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Parkinson's disease: treatment
Last reviewed: 19.11.2021
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Parkinson's disease can be treated by replacing or replacing the deficiency of dopamine in the brain. At an early stage with the regular intake of dopamine receptor agonists or dopamine precursor levodopa (L-DOPA), virtually complete elimination of symptoms is possible.
[Symptomatic treatment of Parkinson's disease
Currently, for the treatment of Parkinson's disease, both standard levodopa preparations and sustained-release drugs are used, differing in the rate of dissolution in the stomach. Opening the gatekeeper's valve opens the way for the drug to enter the small intestine, in which its absorption takes place. Absorption of levodopa into the blood provides a special transport system for neutral and aromatic amino acids. In this regard, food rich in protein, can make it difficult to absorb levodopa from the intestine. The blood-brain barrier of levodopa is also overcome by a special transport system. Thus, neutral amino acids not only in the small intestine, but also in the blood slow the accumulation of levodopa in the brain.
At an early stage of Parkinson's disease, the therapeutic response to levodopa depends little on the rate of levodopa intake into the brain, since dopamine, formed from previously accepted levodopa, accumulates in the surviving dopaminergic endings and is released as needed. At a later stage, patients develop fluctuations (fluctuations), with the onset of the dose the condition of the patients improves, and by the end of its action the symptoms increase again (the phenomenon of "depletion of the end of the dose"). The change in the effect of levodopa at a late stage appears to be associated with a progressive loss of presynaptic dopaminergic endings. At an early stage of Parkinson's disease, the remaining dopaminergic endings are probably enough to accumulate the required amount of dopamine and isolate it in accordance with neuronal needs. As the disease progresses, the dopaminergic endings become too small, and they are unable to provide for the accumulation of dopamine. Therefore, the clinical effect reflects only immediate action of levodopa. The phenomenon of "end-of-dose depletion" is characterized by a decrease in the duration of the effect of a single dose, as a result, the effect of the previous dose is not maintained until the next dose begins. Over time, the transitions from a relatively prosperous state to a state of immobility are becoming more abrupt and sudden (the phenomenon of "on-off"). As the disease progresses, the synaptic dopamine level increasingly depends on the momentary level of levodopa in the brain, and hence on the fluctuations in the level of levodopa and amino acids in the blood. So, deterioration of the state ("shutdown") occurs against the background of insufficient concentration of the drug in the blood, and improvement ("inclusion") - against the background of an adequate or excessive level of the drug in the blood. As a result, fluctuations become more pronounced. The development of dyskinesias indicates a relative overdose of levodopa, which can arise because a small number of surviving endings can not cope with the task of removing excess dopamine from the synaptic cleft. A certain role may also play an increase in the sensitivity of postsynaptic receptors to dopamine and a change in the functional state of postsynaptic striatal neurons.
Treatment with levodopa increases the bioavailability of dopamine in the brain. Since dopamine is metabolized by MAO, it can 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 confirmation of this phenomenon. A number of specialists believe that the time of the appointment of levodopa should be postponed for the maximum possible period to minimize the possible damaging effect of free radicals. While others recommend, on the contrary, to inject levodopa as quickly as possible to reduce disability and mortality. Currently, prospective controlled trials are being conducted to resolve this issue.
Dopamine D1 and D2 receptors play a key role in Parkinson's disease. Achieving the optimal antiparkinsonian effect, apparently, requires simultaneous stimulation of both types of receptors. However, most of the currently used dopamine receptor agonists - bromocriptine, pergolide, ropinirole, pramipexole - act primarily on D1 receptors. Although all these drugs can be effective as monotherapy in the early stages of Parkinson's disease, according to some sources, some stimulation of D1 receptors is also necessary to achieve maximum effect.
Although dopamine D-receptor agonists increase dyskinesia when they have already developed under the influence of levodopa, patients not taking dopamine receptor agonist have not been informed of the development of dyskinesias or the phenomenon of "on-off". Whether stimulation of D1-receptors is necessary for the development of dyskinesias remains unclear. It is possible that in patients who tolerate monotherapy with D2-receptor agonist, the disease simply has not yet reached the stage at which dyskinesias develop. At the same time, prospective controlled trials conducted in recent years have shown that starting treatment with an agonist of dopamine receptors, and then adding if necessary a preparation of levodopa, you can delay the development of fluctuations and dyskinesias.
Occasionally patients lose their reaction to levodopa. The mechanism of development of resistance to levodopa remains unclear, since levodopa can be converted to dopamine and outside dopaminergic endings. More often, treatment is limited to serious side effects of levodopa.
Drugs that increase the release of dopamine, block its re-uptake or its metabolism, can also be useful in Parkinson's disease. In some cases, even amphetamines are used. As an auxiliary therapy, tricyclic antidepressants are useful. Inhibitors of monoamine oxidase B and catechol-O-methyltransferase are used to enhance or prolong the action of levodopa, especially at a late stage in patients with fluctuations.
Exposure to other (excellent odd-moderating) neurotransmitter systems can also have an effect in Parkinson's disease. For many years antagonists of muscarinic cholinergic receptors have been the main treatment for Parkinsonism, and drugs such as triethoxyphenidyl and benzotropin have been the most commonly used antiparkinsonian drugs. The use of these drugs is usually limited to their side effects (confusion, dry mouth, urinary retention), which are especially common in the elderly.
Enhancement of GABA-ergic transmission with benzodiazepines can be useful in patients experiencing panic attacks against the background of "depletion of the end of dose" or "shutdown". Currently, another approach is being developed, based on the use of glutamate receptor antagonists. Since glutamate is a neurotransmitter in corticostrial, corticosubthalamic, subthalomophugal ways, glutamate receptor antagonists can reduce certain symptoms of parkinsonism by weakening the hyperactivity of these circles. Of the currently used drugs, the ability to block NMDA receptors is possessed by amantadine. Although initially effective, its effectiveness is limited, as recent studies have shown, it is able to reduce the severity of dyskinesia in patients at a late stage of Parkinson's disease.
Preventive treatment of Parkinson's disease
Preventive (neuroprotective) therapy aims to halt or slow down the further death of dopaminergic neurons and their endings in patients with clinically evident Parkinson's disease or its preclinical stage. Several clinical approaches have been experimentally developed. One of them envisaged the blockade of MAO, as it was supposed that this enzyme is able to convert exogenous compounds into toxic metabolites. Another approach was aimed at reducing the content of free radicals in the brain, the third approach was to limit the potential glutamate-induced excitotoxicity by blockade of NMDA receptors. Tests of selegiline, a selective MAO inhibitor of type B, and alpha-tocopherol, an antioxidant agent that detoxifies free radicals, have not confirmed their ability to slow the progression of the disease. Currently, other antioxidant drugs are being tested, since vitamin E does not penetrate the brain well enough.
Slowing the loss of dopaminergic terminals with the help of preventive therapy will make it possible for a considerable lengthening of the time during which the patient responds well to symptomatic therapy. In recent years, using the methods of functional neuroimaging (PET, SPECT), it has been shown that against the background of dopamine receptor agonists (for example, ropinirole or pramipexole), the rate of loss of markers of dopaminergic endings in the striatum is lower than when treated with levodopa, however, additional studies are needed to confirm this conclusion and determine its clinical significance.