Introduction to Parkinson’s disease
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by selective neuronal loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and decreased DA levels in the nigrostriatal DA pathyway in the brain.
The earliest and most striking physical disabilities resulting from these changes are motor impairments that, together, are called ‘parkinsonism’.
These include paucity and slowness of movement (akinesia, bradykinesia), muscle stiffness (rigidity), and tremor at rest.
In large part, these problems result from the prominent degeneration of dopaminergic neurons in the midbrain, and the consequent deficiency of dopamine in brain areas that receive dopaminergic inputs from those neurons, specifically the post-commissural putamen and other basal ganglia regions.
Causes of Parkinson’s disease
The majority of Parkinson’s disease seem to occur sporadically, but in rare cases the disease can also be inherited in an autosomal dominant or recessive fashion.
- Genetic mutations in three proteins have been identified thus far. These genes encode for α synuclein, a protein found in abundance in vesicles and synaptic regions, and for parkin and ubiquitin carboxy-terminal hydroxylase, both of which are involved with protein degradation.
- Some forms of parkinsonism have been traced to specific entities, such as viral inflammation (e.g., the post encephalitic parkinsonism of the early 1900s), brain trauma, stroke, and poisoning by manganese, carbon monoxide, pesticide, or 1-methyl-4-phenyl,-1,2,3,6-tetra-hydropyridine (MPTP). Although the causes of some forms of parkinsonism are known, most cases are sporadic and are of unknown origin (idiopathic Parkinson’s disease). The causes are likely multifactorial, with genetic predisposition, environmental toxins, and aging contributing to the initiation and progression of the disease. The dopaminergic neurons in the substantia nigra (SN) and the noradrenergic neurons in the locus coeruleus frequently exhibit characteristic filamentous inclusion bodies (IBs) in PD called “Lewy bodies” (LBs). There is a progressive loss of dopamine neurons with age . Relatively smooth functioning of motor control is maintained until neuronal loss is such that it causes an 80% reduction of dopamine in the striatum. At this time, clinical symptoms appear and then worsen with increasing neuronal loss.
- Another form of parkinsonism is drug-induced, that is, iatrogenic parkinsonism, which often is a complication of antipsychotic therapy, especially following the use of the butyrophenone and phenothiazine drug classes. Unlike idiopathic parkinsonism, striatal content of dopamine is not reduced by administration of these drugs. In contrast, they produce a functional decrease in dopamine activity by blocking the action of dopamine on postsynaptic dopamine receptors.
Pharmacological Intervention for Parkinson’s disease
The aim of pharmacological therapy is to provide symptomatic relief. This is obtained through the use of drugs that either increase dopaminergic actions or diminish neuronal out-flow from the striatum. These drugs include:
- Levodopa, which increases brain dopamine levels;
- dopamine agonists, which directly stimulate dopamine receptors
- monoamine oxidase (MAO) inhibitors, which prevent dopamine metabolism;
- anticholinergic agents, which reduce the excitatory activity within the striatum.
1. Levodopa (L-DOPA):
Levodopa is the most reliable and effective drug used in the treatment of parkinsonism. It can be considered a form of replacement therapy.
Levodopa is the biochemical precursor of dopamine. It is used to elevate dopamine levels in the neostriatum of parkinsonian patients.
Dopamine itself does not cross the blood-brain barrier and therefore has no CNS effects. However, levodopa, as an amino acid, is transported into the brain by amino acid transport systems, where it is converted to dopamine by the enzyme L-aromatic amino acid decarboxylase.
Levodopa is usually co- administered with carbidopa to prevent peripheral metabolism by L-aromatic amino acid decarboxylase in the liver, kidney, and gastrointestinal tract.
Side Effects of Levodopa
- Dyskinesia
Peripheral side effects include
- anorexia
- nausea, and vomiting (likely due to dopamine’s stimulation of the chemoreceptor trigger zone of the area postrema in the medulla oblongata).
- Orthostatic hypotension.
