This document discusses neurodegenerative disorders like Parkinson's disease, Huntington's disease, and Alzheimer's disease. It describes how Parkinson's disease results from the loss of dopaminergic neurons in the substantia nigra pars compacta. The history of Parkinson's disease is discussed, with James Parkinson first describing it in 1817. The clinical features of Parkinsonism including tremor, rigidity, and hypokinesia are also summarized.

2. INTRODUCTION
Neurodegenerative disorders are characterized
by progressive and irreversible loss of neurons from specific
regions of the brain.
 Prototypical neurodegenerative disorders.
1. Parkinson's disease (PD)
2. Huntington's disease (HD)
-In both there is loss of neurons from structures of the basal
ganglia results in abnormalities in the control of movement.
3. Alzheimer's disease (AD)
-Where the loss of hippocampal and cortical neurons leads to
impairment of memory and cognitive ability.
4. Amyotrophic lateral sclerosis (ALS)
-Where muscular weakness results from the degeneration of
spinal, bulbar, and cortical motor neurons.
Rang and Dale’s
Pharmacology, 6th ed.

3. Mechanisms of selective neuronal
vulnerability in neurodegenerative diseases.
Goodman & Gilman's The Pharmacologic Basis of Therapeutics -
11th Ed. (2006)

5.  Organization of the extrapyramidal
motor system and the defects that
occur in Parkinson's disease (PD)
and Huntington's disease.
 Normally, activity in nigrostriatal
dopamine neurons causes excitation
of striatonigral neurons and inhibition
of striatal neurons that project to the
globus pallidus.
 In either case, because of the different
pathways involved, the activity of
GABAergic neurons in the substantia
nigra is suppressed, releasing the
restraint on the thalamus and cortex,
causing motor stimulation.
 In PD, the dopaminergic pathway from
the substantia nigra (pars compacta)
to the striatum is impaired.
 In Huntington's disease, the
GABAergic striatopallidal pathway is
impaired, producing effects opposite to
the changes in PD.
Rang and Dale’s Pharmacology, 6th ed.

6. Parkinson’s disease is neurodegenerative disorder
characterized by a preferential loss of the dopaminergic
neurons of the substantia nigra pars compacta (SNpc).
www.google.com images

7. HISTORY
JAMES PARKINSON
 Parkinson's disease was first
formally described in modern times
in "An Essay on the Shaking
Palsy," published in 1817 by a
London physician named James
Parkinson (1755-1824).
 James Parkinson systematically
described the medical history of
six individuals who had symptoms
of the disease that eventually bore
his name.
 Unusually for such a description,
he did not actually examine all
these patients himself but
observed them on daily walks.
VIARTIS, AMEZON. COM, PD
HEALTH

8.  The purpose of his essay was to document the
symptoms of the disorder, which he described as
"Involuntary tremulous motion, with lessened muscular
power, in parts not in action and even when supported;
with a propensity to bend the trunk forwards, and to pass
from a walking to a running pace ; the senses and
intellect being uninjured."
 It was not until 1861 and 1862 that Jean-Martin Charcot
(1825-1893) with Alfred Vulpian (1826-1887) added
more symptoms to James Parkinson's clinical
description (Charcot and Vulpian, 1861, 1862) and then
subsequently confirmed James Parkinson's place in
medical history by attaching the name Parkinson's
Disease to the syndrome.
VIARTIS, AMEZON. COM, PD
HEALTH

10. Parkinsonism
Pharmacotherapy
Increasing the dopaminergic activity
Decreasing the cholinergic activity
Treatment of
Parkinsonism
Parkinsonism

12. Tremor : Tremor can occur in the fingers, hands,
arms, legs, chin, tongue, lips, eyelids, and the head.
It is most commonly in the hand and fingers because
of the large size of the colony of pyramidal tract cells
concerned with hand and finger movement. It often
ceases during sleep only to return again on waking.
Rigidity : Rigidity and stiffness occurs in the
muscles as a primary symptom, because of their
constant muscle contraction. This can lead to pain in
rigid areas.
Hypokinesia: Hypokinesia, which is a poverty of
movement of muscles goes through three stages.
Firstly, there is hypokinesia, which is impaired
movement without any obvious disturbance of power
or of coordination. Movement tends to be interrupted
by pauses. There can also be difficulty with small
movements. Secondly, there is bradykinesia, which
is when voluntary movements can be performed, but
slowly. Thirdly, there is akinesia, which is a loss of
physical movement, which can begin with brief
periods of complete immobility called akinetic
attacks.
VIARTIS, AMEZON. COM, PD

13. PATHOPHYSIOLOGY
 In PD, nigral dopamine neurons and other cells die from
a combination of factors, including:
(1) Genetic vulnerability (e.g., abnormal processing or
folding of α-synuclein)
(2) Oxidative stress
(3) Proteosomal dysfunction
(4) Abnormal kinase activity
(5) Environmental factors, most of which have yet to be
identified.
Rang and Dale’s Pharmacology, 6th ed.

