Pathophysiology and neurochemical imbalance
Parkinson's disease is a chronic neurodegenerative disorder historically known as "shaking palsy" (first described by James Parkinson in 1817). The pathology belongs to extrapyramidal disorders. Key structures involved in the pathogenesis are the caudate nucleus (nucleus caudatus) and putamen (putamen), which together form the neostriatum.
The morphological basis of the disease is the damage and massive loss of pigment-containing dopaminergic neurons located in the substantia nigra (substantia nigra).
Normally, the extrapyramidal system regulates and refines voluntary movements. In parkinsonism, a pronounced neurotransmitter imbalance occurs in the neostriatum:
- Inhibitory dopaminergic influences sharply decrease.
- Stimulatory glutamatergic signals begin to predominate.
- The activity of cholinergic neurons secondarily increases.
It is precisely this excessive cholinergic activity against the backdrop 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 syndrome
In addition to idiopathic Parkinson's disease, the occurrence of which is associated with genetic predisposition and oxidative stress (the formation of free radicals during dopamine oxidation), secondary parkinsonism is also distinguished. It is clinically similar to the primary disease but has an established external or internal cause:
- Infectious factor: develops as a consequence of viral encephalitis or syphilitic involvement of the nervous system.
- Vascular factor: occurs against the background of various cerebrovascular diseases.
- Traumatic factor: is a consequence of traumatic brain injuries.
- Toxic factor: appears during intoxication with carbon monoxide, manganese compounds, or ethanol.
A special place is occupied by drug-induced parkinsonism. Its main cause is long-term therapy with typical neuroleptics (antipsychotics). It is most frequently provoked by drugs from the phenothiazine and butyrophenone derivative groups.
Classification of anti-Parkinsonian drugs
The pharmacotherapy strategy is built on restoring balance: it is necessary to enhance dopaminergic transmission, suppress glutamatergic stimuli, and reduce the activity of cholinergic neurons. Therefore, drugs are divided into two large groups.
1. Drugs stimulating the dopaminergic system:
- Dopamine precursors: levodopa. It is the baseline agent capable of penetrating the CNS and converting into dopamine.
- Monoamine oxidase type B (MAO-B) inhibitors: selegiline (eldepryl, jumex). They inhibit the breakdown of endogenous dopamine in the brain.
- Drugs increasing dopamine release: amantadine (midantan). They promote the release of the neurotransmitter from presynaptic terminals.
- Dopamine receptor agonists: bromocriptine (parlodel), pergolide (permax), pramipexole (mirapepex). They exert a direct stimulating effect on receptors.
2. Drugs depressing the cholinergic system:
- Central anticholinergics: trihexyphenidyl (cyclodol), biperiden (akineton). They block acetylcholine receptors in the CNS, reducing the secondary hyperactivity of cholinergic pathways and decreasing the severity of tremor and rigidity.
Briefly: answers to topical questions
Which drugs belong to dopamine precursors and what enzyme inhibitors are they combined with?
Dopamine precursors include levodopa, which is combined with peripheral DOPA decarboxylase inhibitors.
- Levodopa (Levodopa) is a direct precursor of dopamine that crosses the blood-brain barrier.
- Carbidopa is a peripheral DOPA decarboxylase inhibitor (included in medications such as Nakom, Sinemet, Duellin).
- Benserazide is a peripheral DOPA decarboxylase inhibitor (included in the medication Madopar).
Levodopa can also be combined with COMT inhibitors (entacapone) as part of triple-combination drugs to correct motor fluctuations.
Which drugs belong to COMT (catechol-O-methyltransferase) inhibitors?
Catechol-O-methyltransferase (COMT) inhibitors include the drug entacapone.
- Entacapone is an inhibitor of dopamine catabolism that blocks the catabolic pathways of levodopa and dopamine.
This drug is used as part of combination therapy (together with levodopa and carbidopa) to correct motor fluctuations in patients with Parkinson's disease.
What are the main side effects of long-term use of levodopa preparations?
The use of levodopa preparations can lead to central and peripheral side effects.
- Psychoneurological disorders — psychosis, hallucinations, anxiety, depression, insomnia, somnolence, and coordination disturbances.
- Cardiovascular disorders — tachycardia and various types of cardiac arrhythmias associated with the peripheral conversion of levodopa to dopamine and stimulation of myocardial $\beta$-adrenoreceptors.
- Gastrointestinal disorders — dyspeptic symptoms, particularly vomiting.
To remember the essence of parkinsonism treatment, use the "D-A" formula: Add Dopamine, Antagonize Acetylcholine.
Class and exam questions
At what stage do the first motor symptoms of Parkinson's disease appear?
Clinical manifestation (bradykinesia, tremor, rigidity) begins only after 70% to 80% of dopaminergic neurons in the substantia nigra have died.
What is drug-induced parkinsonism and what causes it?
This is a form of secondary parkinsonism that develops against the background of long-term intake of certain drugs, most commonly typical neuroleptics (phenothiazine and butyrophenone derivatives).
Why are anticholinergics prescribed in parkinsonism if the problem is a dopamine deficiency?
The decrease in dopamine levels leads to a secondary increase in the activity of neostriatal cholinergic neurons. Central anticholinergics (e.g., cyclodol) eliminate this imbalance by halting excessive stimulatory influences.
What else to study on this topic
- The role of oxidative stress in the destruction of substantia nigra neurons
- Mechanism of action of dopamine precursors (pharmacokinetics of levodopa)
- Differences between direct dopamine receptor agonists and MAO-B inhibitors
- Features of the use of central anticholinergics and their side effects
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