drugs

Pharmacological treatment of Parkinson's disease

The purpose of Parkinson's disease drug therapy is to replace dopamine deficiency at the striatum level by mimicking physiological stimulation. It is known that the main treatment consists in the administration of levodopa, which has the function of increasing the concentration of dopamine in the brain .

The latter, in fact, is not able to cross the blood-brain barrier, which is instead overcome by levodopa.

The positive effects of levodopa are oriented towards the motor symptoms of the disease, but often this drug is responsible for the onset of the dyskinesias discussed above. This is why we tend to postpone levodopa treatment as much as possible.

Unfortunately, even today, therapeutic remedies for Parkinson's disease are symptomatic and cannot lead to a remission of the disease.

drugs

To learn more: Drugs for the treatment of Parkinson's disease

The most used drugs will be described below:

  • Levodopa : (L-3, 4-dihydroxyphenylalanine or L-dopa), is the physiological precursor of dopamine and for this reason it is able to improve the symptoms of Parkinson's disease. Unfortunately, the motor and non-motor side effects severely limit its therapeutic potential. Despite everything, after 40 years of clinical use, it is still the optimal treatment for Parkinson's disease. It is generally administered orally and part of its absorption occurs at the proximal level of the duodenum, from which, thanks to an active transport system, it reaches the bloodstream. To diffuse into the central nervous system, levodopa must cross the blood-brain barrier. This is allowed by a sodium-dependent saturable transport system common to other aromatic amino acids.

    The degree of intestinal absorption depends on the type of formulation used (tablets or liquid form), but also on the degree of gastric filling and emptying. There are limiting factors that can negatively influence the passage of the drug in the central nervous system, such as protein-rich meals (due to the competition that can be established between other amino acids present in the intestine and levodopa). Other limiting factors may be, for example, physical activity, because it reduces the mesenteric blood flow, the age of the individual (for example in the elderly, levodopa is more absorbed) and the transit speed of the tablets at the intestinal level. Finally, a reduced speed of gastric emptying and the use of anticholinergic drugs cause a delay in reaching the plasma level of levodopa.

    After absorption, levodopa rapidly disappears from the bloodstream and is mostly metabolized at peripheral level by dopa-decarboxylases, which are found in the liver, intestine and capillaries. It is now known that, unlike L-dopa, dopamine is not able to cross the blood-brain barrier due to its chemical structure. Therefore remaining at peripheral level, it causes adverse effects such as nausea, vomiting and orthostatic hypotension. This leads to an increase in the dose of levodopa in order to obtain a therapeutic benefit.

    To overcome this problem, peripheral dopa-decarboxylase inhibitors have been formulated, such as beserazide and carbidopa, which must be administered in combination with levodopa in order to improve absorption and passage into the central nervous system. These inhibitors therefore make it possible to reduce the daily dose of medication used. Since only 1-3% of the levodopa administered is able to reach the central nervous system (where it is transformed into dopamine), the quantity available to perform its action at the striatum level is very small; slow release preparations have therefore been formulated to improve the pharmacological properties of the medicinal product. These formulations make it possible to maintain striatal dopamine levels as stable as possible and reduce motor fluctuations in patients suffering from Parkinson's disease. The main advantage of these slow-release preparations is that they increase the effect of the drug and improve night and morning mobility. The two main slow-release formulations are Madopar ®, consisting of levodopa and beserazide in a 4: 1 ratio, and Sinemet ®, which instead contains the association of levodopa and carbidopa in association with 4: 1.

    There are also preparations that have a rapid absorption like the dispersible Madopar, soluble in water. It quickly reaches the absorption site and allows to resolve the so-called "prandial off" periods. One of the advantages that this type of preparation offers is the fact that it can be used in patients with swallowing problems, and offer a quick effect response.

    Other types of formulations through which levodopa can be administered may vary from patient to patient depending on the adverse effects the individual presents. It is recalled that a pharmaceutical preparation has recently been patented which allows the transdermal administration of levodopa . This preparation would be able to provide the continuous penetration of the drug through the skin, making its concentration stable at the level of the blood circulation and thus overcoming the limits due to the non-continuous administration of levodopa.

