NJN - Parkinson -Basal Ganglia Anatomy and Function

• Parkinson's medications address the pharmacology of Parkinson's disease.

Basal Ganglia Anatomy

• Key structures of the basal ganglia include the caudate nucleus, lentiform nucleus, thalamus, subthalamic nucleus, and substantia nigra.
• Destruction of neurons in the substantia nigra leads to decreased dopamine levels, a hallmark of Parkinson's disease.
• The lentiform nucleus comprises the putamen, globus pallidus externus, and globus pallidus internus.
• The striatum consists of the caudate and putamen, receiving dopaminergic input.
• The nigrostriatal pathway, connecting the substantia nigra to the striatum, is significantly affected in Parkinson's disease.

Direct vs. Indirect Pathway

• The direct pathway facilitates desired motor movements, while the indirect pathway prevents unwanted movements.
• Cortical neurons release glutamate onto striatal neurons, initiating both pathways.
• Glutamate is a stimulatory neurotransmitter, while GABA is an inhibitory neurotransmitter.
• In the direct pathway, stimulation of striatal neurons leads to GABA release, inhibiting the globus pallidus internus, ultimately promoting motor movement.
• The substantia nigra releases dopamine onto D1 receptors in the striatum, stimulating the direct pathway and increasing motor movement.
• In the indirect pathway, cortical neurons stimulate striatal neurons, which then inhibit the globus pallidus externus, leading to increased activity in the subthalamic nucleus and inhibition of motor movement.
• The substantia nigra releases dopamine onto D2 receptors in the striatum, inhibiting the indirect pathway.
• The nigral pathway aims to increase motor movement through both direct and indirect pathways.
• The direct pathway increases desired motor movements, and the indirect pathway inhibits undesired motor movements.
• Destruction of substantia nigra neurons decreases motor movement, leading to bradykinesia, hypokinesia, or akinesia.
• Cholinergic fibers release acetylcholine, influencing both pathways; it inhibits the direct and stimulates the indirect pathway.
• Cholinergic influence is opposite to dopamine's influence in each pathway.

Pathophysiology of Parkinson’s Disease

• Parkinson's is characterized by destruction of the substantia nigra, leading to decreased dopamine in the striatum.
• There is an imbalance between dopamine and acetylcholine, with unopposed acetylcholine activity.
• This imbalance causes decreased movement, tremors, rigidity, and postural instability.
• Treatment strategies involve increasing dopamine and decreasing acetylcholine in the striatum.

Drug Classes for Parkinson’s Disease

• Medications aim to increase dopamine or decrease acetylcholine to restore balance.
• L-Dopa is a primary medication that increases dopamine levels.
• Dopamine agonists mimic dopamine's action on receptors.
• Catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors prevent dopamine breakdown.
• Amantadine increases dopamine release and inhibits reuptake.

Mechanism of Action

• L-Tyrosine is converted to L-Dopa by tyrosine hydroxylase and then to dopamine by Dopa decarboxylase.
• Dopamine is stored in vesicles and released upon neuron stimulation.
• Released dopamine binds to D1 or D2 receptors on striatal neurons.
• After exertion of effect, dopamine is either reuptaken or broken down.
• Monoamine oxidase B (MAO-B) breaks down dopamine inside neurons.
• Catechol-O-methyltransferase (COMT) breaks down dopamine in the synaptic cleft.
• Dopamine cannot cross the blood-brain barrier, but L-Dopa can.
• Peripheral Dopa decarboxylase converts L-Dopa to dopamine, preventing it from crossing the blood-brain barrier.
• COMT converts L-Dopa into an inactive metabolite, also preventing it from crossing the blood-brain barrier.
• COMT inhibitors and MAO-B inhibitors prevent dopamine breakdown thus increasing its availability.
• Dopamine agonists bind directly to dopamine receptors.
• Amantadine stimulates dopamine release and inhibits reuptake.
• Anticholinergics block muscarinic receptors, reducing acetylcholine's effect.

