1. 05,FEB,2013
PARKINSON’S Disease
PD
M.MURALI KRISHNA
M.Pharm
PRD-trainee
GVK BIO

2.  Parkinsonism is a progressive
degenerative, extra pyramidal disorder of
muscle movement, due to dysfunction in basal
ganglia, comprising four cardinal features:-
 Brady kinesia or hypo kinesia.
 Muscle rigidity.
 Resting tremor.
 Impairment of postural balance leading to
disturbances of gait, and falling. The secondary
manifestations are mask-like face, difficulty in
speech, slowing of mental process and dementia.
2

3. Prone
to
falling

5.  It is slowness in initiating and carrying out
voluntary movements. It is called poverty and
suppression of voluntary movements. It is
caused partly by muscle rigidity and partly by
inertia of the motor system, which means that
motor activity is difficult to stop as well as to
initiate. It is hard to start walking, and once in
progress, the patient can not stop quickly.
5

6. • Neurotransmitters are endogenous chemicals that
transmit signals from a neuron to a target cell across a
synapse.
• Neurotransmitters are packaged into synaptic
vesicles clustered beneath the membrane on the
presynaptic side of a synapse, and are released into
the synaptic cleft, where they bind to receptors in the
membrane on the postsynaptic side of the synapse.
• Release of neurotransmitters usually follows arrival of an
action potential at the synapse, but may also follow graded
electrical potentials.

7. • Major neurotransmitters
 Amino acids:
 glutamate, aspartate, D-serine, γ-amino butyric acid
(GABA), glycine
 Monoamines and other biogenic amines:
 dopamine (DA), nor epinephrine, epinephrine ,histamine,
serotonin (5-HT)
 Others:
 acetylcholine (ACh), adenosine, anandamide, nitric oxide,
etc.

8. • Dopamine neurons are more widely distributed than those
of other monoamines, residing in the midbrain substantia
nigra and ventral tegmental area and in the
periaqueductal gray, hypothalamus, olfactory bulb, and
retina.
• In the periphery, dopamine is found in the kidney where it
functions to produce renal vasodilation, diuresis, and
natriuresis.
• Three dopamine systems are highly relevant to psychiatry:
The nigrostriatal, mesocorticolimbic, and
tuberohypophyseal system.

9. Tyrosine, a precursor to dopamine, is taken up into dopamine nerve
terminals via a tyrosine transporter and converted into DOPA by the enzyme
tyrosine hydroxylase (TOH). DOPA is then converted into dopamine (DA) by
the enzyme DOPA decarboxylase (DDC). After synthesis, dopamine is
packaged into synaptic vesicles via the vesicular monoamine transporter
(VMAT2) and stored there until its release into the synapse during

10.  The degeneration of neurons occurs in substantia nigra
pars compacta and the nigrostriatal tract that are
dopaminergic and inhibit the activity of striatal GABA
ergic neurons. This results in deficiency of dopamine in
striatum which controls muscle tone and coordinates
movements. Nerve fibers from cerebral cortex and
thalamus secrete acetylcholine in the neostriatum
causing excitatory effects that initiate and regulate
gross intentional movements of the body. In
Parkinson’s disease, due to deficiency of dopamine in
striatum, an imbalance between dopaminergic
(inhibitory) and cholinergic (excitatory) system
occurs, leading to excessive excitatory actions of
cholinergic neurons on striatal GABA ergic neurons.
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11.  Degeneration of
neurones in the
substantia nigra pars
compacta
 Degeneration of
nigrostriatal
(dopaminergic) tract
 Results in deficiency
of Dopamine in
Striatum - >80%

12.  Imbalance primarily between the
excitatory neurotransmitter
Acetylcholine and inhibitory
neurotransmitter Dopamine in the
Basal Ganglia

13. • Two enzymes that play major roles in the degradation of dopamine are
monoamine oxidase and catechol O-methyltransferase (COMT).
• MAO is located on the outer membrane of mitochondria.
• Two MAO isozymes
 MAO-A : Which preferentially deaminates serotonin and norepinephrine.
 MAO-B : Which deaminates dopamine, histamine, and a broad spectrum of
phenylethylamines.
 COMT is located in the cytoplasm and is widely distributed
throughout the brain and peripheral tissues.
 It has a wide substrate specificity, catalyzing the transfer of
methyl groups from S-adenosyl methionine to the m-hydroxyl
group of most catechol compounds.
 The predominant metabolites of dopamine is Homovanillic
acid (HVA)