Centrally mediated adverse effects of levodopa therapy include
- vivid dreams
- delusions
- hallucinations
- confusion, and
- sleep disturbances, especially in the elderly.
2. Dopamine Agonists:
Dopamine receptor agonists are considered by many clinicians as the first approach to therapy.
They have a long duration of action and are less likely to cause dyskinesias than levodopa. The rationale for the use of dopamine agonists is that they provide a means of directly stimulating dopamine receptors and do not depend on the formation of dopamine from levodopa.
As monotherapy, the dopamine agonists are less effective than levodopa but are often used early in the disease to delay initiation of levodopa therapy.
When used as an adjunct to levodopa in advanced stages, the dopamine receptor agonists may contribute to clinical improvement and reduce levodopa dosage needs.
Examples of dopamine agonists are:
- bromocriptine (Parlodel)
- pergolide (Permax)
- pramipexole (Mirapex), and
- ropinirole (Requip)
Side Effects of Dopamine Agonists
- Postural hypotension
- Nausea
- somnolence and
- fatigue
3. monoamine oxidase (MAO) inhibitors
An example of monoamine oxidase inhibitor is Selegiline.
Selegiline (also known as deprenyl, or Eldepryl) is an irreversible inhibitor of MAO-B, an important enzyme in the metabolism of dopamine.
Selegiline might be used as monotherapy in the newly diagnosed patient with parkinsonism because its pharmacological effect enhances the actions of endogenous dopamine.
Selegiline is also used in conjunction with levodopa–carbidopa in later-stage parkinsonism to reduce levodopa dosage requirements and to minimize or delay the onset of dyskinesias and motor fluctuations that usually accompany long-term treatment with levodopa.
Side Effects of Selegiline
- It should not be co-administered with tricyclic antidepressants or selective serotonin uptake inhibitors because of the possibility of a severe adverse drug reaction (e.g., hyperpyrexia, agitation, delirium, coma).
4. Anticholinergic Drugs
Examples of anticholinergics include Trihexyphenidyl, benztropine mesylate, biperiden, and procyclidine.
The efficacy of anticholinergic drugs in parkinsonism is likely due to the ability to block muscarinic receptors in the striatum.
They exert only modest antiparkinsonian actions and thus are most commonly used during the early stages of the disease or as an adjunct to levodopa therapy.
They are also the only class of drug that can provide benefit in the treatment of the drug-induced parkinsonism seen with antipsychotic therapy.
This is because the blockade of dopamine receptors by the antipsychotics leads to increased activity of the striatal neurons.
Blockade of the muscarinic receptors reduces this excitatory activity. The antihistamine diphenhydramine (Benadryl), because it has anticholinergic properties, is used for mild parkinsonism and with the elderly, who may not be able to tolerate the more potent anticholinergics, levodopa, or the dopamine agonists.
Side Effects of Anticholinergics
- Cycloplegia
- Dry mouth
- Urinary retention
- constipation.
- Confusion, delirium, and hallucinations may occur at higher doses.
5. Amantadine:
The drug was originally introduced as an antiviral compound , but it is modestly effective in treating symptoms of parkinsonism.
It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake.
Additional sites of action may include antagonism at muscarinic and N-methyl-D-aspartate (NMDA) receptors.
Side Effects of Amantadine
- Nausea
- Sizziness
- Insomnia
- Confusion
- Hallucinations
- Ankle edema.
6.Catechol-O-Methyl Transferase Inhibitors (COMTIs)
Examples of COMTIs include capone (Tasmar) and entacapone (Comtan).
These drugs are recently introduced for the treatment of parkinsonism.
COMT metabolizes catechol compounds, including dopamine and levodopa producing the inactive compound 3-O-methyl DOPA.
The rationale for the use of COMT inhibitors is analogous to that for carbidopa; that is, since COMT is present in the periphery as well as in the CNS, inhibition of peripheral COMT results in an increase in the plasma half-life of levodopa, thereby making more drug available for transfer to the brain.
Side effect of COMTIs
- Hepatotoxicity.