Pharmacology: Treatment of Parkinsons

Question 1

What are the clinical features of parkinsons?

Answer 1

Tremor: Low frequency, resting tremor so abolished by movement, pill-rolling
Rigidity: Lead pipe or cogwheel - cogwheel can be shown in slowed movement of the wrist
Bradykinesia: small handwriting, dont blink much, reduced amplitude of repetitive movement
Postural instability: forward-flexed shuffling gate, hard to initiate gait and hard to stop

Question 2

What are the non-motor signs and symptoms seen in parkinsons?

Answer 2

• mood changes
• pain
• cognitive change such as hallucinations
• urinary symptoms
• sleep disorders such as REM sleep behaviour disorder where they act out violent dreams
• sweating

Question 3

What is the clinical course of IPD?

Answer 3

Neurodegenerative - 50% of neurones have been lost before any signs or symptoms.
Begins with unilateral symptoms
Progression is very slow
Motor symptoms are very responsive to treatment buy non-motor symptoms tend to be exacerbated by treatment.

Question 4

What are the causes of parkinsonism?

Answer 4

• idiopathic parkinsons disease
• drug induced parkinsonism (eg anti-psychotics,
• vascular parkinsonism
• progressive supranuclear palsy
• multiple system atrophy
• corticobasal degeneration

Question 5

How is idiopathic parkinsons disease diagnosed?

Answer 5

• Clinical features are very characteristic
• Response to treatment, IPD responds very well but other causes of parkinsonism dont
• Structural neuroimaging

Question 6

Outline the synthesis of dopamine

Answer 6

Tyrosine is converted to L-DOPA
DOPA decarboxylase converts it to Dopamine
Dopamine B-hydroxylase converts in to NA
NA is converted to adrenaline

Question 7

Outline the degradation of dopamine

Answer 7

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Question 8

List the drug classes used to treat idiopathic parkinsons disease

Answer 8

• Levodopa
• Dopamine receptor agonists
• MAOI type B inhibitors
• COMT inhibitors
• anticholinergics
• amantadine

Question 9

Why can dopamine not be used to treat parkinsons?

Answer 9

LDOPA crosses the BBB via active transport however dopamine is unable to cross.
Dopamine needs to be in the CNS to be beneficial

Question 10

Why can patients treated with LDOPA get on/off motor fluctuations?

Answer 10

Levodopa must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine.
As parkinsons advances there are fewer dopaminergic cells and therefore they can experience sudden decline in their motor symptoms before their next dose is due.

Question 11

Outline the pharmacokinetics of LDOPA

Answer 11

Absorbed by active transport then 90% is inactivated in the intestinal wall by monoamine oxidase and DOPA decarboxylase.
9% is converted to dopamine in peripheral tissues via DOPA decarboxylase
1% enters the CNS
Half life is 2 hours so needs taking every few hours

Question 12

What are the formulations of LDOPA?

How are these beneficial?

Answer 12

LDOPA is always given in combination with a peripheral DOPA decarboxylase inhibitor - co-claredopa, co-beneldopa.
Benefits: reduces dose required, reduces side effects, increases LDOPA reaching the brain (10% rather than 1%)

Question 13

What are the side effects of LDOPA?

Answer 13

• nausea
• hypotension
• psychosis
• tachycardia
• involuntary movements such as dyskinesias

Question 14

What are the interactions of LDOPA?

Answer 14

• Vitamin B6 increases peripheral breakdown of LDOPA

- Anti-psychotics can block dopamine receptors (therefore common causes of drug-induced Parkinson’s)

Question 15

Why are ergot derived dopamine receptor agonists not used any more?

Answer 15

They cause retroperitoneal, cardiac and pulmonary-pleural fibrosis

Question 16

What are the advantages of dopamine receptor agonists?

Answer 16

• they are direct acting

- cause less dyskinesias and motor complications

Question 17

What are the ADRs of dopamine receptor agonists?

Answer 17

• less efficacy than LDOPA
• impulse control disorders (need to ask every pts about past gambling etc, hypersexuality, compulsive shopping, collecting things)
• psychiatric side effects
• sleep attacks expensive

Question 18

How do monoamine oxidase B inhibitors work?

Answer 18

Monoamine oxidase B is located in the dopamine rich regions of the brain and metabolises it, therefore the effect of the inhibitor is to enhance dopamine.

Question 19

When are monoamine oxidase B inhibitors used?

Answer 19

Can be used alone but also as a booster to prolong the effects of LDOPA and smooth out the motor response.

Question 20

Name some monamine oxidase B inhibitors

Answer 20

selegiline

Rasagaline

Question 21

How do COMT inhibitors work?

Answer 21

Reduce peripheral breakdown on LDOPA so have an LDOPA ‘sparing’ effect so reduces it from wearing off.
Have no therapeutic effect alone, MUST be given with LDOPA

Question 22

What are anticholinergics used?

Answer 22

Ach may have antagonistic effects of dopamine
Anticholinergics play a minor role in the treatment of PD, may reduce the tremor which other drugs tend not to improve very much.

Question 23

What surgery can be done to help PD?

Which patients are suitable?

Answer 23

Deep brain stimulation - electrodes are inserted into the subthalamic nucleus.
Only suitable for patients which are responsive to dopamine, have significant side effects with LDOPA and have no psychiatric illness.

Question 24

What limits the dosage of LDOPA in patients with advanced parkinsons?

Answer 24

Dyskinesia (involuntary writhing movements)

Psychotic side effects