Parkinson's disease is a neurodegenerative disorder caused by low dopamine and high acetylcholine levels in the basal ganglia. Symptoms include tremors, rigidity, bradykinesia, and gait abnormalities. Treatment aims to increase dopamine or block acetylcholine. Levodopa combined with carbidopa replaces dopamine but causes fluctuations. Dopamine agonists, MAO-B inhibitors like selegiline and rasagiline, and COMT inhibitors provide alternative treatment options with varying mechanisms of action and side effect profiles.

1. PARKINSON’S DISEASE
OLORO JOSEPH
(DCM, BSc. MSc. Pharm, PhD Tox. Fellow)

2. References

3. • A chronic progressive neuro-degenarative
disease
• Affects the dopamine producing neurone of
the basal ganglia at the area called substantia
nigra
• Due to imbalance in two neurotransmitters
– Dopamine
– Acetylcholine
• Dopamine low, Ach high

4. • Dopamine play inhibitory role on cholinergic
neurons in the area
• ↓sed dopamine → elevated conc. Of Ach
• elevated conc. Of Ach → unctrolled muscle
contraction.
• PKD is characterized by;
– Tremors
– Muscular rigidity
– Bradykinesia (slowness in initiating and carrying
out voluntary movements), and
– Postural and gait abnormalities.

5. Treatment aims
• Elevating activity of dopaminergic neurons
– Replacing dopamine
– Stimulating dopamine production
– Preventing dopamine breakdown
• Reducing activity of Ach
– Blocking receptors

6. Dopamine replacement
Levodopa [lee-voe-DOE-pa]
• Is a metabolic precursor of dopamine
MOA
• 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.

7. Carbidopa [kar-bi-DOE-pa]
• The effects of levodopa on the CNS can be greatly
enhanced by coadministering carbidopa a dopa
decarboxylase inhibitor that does not cross the
blood-brain barrier.
• Carbidopa diminishes the metabolism of
levodopa in the gastrointestinal tract and
peripheral tissues; thus, it increases the
availability of levodopa to the CNS
• The addition of carbidopa lowers the dose of
levodopa needed by
• four- to five-fold and, consequently, decreases
the severity of the side effects arising from
peripherally formed dopamine.

8. • 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's disease. In approximately
two-thirds of patients with Parkinson's 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.

9. • PK
• Absorption and metabolism: The drug is absorbed
rapidly from the small intestine (when empty of
food).
• Levodopa has an extremely short half-life (1 to 2
hours), which causes fluctuations in plasma
concentration.
• Ingestion of meals, particularly if high in protein,
interferes with the transport of levodopa into the
CNS.
• Large, neutral amino acids (for example, leucine and
isoleucine) compete with levodopa for absorption
from the gut and for transport across the blood-brain
barrier.
• Thus, levodopa should be taken on an empty
stomach, typically 45 minutes before a meal.
• Withdrawal from the drug must be gradual.

11. Selegiline [seh-LEDGE-ah-leen]
• also called deprenyl [DE-pre-nill],
MOA
• Selectively inhibits MAO Type B (which
metabolizes dopamine) at low to moderate
doses
• Does not inhibit MAO Type A (which
metabolizes norepinephrine and serotonin)
• By decreasing the metabolism of dopamine,
selegiline increase dopamine levels in the
brain

12. • Administered orally
• Metabolized to Methamphetamine and
amphetamine, whose stimulating properties
may produce insomnia if the drug is
administered later than mid afternoon.
Adverse effects
• severe hypertension.

13. Rasagiline [ra-SA-gi-leen]
• 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.

14. Catechol-O-methyltransferase
inhibitors
• methylation of levodopa by catechol-O-
methyltransferase (COMT) to 3-O-methyldopa is a
minor pathway for levodopa metabolism.
• when peripheral dopamine decarboxylase activity
is inhibited by carbidopa, a significant
concentration of 3-O-methyldopa is formed that
competes with levodopa for active transport into
the CNS

15. • Entacapone [en-TA-ka-pone] or Tolcapone
[TOLE-ka-pone]
• Are nitrocatechol derivatives that selectively
and reversibly inhibit COMT
• Inhibits COMT → ↓sed plasma con. of 3-O-
methyldopa, increased central uptake of
levodopa, and greater concentrations of brain
dopamine
• Reduce the symptoms of “wearing-off ”
phenomena seen in patients on levodopa–
carbidopa

16. • Pharmacokinetics:
• Administered orally
• Absorption occurs readily and is not influenced by
food.
• Are extensively bound to plasma albumin (>98
percent), with limited volumes of distribution.
• Tolcapone but not entacapone penetrates the blood-
brain barrier and inhibits COMT in the CNS.
• Tolcapone has a relatively long duration of action
(probably due to its affinity for the enzyme) compared
to entacapone, which requires more frequent dosing.
• Both drugs are extensively metabolized and eliminated
in feces and urine.
• Dosage may need to be adjusted in patients with
moderate or severe cirrhosis.

17. Adverse effects:
• Diarrhea
• Postural hypotension,
• Nausea & anorexia,
• Dyskinesias
• Hallucination
• Sleep disorders.
• Fulminating hepatic necrosis is associated
with tolcapone use.

18. Dopamine-receptor agonists
Include;
• Pramipexole & ropinirole
• Apormorphine & Rotigotine
• Amantadine

19. • Pramipexole [pra-mi-PEX-ole] and ropinirole
[roe-PIN-i-role] are agonists at dopamine
receptors.
• Apomorphine [A-po-mor-feen] and rotigotine
[ro-TI-go-teen] are newer dopamine agonists
available in injectable and transdermal
delivery systems, respectively

20. Amantadine
• 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.
• Current evidence supports an action at NMDA
receptors as the primary action at therapeutic
concentrations

21. Adverse effects
• Agitation
• Confusion
• Hallucinations
• At high doses, it may induce acute toxic
psychosis.
• Orthostatic hypotension
• Urinary retention
• Peripheral edema
• Dry mouth also may occur.

22. Antimuscarinic agents
• Benztropine [BENZ-tro-peen]
• Trihexyphenidyl [tri-hex-ee FEN-i-dill]
• Procyclidine [pro-CY-cli-deen]
• Biperiden [bi-PER-i den]
MOA
• Blocks cholinergic transmission producing
effects similar to augmentation of
dopaminergic transmission

23. Adverse effects
• pupillary dilation,
• confusion,
• hallucination, sinus
• tachycardia,
• urinary retention,
• constipation, and
• dry mouth.