Drugs for Movement Disorders

Acetylcholine and Parkinson's Disease

• Acetylcholine becomes overactive when dopamine levels drop in Parkinson's disease, contributing to symptoms.

Basal Motor Pathway

• Dopamine primarily inhibits cholinergic neurons in the basal ganglia, playing a crucial role in motor control.
• In Parkinsonism, the inhibitory pathway becomes overactive due to dopamine deficiency.
• The imbalance between dopamine and acetylcholine results in symptoms like tremor.

Neurotransmitter Imbalance

• Critical neurotransmitter imbalance in Parkinson's disease is between dopamine and acetylcholine.
• GABA activity is affected; it becomes overactive due to excess acetylcholine from dopamine loss.
• Dopamine deficiency increases inhibitory control of muscles through GABAergic signaling.

Treatment Goals in Parkinsonism

• Primary treatment goal is to increase dopaminergic neurotransmission for better symptom management.

Drug Therapy Overview

• Drug therapy aims to improve dopaminergic neurotransmission.
• Bradykinesia is a common symptom of Parkinsonism.
• Dopamine agonists constitute a major class of drugs used in treatment.

Neuroanatomy of Parkinson's Disease

• The substantia nigra is the neuroanatomical structure most affected in Parkinson's disease.
• Resting tremor is a characteristic sign of Parkinsonism.
• Antipsychotics can induce Parkinsonism symptoms as a side effect.

Etiology and Pathogenesis

• Proposed causes of Parkinson's disease include oxidative stress.
• Mutations in the Parkin gene are associated with juvenile Parkinsonism.
• Parkinson's disease typically manifests between ages 50-60.

Motor Control Pathways

• Basal ganglia are primarily involved in motor control affected by Parkinson's disease.
• Dopamine is the deficient neurotransmitter leading to motor dysfunction.

Carbidopa/Levodopa Treatment

• Carbidopa inhibits peripheral conversion of levodopa to dopamine, enhancing efficacy.
• Levodopa is most effective for relieving bradykinesia, a major symptom.
• High-protein meals can delay the absorption of levodopa.

Formulations of Carbidopa/Levodopa

• Inbrija is used for on-demand relief of motor fluctuations.
• Rytary is an extended-release capsule formulation for consistent symptom control.
• Dyskinesia is the most common side effect of long-term Carbidopa/Levodopa therapy.

Dopamine Agonists

• Dopamine agonists, such as Pramipexole, are less associated with dyskinesia compared to levodopa.
• They are effective for managing the on-off phenomena associated with Parkinson's disease.

MAO-B Inhibitors

• MAO-B inhibitors, like Rasagiline, inhibit dopamine breakdown and may provide neuroprotective effects.
• Common side effect of MAO-B inhibitors is nausea.

COMT Inhibitors

• Tolcapone is a COMT inhibitor known for hepatotoxicity, while Entacapone is safer.
• They reduce motor fluctuations by increasing dopamine availability in the brain.
• A harmless side effect of COMT inhibitors includes red-brown discoloration of urine.

Long-Term Side Effects of Treatment

• Long-term Carbidopa/Levodopa use can lead to dyskinesia.
• Adding a dopamine agonist can help reduce dyskinesia.
• The use of Carbidopa/Levodopa is contraindicated in closed-angle glaucoma patients.

Motor Complications

• The on-off phenomenon involves sudden loss of levodopa effectiveness, unrelated to dosage timing.
• Increasing the dose frequency can help reduce the "wearing-off" effect of levodopa.
• A "drug holiday" can lead to severe immobility as a potential complication.

Transdermal Dopamine Agonists

• Rotigotine is a dopamine agonist that can be administered via a transdermal patch.
• Common side effects of dopamine agonists include impulse control disorders, particularly with Pramipexole and Ropinirole.

Dopamine Agonists (Pramipexole, Ropinirole)

• Pramipexole primarily acts as an agonist for D2 and D3 receptors, enhancing dopamine signaling.
• Ropinirole is more selective for D2 receptors compared to other dopamine agonists.
• Common side effect of pramipexole and ropinirole includes sleep attacks, which can impact daily functioning.

Dopamine Agonists (Rotigotine)

• Rotigotine is administered via a transdermal patch, allowing for continuous drug delivery.
• Diarrhea is not a side effect associated with rotigotine treatment.
• A unique feature of rotigotine is its ability to provide continuous dopaminergic stimulation, beneficial for managing Parkinson's symptoms.

MAO-B Inhibitors

• MAO-B inhibitors, such as selegiline and rasagiline, specifically inhibit the enzyme monoamine oxidase-B, which breaks down dopamine.
• Nausea is a commonly reported side effect of selegiline.
• At high doses, selegiline may lose selectivity and inhibit monoamine oxidase-A, potentially leading to undesirable effects.

Rasagiline and Safinamide

• Rasagiline is recognized for its neuroprotective properties, making it a preferred choice among MAO-B inhibitors.
• Safinamide acts as a reversible inhibitor of monoamine oxidase-B, aiding in dopamine metabolism.
• Rasagiline is noted for higher potency compared to selegiline, enhancing therapeutic efficacy in Parkinson's disease management.

MAO-B Inhibitors (Continued)

• MAO-B inhibitors specifically target dopamine, increasing its availability in the brain.
• Rasagiline is regarded as more potent and has neuroprotective effects, beneficial for long-term treatment.
• Hallucinations can occur as a rare side effect in patients using MAO-B inhibitors, necessitating monitoring.

