripheral side effects

36. Adverse effects

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At the initiation of therapy:
• GASTROINTESTINAL EFFECTS
• When levodopa is given without a peripheral
decarboxylase inhibitor, anorexia and nausea
and vomiting occur in about 80% of patients
• Nausea and vomiting in almost every patient. It
is due to action of dopamine on CTZ
.

38. CARDIOVASCULAR EFFECTS
• Postural hypotension: it occurs in about
1/3 of patients, more common in the
patients receiving antihypertensives.

39. • Tachycardia and cardiac arrhythmias: They
are due to  - adrenergic actions of
dopamine formed peripherally.
• Exacerbation of angina may occur especially
in patients with pre-existing heart disease.
• Alteration of taste sensation.

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After prolonged therapy
• :
 DYSKINESIAS
 Dyskinesias occur in up to 80% of patients
receiving levodopa therapy for long periods.
 Abnormal movements: Facial tics, grimacing,
choreoathetoid movements of face and limbs, start
appearing after a few months of use.

41. • Behavioral effects:
• Range from mild anxiety, nightmares to depression,
mania, hallucinations or psychosis,
• Common in patients taking levodopa in combination
with a decarboxylase inhibitor rather than levodopa
alone

42. MISCELLANEOUS ADVERSE EFFECTS
• Mydriasis may occur and may precipitate an
attack of acute glaucoma in some patients
• 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

43. FLUCTUATIONS IN RESPONSE
After few years of therapy, the level of control of
symptoms starts showing fluctuation.
1.End of dose akinesia
2.On-off phenomena

44. End of dose akinesia
• In some patients, the loss of response is
seen just before the next dose which is
termed ‘end of dose akinesia’ or ‘wearing-
off reactions’.

45. on-off phenomenon
• In other cases, the fluctuations in clinical
response are unrelated to the timing of the dose,
termed ‘on-off phenomenon’.
• In this the period of good therapeutic
response alternates with the periods of loss of
therapeutic response, all within few hours.

46. • On/off effect is like a light switch.
• Without warning all of a sudden person goes
from full control into complete reversion back
to bradykinesia and tremors
• Lasting for 30 minutes to several hours and
then get control again.
• Takes place after 2 or more years of treatment

47. Drug Holidays
• A drug holiday means discontinuance of the
drug for 3–21 days
• It may temporarily improve responsiveness
to levodopa and relieve some of its adverse
effects but is usually of little help in the
management of the on-off phenomenon.

48. • Furthermore, b/c of immobility accompanying
severe parkinsonism a drug holiday carries
the risks of
– aspiration pneumonia
– venous thrombosis
– pulmonary embolism
– depression
• For these reasons and because of the
temporary nature of any benefit, drug
holidays are not recommended

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PERIPHERAL DECARBOXYLASE
INHIBITORS
• Carbidopa and Benserazide are extracerebral
(peripheral) decarboxylase inhibitors.
• They do not inhibit conversion of levodopa to
dopamine in brain.
• They increase the half-life of levodopa in the
periphery and make more of it available to enter
the brain. The benefits obtained are:

50. Benefits
 The plasma half-life of levodopa is prolonged and
dose is reduced to approximately ¼
 Due to reduced systemic concentration of
dopamine, nausea and vomiting are not prominent
 Cardiac adverse effects are minimized
 ‘On-off’ effect is minimized since cerebral
dopamine levels are more sustained.
• Combination treatment of levodopa and
carbidopa is called Sinemet

51. Dopamine agonists

52. • Drugs directly acting on dopamine receptors
• Their use is associated with
– lower incidence of the response fluctuations
– lower chance of dyskinesias that occur with long-
term levodopa therapy

53. • Dopamine agonists may also be given
to patients with parkinsonism
– Who are taking levodopa and
– Who have end-of-dose akinesia or on-off
phenomenon
– Who are becoming resistant to treatment with
levodopa.

