Dr.

Fatima
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Parkinsons disease
Parkinsonism is a progressive
degenerative, extrapyramidal disorder of
muscle movement, due to dysfunction in
basal ganglia, comprising four cardinal
features:-
Bradykinesia or hypokinesia.
Muscle rigidity.
Resting tremor.
Impairment of postural balance leading to
disturbances of gait, and falling. The
secondary manifestations are mask-like face,
siallorrhoea, difficulty in speech, slowing of
mental process and dementia.

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Bradykinesia:

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.
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Muscle rigidity:
Rigidity is due to increased muscle
tone. The rigidity affects the
opposing muscles equally, flexors
and extensors. Rigidity is detectable
as an increased resistance in passive
limb movement.
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Tremors:
Tremors are defined as rhythmic
oscillatory movements caused by the
opposing muscles around a joint.
Tremors of Parkinsonism are slow.
Hand tremors involve all the fingers
and thumb (pill rolling tremor) which
tend to diminish during voluntary
activity. The resting tremors are
present at rest and disappear (abate)
during voluntary movements.
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Dyskinesia: Abnormal involuntary movements

Chorea: It consists of irregular, unpredictable, involuntary
muscle jerks that occur in different parts of the body and
impaired voluntary activity.

Athetosis: Abnormal movements are slow and writhing in
character

Dystonia: The abnormal movements are slow in character
and are sustained so that they are regarded as abnormal
postures

Tics: They are coordinated abnormal movements that tend
to occur repetitively particularly about the face and head,
especially in children
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Etiology
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 Parkinsons 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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Substantia Nigra:
The substantia nigra pars compacta is the
source dopaminergic neurons that travel
through nigrostriatal tract to terminate in the
striatum. These dopaminergic neurons from
the substantia nigra fire tonically, to produce a
sustained influence on motor activity.
Striatum:
The striatum is connected to the substantia
nigra par reticulata by neurons that secrete the
inhibitory transmitter GABA at their endings in
the substantia nigra. In turn, cells of the
substantia nigra send neurons back to the
striatum, secreting the inhibitory transmitter
dopamine at their endings. Nerve fibers from
the cerebral cortex and thalamus secrete
Acetylcholine in the neostriatum causing
excitatory effects.
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Strategy of Treatment
In Parkinsons 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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Drugs used for Parkinsonian Disease:
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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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: They mimic the
action of dopamine at D
2
or D
3
receptors
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.
Dopamine receptor agonist:
Bromocriptine, Pergolide, Lisuride,
pramipexole. They mimic the actions
of dopamine at D
2
or D
3
receptors
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
transported by a neutral aminoacid
transporter into the brain. It is taken up by
the surviving dopaminergic neurons,
decarboxylated to dopamine, which is
stored and released as a transmitter. The
effect of levodopa may be due to an
increased release of dopamine from
surviving dopaminergic neurones because
the effectiveness of levodopa decreases
as the diseases advances. Part of the
action of levodopa may be due to
flooding of the striatum with exogenous
dopamine.
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LEVODOPA
Pharmacokinetics
Levodopa, when given without a
decarboxylase inhibitor, about 70% of
the dose is metabolized in the gut wall
and liver, 27-29% goes to peripheral
tissues to exert adverse effects and
only 1-3% enters the brain. When
levodopa is administered with
Carbidopa, about 10% of the dose
reaches the brain.
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LEVODOPA
Levodopa is rapidly absorbed from small
intestine by the active transport process
meant for aromatic amino acids.
Bioavailability of levodopa is effected by:
Gastric pH: Increased pH decreases its
absorption
Gastric emptying: If slow (delayed), levodopa
is exposed to degenerative enzymes of gut
wall and liver for longer time and availability is
decreased
Aminoacids present in the food compete for
the same carrier for absorption. So absorption
is less when taken with meals.
Levodopa undergoes high first pass
metabolism in the gastrointestinal mucosa and
liver.
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Periphery Brain
3-O-Methyldopa 3-OMD

