Parkinsonism Overview

Parkinsonism

• Parkinsonism is an extrapyramidal motor disorder characterized by rigidity, tremor, and hypokinesia.
• Secondary symptoms include impaired posture and gait, a mask-like face, and excessive saliva production. Dementia can also be a secondary issue.
• Untreated, symptoms worsen progressively over years, leading eventually to immobility, difficulty breathing, and vulnerability to infections.
• Parkinson's Disease (PD) is the most common form, a progressive degenerative disorder, primarily affecting older individuals. Idiopathic cases are the most common, while arteriosclerotic and post-encephalitic cases are less common.
• Wilson's disease, a rare cause of copper poisoning is also a rare cause.
• The primary pathological finding in PD is degeneration of neurons in the substantia nigra pars compacta (SN-PC) and the nigrostriatal dopaminergic tract. This deficiency in dopamine (DA) within the striatum disrupts muscle tone and coordinated movement.
• An imbalance between the dopaminergic (inhibitory) and cholinergic (excitatory) systems, creates the motor defects, though the cholinergic system is not primarily impacted.
• The exact cause of nigrostriatal neuron degeneration appears multifactorial.
• Oxidative stress from dopamine metabolism and age-related/acquired defects in protective mechanisms contribute to neuronal damage.
• Environmental toxins and genetics may also contribute.
• Exposure to MPTP, a synthetic toxin, causes nigrostriatal degeneration and PD-like symptoms by affecting energy metabolism in dopaminergic neurons.
• Glutamate excess can induce 'excitotoxic' neuronal death. 
• Medications like neuroleptics and metoclopramide can induce temporary parkinsonism.
• Reserpine use historically caused this.

Antiparkinsonian Drugs

• A breakthrough in treating PD occurred in 1967, when levodopa was found to dramatically improve symptoms.
• Levodopa (L-dopa) is a precursor of dopamine which is used to treat PD because dopamine itself cannot cross the blood-brain barrier.
• Dopamine precursor, peripheral decarboxylase inhibitors, and dopamine agonists are important types of drugs used to treat PD.
• MAO-B Inhibitors and COMT Inhibitors are also used to potentiate levodopa to extend the efficacy  of the drug.

Classification of Antiparkinsonian Drugs

• Drugs affecting the brain's dopaminergic system are crucial and include dopamine precursors (levodopa); peripheral decarboxylase inhibitors (carbidopa, benserazide); dopamine agonists (bromocriptine, ropinirole, pramipexole); MAO-B inhibitors (selegiline, rasagiline); and COMT inhibitors (entacapone, tolcapone).
• Drugs affecting the brain's cholinergic system are also used and include central anticholinergics (trihexyphenidyl, procyclidine, biperiden) and antihistamines (orphenadrine, promethazine).
• Glutamate (NMDA receptor) antagonists (amantadine) are also used.

Actions and Effectiveness of Drugs

• Levodopa, the most effective treatment, greatly improves movement disorders in Parkinson's Disease.
• Levodopa's efficacy is high in early-stage disease. 
• Side effects like nausea, vomiting, postural hypotension, cardiac arrhythmias, and psychiatric symptoms may be problematic. Dyskinesias are common and often dose-related, potentially impairing function.
• Additional drugs such as COMT inhibitors and MAO-B inhibitors are given with levodopa to enhance treatment efficacy  and reduce the dose needed.
• Non-ergoline dopamine agonists, such as ropinirole, pramipexole are being used increasingly as effective treatments that are less prone to early dopaminergic neuron damage and offer similar efficacy to levodopa.
• Central anticholinergics like trihexyphenidyl produce substantial improvement, especially to tremor. 
• These drugs have little effect on the underlying disease pathology, only mitigating manifestations.
• The effects of levodopa include a 'general alerting response', which can at times manifest as mild excitement or even frank psychosis. 
• Excessive dopamine can also lead to unwanted side effects such as increased sexual activity.
• Dementia is not reversed by levodopa.

Problems in Long-term Therapy

• Fluctuations in motor performance ("on-off" phenomenon) can develop after several years of levodopa treatment.
• "End-of-dose" deterioration and rapid motor fluctuations are among consequences.
• Progressive neuronal damage usually leads to more frequent and more severe fluctuations.
• Combination therapy, with additional drugs, helps manage fluctuation issues and improves quality of life.