Clinical Pharmacology of Parkinson's Disease & Myasthenia Gravis

Question 1

List some of the clinical features of Parkinsonism

Answer 1

Tremor

Rigidity

Bradykinesia

Postural instability

Question 2

What is the difference between clasp-knife, lead-pipe and cog-wheel signs?

What type of neurological signs do each indicate?

Answer 2

Clasp-knife: spasticity- initial resistance followed by sudden release (UMN sign)

Lead-pipe: continuous rigidity when moving (Parkinsonism)

Cog-wheel: intermitent rigidity when moving (Parkinsonism)

Question 3

List some non motor manifestations of Parkinsonism

Answer 3

Mood changes

Pain

Cognitive change

Urinary symptoms

Sleep disorder

Sweating

Question 4

Explain the prognosis of PD by using 15 year follow up %s

Answer 4

Dyskinesia- 94%

Cognitive Decline- 84%

Falls- 81% Somnolence- 80%

Difficulty swallowing- 50%

Severe speech problems- 27%

Question 5

What features need to be present to diagnose idiopathic parkinsons disease?

Answer 5

Clinical features

Exclusion of other causes of Parkinsonism

Response to treatment

Structural neurology imaging is normal

Question 6

Where are the cell bodies of dopaminergic neurones found?

Answer 6

In the substantia nigra of the basal ganglia

Question 7

What effect does dopaminergic neurone stimulation have on the neostriatium in “normal” circumstances?

Answer 7

Inhibitory effect on ACh production

Question 8

How does loss of dopaminergic neurons in the substantia nigra lead to impaired mobility (as in Parkinsonism)?

Answer 8

Loss of dopaminergic neurons

Loss of inhibiton of Ach production in the neostratum

Stimulation of motor cortex and spinal cord

Leads to problems starting and planning movement

Question 9

L-DOPA is generated from _________ by the enzyme, ______________

Answer 9

L-Tyrosine

Tyrosine hydroxylase

Question 10

L-DOPA is converted to what by DOPA decarboxylase?

Answer 10

Dopamine

Question 11

Dopamine is converted to what using dopamine B-hydroxlase?

This can then be converted by further enzymatic action to what?

Answer 11

Noradrenaline

Adrenaline

Question 12

What are the 6 classes of drugs that can be used in the treatment of idopathic PD?

Answer 12

Levodopa

Dopamine receptor agonists

MAOI type B inhibitors COMT inibitors

Anticholinergics Amantidine

Question 13

Why can we not just use dopamine in the treatment of IPD?

Answer 13

It does not cross the BBB whereas L-DOPA can cross via active transport

Question 14

Why is treatment with L-DOPA less effective with advancing IPD?

Answer 14

L-DOPA must be taken up by dopaminergic neurons in the substantia nigra to be converted to dopamine

The less cells there are here, the less reliable L-DOPAs effects

Question 15

How is Levodopa administered?

Answer 15

Orally

Question 16

How is Levodopa absorbed?

Answer 16

By active transport

In competition with amino acids (no high protein meals with it)

Question 17

What is the half life of Levodopa?

What does this mean in relation to administration?

Answer 17

2 hours

Should be given in short dose intervals

Fluctuations in blood levels and symptoms

Question 18

How can we prevent Levodopa from being converted to dopamine in the peripheral tissues?

Give three reasons why we would want to prevent peripheral dopamine production

Answer 18

Use in combination with a peripheral DOPA decarboxylase inhibitor

1. Reduce the required dose of L-DOPA
2. Reduced side effects
3. Increased L-DOPA reaching the CNS

Question 19

Give two examples of L-DOPA formulations that are used to treat IPD?

Answer 19

Co-careldopa (Sinemet)

Co-beneldopa (Madopar)

Question 20

What are some advantages of L-DOPA over other classes of drugs used to treat IPD?

Answer 20

Highly efficacious

Low side effects

Question 21

List some of the side effects of L-DOPA

Answer 21

Nausea

Anorexia

Hypotension

Psychosis

Tachycardia

Question 22

Give some disadvantages of L-DOPA compared to other IPD therapy

Answer 22

It is a precursor- requires enzymatic conversion

In the long-term: loss of efficacy involuntary movements and motor complications

Question 23

_______ increases peripheral breakdown of L-DOPA

Answer 23

Pyridoxine (Vitamin B6)

Question 24

What is the risk when combining MAOIs with L-DOPA?

Answer 24

Hypertensive crisis

Question 25

Dopamine receptor agonists can be separated into which categories?

