Parkinson's Disease - Treatment

Parkinson's disease can be treated by replacing or compensating for the deficiency of dopamine in the brain. In the early stages, with regular use of dopamine receptor agonists or the dopamine precursor levodopa (L-DOPA), almost complete elimination of symptoms is possible.

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Symptomatic treatment of Parkinson's disease

Currently, both standard levodopa preparations and prolonged-release preparations, which differ in the rate of dissolution in the stomach, are used to treat Parkinson's disease. Opening of the pyloric valve clears the way for the drug to enter the small intestine, where it is absorbed. The absorption of levodopa into the blood is ensured by a special transport system for neutral and aromatic amino acids. In this regard, protein-rich food can hinder the absorption of levodopa from the intestine. Levodopa also overcomes the blood-brain barrier with the help of a special transport system. Thus, neutral amino acids not only in the small intestine, but also in the blood slow down the accumulation of levodopa in the brain.

In the early stages of Parkinson's disease, the therapeutic response to levodopa depends little on the rate of levodopa delivery to the brain, since dopamine formed from previously administered levodopa accumulates in the remaining dopaminergic endings and is released as needed. At a later stage, patients develop fluctuations, with the condition of patients improving at the beginning of the dose, and symptoms increasing again by the end of its action (the phenomenon of "end-of-dose exhaustion"). The change in the effect of levodopa at a late stage is apparently associated with a progressive loss of presynaptic dopaminergic endings. In the early stage of Parkinson's disease, the remaining dopaminergic endings are probably sufficient to accumulate the required amount of dopamine and release it in accordance with the needs of neurons. As the disease progresses, dopaminergic endings become too few and they are unable to ensure the accumulation of dopamine. Therefore, the clinical effect reflects only the immediate action of levodopa. The phenomenon of "end-of-dose wear-off" is characterized by a decrease in the duration of the effect of a single dose, as a result of which the effect of the previous dose does not persist until the onset of the next dose. Over time, transitions from a relatively favorable state to a state of immobility become increasingly abrupt and sudden (the "on-off" phenomenon). As the disease progresses, the synaptic level of dopamine increasingly depends on the momentary level of levodopa in the brain, and therefore on fluctuations in the level of levodopa and amino acids in the blood. Thus, deterioration of the condition ("off") occurs against the background of insufficient drug concentration in the blood, and improvement ("on") - against the background of adequate or excessive drug levels in the blood. As a result, fluctuations become increasingly pronounced. The development of dyskinesias indicates a relative overdose of levodopa, which can occur due to the fact that a small number of surviving endings cannot cope with the task of removing excess dopamine from the synaptic cleft. An increase in the sensitivity of postsynaptic receptors to dopamine and a change in the functional state of postsynaptic striatal neurons may also play a certain role.

Levodopa treatment increases the bioavailability of dopamine in the brain. Since dopamine is metabolized by MAO, this may be accompanied by increased formation of free radicals. Some suggest that free radicals can accelerate the progression of the disease, but there is no clinical evidence of this phenomenon. Some experts believe that the moment of prescribing levodopa should be postponed as long as possible to minimize the possible damaging effect of free radicals. While others recommend, on the contrary, administering levodopa as soon as possible to reduce disability and mortality. Prospective controlled studies are currently being conducted to resolve this issue.

Dopamine D1 and D2 receptors play a key role in Parkinson's disease. Achieving optimal antiparkinsonian effect apparently requires simultaneous stimulation of both types of receptors. However, most currently used dopamine receptor agonists - bromocriptine, pergolide, ropinirole, pramipexole - act primarily on D1 receptors. Although all of these drugs can be effective as monotherapy in early Parkinson's disease, some data suggest that some stimulation of D1 receptors is also necessary to achieve maximum effect.

Although dopamine D receptor agonists exacerbate dyskinesias that have already developed under the influence of levodopa, no dyskinesias or the "on-off" phenomenon have been reported in patients receiving only a dopamine receptor agonist. Whether stimulation of D1 receptors is necessary for the development of dyskinesias remains unclear. It is possible that in patients who tolerate monotherapy with a D2 receptor agonist, the disease has simply not yet reached the stage at which dyskinesias develop. At the same time, prospective controlled studies conducted in recent years have shown that by starting treatment with a dopamine receptor agonist and then adding a levodopa drug if necessary, it is possible to delay the development of fluctuations and dyskinesias.

Rarely, patients lose their response to levodopa. The mechanism of development of resistance to levodopa remains unclear, since levodopa can be converted to dopamine outside the dopaminergic endings. More often, treatment is limited by the serious side effects of levodopa.

Drugs that enhance dopamine release, block its reuptake, or block its metabolism may also be useful in Parkinson's disease. In some cases, even amphetamines are used. Tricyclic antidepressants are useful as adjuvant therapy. Monoamine oxidase B and catechol-O-methyltransferase inhibitors are used to enhance or prolong the action of levodopa, especially in late-stage patients with fluctuations.

Targeting other (non-dopaminergic) neurotransmitter systems may also be effective in Parkinson's disease. For many years, muscarinic cholinergic receptor antagonists have been the mainstay of treatment for Parkinsonism, and drugs such as tritexyphenidyl and benzotropine have been the most commonly used antiparkinsonian agents. The use of these drugs is usually limited by their side effects (confusion, dry mouth, urinary retention), which are particularly common in the elderly.

Enhancement of GABAergic transmission with benzodiazepines may be useful in patients experiencing panic attacks associated with "end-of-dose wear-off" or "switch-off." Another approach currently being developed is glutamate receptor antagonists. Since glutamate is a neurotransmitter in the corticostriatal, corticosubthalamic, and subthalamofugal pathways, glutamate receptor antagonists can reduce some symptoms of parkinsonism by reducing hyperactivity in these circuits. Among the currently used drugs, amantadine has the ability to block NMDA receptors. Although its effectiveness is limited when used at the initial stage, recent studies have shown that it can reduce the severity of dyskinesias in patients with late-stage Parkinson's disease.

Preventive treatment of Parkinson's disease

Preventive (neuroprotective) therapy aims to halt or slow down further loss of dopaminergic neurons and their endings in patients with clinically evident Parkinson's disease or its preclinical stage. Several clinical approaches have been developed experimentally. One involved blocking MAO, since it was assumed that this enzyme is capable of converting exogenous compounds into toxic metabolites. Another approach aimed at reducing the content of free radicals in the brain, and a third at limiting potential glutamate-induced excitotoxicity by blocking NMDA receptors. Trials of selegiline, a selective MAO type B inhibitor, and alpha-tocopherol, an antioxidant that neutralizes free radicals, did not confirm their ability to slow disease progression. Other antioxidant drugs are currently being tested, since vitamin E does not penetrate the brain well enough.

Slowing down the loss of dopaminergic terminals by preventive therapy will make it possible to significantly prolong the time during which the patient responds well to symptomatic therapy. In recent years, functional neuroimaging methods (PET, SPECT) have shown that the rate of loss of dopaminergic terminal markers in the striatum is lower with dopamine receptor agonists (e.g., ropinirole or pramipexole) than with levodopa, but additional studies are needed to confirm this finding and determine its clinical significance.