15.6: Parkinson’s Disease: Treatment

Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.

Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of its treatment is levodopa (L-DOPA), a dopamine precursor that alleviates symptoms. However, long-term use can lead to motor complications such as response fluctuations and dyskinesias. Although levodopa can induce hallucinations and confusion, especially in older people and those with preexisting cognitive dysfunction, it does not adversely affect the course of PD. Atypical antipsychotics, including clozapine (Clorazil) and quetiapine (Seroquel), effectively treat levodopa-induced psychosis. Levodopa and dopamine agonists can lead to impulse control disorders, and there's an associated risk of suicidality with PD.
To enhance the effectiveness of levodopa and reduce its peripheral side effects, it is typically combined with carbidopa. Carbidopa inhibits peripheral decarboxylation of levodopa, allowing more of the medication to cross the blood-brain barrier and minimizing side effects such as nausea and vomiting. Still, whether this is linked to the disease or a specific treatment is unclear.

Dopamine receptor agonists like ropinirole (Requip) and pramipexole (Mirapex) have longer durations of action than levodopa, aiding in managing motor fluctuations. These agonists can cause hallucinosis, confusion, nausea, and orthostatic hypotension, and should be initiated at low doses and titrated slowly. Apomorphine (Apokyn) is a "rescue therapy" for acute intermittent treatment of "off" episodes in PD. Like oral DA agonists, it can cause side effects like QT prolongation, injection site reactions, and potential abuse patterns. COMT inhibitors such as tolcapone (Tasmar) and entacapone (Comtan) reduce "wearing off" symptoms in patients treated with levodopa/carbidopa. Selective MAO-B inhibitors like selegiline (Eldepryl) and rasagiline (Azilect) are also used for treating PD and do not substantially inhibit the peripheral metabolism of catecholamines. Muscarinic receptor antagonists like trihexyphenidyl (Artane) and benztropine mesylate (Cogentin) are used in early PD treatment or as an adjunct to dopamimetic therapy. However, they can cause sedation and confusion and are not well-tolerated in older individuals. Amantadine (Gocovri), an antiviral agent, has antiparkinsonian activity and is used as initial therapy for mild PD and as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias. It is an effective treatment, despite mild side effects such as dizziness and lethargy, which can be minimized by titrating the dose.

Parkinson's Disease or PD is a neurodegenerative disorder characterized by an imbalance between cholinergic and reduced dopaminergic neurons.

The cornerstone of PD treatment is levodopa, a dopamine precursor converted into dopamine in the brain, alleviating symptoms.

It is co-administered with carbidopa, a peripheral decarboxylase inhibitor, to enhance efficacy and minimize side effects.

Additionally, COMT inhibitors block the enzyme that degrades levodopa, allowing higher concentrations to reach the brain and enhancing its therapeutic effect.

Dopamine receptor agonists stimulate dopamine receptors, reducing symptoms like tremors and stiffness. MAO-B inhibitors inhibit dopamine breakdown in the brain, increasing its bioavailability.

Anticholinergics, such as benztropine and trihexyphenidyl, prevent binding of acetylcholine, a neurotransmitter involved in movement control, helping manage tremors and rigidity.

Amantadine ameliorates symptoms and dyskinesias by boosting dopamine release and blocking glutamate receptors.

Besides pharmacological interventions, surgical procedures like deep brain stimulation can mitigate severe symptoms or levodopa therapy complications.