Parkinson's Disease Overview

Parkinson's Disease

Parkinson's disease is a progressive neurodegenerative disease characterized by tremors, muscle rigidity, bradykinesia, and postural and gait abnormalities.
Bradykinesia must be present for a diagnosis of Parkinson's disease.
Cognitive decline is common as the disease progresses.
Non-motor symptoms include anxiety, depression, confusion, personality changes, apathy, fatigue, autonomic dysfunction, dysphagia, choking, sweating abnormalities, sialorrhea, blood pressure disturbances, sleep disorders, and sensory complaints/pain.
The cause of Parkinson's disease is unknown, but risk factors include hereditary basis, exposure to toxins like manganese dust, carbon disulfide, and carbon monoxide, multiple subcortical white matter infarcts, recurrent head injury, and association with other neurological disorders.
Parkinson's disease is linked to the destruction of dopaminergic neurons in the substantia nigra, leading to a reduction of dopamine in the corpus striatum, a part of the basal ganglia involved in motor control.
The substantia nigra is the source of dopaminergic neurons that terminate in the neostriatum.
Dopaminergic neurons from the substantia nigra fire tonically, suggesting a sustaining influence on motor activity, rather than specific movements.
The neostriatum is connected to the substantia nigra through neurons that release the inhibitory transmitter GABA.
Cells in the substantia nigra send neurons back to the neostriatum, releasing the inhibitory transmitter dopamine.
This mutual inhibitory pathway maintains a balance of inhibition in both areas.
In Parkinson's disease, destruction of cells in the substantia nigra leads to degeneration of nerve terminals that release dopamine in the neostriatum.
This reduces the normal inhibitory influence of dopamine on cholinergic neurons in the neostriatum, resulting in an overproduction or relative overactivity of acetylcholine.
Certain amino acids (proteins) from ingested food compete for absorption from the gut and transport from the blood to the brain.

Anti-Parkinson's Drugs

Anti-Parkinson's drugs aim to manage the symptoms of Parkinson's disease by increasing dopamine levels in the brain or mimicking its effects.

Levodopa/Carbidopa

Levodopa is a precursor to dopamine that crosses the blood-brain barrier and is converted into dopamine.
Carbidopa is a decarboxylase inhibitor that prevents the breakdown of levodopa in the periphery, increasing levodopa's bioavailability.
Levodopa/Carbidopa is the mainstay treatment for Parkinson's disease.
Therapeutic uses include management of bradykinesia and other motor symptoms.
Commonly available in 25mg carbidopa/250mg levodopa or 25mg carbidopa/100mg levodopa formulations.
Extended-release formulations like Rytary (capsules with a 1:4 ratio of carbidopa: levodopa) and oral disintegrating formulations like Parcopa (10/100, 25/100, and 25/250mg combinations) are available.
Stalevo, a combination of levodopa, carbidopa, and the COMT inhibitor entacapone, is also used.
Infusion therapy of levodopa-carbidopa into the duodenum and upper jejunum is available and safer than oral formulations in advanced disease with response fluctuations.
Gel formulations delivered via a nasoduodenal tube and portable infusion pumps are available.
Withdrawal should be gradual.

Peripheral Adverse Effects of Levodopa/Carbidopa

Anorexia, nausea, and vomiting due to stimulation of the chemoreceptor trigger zone.
Tachycardia and ventricular extrasystoles from dopaminergic action on the heart (rarely atrial fibrillation).
Hypotension.
Mydriasis from adrenergic action on the iris.
Blood dyscrasias (positive Coomb's test).
Brownish urine/saliva due to melanin pigment produced from catecholamine oxidation.

CNS Adverse Effects of Levodopa/Carbidopa

Visual and auditory hallucinations.
Dyskinesia (abnormal involuntary movements).
Mood changes, including depression, psychosis, anxiety, and the on-off phenomenon.

Drug Holiday (Levodopa/Carbidopa)

Temporary discontinuation of levodopa/carbidopa for 3-21 days can temporarily improve responsiveness, but has limited effectiveness in the on-off phenomenon.
There is a risk of aspiratory pneumonitis, venous thrombosis, pulmonary embolism, and depression due to immobility in severe parkinsonism.

Drug Interactions (Levodopa/Carbidopa)

Pyridoxine (Vitamin B6) increases the peripheral breakdown of levodopa, reducing its effectiveness unless a decarboxylase inhibitor is used.
Concomitant administration of levodopa and MAOIs like phenelzine can lead to a hypertensive crisis due to increased catecholamine production.
Antipsychotic drugs are generally contraindicated in Parkinson's patients.

Contraindications (Levodopa/Carbidopa)

Psychotic patients (low-dose quetiapine or clozapine may be used in some cases).
Arrhythmias.
Closed-angle glaucoma.
Active peptic ulcer disease (GIT bleeding with levodopa).
Melanoma or suspicious skin lesions (levodopa is a precursor to skin melanin).

Dopamine Receptor Agonists

This group of drugs includes bromocriptine, pergolide, pramipexole, rotigotine, and ropinirole.
They have a longer duration of action than levodopa and are effective in patients with response fluctuations to levodopa.
They act directly on postsynaptic dopamine receptors without enzymatic conversion to an active metabolite.
They do not compete with other substances for active transport into the blood and across the blood-brain barrier.

