Pathophysiology and Neurochemical Imbalance
Parkinson's disease is a chronic neurodegenerative disorder, historically known as "paralysis agitans" (first described by James Parkinson in 1817). The pathology belongs to extrapyramidal disorders. Key structures involved in pathogenesis are the caudate nucleus (nucleus caudatus) and the putamen (putamen), which form the neostriatum.
The morphological basis of the disease is the degeneration and massive loss of pigment-containing dopaminergic neurons located in the substantia nigra (substantia nigra).
Normally, the extrapyramidal system modulates and fine-tunes voluntary movements. In parkinsonism, a prominent neurotransmitter imbalance develops in the neostriatum:
- Inhibitory dopaminergic influences drop sharply.
- Stimulatory glutamatergic signals begin to predominate.
- Cholinergic neuronal activity is secondarily upregulated.
It is this excessive cholinergic activity against the background of dopamine deficiency that leads to the development of the classic clinical triad: bradykinesia (slowness of movement), rigidity (increased skeletal muscle tone), and tremor.
Etiology of Parkinsonism
In addition to idiopathic Parkinson's disease—whose onset is linked to genetic predisposition and oxidative stress (free radical generation during dopamine oxidation)—secondary parkinsonism is also distinguished. It is clinically similar to the primary disease but has an identified external or internal cause:
- Infectious factor: develops as a sequela of viral encephalitis or neurosyphilis.
- Vascular factor: arises from various cerebrovascular diseases.
- Traumatic factor: is a consequence of traumatic brain injuries.
- Toxic factor: appears due to poisoning with carbon monoxide (carbon monoxide), manganese compounds, or ethanol.
Of particular note is drug-induced parkinsonism. Its main cause is long-term therapy with typical neuroleptics (antipsychotics). Phenothiazine and butyrophenone derivatives most frequently provoke this condition.
Classification of Antiparkinsonian Drugs
Pharmacotherapy strategy relies on restoring balance: enhancing dopaminergic transmission, suppressing glutamatergic stimuli, and reducing cholinergic neuronal activity. Accordingly, drugs are divided into two major groups.
1. Dopaminergic System Stimulants:
- Dopamine precursors: Levodopa. It serves as the cornerstone agent capable of crossing the blood-brain barrier and converting into dopamine.
- Monoamine oxidase type B (MAO-B) inhibitors: Selegiline. They inhibit the breakdown of endogenous dopamine in the brain.
- Dopamine releasers: Amantadine. They promote neurotransmitter release from presynaptic terminals.
- Dopamine receptor agonists: Bromocriptine, pergolide, pramipexole. They exert a direct stimulating effect on receptors.
2. Cholinergic System Inhibitors:
- Central anticholinergics: Trihexyphenidyl, biperiden. They block acetylcholine receptors in the central nervous system, reducing the secondary hyperactivity of cholinergic pathways and mitigating tremor and rigidity.