DRUGS FOR PARKINSON’S DISEASE
Parkinsonism
• Characterized by combination of rigidity, bradykinesia, tremors, and postural instability that can occur for a reason but usually is idiopathic (Parkinson’s
disease or paralysis agitans); Most common sa mga matatanda
• Cognitive decline + non-motor symptoms (affective disorders-anxiety or depression), personality changes, abnormalities of autonomic function-sphincter
or sexual functions, choking, sweating abnormalities and disturbances in blood pressure regulation, sleep disorders, and sensory complaints or pain.
\ Motor (movement) related problem
\ Accompanied with cognitive decline.
Pathogenesis
• Related to a combination of impaired degradation of proteins, intracellular protein accumulation and aggregation, oxidative stress mitochondrial damage,
inflammatory cascades, and apoptosis.
• Genetic factors → relevant when the disease occurs at age below 50.
o Mutations of 𝛼-synuclein gene at 4q21 or duplication and triplication of normal synuclein gene → associated with Parkinson’s disease
o Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen and the UCHLI gene → autosomal dominant parkinsonism
o Mutations in the parkin-gene → early onset, autosomal recessive, familial parkinsonism or sporadic juvenile-onset parkinsonism
• Environmental or endogenous → also important in the etiology of the disease → cigarette smoking, coffee, anti-inflammatory drug use and high serum
uric acid levels are protective whereas incidence is high in those working in teaching, health care, or farming and those with lead or manganese exposure
or Vitamin D deficiency.
\ Parkinsonism = ↓ dopamine → excessive firing of 𝛼-synuclein → clumping results to Levy bodies → Parkinson’s Disease
§ Accumulation of 𝛼-synuclein → aggregation (clumping) → symptoms depends where the clumping occurs:
• Brain stem = constipation, depression
• Substantia nigra = hallmark; motor symptoms (stiffness, tremors, and slowness)
• Outside the brainstem = cognitive problems
• Lewis bodies (intracellular inclusion bodies containing 𝛼-synuclein) in fetal dopaminergic cells transplanted into the brain of parkinsonian patient →
Parkinson’s disease may represent a prion disease.
• Staining for 𝜶-synuclein (determinant of stage: Braak Scale) revealed a more widespread pathology:
Stages Affected Parts
Stage 1 Initially developing pathology at olfactory nucleus and lower brainstem
Stage 2 Higher brainstem
Stage 3 Substantia nigra (hallmark motor symptoms)
Stage 4 Mesocortex and thalamus
Stage 5 Entire neocortex
NOTE: motor features of Parkinson’s disease develop at Stage 3
• ↓ dopamine in the basal ganglia of the brain
, Etiology
Substantia nigra Neostriatum
• Source of dopamine (If destroyed → affects the ability of the substantia nigra to secret • Connected to the substantia nigra by neurons that secreted GABA at their termini and the
the dopamine in the neostriatum) cells of the substantia nigra send neurons back to the neostriatum secreting the inhibitory
neurotransmitter dopamine at their termini.
• Part of the extrapyramidal system that is the source of dopaminergic neurons that terminate
in the neostriatum. • In Parkinson’s disease → destruction of cells in the substantia nigra → degeneration of the
nerve terminals that secrete dopamine in the neostriatum → decreased inhibitory influence
• The dopaminergic projections → fire tonically rather than in response to specific muscular of dopamine on cholinergic neurons → overactivity of acetylcholine by stimulatory neurons
movements or sensory impute → serve as a tonic sustaining influence on motor activity → loss of control of muscle movements
rather than participating in specific movements.
NOTE: acetylcholine → cholinergic (controls body movements)
o PD = imbalance between inhibitory of dopamine and excitatory (acetylcholine; dominant)
o Dapat balanace yung dopamine and acetylcholine
Secondary Parkinsonism Strategy of Treatment
• Phenothiazine and Haloperidol • Restore dopamine in the basal ganglia
• Action: Blockade of dopamine receptors → produce parkinsonian symptoms (pseudo • Antagonize the excitatory effect of cholinergic neurons to re-establish correct
parkinsonism) hence the drugs should be used in caution in patients with Parkinson’s dopamine/acetylcholine balance
Disease
o People who take antipsychotic may exhibit PD symptoms
o No PD but shows symptoms
Dopamine Receptor Agonist
• Acts directly on post-synaptic dopamine receptors.
• Have beneficial effect in addition of that of Levodopa.
• Do not require enzymatic conversion to an active metabolite, have no potentially toxic metabolites and do not compete with other substances for active
transport into the blood and across the BBB.
• Affect only certain dopamine receptors → limited adverse effects than Levodopa.
o Given to patients with parkinsonism who are taking Levodopa and who have end-of-dose akinesia or on-off phenomenon or are becoming
resistant to treatment with Levodopa.
