Treatment of Parkinson Disease, Classification, MOA, Uses and Side Effects

1. By
Dr. Faraza Javaid

2. PARKINSON'S DISEASE?
Parkinsonism is a neurodegenerative disorder
which affects the basal ganglia and is associated
with:
- a loss of dopaminergic neurons in the substantia
nigra and
- degeneration of nerve terminals in the striatum
PARKINSON ´S SYNDROME:
• Is the adverse effect of antipsychotic agents due to
D2-receptor blockade in the basal ganglia.
• Its acute form is reversible.

3. FEATURES OF PARKINSON'S DISEASE:
• Parkinson's disease is a progressive disorder of movement
that occurs mainly in the elderly. The chief symptom are:
• Tremors at rest, usually starting in the hands ('pill-rolling'
tremor), which tends to diminish during voluntary activity.
• Muscle rigidity, detectable as an increased resistance in
passive limb movement.
• Suppression of voluntary movements (hypokinesis), due
partly to muscle rigidity and partly to an inherent inertia of
the motor system, which means that motor activity is difficult
to stop as well as to initiate.

4. Hoehn and Yahr Staging of
Parkinson's Disease
• Stage 1: Mild signs and symptoms on one side only,
not disabling but friends notice.
• Stage 2: Symptoms are bilateral, minimal disability,
posture and gait affected.
• Stage 3: Significant slowing, dysfunction that is
moderately severe.
• Stage 4: Severe symptoms, walking limited, rigidity,
bradykinesia, unable to live alone.
• Stage 5: Cachectic, complete invalidism, unable to
stand, walk, require nursing care.

5. Aetiology and Pathogenesis:
• Remain largely unknown
• Heredity have a limited role
• Defective gene responsible for a rare condition called
autosomal recessive juvenile parkinsonism (teens and 20s)
• The damage is caused by:
• EXCITOTOXICITY
• OXIDATIVE STRESS
• APOPTOSIS /NECROSIS OF NEURONS

6. • Parkinson's disease often occurs with no obvious underlying
cause, but it may be the result of cerebral ischemia, viral
encephalitis or other types of pathological damage.
• The symptoms can also be drug-induced, the main drugs
involved being those that reduce the amount of dopamine in
the brain e.g. reserpine or block dopamine receptors (e.g.
antipsychotic drugs such as chlorpromazine.
• There are rare instances of early-onset PD that runs in
families, and several gene mutations have been identified, the
most important being synuclein and parkin.
• Study of these gene mutations has given some clues about the
mechanism underlying the neurodegenerative process.

7. In normal conditions:
• Acetylcholine release from the striatum
(cholinergic neurons)
• is strongly inhibited by dopamine (depleted
from the nigrostriatal neurons).
• Joint GABA-ergic neurons then opposite
excitatory function of glutamate neurones
connected to the motor cortex.

8. motor cortex glutamate
Corpus striatum
Substantia nigra
dopamine
ACH
GABA
glutamate
MOVEMENT
GABA

10. In Neurodegeneration:
• Neurodegeneration of the dopaminergic neurons
(Subs.nigra) + loss of dopamine (the striatum) leads to
both hyperactivity of these cholinergic striatal neurons
+ blockade of GABA-ergic cells (Subst.nigra).
• The result is an increase in excitatory activity of
glutamate + the motor cortex
muscle rigidity, tremor, hypokinesia

12. Molecular aspects
• Parkinson's disease, as well as several other
neurodegenerative disorders, is associated with the
development of intracellular protein aggregates known
as Lewy bodies in various parts of the brain.
• They consist largely of α-synuclein, a synaptic protein
present in large amounts in normal brains.
• Mutations occur in rare types of hereditary PD , and it is
believed that such mutations render the protein resistant
to degradation within cells, causing it to pile up in Lewy
bodies.

13. • It is possible that the normal function of α-synuclein is related
to synaptic vesicle recycling, and that the mutated form loses
this functionality, with the result that vesicular storage of
dopamine is impaired.
• This may lead to an increase in cytosolic dopamine,
degradation of which produces reactive oxygen species and
hence neurotoxicity.
• Other gene mutations that have been identified as risk factors
for early-onset PD code for proteins involved in
mitochondrial function, making cells more susceptible to
oxidative stress.

