CPPS 306 Pharmacotherapy of Basal Ganglia Disorders

What is the key difference between the pyramidal and extrapyramidal motor systems?

Pyramidal: direct motor pathway (upper → lower → muscle innervation)

Extrapyramidal: indirect pathway that modulates and refine movement before it reaches motor nuerons

What is the main function of the extrapyramidal system and where are the extrapyramidal tracts located?

To modulate motor activity (posture, reflexes, locomotion, complex movements) without directly innervating motor nuerons

• Located in the reticular formation of the pons and medulla which influence spinal cord motor circuits

Which brain structures / pathways modulate the extrapyramidal tracts?

Nigrostriatal pathway

Basal ganglia

Cerebellum

Vestibular nuclei

Sensory areas of the cerebral cortex

What is the primary role of the extrapyramidal motor system (EPS)?

To regulate fine motor activity by coordinating activation of desired muscles and inhibition of antagonistic muscles, allowing smooth and controlled movement

How do dopamine, acetylcholine, and GABA interact in the extrapyramidal motor system

Dopamine → inhibits excessive GABA output

Acetylcholine → excites GABA output neurons

Normal movement requires a balance between dopamine-mediated inhibition and acetylcholine mediated excitation of GABA neurons.

What happens to extrapyramidal motor output when dopamine is reduced (e.g., Parkinsons Disease)?

Loss of dopamise → excessive GABA output → increased inhibition of motor pathways → impaired timing, rigidity, and reduced movement

Why does EPS dysfunction impair coordination rather than just causing paralysis?

Because the EPS modulates motor timing and balance, not direct muscle innervaiton, so movement is present but poorly controlled

When dopamine inhibition is lost in parkinsons disease, how can imbalance be corrected pharmacologically?

Balance can be restored by

• Increasing dopamine

• Reducing acetylcholine

Symptoms of Parkinsons

Akinesia = cant initiate movement

Bradykinesia = slow movement, shuffle

Muscle rigidity

Tremor at rest

Mask-like faces

Cogwheel locomotion

What is the neurpathology causing Parkinson’s disease

Death of dopamine cell bodies in substantia nigra (provides dopamine to basal ganglia to facilitate movement)

Loss of dopamine nerve terminals in neostriatum

When do symptoms appear in parkinsons disease patients

When 80% of original number of dopamine neurons in the substantia nigra have died

What is the treatment for parkinsons disease?

Dopamine Replacement Therapy

Dopamine cannot cross the BBB so levodopa (L-dopa) is given which can cross the BBB which is taken up by remaining dopamine neurons and released under physiological conditions

What is the main purpose of Dopamine Replacement thehrapy

Restores the dopamine / acetycholine balance and normal output of the extrapyramidal motor system

How is levodopa metabolized, and why does this matter clinically?

Levadopa is metabolized by aromatic amino acid decarboxylase (AAAD) into dopamine

In the periphery, dopamine → noradrenaline → adrenaline, causing side effects

Carbidopa inhibits peripheral AAAD → increasing levodopa reaching the brain

COMT inhibitors (entacapone, tolcapone) reduce peripheral breakdown

End result:

• More dopamine in the brain

• Reduced excessive GABA inhibition

• Disinhibiiton of motor pathways

What does levodopa increase in the brain and periphery?

Brain: increase in dopamine → improves motor symptoms

Periphery: increase dopamine, noradrenaline, adrenaline → autonomic side effects (disruption in the normal function of the autonomic nervous system)

What are the peripheral effects of levodopa

Increases SNS activity leading to hypertension, tachycardia, and arrhthmias

Dopamine stimulation of CTZ (outside BBB) → nausea and vomitting

Why does levodopa cause central side effects?

Because excess dopamine (and noradrenaline) overstimulates non-motor brain pathways

Overstimulation of dopamine receptors in different brain regions causes different side effects. Which dopamine pathway overstimulation causes psychosis

Overstimulation of mesolimbic dopamine pathways

Overstimulation of dopamine receptors in different brain regions causes different central side effects. Which dopamine pathway stimulation causes what hormonal effect?

Stimualtion of dopamine receptors in pituitary inhibits prolactin release

Overstimulation of dopamine receptors in different brain regions causes different central side effects. Which dopamine pathway overstimulation causes abnormal motor movements (dyskinesias)

Over stimulation of dopamine receptors in motor control areas produces abnormal motor movements

Overstimulation of noradrenaline receptors in the reticular activating system and limbic system during L-DOPA therapy leads to what central side effects?

