Pharmacology
Summary
Parkinsonism primarily manifests as a motor syndrome with characteristic symptoms like resting tremors, bradykinesia, rigidity, and postural instability, stemming most commonly from Parkinson's disease. Beyond these motor symptoms, Parkinson’s disease also brings about non-motor challenges such as cognitive impairments, mood alterations, and sleep disturbances. A cornerstone of treatment for these symptoms is levodopa. This compound is specifically designed to traverse the blood-brain barrier, subsequently converting to dopamine in the brain, where it stimulates D2 dopamine receptors and bolsters central dopaminergic activity. However, levodopa’s effectiveness is marred by the fact that only a scant amount reaches the CNS. Most of it undergoes extra-cerebral absorption and decarboxylation into dopamine. This can lead to peripheral side effects including nausea and vomiting, cardiac arrhythmias, and orthostatic hypotension.
Enhancing the bioavailability of levodopa is essential for its effectiveness. This is achieved primarily through two methods: the use of carbidopa, an inhibitor of peripheral DOPA decarboxylase, and COMT inhibitors such as entacapone and tolcapone, which inhibit the conversion of levodopa to 3-O-methyldopa by inhibiting catechol-O-methyl transferase. Long-term levodopa treatment is associated with response fluctuations, with patients often experiencing clinical response fluctuations manifesting as ""wearing off"" and ""on-off"" phenomena. As an alternative, dopamine agonists like ropinirole and pramipexole have proven useful in staving off the early introduction of levodopa. For treating tremor and rigidity, centrally-acting antimuscarinic medications, notably benztropine and trihexyphenidyl, offer relief by rebalancing cholinergic and dopaminergic interactions within the striatum, though they have no effect on bradykinesia.
Lesson Outline
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FAQs
Levodopa, commonly referred to as L-DOPA, serves as a dopamine precursor that can efficiently traverse the blood-brain barrier (BBB). Once inside the CNS, it undergoes conversion to dopamine via the enzyme DOPA decarboxylase. This compensates for the diminished dopamine levels characteristic of Parkinson's disease. However, peripheral metabolism of dopamine can cause side effects like gastrointestinal distress, cardiac arrhythmias, orthostatic hypotension.
Carbidopa is administered with levodopa to inhibit DOPA decarboxylase outside the CNS, preventing premature conversion of levodopa into dopamine. This ensures a larger quantity of levodopa enters the CNS and helps to reduce peripheral side effects like gastrointestinal distress, cardiac arrhythmias, orthostatic hypotension. Catechol-O-methyltransferase (COMT) inhibitors, such as tolcapone and entacapone, enhance levodopa's bioavailability by minimizing its peripheral conversion to 3-O-methyldopa.
Dopamine receptor agonists, such as ropinirole (D2 agonist) and pramipexole (D3 agonist), work by directly stimulating dopamine receptors in the CNS. These drugs can be an effective initial treatment for Parkinson's. These drugs are also indicated in restless leg syndrome (RLS). However, they can exacerbate impulse control disorders.
Over time, the effectiveness of levodopa therapy can decrease due to the progressive loss of dopaminergic neurons. This may lead to unpredictable responses to therapy, known as the "on-off" phenomenon where periods of improved mobility alternate with periods of akinesia unrelated to the levodopa dosing schedule. Additionally, long-term use can cause further side effects, such as dyskinesias and a wearing-off reaction.
Other drugs used in parkinsonism therapy include amantadine, which enhances the effects of dopamine, and antimuscarinic agents like trihexyphenidyl and benztropine, which can help control tremor and rigidity. MAO-B inhibitors like selegiline are also used to slow down the breakdown of dopamine in the CNS.