16.  Dopamine synthesized within neurons from common amino
acid precursors (step 1) and taken up into synaptic vesicles via a
vesicular monoamine transporter (step 2).
 Upon stimulation, vesicles within nerve terminals fuse with the
presynaptic terminal and release the neurotransmitter into the
synaptic cleft (step 3).
 Once released, the monoamines interact with postsynaptic
receptors to alter the function of postsynaptic cells (step 4), and
they may also act on presynaptic autoreceptors on the nerve
terminal to suppress further release (step 5).
 In addition, released dopamine may be taken back up from the
synaptic cleft into the nerve terminal by DAT Dopamine
Transpoter(step 6), a process known as reuptake.
 Once monoamines are taken up, they may be subject to
enzymatic degradation (step 7), or they may be protected from
degradation by uptake into vesicles.

17. Adenyl cyclase = produce cyclic AMP

18. Dopamine transporter (DAT) exists presynaptically and is responsible for clearing excess
dopamine out of the synapse. The vesicular monoamine transporter (VMAT2) takes
dopamine up into synaptic vesicles for future neurotransmission. There is also a
presynaptic dopamine-2 autoreceptor, which regulates release of dopamine from the
presynaptic neuron. In addition, there are several postsynaptic receptors. These include
dopamine-1, dopamine-2, dopamine-3, dopamine-4, and dopamine-5 receptors. The
functions of the dopamine-2 receptors are best understood, because this is the primary
binding site for virtually all antipsychotic agents as well as for dopamine agonists used
to treat Parkinson's disease.

19. Presynaptic dopamine-2 autoreceptors are "gatekeepers" for dopamine. That
is, when these gatekeeping receptors are not bound by dopamine (no
dopamine in the gatekeeper's hand), they open a molecular gate, allowing
dopamine release (A). However, when dopamine binds to the gatekeeping
receptors (now the gatekeeper has dopamine in his hand), they close the
molecular gate and prevent dopamine from being released (B).

20.  In Parkinson’s disease dopaminergic inhibitory
activity is reduced and cholinergic excitatory
activity is increased. Therefore, therapy is
aimed at restoring dopamine in the basal
ganglia and antagonizing the excitatory effects
of cholinergic neurons.
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22.  Drug therapy is aimed at restoring the balance
between the dopaminergic and cholinergic
components, which is achieved by:
 Increasing the central dopaminergic activity
OR
 Decreasing the central cholinergic activity
OR BOTH.
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23.  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
.
 Drugs which increase release or inhibit
reuptake of dopamine (also called dopamine
facilitator)
 Amantadine.
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24. MAO-B INHIBITORS
There are two forms of MAO, MAO-A and MAOB.
MAO-B predominates in brain and blood platelets.
MAO-A predominant in GI tract – oxidation of
tyramine – cheese reaction
MAO-B predominant in human brain- breakdown
of dopamine , de amination of phenyl
ethylamine.
In Parkinsonian brain MAO-B inhibitors block the oxidative
metabolism of dopamine in basal ganglia there by
conserving the depleted dopamine supply and
prolonging its action.

26. Selegiline. They prolong the action of dopamine
Selegiline, in low doses, does not interfere with peripheral
metabolism of dietary amines. Catecholamine
accumulation and hypertension does not occur, while
intracerebral degradation of dopamine is retarded.
Administered with levodopa, it prolongs levodopa
action, decreases motor fluctuations and decreases
‘wearing off’ effect. Adverse effects are – postural
hypotension, nausea and accentuation of levodopa
induced involuntary movements.
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29. • Dopamine and Tyrosine Are Not Used for
Parkinson Disease Therapy, Why?
– Dopamine Doesn't Cross the Blood Brain
Barrier
– Huge amount of tyrosine decreases activity of
rate limiting enzyme Tyrosine Hydroxylase