15. Parkinsonism
L-dopa : Prodrug
Orally absorbed and metabolized in the
intestine by MAO and de-carboxylation
(~90%).
Metabolized in the periphery by COMT and
de-carboxylation (~ 9%).

16. DA
L-dopa
MOA:

17. 1- Levodopa
Adverse effects:
A) Central:
- Long-term therapy leads to "wearing off"
phenomenon: (t1/2 4 h)
 Patients may fluctuate between being "off,"
having no beneficial effects from their medications,
and being "on" but with dyskinesias, a situation
called the on/off phenomenon.
- Increasing the dose and frequency of administration
can improve this situation,
DA neurons

18. 1- Levodopa
B. Peripheral:
Due to formation of dopamine peripherally
1. Anorexia, nausea, and vomiting
(likely due to dopamine’s stimulation of the
chemoreceptor trigger zone in the medulla
oblongata).
2. Cardiovascular side effects - cardiac arrhythmias

19. 1- Levodopa
Drug Interactions:
1. Pyridoxine (vitamin B6) enhance the
extracerebral metabolism of levodopa and prevent
its therapeutic effect
2. Levodopa + monoamine oxidase inhibitors -
hypertensive crises.

20. 1- Levodopa
Contraindications
1. Psychotic patients
2. Cardiac disease

21. Parkinsonism
L-dopa is usually administered with
peripheral de-carboxylation inhibitor
(PDDC inhibitor).
Peripheral de-carboxylation inhibitor are
Carbidopa and Benserazide.
These are incapable of crossing BBB.

22. Parkinsonism
L-dopa with carbidopa helps in
 Reduction of dose of l-dopa
 Decreased incidence of nausea, vomiting and cardiac
arrhythmia
 “on-off” effect minimised
 Carbidopa and l-dopa are used in ratio of 1:4 or 1:10
 Carbidopa + l-dopa (Sinemet)

23. Dopamine receptor agonist :
 MOA : as D-2 receptor agonist
 No decarboxylation required
 More effective in the late stages of PD
 More selective action
 Longer acting
Bromocriptine (Parlodel)
Ropinirole (Requip)
Pramipexole (Mirapex)

24. Contraindications
1. Psychotic patients
2. Cardiac disease
3. Peripheral vascular
disease
Adverse effects:
I. Central:
 Dyskinesias , mental Disturbances
II. Peripheral:
A) Gastrointestinal Effects:
 Anorexia, nausea and vomiting
B) Cardiovascular effects:
1. postural hypotension
2. cardiac arrhythmias
3. peripheral vasospasm

25. Parkinsonism
COMT inhibitors :
MOA : They block the peripheral
conversion of l-dopa to methyl dopa.
They increase the half life of l-dopa
Reduce the wearing off with l-dopa.
Entacapone, Tolcapone

26. Parkinsonism
COMT inhibitors :
ENTACAPONE (Comtan): Short acting,
Only peripheral COMT inhibitor.
ADR: Dyskinesia and diarrhea
Stalevo (carbidopa, l-dopa and entacapone)
TOLCAPONE (Tasmar): Long acting,
peripheral and central COMT inhibition.
ADR: Hepatotoxicity is a serious adverse
effect.

27. TOLCAPONE
TOLCAPONE

28. Parkinsonism
MAO – B inhibitor : Selegiline (l-deprenyl)
 It is used for the treatment of early-stage Parkinson's
disease.
 MOA : It is a specific MAO-B I

29. Amantadine (Symmetrel) : DA Facilitator
 MOA: It acts by increasing the release of
dopamine
 It has anticholinergic activity
 ADR: sleep disturbances.

30. Parkinsonism
Anticholinergics :
 Controls mainly resting
tremors.
 Preferred choice in drug
induced Parkinsonism
 Benztropine (Cogentin)
 Trihexyphenidyl (Artane)
Effects Effects
Anti-cholinergics

31. Pharmacotherapy of Parkinsonism
Novel therapies for Parkinson
Vit –E antioxidants
Neuronal growth factors
Neuronal transplant.