Pharmacology 2: Pharmacologic Management of Parkinsonism

Parkinsonism

• Parkinsonism is a common movement disorder characterized by dysfunction in the basal ganglia and associated brain structures.
• Signs include rigidity of skeletal muscles, akinesia (or bradykinesia), flat facies, and tremor at rest (mnemonic RAFT).

Facts about Parkinson's Disease

• Parkinsonism can occur for a variety of reasons, but is usually idiopathic (Parkinson's disease or paralysis agitans).
• Bradykinesia should be present before a diagnosis of Parkinson's disease is made.
• Focal dystonic features may be present.
• Cognitive decline occurs in many patients as the disease advances.
• The disease is incurable, generally progressive, and leads to increasing disability with time, but pharmacologic treatment may relieve motor symptoms and improve the quality of life for many years.

Pathogenesis of Parkinsonism

• Pathogenesis seems to relate to a combination of impaired protein degradation, intracellular protein accumulation and aggregation, oxidative stress, mitochondrial damage, inflammatory cascades, and apoptosis.
• Epidemiologic studies reveal that cigarette smoking, coffee, anti-inflammatory drug use, and high serum uric acid levels are protective, whereas the incidence of the disease is increased in those working in teaching, health care, or farming, and in those with lead or manganese exposure or with vitamin D deficiency.

Drug Therapy of Other Movement Disorders

A. Tremor

• Physiologic and essential tremor are clinically similar conditions characterized by postural tremor.
• Conditions may be accentuated by anxiety, fatigue, and certain drugs, including β-adrenergic blockers, tricyclic antidepressants, and lithium.
• β-blockers, including propranolol, may alleviate symptoms.
• Metoprolol, a β1-selective antagonist, is also effective, and its use is preferred in patients with concomitant pulmonary disease.
• Antiepileptic drugs, including gabapentin and topiramate, as well as intramuscular injection of botulinum toxin, have also been used to treat essential tremor.

B. Huntington's Disease and Tourette's Syndrome

• Huntington's disease is an inherited disorder resulting from a brain neurotransmitter imbalance, with diminished GABA functions and enhanced dopaminergic functions.
• Pharmacologic attempts to enhance brain GABA and acetylcholine activities have not been successful in patients with this disease.
• Drug therapy usually involves the use of amine-depleting drugs (e.g., reserpine, tetrabenazine) and dopamine receptor antagonists (e.g., haloperidol, perphenazine).
• Tourette's syndrome is a disorder of unknown cause that frequently responds to haloperidol and other dopamine D2 receptor blockers, including pimozide.

Dopamine Agonists

1. Bromocriptine

• Bromocriptine is an ergot alkaloid that acts as a partial agonist at dopamine D2 receptors in the brain.
• The drug increases the functional activity of dopamine neurotransmitter pathways, including those involved in extrapyramidal functions.
• Common adverse effects include anorexia, nausea and vomiting, dyskinesias, and postural hypotension.
• Behavioral effects, including confusion, hallucinations, and delusions, occur more commonly with bromocriptine than with newer dopamine agonists.

2. Pramipexole

• Pramipexole is a non-ergot dopamine receptor agonist with high affinity for the dopamine D3 receptor.
• It is effective as monotherapy in mild parkinsonism and can be used together with levodopa in more advanced disease.
• Adverse effects include anorexia, nausea and vomiting, postural hypotension, and dyskinesias.
• Mental disturbances, including confusion, delusions, hallucinations, and impulsivity, are more common with pramipexole than with levodopa.