Answer 25

Ergot derived Non-ergot derived Patches Subcutaneous

Question 26

Give some examples of ergot-derived dopamine receptor agonists

Answer 26

Bromocryptine Pergolide Cabergoline

Question 27

Give some examples of non ergot-derived dopamine receptor agonists

Answer 27

Ropinirole Pramipexole

Question 28

List some advantages of Dopamine Receptor Agonists compared to other treatments for IPD

Answer 28

Direct acting Less motor complications Possible neuroprotection

Question 29

List some disadvantages of Dopamine Receptor Agonists compared to other treatments for IPD

Answer 29

Less efficacy than L-DOPA Impulse control disorders More psychiatric side effects Expensive

Question 30

List some side effects of Dopamine Receptor Agonists

Answer 30

Sedation Hallucinations Confusion Nausea Hypotension Impulse control disorders

Question 31

What is the method of action of Monoamine oxidase B inhibitors?

Answer 31

MAOB inhibits the metabolism of dopamine to enhance the effects of dopamine

Question 32

Give some examples of MAOB inhibitors

Answer 32

Selegiline Rasaglaine

Question 33

List some of the advantages of MAOB inhibitors for the treatment if IPD over other treatment methods

Answer 33

Can be used alone Can be used with L-DOPA to prolong its action Smooths out the motor response May be neuroprotective

Question 34

What is the mechanism of action of COMT inhibitors in the treatment of IPD?

Answer 34

Inhibition of catechol-O-methyl Transferase Reduce the breakdown of L-DOPA in the peripheral as the product of this breakdown competes with L-DOPA transport into the CNS NOT USED ALONE

Question 35

What use to COMT inhibitors have in the treatment of IPD?

Answer 35

Used as an "add on" as they have a L-DOPA sparing effect It prolongs the motor response to L-DOPA (reduces symptoms of "wearing off")

Question 36

Give some disadvantages of Anticholinergics in the treatment of IPD

Answer 36

No effect on bradykinesia Generally poorly tolerated Side effects: confustion, drowsiness, anticholinergic side effects Not much place for these in the treatment of PD

Question 37

What is the mechanism of action of Amantadine? When is it used in the treatmne if PD?

Answer 37

The mechanism of action is uncertain Possible enhanced dopamine release It isn't!!!!! Used for fatigue in MS

Question 38

Surgery can be of high value in selected cases of IPD, which patients would make good candidates for surgery?

Answer 38

Dopamine responsive patients Significant side effects with L-DOPA No psychiatric illness

Question 39

What is Myasthenia Gravis?

Answer 39

An autoimmune condition in which antibodies are produced against ACh receptors at the neuromuscular junction

Question 40

What is the main presenting symptom of myasthenia gravis? Where is this most commonly seen?

Answer 40

Fluctuating, **FATIGUABLE,** weakness of skeletal muscle Most common in the extraocular muscles: causing **PTOSIS and DIPLOPIA**

Question 41

How might a patient with bulbar involvement myasthenia gravis present?

Answer 41

Dysphagia Dysphonia Dysarthria

Question 42

Describe the pattern of limb weakness seen in myasthenia gravis

Answer 42

Proximal and symmetric

Question 43

Which kind of drugs exacerbate myasthenia gravis?

Answer 43

Drugs affecting NMJ transmission: Aminoglycosides, beta blockers, CCBs, ACE inhibitors, Magnesium

Question 44

Give examples of some of the complications of myasthenia gravis

Answer 44

Acute exacerbation--\> Myasthenic crisis Overtreatment--\> Cholinergic crisis (depolarising block)

Question 45

What is the main way to therapeutically manage myasthenia gravis? Give an example How is this administered?

Answer 45

Acetylcholinerase inhibitors e.g. Pyridostigmine Orally

Question 46

What is the onset, peak and duration of Pyridostigmine? What is the relevance of these in relation to timing of taking medication?

Answer 46

Onset: 30 minutes Peak: 60-120 minutes Duration: 3-6 hours Needs to be given 30-40 minutes before mealtimes (otherwise risk of aspiration) Needs to be given regularly (TDS initially can go up to 6 times a day)

Question 47

What are the antimusclarinic side effects of acetylcholinesterase inhibitors? What is the mneumonic used to remember these?

Answer 47

**S**alivation **S**weating **L**acrimation **U**rinary incontinence **D**iarrhoea **G**I upset and hypermotility **E**mesis "SSLUDGE"