    The individual suffering from Parkinson's disease, following therapy with levodopa, spends an initial period called " therapeutic honeymoon ", which lasts from 2 to 5 years, where the therapy almost totally controls the symptoms and the individual plays a almost normal life. In fact, the drug is effective in any Parkinson's disease patient, regardless of the duration, severity and age of onset of the disease. Subsequently, however, a phase occurs in which there is a decrease in the efficacy of levodopa, consequently there is an aggravation of the symptoms of the disease. However, even today, compared to other available dopaminergic therapies, dopamine replacement therapy with levodopa is however associated with a greater improvement in motor function and a greater slowdown in the progression of disability. Furthermore, levodopa, is one of the best tolerated drugs, particularly in elderly individuals.

Another class of drugs used in the treatment of Parkinson's disease is that of dopamine agonists, which directly stimulate dopamine receptors located at the level of the post-synapse, without having to be previously converted to dopamine. These drugs are represented by a heterogeneous group of molecules, divided according to their chemical structure into two subgroups, ergolinics and non-ergolinics . Let's see them in detail.

  • Bromocriptine, known for the commercial name PARLODEL ®: it is an alkaloid of the ergotamine that mainly stimulates the D2 receptors, serotonergic and noradrenergic of the brain stem. The use of this drug occurs orally, characterized by rapid absorption; excretion occurs in the bile. A single dose of bromocriptine is sufficient to achieve clinical improvement in the patient 30-60 minutes after administration. It is therefore an effective drug both at low and high doses, where however the manifestation of side effects is dose-dependent. Among the most frequent side effects of bromocriptine there is nausea, vomiting, orthostatic hypotension, hallucinations, mental confusion, vasospasm at the extremities. Compared to monotherapy, its use in combination with levodopa is preferable.
  • Lisuride (DOPERGIN ®, CUVALIT ®): is a water soluble ergolinic alkaloid alkaloid that stimulates D2 post-synaptic receptors in the striatum. It also acts as a partial antagonist of D1 and from weak agonist to post-synaptic 5HT. Also in this case oral administration is provided and the drug is characterized by good absorption. The effect lasts for 2-4 hours. Lisuride is used orally both as monotherapy and in combination with other drugs and is very effective in reducing symptoms of Parkinson's disease, including tremor. The lisuride can also be used subcutaneously or intravenously, achieving a reduction in motor fluctuations and side effects.

    While the presence of presynaptic dopamine is necessary for the action of bromocriptine, the action of the lysuride is independent.

  • Pergolide (NOPAR®): semi-synthetic ergoline derivative, structurally similar to bromocriptine, but with a long duration of action (over 16 hours). Pergolide stimulates D2 and weakly also D1, and this improves its effectiveness, because it has positive effects on motor fluctuations. However, over time, pergolide appears to lose efficacy, perhaps due to a mechanism of down-regulation of dopaminergic receptors.
  • Cabergoline (CABASER®, DOSTINEX®): ergolinic agonist of D2 and D1 receptors, and weak 5HT receptor agonist. It has a half-life ranging from 24 to 65 hours, so the advantage would be to maintain constant and prolonged drug levels. The use is for oral administration, in which there is a good absorption at the gastrointestinal level. It was found to be particularly useful when given in combination with levodopa, because together the two drugs cause a reduction in the "off" period and are particularly useful in the advanced stages of Parkinson's disease. It has also been observed that in monotherapy it is effective in the early stages of the disease, although after five years, approximately 64% of patients require the use of cabergoline in combination with levodopa.
  • Apomorphine : selective agonist of D1 and D2 receptors. The administration is subcutaneous or intravenous and small doses of levodopa are associated with it. It has a half-life of 40-50 minutes, the effect occurs quickly and lasts 45-90 minutes. Apomorphine is also used for clinical tests to diagnose parkinsonian syndromes. At the beginning of the therapy side effects can arise such as nausea, vomiting, drowsiness and hypotension, which is why it is generally used in combination with domperidone, a selective antagonist of peripheral D2 receptors.
  • Ropinirole (REQUIP ®): potent selective agonist of D2 and D3 receptors, with a half-life of about six hours. It reaches plasma concentration in 90 minutes. Oral absorption is rapid and the drug has a bioavailability of 55%, because it is subjected to hepatic first pass metabolism. It is very well tolerable and is effective both in the early stages, where it is used alone or in the advanced stages of Parkinson's disease, where it is used in combination with levodopa.
  • Pramipexole (MIRAPEX ®): selective agonist for D3 receptors. It is used orally and has a good gastrointestinal absorption. This drug has a half-life of 8-12 hours and a bioavailability of over 90%. Levodopa and pramipexole based therapy in the advanced stages of the disease induces a 27-30% decrease in Parkinson's disease. Although the drug has good tolerability, various side effects can occur such as drowsiness, nausea, hypotension and hallucinations.