Insomnia and anxiety

What is the main pharmacological strategy used to limit adverse effects of L-DOPA

Prevent peripheral conversion of L-DOPA to dopamine (by inhibiting AAAD and COMT outside the brain) so more L-DOPA reaches the CNS, where it is converted to dopamine, improving motor function while reducing peripheral side effects

Why is carbidopa given with L-DOPA

Carbidopa inhibits AAAD in the periphery, preventing conversion of L-DOPA to dopamine outside the brain

• Reduces peripheral dopamine side effects

• Increases the amount of L-DOPA crossing the BBB

• Raises dopamine levels in the central

What is the benefit of adding entacapone or tolcapone to L-DOPA therapy

COMT inhibitors block catechol-Omethyltansferase-mediated metabolism of L-DOPA

• Prevents converstion of L-DOPA to inactive 3-Omethyldopa by COMT

• Prolongs L-DOPA plasma half life

• Reduces “wearing-off” motor fluctuations

  • Stabilizes dopamine delivery to the brain

How do MAO-B inhibitors improve Parkinson’’s symptoms?

They slow the breakdown of dopamine in the brain, so:

Dopamine lasts longer at synapses in the striatum

Motor circuits get stronger, more sustained dopamine signaling

Patients can use lower doses of L-DOPA

What do Selegiline/rasagiline/safinamide, MAO-B inhibitors do

Inhibit the breakdown of dopamine (lower dose necessary for l-dopa)

Name the 4 dopamine receptor agonists mentioned and explain them

Bromocriptine = has a halftime of 5 hours, improves symptoms of Parkinsons disease when added to L-dopa plus carbidopa or bensarazide

Pramipexole

Ropinirole

Rotigotine

Bromocriptine

• All have fewer side effects than bromocriptine

What is another way for the inbalance of dopamine induced inhibition and ACh induced excitation of GABA to be levelled out

By blocking muscarinic acetylcholine receptors using anticholinergic drugs (benztropine, trihexyphenidyl), which reduces acetylcholine overactivity in the basal ganglia and helps restore motor balance

What role does oxidative stress play in Parkinson’s Disease?

Oxidative stress is thought to contirbute to dopamine neuron death in the substantia nigra, but antioxidant therapy has not been proven to slow disease porgression

Why is antioxidant or neuroprotective therapy unliekly to reverse Parkinson’s disease once symptoms appear?

Because at diagnoses, 80% of dopamine neurons are already lost, and neuron degeneration continues, limiting the effectiveness of protective strategies

What is selegiline

A MOA-B inhibitor that has some neuroprotective actions THAT HAS TOXIC METABOLITES

What is rasagiline

a MAO-B inhibitor used in parkinson’s disease that reduces dopamine breakdown in the brain and has neuroprotective proeprties without toxic metabolites

What type of movement disorder is Huntington’s disease?

A hyperkinetic basal ganglia degeneration disorder characterized by chorea (excess, involuntary movements)

What is chorea and why is it associated with Huntington’s disease?

A rapid, involuntary, dance-like movements caused by basal ganglia degeneration, which is central to Huntington’s disease

How do motor symptoms progress in hungtingtons disease

Early uncontrolled, involuntary movements, later loss of coordinated movement, speech difficulty, and severe disability

How does huntington’s disease affect cognition

Progressive decline in mental abilities leading to dementia

What is the genetic cause of Huntington’s disease

A trinucleotide (CAG) repeat expansion in the huntingtin (HTT) gene, producing a toxic mutant huntingtin protein

How is huntingtons disease inherited, and when do symptoms usually appear?

Autosomal dominant inheritance with symptom onset typically between 30-50 years

What brain changes are see in huntington’s disease

Atrophy of the basal ganglia with enlarged ventricles due to loss of surrounding brain tissue

What is the core pharmacologic strategy for treating chorea in huntington’s disease

Reducing dopamine signaling to suppress excessive involuntary movements by using Tetrabenazine / deutetrabenazine or making it inactive by using Risperidone

How do tetrabenazine and deutetrabenazine reduce chorea in huntingtons disease

By inhibiting VMAT2, preventing dopamine form being packaged into vesicles - less dopamine release

Why is deutetrabenazine often preferred over tetrabenazine?

Deuterium substituion slows metabolism, allowing lower or less frequent dosing with imporved tolerability

Why are VMAT2 inhibitors contraindicated (shouldnt be used) in patients with depression

Because monamine depletion (especially dopamine and serotonin) can worsen depression and increase suicidality

How does ripseridone improve huntingtons disease symptoms

By blocking dopamine receptors, reducing dopamines effects on motor and psychiatric symptoms