Treatment of Parkinson's Disease
Drugs for Parkinson's Disease
Traditionally, the first drug is levodopa, but many believe that its early use speeds up the development of side effects and reduces the sensitivity to the drug; they prefer, at first, not to prescribe levodopa, but use anticholinergic drugs, amantadine or dopamine agonists.
Levodopa, the precursor of dopamine, passes through the blood-brain barrier and enters the basal nuclei, where it is decarboxylated into dopamine. Parallel administration of a carbidopa decarboxylase inhibitor prevents the catabolism of levodopa, which allows to reduce its dose, minimizing side effects.
Levodopa is most effective against bradykinesia and rigidity, although it also significantly reduces tremor. With an easy course of the disease, levodopa can return to almost normal state, and the patient, bedridden, is transferred to an outpatient schedule.
Among the major central side effects of levodopa are nightmares, orthostatic hypotension, drowsiness, dyskinesia, as well as hallucinations or delirium, especially in elderly people with dementia. To the peripheral include nausea, vomiting, hyperhidrosis, abdominal muscle spasm and tachycardia. The dose at which dyskinesias develop, decreases with the continuation of treatment. Sometimes a minimal dose, leading to a decrease in the symptoms of parkinsonism, also gives dyskinesia.
Carbidopa / levodopa in various ratios are available in tablets of 10/100, 25 / 100.25 / 250.25 / 100.25 / 250 and tablets with a sustained release of 50/200 mg. Treatment begins with a tablet of 25/100 mg 3 times / day. The dose is increased every 4-7 days until the maximum positive effect or side effects are achieved. Side effects are minimized by the gradual increase in the dose and the administration of the drug during or after meals (high-protein food may worsen the absorption of levodopa). If peripheral side effects predominate, the dose of carbidopa should be increased. Usually it takes 400-1000 mg / day of levodopa for several doses every 2-5 hours. Sometimes it is necessary to increase the daily dose to 2000 mg2.
Sometimes levodopa has to be used to support motor functions, despite the hallucinations or delirium caused by it. Psychosis can sometimes be treated with quetiapine or clozapine inside. They practically do not aggravate the symptoms of parkinsonism or do it to a lesser degree than other neuroleptics (for example, risperidone, olanzapine). Do not prescribe haloperidol. The starting dose of quetiapine 25 mg 1-2 times / day, it is increased by 25 mg every 1-3 days, with tolerability up to 800 mg / day. The initial dose of clozapine is 12.5-50 mg once a day, it is increased to 12.5-25 mg 2 times / day under a weekly control of the clinical blood test for 6 months, then the analysis is taken once every 2 weeks.
- A combination of levodopa with a decarboxylase inhibitor, benserazide, and catecholomethyltransferase inhibitors (KOMT) is also used.
- A similar tactic is used when using the combined agent benserazide / levodopa).
After 2-5 years of treatment with levodopa, motor fluctuations (the phenomenon of "on-off") occur in most cases, which may be a consequence of levodopa therapy, and the result of the underlying disease. As a result, the period of improvement after each intake is shortened, and one can distinguish phases from pronounced akinesia to uncontrolled hyperactivity. Traditionally, when such fluctuations occur, levodopa is administered in minimally effective doses, and the intervals between doses are reduced to 1-2 hours. Alternatively, dopamine agonists are added, levodopa / carbidopa (200/50 mg) and selegiline are prescribed.
For monotherapy of the initial stages of parkinsonism, amantadine 100 mg orally 1-3 times a day is effective in 50% of cases, it can be used further to increase the effect of levodopa. The drug increases dopaminergic activity and anticholinergic effects. After several months of monotherapy, amantadine often loses its effectiveness. Amantadine facilitates the course of Parkinson's disease with the use of neuroleptics. Among the side effects of amantadine is swelling of the legs, symptomatic and confusion of the mind.
