Pharmacology of Parkinson's Disease

Pharmacology of Basal Ganglia Disorders

• Focuses on drugs used to treat Parkinson's Disease.
• Phase 1 Block 3 course material.

Learning Objectives

• Describe common drug classes used to treat Parkinson's Disease, their mechanisms of action within the central nervous system.
• Describe common side effects of drugs used to treat Parkinson's Disease.

Parkinson's Disease (Parkinsonism)

• Major movement disorder characterized by a triad of symptoms:
  • Resting tremor
  • Skeletal muscle rigidity
  • Bradykinesia (poorer quality movement)
• Non-motor symptoms can also occur, like mood disorders, sleep disorders, and gastrointestinal dysfunction.
• Approximately 150,000 individuals in the UK currently have Parkinson's.

Parkinson's Disease Pathology

• Neurodegenerative process involving irreversible loss of dopaminergic neurons, especially in the substantia nigra region of the basal ganglia.
• Evidence of protein synuclein aggregates and neuroinflammation.
• Progressive neuronal death.
• Loss of dopaminergic neurons leads to Parkinson's symptoms.

Pharmacological Strategy for Parkinsonism

• Aims to restore and sustain dopamine activity in the central nervous system (CNS).
• Various drugs affect different steps in dopamine synthesis, transport, and breakdown.
• Diagram shows the different ways in which drugs can interact with dopamine within the CNS

Dopaminergics - Levodopa

• Metabolic precursor to dopamine.
• Naturally converted to dopamine in neurons for dopaminergic neurotransmission.
• Required in the CNS but broken down in the periphery by the enzyme Dopa Decarboxylase.
• For Parkinson's treatment, levodopa is usually combined with a Dopa Decarboxylase inhibitor (e.g., Carbidopa) to reduce peripheral breakdown, increasing the amount reaching the CNS.
• Common side effects include nausea (affecting the chemoreceptor trigger zone), dyskinesia (especially involuntary movements in the face and neck), and psychological symptoms (e.g., hallucinations, compulsive behavior).

Dopaminergics - Dopamine Receptor Agonists

• Synthetic compounds (e.g., Pramipexole, Ropinirole) directly interact with dopamine receptors.
• Mimic the function of dopamine, causing agonist effects.
• Contribute to motor control and may promote the survival of neural tissues.
• Common side effects include nausea and vomiting, dyskinesia, agitation, and hallucinations and confusion. Side effects of these drugs are often more frequent compared to levodopa.

Monoamine Oxidase B (MAO-B) Inhibitors

• Selegiline is an example of a MAO-B inhibitor
• Selectively inhibits the enzyme monoamine oxidase B, which breaks down dopamine in neurons.
• Sustains neuronal dopamine levels to support dopaminergic transmission, relieving Parkinsonism symptoms.
• Common side effects: nausea, sleep disturbances, and constipation.

Catechol-O-methyltransferase (COMT) Inhibitors

• Entacapone is an example
• Inhibits the COMT enzyme, which inactivates dopamine within the CNS.
• Sustains dopamine levels in the CNS, maintaining dopaminergic function and alleviating symptoms.
• Common side effects include nausea, abdominal pain, dyskinesia, and constipation.

Other Drugs (More in Phase 2/3)

• Other receptor systems and neurotransmitters influence motor control.
• Targeting cholinergic and N-methyl-D-aspartate (NMDA) receptors has proven valuable in Parkinsonism treatment.

Further Resources

• Medical Pharmacology & Therapeutics (6th Edition), Chapter 24.
• Healthtalk.org (coverage on dopamine receptor agonists and levodopa).
• DrugBank database (wealth of information on drug mechanisms of action).

This quiz covers the pharmacological treatments for Parkinson's Disease, including key drug classes and their mechanisms of action. You'll learn about the common side effects of medications used to manage this movement disorder, providing a comprehensive understanding of treatment options in the context of basal ganglia disorders.