L-Dopa + Carbidopa

• L-Dopa is a first-line drug, particularly for those over 65.
• Combine L-Dopa with Carbidopa, which inhibits peripheral dopa decarboxylase to increase L-Dopa crossing the blood-brain barrier.
• Carbidopa reduces peripheral dopamine thereby minimizing adverse effects.
• High levels of dopamine can cause cardiac stimulation leading to tacchycardia.
• Dopamine can cause vasodilation via D2 receptors, potentially leading to orthostatic hypotension.

Dopamine and the Miso-limbic Path

• Excessive dopamine in the mesolimbic pathway leads to anxiety, delirium, hallucinations, delusions, psychosis, or impulse control issues.
• Stimulation of the chemo trigger zone in the medulla causes nausea and vomiting.
• Dyskinesia, characterized by unorganized movements, can result from excessive dopamine.
• Long-term L-Dopa use leads to the "on-off phenomenon," where drug effectiveness fluctuates.
• As Parkinson's progresses and substantia nigra neurons decrease, lower doses can result so prevent adverse effects from L-dopa over-dosage
• Higher doses mitigate “off” periods but elevate risk of toxic adverse reactions such as dyskinesia so you can decrease time intervals between doses
• Administer L-Dopa with other dopaminergic drugs

Dopamine Agonists

• Dopamine agonists directly stimulate dopamine receptors and bypass the need for neuronal conversion.
• Ergot derivatives (e.g., bromocriptine) are less favored due to more side effects.
• Non-ergot options (e.g., pramipexole, ropinirole) are alternatives to L-Dopa, especially for those under 65.
• These agonists increase dopamine, potentially causing behavioral changes via the mesolimbic pathway.
• Nausea and vomiting due to stimulation of medulla's emetic center.
• Ergot derivatives increase risk pulmonary and cardiac fibrosis and vasospasm.

COMT-Inhibitors

• COMT inhibitors prevent dopamine breakdown in the synapse and enhance L-Dopa uptake.
• Tolcapone inhibits central and peripheral COMT but is significantly hepatotoxic.
• Entacapone inhibits peripheral COMT, increasing L-Dopa availability.
• COMT inhibitors are adjuncts to L-Dopa/Carbidopa, particularly for the "on-off" phenomenon.
• High dosages can cause nausea, vomiting, altered behavior and hepatotoxicity.

MAO-B-Inhibitors

• Monoamine oxidase B (MAO-B) inhibitors prevent dopamine breakdown, increasing synaptic dopamine.
• Selegiline and rasagiline can be prescribed in conjunction with levodopa carbidopa to mediate the “off” effect, or as a monotherapy
• At high levels the selectivity is lost, which inhibits monoamine oxidase A, responsible for breaking down norepinephrine, epinephrine and serotonin may cause hypertensive crisis
• If a patients takes too much MAOB inhbitors, the monoamine oxidase, or is taken with tyramine or tricyclic antidepressants it can lead to hypertensive crisis and serotonin syndrome.

Amantadine

• Amantadine stimulates dopamine synthesis and release, and inhibits reuptake.
• It may have neuroprotective qualities.
• Amantadine is used as an adjunct to L-Dopa/Carbidopa, or for akinetic crisis.
• Akinetic crisis often happens due to discontinuation of taking medication
• If a patients suffers with akinetic crisis give levodopa cardopa, amantadine and apomorphine.
• High dosages can lead to vomiting and nausea, behavioral changes and or mild ataxia.
• Additionally the side effects can be peripheral and pedal edema.

Anticholinergics

• Anticholinergics counterbalance dopamine loss by reducing acetylcholine effects.
• Benztropine and trihexyphenidyl are muscarinic antagonists, counteracting tremors/rigidity.
• Side effects can present as delirium, dilated pupils and decreased salivation in the central nervous system
• Additionally tachycardia and hypertension can be present.

Explore the intricate anatomy and function of the basal ganglia, including the lentiform nucleus, striatum, and related structures. Understand the role of key neurotransmitters and the impact of neuronal degeneration in conditions like Parkinson's disease. Focus on the location and relationship between structures in the brain.