Anti-Parkinsonism

Background


Parkinson’s disease is a common and complex neurological disorder. The first detailed description of Parkinson’s disease was made almost two centuries ago, but the conceptualisation of the disease continues to evolve. It is recognised as the most common neurodegenerative disorder after Alzheimer’s disease. The percentage of affected individuals within the population rises from 1 % at 65 years to 5 % at 85 years, making age the main risk factor for Parkinson’s disease. The majority of cases are thought to be idiopathic. However, in 5–10% of cases, Parkinson’s disease is thought to have a genetic component, showing both recessive and dominant modes of inheritance. Gender is an established risk factor, with the male-to-female ratio being approximately 3:2. Ethnicity is also a risk factor for the disease. In the USA, incidence is highest in people of Hispanic ethnic origin, followed by non-Hispanic Whites, Asians, and Blacks. Until the recent advances in the identification of some of the genes that underlie rare familial forms of the disease, little was known about the 2 molecular pathogenesis of Parkinson’s disease. The prevalence of this disease is also alarming. Other risk factors for Parkinson’s disease include environmental exposures. Such as pesticide exposure, prior head injury, rural living, β-blocker use, agricultural occupation, and well-water drinking.

The mechanism of Parkinson’s disease medications

Motor features in patients with Parkinson’s disease are heterogeneous, which has prompted attempts to classify subtypes of the disease. A consensus on the classification of Parkinson’s disease subtypes has not yet been established, but empirical clinical obser vations suggest two major subtypes: tremor-dominant Parkinson’s disease (with a relative absence of other motor symptoms). and non-tremor-dominant Parkinson’s disease (which includes phenotypes described as akinetic-rigid syndrome and postural instability gait disorder). An additional subgroup of patients with Parkinson’s disease has a mixed or indeterminate phenotype with several motor symptoms of comparable severity.

At its core, Parkinson’s disease is a neurodegenerative disease with early prominent death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The resultant dopamine deficiency within the basal ganglia leads to a movement disorder characterised by classical parkinsonian motor symptoms. So the cardinal symptoms of Parkinson’s disease include tremor (involuntary movement), muscular rigidity and bradykinesia (difficulty in initiating movement or slowness of movement). The patients at various stages of disease progression can have various degree of severity of either one or two of those main symptoms or may have all three with varying degree of severity. Parkinson’s disease also has symptoms of depression as well as dementia. While it is also associated with numerous non-motor symptoms, some of which precede the motor dysfunction by more than a decade.

Dopamine, which is an important substance in Parkinson’s disease, is normally synthesized from our diet. A simplified metabolic cycle of dopamine as it pertains to Parkinson’s disease is as follows. The amino acid tyrosine is absorbed from the intestine into the blood and crosses the blood-brain barrier via the large neutral amino acid transport system. Tyrosine is taken up by a SNC cell and converted to L-dopa via tyrosine hydroxylase (the rate-limiting step of dopamine production). L-dopa is converted to dopamine by an aromatic acid decarboxylase, and the dopamine is packaged into vesicles. When dopamine is released into the synapse, it can (1) bind a postsynaptic D1 receptor to stimulate the Direct / “go” pathway, (2) bind a postsynaptic D2 receptor to stimulate the Indirect / “stop” pathway, (3) bind a D3 autoreceptor to prevent more dopamine release, (4) be degraded by catechol-O-methyltransferase (COMT), or (5) be taken up by the presynaptic dopamine transporter (DAT) and subsequently degraded by monoamine oxidase type B (MAO-B). Parkinson’s disease involves dopaminergic SNC cell death, thus reducing the amount of dopamine released into the SNc-striatal synapse. To repair and maintain dopaminergic signaling, one must replace (presynaptic), protect (presynaptic/synaptic), or mimic (postsynaptic) dopamine.

Current treatments (which are effective but not optimal) focus only on the motor symptoms. Specifically, the focus is on restoring the output of the basal ganglia in a consistent fashion. A major goal of Parkinson’s disease research is the development of disease-modifying drugs that slow or stop the underlying neurodegenerative process. There are several medications are used to anti-parkinsonism.

1. Levodopa and carbidopa. Levodopa is a natural compound that pass into the brain and converted into dopamine. Combined with carbidopa can prevent the levodopa from converting into dopamine outside the brain.

2. Dopamine agonists. They work by directly stimulating dopamine receptors in the brain.

3. COMT inhibitors. The catechol-O-methyl transferase (COMT) inhibitors maybe used to prolong and enhance the effect of levodopa.

4. MAO-B inhibitors. Monoamine oxidase B (MAO-B) inhibitors. They work by blocking the effect of enzymes that inactivate dopamine.

5. Anticholinergic agents. These medications help control the tremor associated with Parkinson's disease.

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