It has also been shown that some dopamine agonists seem to have neuroprotective properties, in practice they seem to slow down the progression of neurodegeneration, without, however, removing the causes of the disease.

In conclusion, dopamine-agonist drugs present moderate efficacy and slow down motor symptoms. The problem is determined by the fact that they cause side effects such as gastrointestinal, cardiovascular, fibrosis, sleepiness and, compared to levodopa, a greater frequency of psychiatric problems. It has been observed that the use of such drugs seems to be related to impulse control disorders, such as pathological gambling, hypersexuality and binge eating disorder, which occur approximately in 13-17% of patients using this therapy. For this reason, the treatment starts with low dosages and then gradually passes to higher dosages.

Among the drugs for the treatment of Parkinson's disease, monoamine oxidase inhibitors are also found. MAOs (monoamino-oxidases) are enzymes located in the outer membrane of mitochondria that have the function of catalyzing the oxidative deamination of exogenous and endogenous amines, including dopamine, serotonin and noradrenaline. MAOs can exist in 2 isoforms: MAO-A, located in the adrenergic and serotoninergic nerve endings both at central and peripheral level, and MAO-B, consisting of isoenzymes more expressed in the brain and in the basal ganglia. They have the function of converting dopamine into inactive 3, 4-dihydroxyphenylacetic acid. Therefore the reduction of dopamine catabolism by MAOs can induce an increase in dopaminergic tone. In particular, selective MAO-B isoform inhibitors appear to be better for the treatment of Parkinson's disease. Furthermore, it has also been shown that the inhibition of these isoenzymes reduces the formation of peroxides deriving from the metabolism of dopamine and with it the production of free radicals and oxidative stress at the level of the black substance.

Without going into detail, the drugs most often used as MAO-B inhibitors are:

  • the selegiline, DEPRENYL ®, JUMEX ®. Selegiline has been shown to delay the progression of Parkinson's disease, allowing the required dose of levodopa to be reduced. It is also effective against motor symptoms in the early stages of the disease. However, the improvement does not last over time.
  • Rasagiline, a drug that has also been shown to have a neuroprotective action, not due to the inhibition of MAO-B.

Another category of drugs used for Parkinson's disease is given by the inhibitors of catechol-O-methyltransferases (COMT), ubiquitous enzymes in the body located mainly in the cytoplasm and in the plasma membrane of post-synaptic cells. The COMTs are involved in the central metabolism of dopamine and in the peripheral one of levodopa, consequently their inhibition determines a remarkable increase of the peripheral and central levels of L-DOPA and a block of the central catabolism of dopamine.

COMT inhibitors are used in the treatment of patients with Parkinson's disease who show a floating response to levodopa, due to their ability to maintain more stable plasma dopamine levels. Among them are the Entacapone or COMTAN ® and the Tolcapone or TASMAR®.

Dopamine deficiency, typical of Parkinson's disease, induces cholinergic hyperactivity. For this reason anticholinergic drugs were the first drugs to be used in the treatment of motor deficits related to the disease. The action of these drugs seems to be correlated with the imbalance that is created between acetylcholine and dopamine in the striatum. However, these drugs have a modest clinical efficacy, mostly directed towards muscle stiffness and tremor, while they show a rather poor effect towards akinesia and at the level of structural impairment. Among the most used anticholinergics, we mention ARTANE®, AKINOETON®, DISIPAL® and KEMADRIN®.

The glutamate antagonists have also been studied as potential drugs for the treatment of Parkinson's disease. In fact, the loss of dopamine that occurs in the disease can also cause glutamatergic hyperactivity in NMDA and non-NMDA receptors located in the basal ganglia. This hyperactivity affects the motor deficit of Parkinson's disease. Among these drugs we find amantadine or MANTADAN ® which works by blocking the glutamate NMDA receptors and stimulating the release of dopamine.

Finally, it has been shown that in the basal ganglia the adenosine receptors and those of dopamine interact in an opposite manner, so that by blocking the adenosine receptors, type A2A, the dopamine-mediated response is amplified. It has also been observed that A2A receptors are co-localized with D2-type dopaminergic receptors in striated-pale neurons. Therefore, A2A receptor antagonists (histradefillin) have been proposed for the treatment of Parkinson's disease.