Parkinsonism
• Characterized by combination of rigidity, bradykinesia, tremors, and postural instability that can occur for a reason but usually is idiopathic (Parkinson’s
disease or paralysis agitans); Most common sa mga matatanda
• Cognitive decline + non-motor symptoms (affective disorders-anxiety or depression), personality changes, abnormalities of autonomic function-sphincter
or sexual functions, choking, sweating abnormalities and disturbances in blood pressure regulation, sleep disorders, and sensory complaints or pain.
\ Motor (movement) related problem
\ Accompanied with cognitive decline.
Pathogenesis
• Related to a combination of impaired degradation of proteins, intracellular protein accumulation and aggregation, oxidative stress mitochondrial damage,
inflammatory cascades, and apoptosis.
• Genetic factors → relevant when the disease occurs at age below 50.
o Mutations of 𝛼-synuclein gene at 4q21 or duplication and triplication of normal synuclein gene → associated with Parkinson’s disease
o Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen and the UCHLI gene → autosomal dominant parkinsonism
o Mutations in the parkin-gene → early onset, autosomal recessive, familial parkinsonism or sporadic juvenile-onset parkinsonism
• Environmental or endogenous → also important in the etiology of the disease → cigarette smoking, coffee, anti-inflammatory drug use and high serum
uric acid levels are protective whereas incidence is high in those working in teaching, health care, or farming and those with lead or manganese exposure
or Vitamin D deficiency.
\ Parkinsonism = ↓ dopamine → excessive firing of 𝛼-synuclein → clumping results to Levy bodies → Parkinson’s Disease
§ Accumulation of 𝛼-synuclein → aggregation (clumping) → symptoms depends where the clumping occurs:
• Brain stem = constipation, depression
• Substantia nigra = hallmark; motor symptoms (stiffness, tremors, and slowness)
• Outside the brainstem = cognitive problems
• Lewis bodies (intracellular inclusion bodies containing 𝛼-synuclein) in fetal dopaminergic cells transplanted into the brain of parkinsonian patient →
Parkinson’s disease may represent a prion disease.
• Staining for 𝜶-synuclein (determinant of stage: Braak Scale) revealed a more widespread pathology:
Stages Affected Parts
Stage 1 Initially developing pathology at olfactory nucleus and lower brainstem
Stage 2 Higher brainstem
Stage 3 Substantia nigra (hallmark motor symptoms)
Stage 4 Mesocortex and thalamus
Stage 5 Entire neocortex
NOTE: motor features of Parkinson’s disease develop at Stage 3
• ↓ dopamine in the basal ganglia of the brain
, Etiology
Substantia nigra Neostriatum
• Source of dopamine (If destroyed → affects the ability of the substantia nigra to secret • Connected to the substantia nigra by neurons that secreted GABA at their termini and the
the dopamine in the neostriatum) cells of the substantia nigra send neurons back to the neostriatum secreting the inhibitory
neurotransmitter dopamine at their termini.
• Part of the extrapyramidal system that is the source of dopaminergic neurons that terminate
in the neostriatum. • In Parkinson’s disease → destruction of cells in the substantia nigra → degeneration of the
nerve terminals that secrete dopamine in the neostriatum → decreased inhibitory influence
• The dopaminergic projections → fire tonically rather than in response to specific muscular of dopamine on cholinergic neurons → overactivity of acetylcholine by stimulatory neurons
movements or sensory impute → serve as a tonic sustaining influence on motor activity → loss of control of muscle movements
rather than participating in specific movements.
NOTE: acetylcholine → cholinergic (controls body movements)
o PD = imbalance between inhibitory of dopamine and excitatory (acetylcholine; dominant)
o Dapat balanace yung dopamine and acetylcholine
Secondary Parkinsonism Strategy of Treatment
• Phenothiazine and Haloperidol • Restore dopamine in the basal ganglia
• Action: Blockade of dopamine receptors → produce parkinsonian symptoms (pseudo • Antagonize the excitatory effect of cholinergic neurons to re-establish correct
parkinsonism) hence the drugs should be used in caution in patients with Parkinson’s dopamine/acetylcholine balance
Disease
o People who take antipsychotic may exhibit PD symptoms
o No PD but shows symptoms
Dopamine Receptor Agonist
• Acts directly on post-synaptic dopamine receptors.
• Have beneficial effect in addition of that of Levodopa.
• Do not require enzymatic conversion to an active metabolite, have no potentially toxic metabolites and do not compete with other substances for active
transport into the blood and across the BBB.
• Affect only certain dopamine receptors → limited adverse effects than Levodopa.
o Given to patients with parkinsonism who are taking Levodopa and who have end-of-dose akinesia or on-off phenomenon or are becoming
resistant to treatment with Levodopa.