COMT Inhibitors

• COMT inhibitors help prevent the peripheral breakdown of levodopa, ensuring more levodopa reaches the brain.
• Tolcapone is associated with hepatotoxicity, which restricts its clinical use compared to other COMT inhibitors.
• A harmless side effect of COMT inhibitors, like Entacapone, is the occurrence of red-colored urine, which is due to changes in urine composition.

Adenosine Antagonists

• Istradefylline functions by antagonizing adenosine A2A receptors in the basal ganglia, contributing to the alleviation of Parkinson's symptoms.

COMT Inhibitors

• COMT inhibitors block the enzyme Catechol-O-methyltransferase to boost levodopa bioavailability.
• Diarrhea is a common side effect associated with the use of COMT inhibitors.
• Tolcapone carries a higher risk of hepatotoxicity, which leads to lesser usage compared to entacapone.

Adenosine Antagonist

• Istradefylline (Nourianz®) is primarily used to manage "off" episodes in Parkinson's disease.
• It antagonizes the Adenosine A2A receptor to exert its therapeutic effects.
• Dyskinesia is a notable side effect of istradefylline.

Amantadine

• Amantadine is particularly effective in treating dyskinesia in Parkinson's disease.
• Its primary mechanism of action involves NMDA receptor blockade.
• Livedo reticularis is a common side effect experienced with amantadine use.

Antimuscarinics

• Antimuscarinics are most effective in alleviating tremors associated with Parkinson's disease.
• Memory impairment is a recognized side effect of antimuscarinics like benztropine.
• Benztropine works by inhibiting acetylcholine activity, contributing to symptom relief in Parkinson's disease.

Considerations

• Initiating levodopa treatment in elderly patients often involves starting with dopamine agonists to minimize complications.
• Metoclopramide can worsen Parkinson's symptoms due to its action of blocking dopamine receptors.
• Adding a COMT inhibitor can effectively manage motor complications arising from long-term levodopa therapy.

Essential Tremor

• Beta blockers, particularly propranolol, are first-line treatments for essential tremor.
• Essential tremor is characterized by intention tremors.
• Lithium is known to potentially exacerbate essential tremor symptoms.

Beta Blockers for Essential Tremor

• Propranolol is the most commonly used beta blocker for treating essential tremor.
• Propranolol is effective for essential tremor as it can cross the blood-brain barrier, providing better symptom control compared to other beta blockers like atenolol or metoprolol.

COMT Inhibitors

• COMT inhibitors primarily inhibit the breakdown of L-Dopa, enhancing its effectiveness in managing Parkinson's disease.
• A notable side effect of tolcapone, a COMT inhibitor, is hepatotoxicity, which underscores the need for monitoring liver functions.
• They help reduce fluctuations in motor function, but do not provide immediate symptom relief or eliminate dyskinesias.
• Entacapone is combined with carbidopa/levodopa in the formulation Stalevo® to streamline Parkinson's drug regimens.
• Reddish-brown urine can result from COMT inhibitors; this side effect is harmless and not indicative of toxicity.
• COMT inhibitors are commonly used in conjunction with levodopa/carbidopa therapy.

Adenosine Antagonists

• Istradefylline is an adenosine A2A receptor antagonist indicated for Parkinson's treatment.
• A common side effect associated with adenosine A2A receptor antagonists is dyskinesias.
• Their mechanism of action involves blocking adenosine receptors, leading to improved motor function in Parkinson's patients.

Amantadine

• Amantadine is indicated as adjunctive therapy for dyskinesias in patients with Parkinson's disease.
• A unique side effect of amantadine is livedo reticularis, which requires awareness by healthcare providers.
• The drug was initially developed to treat influenza before being repurposed for Parkinson’s disease.

Antimuscarinics

• Antimuscarinics are particularly effective in targeting tremors in Parkinson's disease.
• Memory impairment is a common side effect of antimuscarinics that can impact patient quality of life.
• Benztropine, an antimuscarinic, is less effective than dopaminergic drugs specifically for improving bradykinesia.

Dopamine Agonists

• Apomorphine serves as a rescue treatment for "freezing" episodes in patients with Parkinson's disease.
• Potential side effects of dopamine agonists, such as pramipexole, include impulse control disorders, which can significantly affect behavior.
• Ropinirole primarily targets the D2 dopamine receptor subtype, influencing motor control in Parkinson's patients.

MAO-B Inhibitors

• Rasagiline is a commonly used MAO-B inhibitor for Parkinson's treatment.
• The primary function of MAO-B inhibitors is to inhibit dopamine breakdown, thus prolonging dopaminergic action in the brain.
• MAO-B inhibitors, like selegiline, are contraindicated in combination with SSRIs due to the risk of serotonin syndrome.

Treatment Strategies

• To manage the "wearing-off" effect of levodopa, adding a COMT inhibitor is a common strategy.
• MAO-B inhibitors are often included to reduce motor complications associated with levodopa therapy.
• Cognitive impairment is the symptom least likely to improve with dopaminergic therapy compared to bradykinesia, tremor, and rigidity.

Amantadine and Antimuscarinics

• Common side effect of amantadine in Parkinson's treatment: Ankle edema.
• Amantadine's mechanism of action: NMDA receptor antagonist.
• Antimuscarinic drug frequently used for Parkinson's tremor: Benztropine.

Essential Tremor

• Essential tremor is characterized by fine motor movement of fingers/hands during intentional movement.
• First-line treatment for essential tremor: Beta-blockers.
• Common aggravating factor for essential tremor: Caffeine.

Additional Treatments for Essential Tremor

• Alternative medication for essential tremor when beta-blockers are ineffective: Topiramate.
• Medication used for essential tremor that may cause sedation as a side effect: Primidone.
• Beta-blockers like propranolol are primarily used to treat postural tremor.