COMT COMT

Blood Brain Barrier
Levodopa Levodopa

Dopadecarboxylase


Dopamine Dopamine

COMT MAO-B


3-Methoxytyramine DOPAC





Homovanillic acid
DOPAC-3,4-dihydroxyphenylacetic acid
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Adverse effects
At the initiation of therapy:
Nausea and vomiting in almost every patient. It is
due to action of dopamine on CTZ
Postural hypotension: it occurs in about 1/3 of
patients, more common in the patients receiving
antihypertensives. This may be a central action.
Dopamine and noradrenaline formed in brain
decreases sympathetic outflow.
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:
Abnormal movements: Facial tics, grimacing,
choreoathetoid movements of limbs, start appearing after a
few months of use.
Behavioral effects: Range from mild anxiety, nightmares to
depression, mania, hallucinations or psychosis, excessive
dopaminergic action in limbic system is probably
responsible.
Fluctuation in motor performances: After 25 years of
therapy, the level of control of symptoms starts showing
fluctuation. 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. 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. With
progressive degeneration of dopaminergic neurons the
ability to regulate storage and release of dopamine may be
largely lost. Then, dopamine is synthesized in the striatum
on a moment to moment basis resulting in rapid
fluctuations in the motor control
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Interactions
Pyridoxine: It enhances peripheral Decarboxylation of
levodopa hence; less is available to cross brain
Drugs which block dopamine receptors: e.g.,
Phenothiazines, butyrophenones, metoclopramide,
reverse the therapeutic effects of levodopa.
The antidopaminergic domperidone blocks levodopa
induced vomiting without abolishing its effects because
domperidone does not cross blood brain barrier.
Reserpine abolishes levodopa actions by preventing the
entry of dopamine into synaptic vesicles.
Non-selective MAO inhibitors prevent degradation of
peripherally synthesized dopamine
Antihypertensives: Postural hypotension is accentuated
Anticholinergic drugs have additive antiparkinsonian
action, but retard the absorption of levodopa
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Pharmacological actions:
CNS
Levodopa produces marked
symptomatic improvement in
Parkinsonian patients. Hypokinesia and
rigidity resolve first, later tremor as well.
Secondary symptoms of posture, gait,
facial expression and mood are
gradually normalized.
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The effect of levodopa on behavior has been described as a
general alerting response. In some patients it may
progress to excitement.
Two types of dopamine receptors, D
1
and D
2
were originally
described. Later, three more (D
3
,D
4
,D
5
) have been identified.
D
1
like (D
1
,D
5
). They are excitatory. Act by increasing cAMP
formation.
D
2
like (D
2
,D
3
,D
4
). They are inhibitory. Act by inhibiting
adenylyl cyclase/opening K channels/depressing voltage
sensitive Ca channels. Both D
1
and D
2
receptors are
present in striatum .They respectively regulate the activity
of two pathways having opposite effects on thalamic input
to the motor cortex. Thus, stimulation of excitatory D
1
as
well as inhibitory D
2
receptors in the striatum achieves the
net effect of smoothening movements and reducing muscle
tone.
Dopamine receptor in substantia nigra pars compacta and
in pituitary is also of D
2
type.
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CVS:
Dopamine formed in periphery can cause
tachycardia by acting on beta receptors.
Dopamine causes postural hypotension. This
may be a central action. Dopamine and
noradrenaline formed in brain decrease
sympathetic outflow.
CTZ:
Dopamine acts as an excitatory transmitter on
dopamine receptors in CTZ. Peripherally
formed dopamine gains access to the CTZ and
causes nausea and vomiting.
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Endocrine:
Dopamine acts on pituitary
mammotropes to inhibit prolactin
release.and prolactin level in blood falls.
Dopamine acts on somatotropes to
increase growth hormone release but
increased growth hormone levels are
not noted in Parkinsonian patients.
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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:
The plasma half-life of levodopa is prolonged
and dose is reduced to approximately
Due to reduced systemic concentration of
dopamine, nausea and vomiting are not
prominent
Cardiac adverse effects are minimized
Pyridoxine reversal of levodopa effect does
not occur as the decarboxylase has been
inhibited already
On-off effect is minimized since cerebral
dopamine levels are more sustained.
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DOPAMINERGIC AGONISTS
Bromocriptine: It acts as an agonist
on D
2
, but as partial agonist or
antagonist on D
1
receptors. It is used
only in late cases of parkinsonism as
a supplement to levodopa.
Ropinirole and Pramipexole: They
are selective D
2
/D
3
receptor agonists.
Their actions are similar to those of
Bromocriptine but they are better
tolerated with fewer gastrointestinal
symptoms.
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MAO-B INHIBITOR.
Selegiline (Deprenyl) : There are two forms of
MAO, MAO-A and MAO-B. Both are present in
peripheral adrenergic structures and intestinal
mucosa, while MAO-B predominates in brain and
blood platelets. 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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COMT INHIBITORS:
When peripheral decarboxylation of
levodopa is blocked by Carbidopa, it
is metabolized by COMT to 3-O-
methyldopa. Blockade of this
pathway by Entacapone prolongs the
t
1/2
of levodopa and allows a larger
fraction of administered dose to
cross to brain.