Parkinsons, Schitzophrenia and Epilepsy Flashcards
Cause of Parkinson’s disease
Degeneration of dopaminergic neurones in the substantia nigra. Formation of Lewy bodies due to deposition of parkin and alpha-synuclein
Describe the pathophysiology of Parkinsons disease
Degeneration of neurones in the substantia nigra results in a loss of dopamine in the nigrostriatal tract of the basal ganglia.
DA transmission influences the output of the striatum and therefore thalamic input to the cortex. The striatum projects to the globus pallidus by direct and indirect pathways.
The Direct pathway projects directly to the GPi and inhibits it. GPi normally inhibits the thalamus so the striatum causes increased activity of the thalamus by blocking GPi. DA released from the substantia nigra to D1R excite this pathway.
In indirect pathway projects to the GPe which reduces inhibition of the subthalamic nucleus. The STN excites the GPi and causes inhibition of thalamic activity. Dopamine binds to D2R in the striatum to inhibit this pathway.
In Parkinsons, lack of DA means there is less excitation of the direct pathway, and less inhibiton of the indirect pathway. Activity of the GPi is increased and the thalamus is inhibited. This leads to akinesa and other Parkinsonian symptoms.
Signs of Parkinson’s disease
Tremor at rest (pill-rolling)
Bradykinesia (affects fine movements e.g. buttons)
Cog-wheel rigidity
Shuffling gait
Stooped posture
What are the four Dopamine pathways
Nigrostriatal - basal ganglia, fine movements
Mesolimbic - VTA to limbic system, reward and desire
Mesocortical - VTA to frontal lobes, motivation and emotional response
Tuberohypophyseal - regulates secretion of prolactin
Chemicals which can induce Parkinsons
Neuroleptics
Anti-emetics
Vestibular sedatives
carbon monoxide,
Wilson’s disease
Autosomal recessive disease that results in defective absorption and excreton of dietary copper. Copper becomes deposited in the body
Causes liver cirrhosis
Kayser-Fleischer rings in the eyes
Young onset Parkinsonian symptoms
Symptoms of Parkisons
Tremor at rest
Postural changes
Dysphagia/dysarthria
Micrographia
Clumpsiness
Symptoms do not appear until 80” of DA neurones have already been lost.
What tests can be used to confirm the diagnosis of Parkinsons?
Challenge with levodopa
MRI/CT scan - rule out space occupying lesion, vascular disease or hydrocephalus
PET scan - localise DA deficiency
Treatment options for Parkinsons
Pharmacological: dopamine replacement. Treats symptoms only.
Deep brain stimulation
Radiosurgery
Surgical intervention
Use of L-Dopa in Parkinson’s
Should be started at the minimal effective dose in combination with a decaarboxylase inhibitor to prevent L-dopa metabolism in the periphery
Can give dopamine antagonist to reduce side effects.
When are DA agonists used in Parkinsons?
Synthetic agonists replace DA loss by acting on receptors.
Given as initial therapy to younger patients and in late stages of disease to reduce ‘off’ effects.
e.g. ropinirole, pramipexole, rotigotine
Mechanism of action of L-dopa
Levodopa is the immediate precursor of dopamine and is able to penetrate the brain where it is converted.
What are anticholinergics given in Parkinson’s
As the nigrotriatal neurones decline in Parkinson’s, the releaase of DA neurones (inhibitory) declines and cholinergic neurones (excitatory) become overactive.
Can be used to reduce tremor.
Useful for drug-induced Parkinsonism
Complication of long term L-dopa treatment
Gradual recurrence of akinesia.
Over time the duration of action of L-dopa shortens, and leads to dyskinesia.
Patients experience on-off effect which corresponds to the peaks and troughs of l-dopa plasma levels.
Define schitzophrenia
Fundamental and characteristic distortions of thinking and perception. Affects (emotional responses) that are innapropriate or blunted.
Enzymes that break down DA in the brain
What drugs inhibit them?
MAO-B and COMT
DA metabolism prevented by giving inhibitors
COMT inhibitors: entacapone
MAOI-B: selegiline, rasagiline
