I HAVE TRIED TO COVER ALL CONVENTIONAL AND SOME LATEST TRENDS FOR THE MANAGEMENT OF PARKINSONISM.I HOPE THIS PPT IS HELPFUL FOR YOU.THANK YOU.

1. DR.HARMANJIT SINGH
DEPARTMENT OF PHARMACOLOGY
GMC , PATIALA.

2.  Neurologic disease
caused by
degeneration of
dopamine neurons
 Only
neurodegenerative
disease whose
symptoms can so
readily be treated
by medication
 Third most common
cause of disability.
 In majoriy of cases it
is IDIOPATHIC.

3.  English physician
Dr James Parkinson in 1817
“ An Essay on the shaking palsy
Also k/a “ Paralysis agitans ”
 In 1960 – pathological and
biochemical changes identified

4. 4
 Annual incidence 0.2/1000 & prevalence of
1.5/1000.
 Prevalence rates are similar throughout the
world, except lower rates in China /West
Africa.
 Affects 1% of those over 55 years, 1.5% of
people 70-79 years of age
 Generally occurs between 50-80 years
 Sex incidence is about equal.

5.  A viral cause:
 In 1918 there was an outbreak of
Encephalitis Lethargica and many
sufferers developed
postencephalitic Parkinsonism.
 A toxic substance:
 For instance, the illegal drug MPTP
(1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine).
 A genetic cause:
 Research by the NHGRI (National
Human Genome Research Institute)
suggests that a mutated gene,
which codes the alpha synuclein
protein located on chromosome 4,
has a role in familial parkinsonism.
 Another mutation occurs in parkin
gene.responsible for early onset of
PD .
 Other causes:
 Head injuries.
 Oxidative stress.
 Heavy metal ion exposure
from fillings etc.
 It is proposed that these
factors cause the neuron's
mechanisms for proteolysis
to go away leading to the
formation of the
characteristic Lewy bodies
seen on autopsy of
Parkinson’s patients. The
cells then fail to function
correctly and ultimately die.

6. Lewy Body Pathology
Dopamine-producing cell (brainstem)
Brown pigment (Melanin)
Cell Nucleus
Two Lewy bodies
inside nerve cell
After: Esiri MM, McShane RH. Cambridge University Press 1997
Gelb DJ. Arch Neurol 1999;56:33–9

7. 7
 Basal Ganglia
 Controls movement
 Dopamine
 Inhibitory neurotransmitter
in the basal ganglia
 Acetylcholine
 Excitatory neurotransmitter
in the basal ganglia
 Without dopamine, inhibitory
influences are lost and
excitatory mechanisms are
unopposed 
 Neurons of basal ganglia are
over stimulated 
 Excess muscle tone, tremors
& rigidity

8.  Normal
movementdependent
on dopamine production
in the substantia nigra
that innervates the
striatum
 PD is associated with
massive degeneration of
dopamine-producing
neurons in substantia
nigra
 When 60 to 80% of these
neurons are lost,
symptoms of PD appear

9.  Resting Tremor (70%)
 Bradykinesia
 Rigidity
 Postural Instability
◦ Signs start in one
limb, usually an arm,
◦ And spread to the
other limb on that
side

10.  Secondary features of the disease:
 Depression
 Dementia
 Dysphagia
 Anxiety
 Orthostatic hypotension
 Constipation

11.  Idiopathic
 Genetic (<50 y/o)
 Exposure to unrecognized neurotoxins
 Oxidation reaction with generation of free
radicals
 Reduced level of dopamine in the basal
ganglia

12. The main Pathological feature of Parkinson’s
disease is the loss of the dopaminergic
nigrostriatal pathway
 Dopaminergic neurons in the substantia nigra
that normally inhibit the output of GABAergic
cells in the striatum are lost
80% of the Dopamine producing cells must be
lost before symptoms begin to show

