Treatment of Parkinson’s disease

Overview of CNS Act presynaptically by influencing the production, storage, or termination of action of neurotransmitters. Other agents may activate or block postsynaptic receptor.

Neurotransmission in the CNS Similar to autonomic nervous system The circuitry of the CNS is much more complex than the autonomic nervous system Contains powerful networks of inhibitory neurons that are constantly active More than 10 neurotransmitters

Synaptic potentials Receptors at most synapses are coupled to ion channels. Depolarization or hyperpolarization of the postsynaptic membrane, depending on the specific ions that move and the direction

Excitatory pathways Excitatory postsynaptic potential(EPSP) are generated by the following 1. stimulation of an excitatory neuron causes the release of neurotransmitter molecules 2. The influx of Na+ causes a weak depolarization 3. Pass a threshold, and an all-or-none action potential is generated.

Inhibitory pathways Results in a hyperpolarization of the postsynaptic membrane. Inhibitory postsynaptic potentials (IPSP) are 1. releases neurons releases neurotransmitter molecules, such as γ-aminobutyric acid (GABA) or glycine. Increase in the permeability of specific ions, such as, potassium and chloride ions 2. the influx of chloride and efflux of potassium cause a weak hyperpolarization or IPSP that moves the postsynaptic potential away from its firing threshold.

Overview of parkinson’s disease Parkinson's disease (PD) is a progressive disorder of the nervous system. With an annual incidence of approximately 20 new cases per 100,000 people. PD is generally age-specific; it is estimated that approximately 1% of the population over age 60 has PD.

Etiology Is correlated with a reduction in the activity of inhibitory dopaminergic neurons in the substantia nigra and corpus striatum.

Cross-section of the human brain showing the substantia nigra, the region affected by Parkinson's disease

Substantia nigra striatum Fire tonically, rather than in response to specific muscular movements or sensory input. GABA dopamine

etiology( in summary) Destruction of cells in the substantia nigra results in the degeneration of neurons responsible for secreting dopamine in the neostriatum.

Strategy of treatment Therapy is aimed at restoring dopamine in the basal ganglia and antogonizing the excitatory effect of cholinergic neurons.

Drugs used in PD levodopa(L-dopa) and carbidopa

Mechanism of action Levodopa: replenish the dopamine deficiency. Dopamine itself does not cross the blood-brain barrier. Levodopa is readily transported into the CNS and is coverted to dopamine in the brain. But side effects in the periphery.

Carbidopa A dopamine decarboxylase inhibitor that does not cross the blood-brain barrier Diminishes the metabolism of levodopa in the GI tract and peripheral tissues

Actions Levodopa decreases the rigidity, tremors, and other symptoms of PD

Therapeutic uses Levodopa in combination with carbidopa is a potent and efficacious

Absorption and metabolism Levodopa has extremely short half-life(1 to 2 hours) Taken on an empty stomach, typically 45 min before a meal.

Adverse effects Peripheral effects: anorexia, nausea, and vomitting Hypotension

CNS effects Visual and auditory hallucinations and dyskinesia Depression and anxiety

Interactions The vitamin pyridoxine(V6) increases the peripheral breakdown of levodopa and diminishes its effectiveness

Bromocriptine Is a dopamine receptor agonist Produces little response in patients who do not react to levodopa