14. TREATMENT OF PARKINSON’S
DISEASE
• How to treat deficit of dopamine?
INCREASE IN DOPAMINERGIC ACTIVITY:
(1) dopamine precursors (replacement of dopamine)
(2) MAO-B blockade
(3) Catechol-O-methyltransferase inhibitors
(4) increase in dopamine release
(5) blockade of amine neuronal reuptake
(6) dopamine receptors agonists

15. • How to treat excitatory function of cholinergic
and glutaminergic neurons?
• MUSCARINIC ACETYLCHOLINE RECEPTOR
ANTAGONISTS.

17. (1) Dopamine precursors (replacement of
dopamine):
Levodopa:
• Levodopa is a metabolic precursor of dopamine.
• It restores dopaminergic neurotransmission in the
corpus striatum by enhancing the synthesis of dopamine
in the surviving neurons of the substantia nigra.
• In patients with early disease, the number of residual
dopaminergic neurons in the substantia nigra (typically
about 20 percent of normal) is adequate for conversion
of levodopa to dopamine.
• Thus, in new patients, the therapeutic response to
levodopa is consistent, and the patient rarely complains
that the drug effects “wear off .”

18. • Unfortunately, with time, the number of neurons
decreases, and fewer cells are capable of taking up
exogenously administered levodopa and converting
it to dopamine for subsequent storage and release.
• Consequently, motor control fluctuation develops.
Relief provided by levodopa is only symptomatic,
and it lasts only while the drug is present in the
body.

19. Mechanism of action:
• Because parkinsonism results from insufficient
dopamine in specific regions of the brain, attempts have
been made to replenish the dopamine deficiency.
• Dopamine itself does not cross the blood-brain barrier,
but its immediate precursor, levodopa, is actively
transported into the CNS and is converted to dopamine
in the brain .
• Large doses of levodopa are required, because much of
the drug is decarboxylated to dopamine in the periphery,
resulting in side effects that include nausea, vomiting,
cardiac arrhythmias, and hypotension.

20. Carbidopa:
• Carbidopa, a dopa decarboxylase inhibitor,
diminishes the metabolism of levodopa in the
gastrointestinal tract and peripheral tissues, thereby
increasing the availability of levodopa to the CNS.
• The addition of carbidopa lowers the dose of
levodopa needed by four- to fivefold and,
consequently, decreases the severity of the side
effects arising from peripherally formed dopamine.

22. Actions:
• Levodopa decreases the rigidity, tremors, and other
symptoms of parkinsonism.
• Therapeutic uses:
• Levodopa in combination with carbidopa is a potent and
efficacious drug regimen currently available to treat
Parkinson disease.
• In approximately two-thirds of patients with Parkinson
disease, levodopa–carbidopa treatment substantially
reduces the severity of the disease for the first few years
of treatment.
• Patients then typically experience a decline in response
during the third to fifth year of therapy.

23. Interactions:
• The vitamin pyridoxine (B6) increases the peripheral
breakdown of levodopa and diminishes its effectiveness.
• Concomitant administration of levodopa and monoamine
oxidase inhibitors (MAOIs), such as phenelzine, can produce
a hypertensive crisis caused by enhanced catecholamine
production. Therefore, caution is required when they are used
simultaneously.
• In patients with glaucoma, the drug can cause an increase in
intraocular pressure.
• Cardiac patients should be carefully monitored because of the
possible development of cardiac arrhythmias.

24. (2) MAO-B blockade:
Selegiline and rasagiline:
• Selegiline also called deprenyl, selectively inhibits MAO
Type B (which metabolizes dopamine) at low to moderate
doses but does not inhibit MAO Type A (which metabolizes
norepinephrine and serotonin).
• By, thus, decreasing the metabolism of dopamine, selegiline
has been found to increase dopamine levels in the brain
Therefore, it enhances the actions of levodopa when these
drugs are administered together.
• Selegiline substantially reduces the required dose of
levodopa. Unlike nonselective MAOIs, selegiline at
recommended doses has little potential for causing
hypertensive crises.

25. • Selegiline is metabolized to methamphetamine and
amphetamine, whose stimulating properties may
produce insomnia if the drug is administered later
than midafternoon.
• Rasagiline , an irreversible and selective inhibitor
of brain monoamine oxidase Type B, has five times
the potency of selegiline.
• Unlike selegiline, rasagiline is not metabolized to
an amphetamine like substance.