16.  Pharmacologic
attempt to
restore
dopaminergic
activity with
levodopa and
dopamine
agonists
 Restore normal
balance of
cholinergic &
dopaminergic
influences on the
basal ganglia

18.  In 1967 George Cotzias
invented levodopa
 Prodrug
 Gold standard therapy for
parkinsonism
 Chemical name is Dihydroxy
Phenyl Alanine
18
GEORGE
COTZIAS

19.  Rapidly absorbed from the SI
 Food delays absorption
 Amino acids in food compete with drug
 Peak plasma concentration: 1-2 hrs
 Plasma t ½ : 1-3 hrs
 HVA, DOPAC (dihydroxyphenylacetic acid) are
main metabolites
 1-3% enters the brain
 Resolve hypokinesia & rigidy first and tremor
later
 Plasma t½ is 1-2 hours & metabolised by MAO
and COMT enzymes

20. 20

21.  Early use lowers mortality rate
 Combined with Carbidopa &
Benseraside
 Sinemet – dopa preparation containing
levodopa in fixed proportion (1:10 or
1:4)
 Sinemet 25/100 TID
 30 -60 minutes before meals

22.  Fluctuations in response
 Misc: mydriasis, brownish discoloration
of the urine, abnormal smell, transient
elevations of transaminases & BUN
 GIT effects: vomiting (CTZ)
◦ Reduced by carbidopa
◦ Phenothiazenes are contraindicated
◦ ( Domperidone is the doc)
 Cardiovascular: tachycardia,
ventricular extrasystoles, atrial
fibrillation

23.  Dyskinesias
◦ Common in patients receiving carbidopa
 Behavioral effects:
◦ Common in patients receiving levodopa
◦ controlled by clozapine, olanzapine,
resperidone

24.  "On/off" Effect Is like a Light Switch ;
Without Warning, All of a Sudden,
Person Goes from Full Control to
Complete Reversion Back to
Bradykinesia, Tremor, Etc.lasting from
30 Minutes to Several Hours and Then
Get Control Again
 "On/off" Effect Occurs after usually
after 2 or more years on L Dopa
 Related with continous destruction of
dopaminergic neurons.

25.  Treat by Giving Small Dose Regiments
from 16 to 20 Hours
 "On/off" Effect May Be Due to Composite
of Amino Acids that use same Dopamine
Transportor , causing extremely low levels
of L Dopa in CNS thereby causing
symptoms of Parkinsonism to reappear.
 Changing diet (to low protein), may cause
large conc of L Dopa in CNS.

26.  Vitamin B6 enhance extracerebral
metabolism of levodopa
◦ Prevented by decarboxylase inhibitors
 MAO – A inhibitors : Hypertensive crisis
CONTRAINDICATIONS
 Psychoses
 Angle closure glaucoma
 Cardiac dysrhythmia
 Melanoma or suspicious undiagnosed skin
lesions

27.  Carbidopa, Benseraside
 Does not penetrate the BBB
 Reduce the peripheral metabolism of
levodopa
 Increase plasma levels of levodopa
 Prolongs the plasma half life of levodopa
 Increase available amounts of dopa for entry
into the brain
 Reduce the daily requirement of levodopa by
75%

28.  Do not require enzymatic conversion for an
active metabolite
 No potential toxic metabolites
 Do not compete with other substances for an
active transport
 First line in parkinsonism
 End of dose akinesia to levodopa
 On & off phenomenon refractory to levodopa

29. ERGOT ALKALOIDS
BROMOCRIPTINE
◦ D2 agonists
◦ Endocrinologic disorders (hyperprolactinemia)
◦ Peak plasma levels: 1-2 hrs
◦ 7.5 mg & 30 mg
◦ 1. 25 mg BID after meals X 2-3 months and
increase 2.5 mg q 2 wks
PERGOLIDE
◦ Stimulates both D1 and D2
◦ More effective than bromocriptine
◦ Associated with clinical or subclinical valvular heart
disease
DOSE : 3 mg daily
- 0.05 mg starter dose

