Parkinson's Disease

Question 1

List common symptoms / signs of Parkinson’s Disease.

Answer 1

• Tremor at rest
• Pill rolling tremor
• Small suffling gait
• Cog wheel rigidity
• Expressionless face

Question 2

What is the pathophysiology of Parkinson’s Diseases

Answer 2

Loss of Dopaminergic neurons within the Corpus Striatum - symptom onset at 70-80% loss of neurons.
Therefore reduced dopamine in the nigrostraital pathway is the cause for symptoms of PD.

Question 3

Parkinsonism classification

Answer 3

1. Bradykinesia (slowness in initiation & execution of voluntary mvmts).
2. Rigidity (muscle stiffness / increased tone).
3. Tremors (at rest).
4. Postural instability (abnormal fixed posture).
5. Gait disturbance (shuffling feet).

Question 4

Drug treatment goals / target of Parkinson’s Disease management.

Answer 4

Increase the levels of Dopamine within the CNS.

Question 5

Approx what precentage of L-dopa crosses the blood brain barrier?

Answer 5

1-3% which is then converted by AADC / DDC
(dopamine decarboxylases) to Dopamine (DA) = action on D1 and D2 receptors for theraputic effect.

Question 6

Treatment options for Parkinson’s Disease

Answer 6

1. Provide a Dopamine precurser (Levodopa).
2. Peripheral Dopamine Decarboxylase inhibitors (Carbidopa).

Question 7

What causes the majority of adverse effects of Dopamine precursers?

Answer 7

The 97% of L-dopa that doesn’t cross the blood brain barrier is converted to dopamine which acts on the peripheral nervous system producing adverse effects such as:
D1 receptors on blood vessels = hypertension.
B1 receptors on the heart = tachycardia /palpitations / exaggerates arythmias
A1 receptors on blood vessels = hyptertension.
CT2 (chemoreceptor trigger zones) = nausea and vomitting.
*tolerance can develop to these side effects.

Question 8

What is the role of Peripheral Dopamine Decarboxylase inhibitors (Carbidopa).

Answer 8

The role of DDC inhibitors is to reduce the amount of L-dopa converted to dopamine in the peripheral system.
Recall 97% does not cross the blood brain barrier and therefore causes various symptoms (hypertension, tacycardia, exaggerated arythmias and nausea and vomitting).
Therefore by inhibiting the enzyme that converts L-dopa to dopamine peripherally these peripheral side effects are reduced.

Question 9

What is the role of COMPT inhibitors in the treatment of Parkinson’s Disease?

Answer 9

The role of COMPT inhibitors is to reduce the amount of L-Dopa being converted to 3-MEO Dopa which is ultimately converted to dopamine in the peripheral system.

Recall that L-Dopa can be degrated by both COMPT and DDC (Dopa-decarboxylase) thus to reduce the amount of L-dopa being converted peripherally (and thus causing side effects) drugs to inhibit both enzymes have been developed.
COMPT inhibitors - Entacapone
DDC inhibitors - Carbidopa