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Parkinsonism:, COMT inhibitors:, MAO-B inhibitors:, E.Drugs inhibiting…
Parkinsonism:
it is a neurodegenerative disease characterized by
rigidity, bradykinesia, dyskinesia, tremors, mask like facies and unstable gait.
Idiopathic parkinsonism is known as parkinsons disease.
COMT inhibitors:
this enzyme metabolizes dopamine as well as L-DOPA to form 3-O-methyldopa.
Tolcapone and entacapone act by inhibiting this enzyme help in parkinsonism
because metabolism of L-DOPA is inhibited, so more is able to cross BBB.
These can be given in combination with l-dopa + carbidopa
as inhibition of dopa decarboxylase diverts the metabolism of L-DOPA to methylation by COMT.
3-O- methyl dopa formed by metabolism of L-DOPA competes with it for entry in the brain.
Tolcapone and entacapone decrease this interaction.
By inhibiting dopamine metabolism in brain by tolcapone only, its duration of action is increased.
Tolcapone inhibits COMT in periphery as well as brain
whereas entacapone acts only in the periphery.
Major beneficial effect of these drugs in parkinsonism is due to peripheral inhibition of COMT.
Tolcapone is more potent and longer acting than entacapone
but is not preferred because of hepatotoxic effects.
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MAO-B inhibitors:
selegiline and rasagiline are irreversible and selective inhibitors of MAO-B.
these drugs can be given in combination with levodopa + carbidopa
to decrease the dose of levodopa
and thus decreased abnormal movements.
At normal doses these inhibit only MAO-B and thus have no interaction with cheese or tricyclic antidepressants.
However at high doses they also inhibit MAO-A and can lead to hypertensive crisis(cheese reaction) with tyramine containing foods
and serotonin syndrome with TCAs.
Rasagiline is more potent than selegiline.
These drugs are thought to reduce the disease progression.
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Carbidopa:
addition increases entry of L-dopa in brain,
decrease adverse effects due to peripherally formed dopamine.
Carbidopa decreases all adverse effects of levodopa therapy
except abnormal movements and behavioural changes.
L-DOPA especially in elderly can result in hallucinations, vivid dreams, sleep disturbances
and even psychosis thus C/I in psychosis.
These behavioural disturbances are not prevented by carbidopa.
Clozapine and quetiapine can be used to treat levodopa induced psychosis.
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C. Dopamine agonists:
these drugs directly activate D2 receptors and can be used as monotherapy in parkinsonism.
Ergot derived dopamine agonists include bromocriptine and pergolide.
These drugs are shorter acting and can cause digital vasospasm leading to gangrene and erythromelalgia.
These drugs can also result in pleural, peritoneal and cardiac fibrosis.
Ergot alkaloids require slow upward titration of dose.
Long term use of pergolide is associated with cardiac valvular defects.
Newer non-ergot dopamine agonists, pramipexole and ropinirole donot have these limitations
as these are long acting and donot cause gangrene.
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Pimavanserin
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Treatment of delusions, hallucinations, and
psychosis in PD
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Major pathology
Major pathology in parkinsonism is
decrease in nigrostriatal dopaminergic neurons
with appearance of lewy bodies
consequently cholinergic activity becomes dominant.
Thus two main strategies for the treatment of parkinsonism
are to increase brain dopaminergic action
or to decrease cholinergic activity.
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A. dopamine precursors:
dopamine itself cant cross BBB
but its precursor levo-dopa can cross BBB.
Levo dopa is metabolized by dopa decarboxylase
which contains pyridoxine as cofactor to dopamine.
This conversion occurs both in periphery as well as in the brain.
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On-off phenomenon
On long term use “wearing off” effect and on-off phenomenon can result.
On means patients is having no symptoms of parkinsonism but abnormal movements are present
and off means patient has full blown symptoms of parkinsonism like no treatment is given.
This effect is due to short half life(1-2 hrs) of levodopa and is reduced by carbidopa.
Long acting dopamine agonists show little tendency to cause on-off phenomenon.
Dyskinesia
Abnormal choreiform movements(dyskinesia) of limbs, trunk and tongue
can occur with prolonged high dose treatment.
Carbidopa doesn’t prevent or decrease this adverse effect.
This adverse effect responds to amantadine and possibly levetiracetam.
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Levodopa + vitamin B6?
Vitamin complexes containing pyridoxine decrease the effectiveness of levo-dopa
(pyridoxine is a cofactor of dopa decarboxylase)
and increases the formation of dopamine in the periphery.
This results in decrease in L-DOPAs central penetration.
other ADRs of levodopa
may precipitate neurolept malignant syndrome.
Levo-dopa should be given carefully in patients with active peptic ulcer(increased risk of bleeding)
and malignant melanoma(levo-dopa is a precursor of melanin).
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Rotigotine
is a dopamine agonist that can be administered through a transdermal patch
but was discontinued due to crystal formation on the patches.
Apomorphine
Apomorphine can be given subcutaneously for temporary relief of off periods.
However it can cause troublesome nausea.
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