30.  PRAMIPEXOLE
Preferential affinity to D3
Monotherapy is effective
Neuroprotective
Rapidly absorbed
Peak plasma concentration: 2 hrs
0.125 mg TID then doubled after 1 wk
Increments of 0.75 mg at weekly intervals
 ROPINIROLE
◦ Pure D2 receptor agonists
◦ 0.25 mg TID then total daily dose is increased by
0.75 mg at weekly intervals until the 4th wk &
increased by 1.5 mg thereafter

31.  GIT: anorexia, nausea,
vomiting, bleeding PUD,
reflux esophagitis
 Cardiovascular: postural
hypotension, painless digital
vasospasm
 Dyskinesias
 Mental disturbances
 Misc: erythromelalgia
 Somnolence, excessive daytime
sleepiness, and sleep attacks

32.  Newer dopamine agonist.
 Approved in 2007 by the FDA.
 Non – Ergot derivative.
 Relatively pure D2 agonist.
 Benefits and adverse effects are similar to those of
other dopamine agonists.
 Delivered through a skin patch .
 Local reactions may occur at the application site.
 Crystal formation on the patches may affect the
bioavailability and efficacy of the agonist.

33.  Potent dopamine agonist
 Temporary relief of off-periods of akinesia
 Rapidly taken by blood and brain (10
minutes) and persists for 2 hours
 Nausea – trimethobenzamide
 Dyskinesias, drowsiness, sweating,
hypotension, bruising at injection site

34.  MAO – A: metabolizes NE & serotonin
 MAO – B: metabolizes dopamine

35.  Selective irreversible inhibitor of
MAO-B (normal doses)
 Inhibits MAO-A (higher doses)
 Retards breakdown of dopamine
 Prolongs & enhances the effect of levodopa
 Adjunct in fluctuating response to levodopa
 5 mg with breakfast & lunch
 Cause insomnia when taken later during the
day

36.  MAO-B inhibitor
 Potent than selegiline in preventing
MAO-B toxins induced parkinsonism
(MPTP)
 Combination with levodopa – HTN
crisis
 Standard dose is 1mg/day.

37.  Compensatory activation pathways of
levodopa metabolism after dopa
decarboxylase inhibition
 Increase 3-O-methyldopa (3OMD)  poor
therapeutic response to levodopa
◦ Competes with levodopa for an active carrier
mechanism in the intestinal mucosa & BBB

38.  TOLCAPONE- central & peripheral
metabolism.
 Hepatotoxic : less preferred.
 DOSE : 100 mg TDS.
 ENTACAPONE
◦ peripheral metabolism
◦ Prolongs the duration of levodopa by decreasing its
peripheral metabolism
◦ Helpful in patients receiving levodopa who have
fluctuations
◦ t ½ = 2 hrs
◦ DOSE : 200 mg upto 5 times a day.
◦

39.  Postural hypotension
 Fatigue
 Somnolence
 Peripheral edema
 Nausea
 Constipation
 Dyskinesias
 Confusion
 Orange discoloration of urine.

40.  Antiviral agent
 Potentiates dopaminergic function by
influencing the synthesis, release, reuptake of
dopamine
PHARMACOKINETICS:
 peak plasma concentration: 1-4 hrs after oral
dose
 Plasma t ½ = 2-4 hrs

41.  Less potent than levodopa and benefits are
short-lived
 100 mg BID-TID
ADVERSE REACTIONS:
 Restlessness, depression, irritability,
insomnia, agitation, excitement,
hallucinations & confusion
 Livedo reticularis (cutaneous finding consisting of a
mottled reticulated vascular pattern that appears like a lace-
like purplish discoloration of the lower extremities )–
clears within a month after drug withdrawal

