Parkinson’s disease involves degeneration of dopaminergic neurons, among other things, causing a dopamine deficiency, resulting in an increase in rigidity (stiffness), bradykinesia and/or tremor (tremor). Dopaminergic neurons secrete dopamine into the synaptic cleft. In Parkinson’s, there is a gradual loss of dopaminergic neurons in the substantia nigra. This causes a deficiency of dopamine in the striatum.
Causes
Degenerative processes associated with the substantia nigra, the locus coeruleus and parts of the dorsal vagal nucleus and reticular formation. Viral infections and metals (such as manganese) may play a role in Parkinsonism.
Parkinson’s can have the following causes:
- Familial: this form is rare; there is a mutated protein, or the Parkin protein. Normally, the Parkin protein causes the breakdown of proteins in the neurons in the substantia nigra. In the case of the mutated Parkin protein, accumulation of proteins occurs in the substantia nigra, causing apoptosis.
- α-synuclein: the exact physiological role of this protein is not yet known, but dysfunction of this protein causes locomotor defects.
- “oxidative stress hypothesis”: accumulation of free radicals leads to degeneration of neurons
- oxidative deamination of dopamine via MAO-B; where hydrogen peroxide is an important end product. Hydrogen peroxide can react with iron or copper ions in the substantia nigra, forming highly reactive radicals.
- non-enzymatic reaction of dopamine with oxygen; This is where quinines, semi-quinine, O2*, OH* and hydrogen peroxide are formed. Autoxidation of dopamine produces toxic quinines, reactive oxygen moieties.
- Degradation of neuromelanin in Substantia negra: Formation of redicals
- Moreover, in Parkinson’s patients there are too few radical “Scavengers” (Anti-oxidants) present in the body in Parkinson’s (Gluthation-peroxidase). The free radicals can possibly destroy the membranes of cells, causing an influx of calcium ions, which would cause apoptosis. This leads to degeneration of neurons.
- Side effects of medicines, Parkinson’s can occur as a result of certain medicines.
- MPTP converted via MAO-B to MPP+ basal ganglia degeneration
- Mechanical damage (trauma)
- Inflammation of the brain tissue and other environmental factors. (Creutzfeld Jacob)
Symptoms
Symptoms that generally occur with more than a 50-60% reduction in dopaminergic activity include:
- Lack of movement/slowness (hypo/bradykinesia).
- Rigidity and disturbed postural reflexes.
- Tremor at rest in approximately 60% of patients.
Medicines
Madopar; ‘125’, 1 tablet three times a day
Madopar consists of a combination of a dopamine precursor that crosses the blood-brain barrier and is enzymatically decarboxylated into the active dopamine and a decarboxylase inhibitor that does not cross the blood-brain barrier. In the brain, levodopa is then converted into dopamine by decarboxylase. By adding a decarboxylase inhibitor, peripheral conversion of levodopa to dopamine is prevented, resulting in a larger amount of levodopa ultimately reaching the brain and fewer peripheral side effects, such as hypotension and nausea, due to dopamine.
Side effects: The motor symptoms of Parkinson’s disease show a good response to levodopa in the first years. The dopamine-producing cells still present form a good buffer for the storage of dopamine produced. The response is therefore stable and independent of the time of intake. With the progression of Parkinson’s disease, patients develop a response that becomes dependent on the time of levodopa intake, with the onset of the so-called motor complications. In general, response fluctuations occur 5-10 years after disease onset.
Entacapone 200 mg; 1 tablet three times a day
Reversible and primarily peripherally acting catechol-O-methyltransferase (COMT) inhibitor. Inhibits the conversion of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine. Entacapone is indicated as an adjunct to standard levodopa/benserazide preparations, for use in patients with Parkinson’s disease and end-of-dose motor fluctuations that cannot be stabilized with these combinations. On theoretical grounds, this drug would allow a less fluctuating course of the condition due to the long excretion half-life. This dopamine agonist partly compensates for the inadequate buffering capacity of these neurons.
Side effects: Very common (>10%): dyskinesia (27%), nausea (11%).
Selegiline 5mg, 1 tablet twice a day
MAO-B inhibitor that inhibits the breakdown of dopamine in the brain by selectively inhibiting the enzyme monoamine oxidase B. Selegiline therefore increases the dopamine concentration in the central nervous system. Use of selegiline in the early stages of Parkinson’s disease may delay initiation of levodopa therapy. The effect of concurrently administered levodopa is prolonged and enhanced.
Side effects: Selegiline may cause euphoria and insomnia. These side effects are explained by the amphetamine-like metabolites of se legiline. Other side effects of selegiline include hallucinations, increased dyskinesias and confusion
Domperidone 10 mg, 1 tablet if necessary
Dopamine antagonist, possibly acts on dopamine receptors in the stomach, which increases the peristalsis of the stomach and duodenum and the pressure of the gastro-oesophageal sphincter and also relaxes the pyloric sphincter. This causes accelerated gastric emptying, which can prevent vomiting; Antagonism of dopamine receptors in the chemoreceptor trigger zone may also play a role.
Domperidone has little or no penetration into the central nervous system and therefore causes fewer extrapyramidal movement disorders. The chemoreceptor trigger zone is located in the floor of the fourth cerebral ventricle, which is functionally outside the blood-brain barrier. The anti-emetic effect is therefore maintained, as is the hyperprolactinemia. Domperidone is a PGP substrate, which means that it acts on the P-glycoprotein. This protein acts as a pump, preventing Domperidone from having an effect in the brain.