Parkinson's disease is a disorder caused by degeneration of basal ganglia resulting in motor impairment. It is hypothesized to be due to genetic and environmental factors. The major neuropathologic findings are loss of substantia nigra dopaminergic neurons and Lewy bodies/neurites containing alpha-synuclein aggregates. Common symptoms include resting tremor, rigidity, bradykinesia, and later postural instability. Diagnosis is clinical without confirmatory tests. Treatment goals are improving motor and nonmotor symptoms to maintain quality of life through medications and management of complications.

1. Parkinson’s Disease
Definition: Parkinsonism is a disorder caused by the degeneration of basal
ganglia, causing impairment of the motor nerves and disabling motor functions.
Etiology: Although the etiology of Parkinson disease is still unclear, most cases
are hypothesized to be due to a combination of genetic and environmental
factors.
Currently known genetic causes of Parkinson disease account for
approximately 10% of cases.
1. Environmental causes:
Use of pesticides
Living in a rural environment
Consumption of well water
Exposure to herbicides
Proximity to industrial plants or quarries.
Note: Higher caffeine intake was associated with lower risk of Parkinson
disease in both men and women. A similar association was found for smoking
and Parkinson disease risk.
2. MPTP interference with mitochondrial function:
The compound N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) has
been identified in underground laboratory preparations(DRUGS) of a potent
analog of meperidine (narcotic analgesic).
MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium
(MPP+) by monoamine oxidase (MAO)-B, which is potent neurotoxin
MPP+ accumulates in mitochondria and interferes with the function of complex I of the
Electron transport chain, which results in the generation of excessive reactive oxygen
species and cell death

2. 3. Oxidation hypothesis:
The oxidative metabolism of dopamine by MAO-B leads to the formation of
hydrogen peroxide.
Normally, hydrogen peroxide is cleared rapidly by glutathione, but if hydrogen
peroxide is not cleared adequately, it may lead to the formation of highly
reactive hydroxyl radicals that can react with cell membrane lipids to cause
lipid peroxidation and cell damage.
In Parkinson disease, levels of reduced glutathione are decreased, suggesting a
loss of protection against formation of free radicals.
Iron is increased in the substantia nigra and may serve as a source of donor
electrons, thereby promoting the formation of free radicals.
4. Genetic factors:
Genetics may play a significant role, particularly if PD begins before age 50
years.
Autosomal dominant forms of parkinsonism are associated with mutations of
the α-synuclein (PARK1 and PARK4) and leucine-rich repeat kinase 2 (LRRK)
genes.
Autosomal recessive forms are associated with mutations of parkin (PARK2)
and PTEN-induced putative kinase 1 (PINK1) genes
(DOPAC- 3,4-
dihydroxyphenyl
aceticacid;
GSH- glutathione;
GSSG-glutathione
disulfide

3. Mechanisms related to genes- abnormal protein aggregation (alpha-synuclein),
defective ubiquitin-mediated protein degradation of alpha-synuclein,
mitochondrial dysfunction, and oxidative damage.
5. Alpha-synuclein conformational changes and aggregation:
Normally, alpha-synuclein is found mainly in neuronal presynaptic terminals
and may play a role in assembly and function of SNARE (soluble N-
ethylmaleimide-sensitive factor activating protein receptor) proteins that are
involved in neurotransmitter release.
Under certain conditions (genetic mutations), alpha-synuclein aggregates into
oligomers that are gradually converted to the beta–sheet-rich fibrillary
structures that form Lewy bodies and neurites in Parkinson disease.
i. oligomeric alpha-synuclein can promote formation of ion-permeable
pores on neuronal membranes, leading to increased calcium influx.
ii. Aberrant pore formation could also lead to neurotransmitter leaks from
synaptic vesicles into the cytosol.
iii. oligomeric alpha-synuclein may have a direct effect on mitochondrial
membranes.
iv. oligomerization of alpha-synuclein could cause cytoskeletal disruption,
possibly by an effect on the microtubule-stabilizing protein, tau.
6. Melanoma
7. Diabetes
Pathophysiology:
The 2 major neuropathologic findings in Parkinson disease are:
i. Loss of pigmented dopaminergic neurons of the substantia nigra pars
compacta
ii. The presence of Lewy bodies and Lewy neurites (alpha-synuclein)

4. Etiological factors
Dopaminergic neurons in substantia nigra starts to die of
(Nigrostriatal pathway)
i. It cannot initiate more movements in Direct pathway
ii. It cannot prevent excessive reduction in movement in the Indirect
pathway
Slowing down and Loss of movements
Motor control by basal ganglia

5. Signs and symptoms:
General Features
Common early motor signs of Parkinson disease include resting tremor, rigidity,
or bradykinesia.
Postural instability (difficulty with maintaining balance) is more common in
advanced IPD.
Motor Symptoms
The patient experiences:
i. Decreased manual dexterity (ability to use your hands in a skillful,
coordinated way to grasp and manipulate objects and demonstrate small,
precise movements),
ii. Difficulty arising from a seated position,
iii. Diminished arm swing during ambulation (ability to walk without the
need for any kind of assistance),
iv. Dysarthria (slurred speech),
v. Dysphagia (difficulty with swallowing),
vi. Festinating gait (tendency to pass from a walking to a running pace),
vii. Flexed posture (axial, upper/lower extremities),
viii. “freezing” at initiation of movement,
ix. Hypomimia (reduced facial animation),
x. Hypophonia (reduced voice volume), and
xi. Micrographia (diminution of handwritten letters/symbols)
Autonomic and Sensory Symptoms
i. The patient experiences:
ii. Bladder and anal sphincter disturbances,
iii. Constipation,
iv. Diaphoresis,
v. Fatigue,
vi. Olfactory disturbance,
vii. Orthostatic blood pressure changes,
viii. Pain, paresthesia,
ix. Paroxysmal vascular flushing, seborrhea, sexual dysfunction, and
sialorrhea (drooling).

6. Mental Status Changes
The patient experiences:
i. Anxiety,
ii. Apathy,
iii. Bradyphrenia (slowness of thought processes),
iv. Confusional state,
v. Dementia,
vi. Depression,
vii. Hallucinosis/psychosis (typically drug induced), and
viii. Sleep disorders (excessive daytime sleepiness, insomnia, obstructive
sleep apnea, and rapid eye movement sleep behavior disorder).
Diagnosis:
 No laboratory tests are available to diagnose PD
 Genetic testing is not routinely helpful.
 Neuroimaging may be useful for excluding other diagnoses.
 Medication history should be obtained to rule out drug induced
parkinsonism.
Treatment:
Goals:
The goal in the management of PD is
To improve motor and nonmotor symptoms so that patients are able to
maintain the best possible quality of life.
Specific objectives to consider when selecting an intervention include
preservation of the ability to perform activities of daily living; improvement of
mobility; minimization of adverse effects, treatment complications; and
improvement of nonmotor features such as cognitive impairment, depression,
fatigue, and sleep disorders.

7. General approach tothe management of early to advancedParkinson’s disease.

8. Drugs with Doses.

9. Drugs and their site of Action
Further Info about drugs in Pharmacology material…