43.  Improve tremor & rigidity of parkinsonism
but have little effect in bradykinesia
 Benztropine mesylate
 Biperiden
 Orphenadrine
 Procyclidine
 Trihexyphenidyl
 DOC FOR DRUG INDUCED PARKINSONISM

44.  CNS
 Mydriasis, urinary retention, constipation,
tachycardia, tachypnea, increase IOP,
palpitations, cardiac arrythmias
 Acute suppurative parotitis
 Dryness of the mouth
CONTRAINDICATIONS.
 Prostatic hyperplasia
 Obstructive GI diseases
 Angle closure glaucoma

45. The net result of all of these medications is
the balancing out of the
acetylcholine/dopamine balance and an
improvement in movement

46. PARKINSONISM AND OXIDATIVE STRESS
•In patients with Parkinson's disease, the iron content is
increased in the substantia nigra, the ferritin level is
decreased in the brain, and the glutathione
concentration is decreased in the substantia nigra.
•Furthermore, although 1-methyl-4-phenyl-1, 2,3,6-
tetrahydropyridine (MPTP) is not itself toxic, when
oxidized by monoamine oxidase B to the
methylphenylpyridium ion, it becomes a selective nigral
toxin that interferes with mitochondrial respiratory
mechanisms. The toxicity of MPTP may be prevented
by pretreatment with a monoamine oxidase B inhibitor
such as selegiline.

47. Copyright ©2003 Canadian Medical Association or its licensors

48.  Thalamotomy –
conspicous
tremor
 Posteroventral
pallidotomy or
deep-brain
stimulation

49. Surgery :
Stereotactic surgery is another option for patients
with advanced Parkinson's disease. The optimal
patient for surgical treatment is someone whose:
• disease is not adequately controlled by
medication,
• with early onset Parkinson's disease (aged <
50 years),
good response to drugs.
Physiotherapy& rehab:
Patients at all stages of Parkinson's disease benefit
from physiotherapy, which helps reduce rigidity&
corrects abnormal posture.
Speech therapy may help in cases where dysarthria
& dysphonia interfere with communication.
49

50. DEEP BRAIN STIMULATION
 Most surgical centres focus on deep brain stimulation
(DBS) of the subthalamic nuclei, globus pallidum or
thalamus depending on the clinical scenario.
 Stimulation of the subthalamic nuclei or globus
pallidum has been associated with improvements in
bradykinesia, rigidity, drug-induced dyskinesias and
off time.
 Exact mechanism of action of DBS is unknown
 Potential benefits of adjustable settings of
stimulator frequency and intensity, no lesion is
created.

51. BRAIN GRAFTING
 By grafting dopamine producing nerve cells into
the brain.
 Cells taken from the brains of aborted fetuses .
 Not a successful tech. mainly because around
ninety eight percent of the grafted cells die.
 fewer than 10% of patients have shown significant
improvement.

52.  Recently a protein related to NGF – brain derived
neurotropic factor (BDNF), was discovered.
 Stimulates the growth of many types of neurons,
including substantia nigra dopamine neurons.
 BDNF stimulates the growth of foetal dopamine
neurons in culture and may prevent progression
and reversal of Parkinsonism.
 Another factor GDNF is also under study.
 Studies suggests that GDNF could slow the
progress of Parkinson’s disease

53.  MAO inhibitors: selegiline & rasagiline
 Antiexcitotoxicity drugs: Riluzole
 Bioenergetic antioxidant agent: coenzyme
Q10
 GDNF
 Anti apoptotic kinase inhibitors(eg CEP-1347)

54.  Adenosine A2A receptor antagonists
(eg, istradefylline)
Gene therapy : introduction of gene into putamen
coding for aromatic acid decarboxylase : it increases
the metabolism L-Dopa to Dopamine.
- Glutamic acid decarboxylase into subthalmic
nucleus : increses GABA and neuronal inhibition.
UNDER PHASE 2 CLINICAL TRIALS

55. Thank You