Bromocriptine

Similar actions to levodopa but with higher rates of hallucinations, confusion, delirium, nausea, orthostatic hypotension, and lower dyskinesia.
Potential to cause pulmonary and retroperitoneal fibrosis due to its ergot derivative nature.
Its use has been superseded by newer agents.

Pramipexole

Non-ergot derivative with preferential affinity for D3 receptors.
Effective as monotherapy for mild parkinsonism, helpful in advanced disease, reducing levodopa dosage and smoothing out response fluctuations.
May ameliorate affective symptoms.
Scavenges H2O2, contributing to a neuroprotective effect.
Rapidly absorbed orally with peak plasma concentration in 2 hours.
Excreted largely unchanged in the urine.
Dosage starts at 0.125mg 3x/day, doubled every week.
Extended-release preparation is available for convenience and to prevent blood level swings.

Ropinirole

Another non-ergot derivative, also used for restless legs syndrome.
Acts as a D2 receptor agonist, effective as monotherapy in mild Parkinson's disease and for smoothing the response to levodopa in advanced disease and response fluctuations.
Dosage starts at 0.25mg 3x/day, increased to 0.75mg/day at weekly intervals.
Extended-release formulation is available.

Rotigotine

Dopamine agonist delivered via a skin patch.
Treats early Parkinson's disease.
Provides more continuous dopaminergic stimulation than oral medication in early Parkinson's disease.

Apormorphine

Used in acute hypomobility (off phenomenon) in advanced Parkinson's disease.
Transdermal patch administered once daily.

Adverse Effects of Dopamine Receptor Agonists

GIT: Anorexia, nausea, vomiting, constipation, dyspepsia, reflux esophagitis, bleeding peptic ulcer.
CVS: Postural hypotension, painless digital vasospasm, cardiac arrhythmias, peripheral edema, cardiac valvulopathy (pergolide).
CNS: Dyskinesias, mental disturbances (confusion, hallucinations, delusions), impulse control disorder (compulsive disorder), withdrawal syndrome.
Miscellaneous: Headache, hallucinations, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis (mainly with ergot-derived dopamine agonists), erythromelalgia (red, tender, swollen, painful feet and arthralgia).
Rarely: Uncontrollable tendency to fall asleep at inappropriate times, especially with pramipexole and ropinirole (discontinuation required).

Contraindications (Dopamine Receptor Agonists)

Psychotic illness.
Recent myocardial infarction.
Active peptic ulcer.
Ergot-derived agonists are best avoided in patients with peripheral vascular disease.

Monoamine Oxidase Inhibitors

Two types of monoamine oxidase enzymes exist in the nervous system:
- MAO A: Metabolizes norepinephrine, serotonin, and dopamine.
- MAO B: Metabolizes dopamine alone (selectively).

Selegiline (Deprenyl)

Selectively inhibits MAO type B, which metabolizes dopamine.
Does not inhibit type A except at higher doses, where it loses its selectivity.
Increases dopamine levels in the brain by decreasing its metabolism.
Enhances the actions of levodopa and reduces its required dose.
At recommended doses, it has a low potential for causing hypertensive crisis.
Risk of severe hypertension at higher doses when selectivity is lost.
Metabolized to methamphetamine and amphetamine, which can cause insomnia.
Used as an adjunct therapy with declining or fluctuating response to levodopa.
Dosage: 5mg with breakfast and 5mg with lunch. Can cause insomnia if taken after mid-afternoon.

Rasagiline

Irreversible and selective inhibitor of brain MAO type B, 5x more potent than selegiline.
Not metabolized to an amphetamine-like substance.
More potent than selegiline in preventing MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinsonism.
MPTP causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra.
Used for early treatment in patients with mild symptoms and as an adjunct therapy at 0.5-1mg/day to prolong the effect of levodopa-carbidopa in patients with advanced disease and response fluctuation.
Dosage: 1mg/day.

Safinamide

Selective MAO-B inhibitor used as an adjunct therapy with levodopa-carbidopa.
Not effective as monotherapy for Parkinson's disease.
Starting dose: 50mg PO once daily, increased to 100mg once daily after 2 weeks.

Precautions (MAO-B Inhibitors)

MAO-B inhibitors should not be taken by patients receiving:
- Meperidine
- Tramadol
- Methadone
- Propoxyphene
- Cyclobenzaprine
- Antitussives (Dextromethorphan) (over-the-counter cold preparations)
MAO-B inhibitors should not be taken with other MAOIs.
Avoid in patients receiving TCAs or SSRIs due to the risk of acute toxic interactions (serotonin syndrome, rare).
MAO-B inhibitors may increase the adverse effects of levodopa, such as dyskinesia, mental changes, nausea, and sleep disorders.
The use of levodopa and a non-selective MAOI should be avoided due to the risk of hypertensive crises caused by peripheral accumulation of NE.

Catechol-O-Methyltransferase Inhibitors

COMT methylates levodopa to 3-O-methyldopa (3-O-MD), a minor pathway for levodopa metabolism.
When peripheral dopamine decarboxylase activity is inhibited by carbidopa, significant levels of 3-O-MD are formed, competing with levodopa for active transport into the CNS (BBB) and across the intestinal lining.
Entacapone and tolcapone selectively and reversibly inhibit COMT.
This decreases plasma levels of 3-O-MD and increases levodopa uptake, leading to higher concentrations of brain dopamine.
Tolcapone has both central and peripheral effects. Half-life is about 2 hours, more potent, and has a longer duration of action than entacapone, taken 100mg 3 times daily.