Clinical Lecture: Pharmacology of Movement Disorders

Question 1

Truth or False: PD symptoms presents unilaterally initially.

Answer 1

Initially, it may present with a mild tremor. It usually starts unilaterally and can become bilaterally later and even get to the point of whole body tremor.

Question 2

What do PD patients usually die of?

Answer 2

Death from PD is usually not due to the lesion but instead indirectly - usually bronchopneumonia or sepsis. Once pharmacological intervention does not work, the patient is bed-ridden, they cannot breath properly and so get infections.

Another major cause of death is falls.

Question 3

What are the symptoms and pathogenesis of Parkinson’s disease?

Answer 3

Symptoms:

• ‘Pill-rolling’ tremor - 4-7 Hz
• Akenisa - including ‘Serpentine stare’ and facial Immobility
• Bradykinesia
• Cog-wheel Rigidity
• Immobility
• Speech is slurred, monotone, dribbles, dysphagia can develop

Pathogenesis: There is loss of neurones in the substance nigra especially those dopamine producing. This leads to a lack of ignited moved via the direct and indirect pathway.

There are also leeway body aggregates see that contain alpha synucleins and amyloid beta.

The cause is unknown. In most causes it is idiopathic - but causes include iatrogenic, MTPT (amphetamine) induced and post-encephalitic.

Question 4

What drugs can be used to treat PD?

Answer 4

• Drugs to replace - L-DOPA
• Prevent the breakdown of Dopamine - MAO and COMT inhibitors
• Promote Dopamine Release (amantadine)
• Activate the Dopamine receptors using agonists (Bromocriptine, pergolide)
• Reduce the activity of cholinergic neurones in the striatum which will have the same effects - anti-muscarinics agent

Question 5

What are the adverse effects of L-DOPA therapy?

Answer 5

• L-DOPA is broken down by the GI tract. Though it crosses the BBB readily only 1% reaches the brain.
• On-Off effect - as the level of dopamine decreases we see a worsening of PD symptoms, worse than baseline before L-DOPA therapy.
• Nausea, Vomiting
• Dyskinesia if the dose is wrong
• Tachycardia, extrasystoles
• Hypotension
• Insomnia, confusion, schizophrenic effects

The side effects become greater with times the effect wears off as neurones die. Ultimately it no longer works as a therapy as you no longer have enough neurones to release dopamine as they die.

Question 6

What combination therapy can we use to overcome the fact only 1% of L-DOPA reaches the brain?

Answer 6

Carbidopa - Carbidopa is an inhibitor of DOPA decarboxylase and has some effects of MAO. Preventing the breakdown, increases the amount of Dopamine that gets to the brain. Carbidopa does not get through the BBB and so inhibits metabolism in the systemic circuit only. A larger dose of LDOPA is therefore available at the target site.

Question 7

What is the most common MAO inhibitor used?

Answer 7

Selegiline

Question 8

What type of drug is Entacapoine?

Answer 8

COMT inhibitors

Question 9

What are side effects of Bromocriptine?

Answer 9

These are Dopamine agonists. Bromocriptine is a mixed D1/D2 receptor agonists. Pergolide is preferred as it is D2 selective. It can be given alone or in combination with L-DOPA.

Side effects are similar to L-DOPA, such as:
○ Dyskinesias - increase dopamine in other areas
○ Nausea, vomiting
○ Severe hypotensive effects

The patient can also experience hallucinations
and a change impulsive behaviours - this has to be considered when prescribing these drugs.

Question 10

What is the pathogenesis of Huntington’s disease?

Answer 10

Huntington’s disease is an inherited disorder affecting a protein called Huntingtin - a polyglutamine repeat disorder. The sequence CAG which codes for glutamine is inserted in the gene. Most of us have 50-20 polyglutamine repeats. In patients with Huntington’s disease, once they have more than 36 repeats, you start to see symptoms. The more repeats, the greater the severity of the disease.

There is loss of inhibitory outputs form the striatum that project to the thalamus and back to the substantia nigra. The patient has difficulty in stopping movement or preventing involuntary movement.

Question 11

Give symptoms of Huntington’s disease.

Answer 11

• Initially irritability, moodiness and antisocial behaviour which gradually develops into dementia
  
  • Initially presents as fidgeting and restlessness that progresses to Gross Choreiform movements (expansive large movements, o f the tongue etc.)
  • There is signs of cerebellar atrophy on MRI

Question 12

What type of drug is Benzhexol?

Answer 12

Antimuscarinic.They are most effective on tremor and drooling. They have many severe central adverse effects (such as confusion, delusions, hallucinations, drowsiness etc.) and so are only used in patients with severe tremor.

Question 13

What changes in neurotransmitters do we see in Huntington’s disease?

Answer 13

• Reduced GABA
• Reduced GAD
• Reduced Ach
• Reduced Choline Acetyltransferase
  There is no effect on Dopamine. It can be normal or raised.

Question 14

What treatments are available for Huntington’s disease?

Answer 14

There is no cure - death inevitable. Drugs to increase GABA or ACh activity don’t work
We can control movement disorders;
- D2 antagonists - haloperidol, chlorpromazine
- DA depletion - reserpine, tetrabenzine

Adverse effects of such treatment include:

- D2 antagonist leads to Parkinsonism and restlessness
- DA depletion - hypotension, depression, sedation, GI disturbances