54. DOPAMINERGIC AGONISTS
Benefits
• They 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 blood-brain barrier

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DOPAMINERGIC AGONISTS
• Bromocriptine and pergolide are ergot
derivatives
• Bromocriptine:
• Acts as an agonist on D2,
• It is used only in late cases of parkinsonism as
a supplement to levodopa. ( better dopamine
agonists are available)

56. • Pergolide
• directly stimulates both D1 and D2 receptors
• it is more effective than bromocriptine in
relieving the symptoms and signs of the disease.
• The drug is no longer available because its use
has been associated with the development of
valvular heart disease.

57. • Ropinirole and Pramipexole: They are
selective D2/D3 receptor agonists.
• Their actions are similar to those of
Bromocriptine but they are better tolerated
with fewer gastrointestinal symptoms.

58. Rotigotine
• The dopamine agonist
• Approved in 2007 by FDA for treatment of
early parkinson’s disease
• Delivered daily through a skin patch,
• It is proposed that it provides a slower and
more continuous action than the oral
dopamine agonists.

59. Apomorphine
• A potent dopamine receptor agonist,
• Injected subcutaneously
• May provide rapid (within 10 min) but
temporary relief (1–2 h) of off-periods of
akinesia in patients on optimized
dopaminergic therapy.
• Nausea is often troublesome

60. GASTROINTESTINAL EFFECTS
• Anorexia
• Nausea and vomiting may occur
constipation
• Dyspepsia
• Symptoms of reflux esophagitis may also
occur.
• Bleeding from peptic ulceration has been
reported.

61. CARDIOVASCULAR EFFECTS
• Postural hypotension
• Painless digital vasospasm is a dose-related
complication of long-term treatment with the
ergot derivatives (bromocriptine or
pergolide).
• Peripheral edema
• When cardiac arrhythmias occur, they are
an indication for discontinuing treatment.

62. DYSKINESIAS
• Abnormal movements similar to those
introduced by levodopa may occur and are
reversed by reducing the total dose of
dopaminergic drugs

63. MENTAL DISTURBANCES
• Confusion, hallucinations, delusions,
• Disorders of impulse control may lead to
compulsive gambling, shopping, betting,
sexual activity, and other behaviors

64. MISCELLANEOUS
• Headache
• nasal congestion
• pulmonary infiltrates
• pleural and retroperitoneal fibrosis
• Erythromelalgia ---- red, tender, painful
and warm, swollen feet and, occasionally,
hands, at times associated with arthralgia

66. Amantadine
• Relatively weak antiparkinsonism properties.
• Its mode of action in parkinsonism is unclear,
but it may potentiate dopaminergic function
by influencing the synthesis, release, or
reuptake of dopamine.
– Antiviral which blocks muscarinic receptors and
inc. dopamine functions

67. Side effects
• Atropine like
• Livedo reticularis

68. Livedo reticularis is a skin condition
• Mottled vascular pattern that appears as
lace-like purplish discoloration of the
skin.
• The discoloration is caused by swelling
of the venules owing to obstruction of
capillaries by thrombi

69. Selegiline (deprenyl)/Rasagiline
• A selective irreversible inhibitor of
monoamine oxidase B (MAO-B) at normal
doses (at higher doses it inhibits MAO-A as
well),
• Retards the breakdown of dopamine in
consequence, it enhances and prolongs the
antiparkinsonism effect of levodopa
• It may reduce mild on-off or wearing-off
phenomena.

70. Tolcapone And Entacapone
• Selective COMT inhibitors
• Prolong the action of levodopa by
diminishing its peripheral metabolism
• May be helpful in patients receiving
levodopa who have developed response
fluctuations—leading to a smoother
response

71. • Tolcapone may cause an increase in liver
enzyme levels and has been associated
rarely with death from acute hepatic failure;
• It should not be used in patients with
abnormal liver function test results
• The commercial preparation named Stalevo
consists of a combination of
Levodopa + Carbidopa+ Entacapone.

74. Drugs Used in Parkinson's Disease
• Drugs decreasing ACh functions
– Benztropine, trihexyphenidyl,
diphenhydramine
– Actions
• Decrease tremors and rigidity but have little
effect on bradykinesia
• Also relieve the reversible extrapyramidal
symptoms caused by antipsychotic drugs
– Side effects like atropine

76. THAT’S ALL