Dopamine agonists directly activate dopamine receptors in the basal nuclei. Ingest bromocriptine 1.25-50 mg 2 times / day, pergolide 0.05 mg 1 times / day to 1.5 mg 3 times / day, ropinirole 0.25-8 mg 3 times / day and pramipexole 0.125-1, 5 mg 3 times / day. With monotherapy, they rarely remain effective for longer than a few years, but can be effective in all stages of the disease. The early administration of these drugs in combination with low doses of levodopa slows the appearance of dyskinesias and the phenomenon of "on-off", perhaps because dopamine agonists stimulate dopamine receptors longer than levodopa. This type of stimulation is more physiological and better retains the receptors. Dopamine agonists are useful in the late stages, when the response to levodopa decreases or the "on-off" phenomenon appears. The use of dopamine agonists limits side effects (eg, sedation, nausea, orthostatic hypotension, impaired consciousness, delirium, psychosis). Reducing the dose of levodopa reduces the side effects of dopamine agonists. Occasionally pergolide provokes fibrosis (pleura, retroperitoneal space or heart valves).
Selegiline, a selective monoamine oxidase B inhibitor (MAOB), inhibits one of the two main enzymes that break down dopamine in the brain. Sometimes with a moderate "on-off" phenomenon, selegiline helps prolong the effect of levodopa. With an early appointment as a monotherapy, selegiline can delay the need for the administration of levodopa for about 1 year. By activating residual dopamine in the early stages of the disease or by reducing the oxidative metabolism of dopamine, selegiline slows the progression of the disease. A dose of 5 mg orally 2 times a day does not give a hypertensive crisis after the use of cheeses containing tyramine, in contrast to nonselective MAO inhibitors blocking isoenzymes A and B. Actually devoid of side effects, selegiline potentiates the side effects of levodopa (eg, dyskinesias, psychotic effects , nausea), dictating the reduction of its dose.
Razagilin, a new MAAA inhibitor not metabolized to amphetamine, seems to be effective and well tolerated at any stage of the disease. Whether rasagiline has only a symptomatic and / or neuroprotective effect is not yet clear.
Anticholinergic drugs can be used as monotherapy in the early stages of the disease, and later - to support the action of levodopa. Among them, benzthropine inside from 0.5 mg per night to 2 mg 3 times / day and trihexyphenidyl 2-5 mg orally 3 times / day. Effective for the treatment of tremor, antihistamines with anticholinergic effect (for example, diphenylhydramine 25-50 mg orally 2-4 times / day, orfenadrine 50 mg orally 1-4 times / day Anticholinergic drugs (for example, benzthropine) are able to alleviate complaints of parkinsonism due to use Neuroleptics Tricyclic antidepressants with an anticholinergic effect (eg, amitriptyline 10-150 mg orally at bedtime) are effective when combined with levodopa, and the dose of anticholinergic drugs is increased very slowly. The effects of anticholinergic drugs, especially unpleasant in the elderly: dry mouth, urinary retention, constipation, visual impairment, confusion, delirium and thermoregulation disorders due to decreased sweating.
Catechol-O-methyltransferase (COMT) inhibitors (eg, entacapone, tolcapone) inhibit the breakdown of dopamine and are therefore effective in combination with levodopa. Combinations of levodopa, carbidopa and entacapone are possible. For each levodopa intake, 200 mg of entacapone is prescribed per dose per day, but not more than 1600 mg / day (if levodopa is used 5 times a day, 1 g of entacapone is prescribed 1 time / day). Because of the toxic effect on the liver, tolcap is rarely used.
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Surgical treatment of Parkinson's disease
If the disease progresses, despite modern therapy, the question arises of surgical treatment. The method of choice is the high-frequency electrical stimulation of the subtalamic body. In dyskinesias induced by levodopa, stereotactic destruction of the posterior segment of the pale sphere (pallidotomy) is carried out. If bradykinesia, the phenomenon of "on-off" and levodopa-induced dyskinesias no more than 4 years, the operation significantly reduces the corresponding complaints. When expressed tremor may be effective stimulation of the medial ventral nucleus of the thalamus. Experiments are carried out with treatment, potentially increasing the content of dopamine in the brain, - transplantation of embryonic dopamine neurons.
Physical treatment of Parkinson's disease
The goal is to maximize the daily activity of patients who have Parkinson's disease. A regular exercise program or physiotherapy helps improve the physical condition of patients and educates their adaptation strategies. Due to the disease, taking antiparkinsonian drugs and decreasing activity, constipation usually develops, so a diet with a high content of plant fibers should be observed. Help food additives (such as psyllium) and light laxatives (for example, bisacodyl 10-20 mg orally 1 time / day).