26. 3. Catechol-O-methyltransferase inhibitors:
Entacapone and tolcapone:
• It inhibits COMT, which converts levodopa to 3OMD in the
gut and liver.
• So it produces a twofold increase oral bioavailability and half-
life of levodopa.
• 3OMD competes with L-dopa for transport across the blood-
brain barrier and may contribute to the “wearing off” and“on-
off” effects seen in patients taking L-dopa
• By inhibiting 3OMD formation, it may stabilize dopamine
levels in striatum.

28. 4. Dopamine-receptor agonists:
• This group of anti-Parkinson compounds includes
bromocriptine, an ergot derivative, and newer, non
ergot drugs, ropinirole, pramipexole, and rotigotine.
• Bromocriptine, pramipexole, and ropinirole are all
effective in patients with advanced Parkinson
disease complicated by motor fluctuations and
dyskinesias.

29. A. Bromocriptine and pergolide:
• Both are ergot alkaloids.
• Bromocriptine, a derivative of the vasoconstrictive
alkaloid, ergotamine, is a dopamine-receptor agonist.
• Bromocriptine is a D2 receptor agonist and a D1 receptor
antagonist.
• Pergolide is a D1 and D2 receptor agonist.
• Pergolide is much more potent than bromocriptine,
higher affinity to D2 receptors, longer duration of
action.

30. • Both are useful adjuncts to levodopa in patients
have advanced parkinson and experience wearing
off and on-off
• Side effects are nausea (50%), confusion,
dyskinesia, sedation, vivid dreams, hallucinations,
orthostatic hypotension, dry mouth, decreased
prolactin levels .

31. B. Apomorphine, pramipexole, ropinirole, and
rotigotine:
• These are non-ergot dopamine agonists that have been
approved for the treatment of Parkinson disease.
• Pramipexole and ropinirole are agonists at dopamine
receptors.
• Apomorphine is meant to be used for the acute
management of the hypomobility “off” phenomenon.
• These agents alleviate the motor deficits in both
levodopa-naïve patients (patients who have never been
treated with levodopa) and patients with advanced
Parkinson disease who are taking levodopa.

32. 5. Amantadine:
• It was accidentally discovered that the antiviral drug
amantadine, which is effective in the treatment of
influenza , has an anti-parkinsonism action.
• Amantadine has several effects on a number of
neurotransmitters implicated in causing parkinsonism,
including increasing the release of dopamine,
blockading cholinergic receptors, and inhibiting the N-
methyl-D-aspartate (NMDA) type of glutamate
receptors.

33. • Current evidence supports an action at NMDA receptors
as the primary action at therapeutic concentrations.
• The drug may cause restlessness, agitation, confusion,
and hallucinations, and, at high doses, it may induce
acute toxic psychosis. Orthostatic hypotension, urinary
retention, peripheral edema, and dry mouth also may
occur.
• The drug has little effect on tremor, but it is more
effective than the anti-cholinergics against rigidity and
bradykinesia.

34. 6. Anti-muscarinic agents:
• Anticholinergic drugs such as benztropine and
trihexyphenedyl are used.
• They are less effective than dopaminergic drugs.
• They are more effective in reducing tremor than the
other symptoms.
• They are useful in treatment of early and advanced
Parkinson’s disease, they can reduce Parkinson’s
symptoms caused by dopamine receptor antagonists e.g.
haloperidol.

35. Neuroprotective Therapy:
• A number of different compounds are currently under
investigation as potential neuroprotective agents that
may slow disease progression.
• These include antioxidants, antiapoptotic agents,
glutamate antagonists, intraparenchymally administered
glial-derived neurotrophic factor, coenzyme Q10, and
anti-inflammatory drugs.
• The role of these agents remains to be established,
however, and their use for therapeutic purposes is not
indicated at this time.

36. References:
• www.studentconsult.com
• Elsvier . Rang et al: pharmacology 6e.
• Lippincott’s Illustrated Reviews: Pharmacology 5th
edition.
• Goodman & Gilman’ Manual of Pharmacology and
Therapeutics 2008.
• Katzung-basic: clinical pharmacology 10th edition.