Basic Pharmacology And Physiology Of Anti-Parkinson’s Disease
Parkinson’s disease (PD) is a gradually progressive neurodegenerative condition. The etiology and pathogenesis remain incompletely understood. There are currently no disease-modifying treatments for PD, and medical management is predominantly focused on controlling the motor symptoms using drugs. The long-term duration of disease means that patients may take sophisticated medication regimes aimed at controlling the motor symptoms, with a likelihood of problematic side effects.
With an aging population the management of Parkinson’s disease is likely to prove an increasingly important and challenging aspect of medical practice. Classically Parkinson’s disease presents with resting tremor, rigidity, and akinesia often in an asymmetric fashion, but later usually bilateral. However, initial symptoms may be subtle and vague, for example discomfort or mild stiffness in the limbs, and may be misinterpreted.
Moreover clinical features are variable with some patients presenting with akinesia and rigidity only and others with a tremor dominant type. About 10%–20% of autopsy cases with a diagnosis of Parkinson’s disease were not considered to suffer from it in life. On the other hand, approximately 25% of patients with a diagnosis of Parkinson’s disease in life are shown to have a different diagnosis when postmortem examination is carried out.
Diagnosis may thus be difficult particularly as there are no biological markers that unequivocally confirm the diagnosis of Parkinson’s disease. The most common differential diagnoses are essential tremor, arteriosclerotic pseudoparkinsonism, drug induced parkinsonism, and the so-called Parkinson plus syndromes namely multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration.
The current treatments available for PD are designed to restore dopaminergic activity in the dopamine-deplete striatum of PD patients, with consequent improvement in motor symptoms. Disappointingly, there is a paucity of pharmacological options for treatment of the non-motor features, which are unfortunately often the most disabling aspects of disease.
At the present time, there are no established treatments able to slow, stop, or modify the disease course. Commonly used drugs for PD include those based on exogenous administration of compounds with dopaminergic activity (e.g. levodopa, dopamine agonists), and those that inhibit the metabolism of endogenous dopamine (e.g. COMT, MAO-B inhibitors). While levodopa can cause significant adverse effects, the vast majority of patients ultimately require treatment with this drug.
It is important to note that there is no standard treatment regime for PD, with each patient being treated with a tailored approach taking into account the severity of their symptoms and temporal nature of these, the side effects that they experience, and their personal priorities.
Dopamine is incapable of crossing the blood–brain barrier (BBB), and it must be produced within the central nervous system (CNS) in order to act in the striatum. It is primarily synthesized in dopamine-producing neurons (dopaminergic neurons) within the brain, with small amounts of dopamine also being produced in the medulla of the adrenal glands.
In neurodegenerative disorders like Parkinson’s disease any therapeutic intervention that halts or reverses the progression of the disease would be desirable. There are currently no disease-modifying drugs for PD, but the treatments that are used can offer significant symptomatic relief of the motor symptoms. They offer little clinical benefit in terms of the non-motor manifestations of PD.
It is usual practice to delay the initiation of treatment until the patient’s symptoms become troubling, to reduce the impact of adverse effects. A development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages.
Novel solutions might be offered by an evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multitarget approaches and network pharmacology. Several promising randomized controlled trials are in progress, and the increased collaboration between pharmaceutical companies and basic and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of PD.