Clinical Pharmacology of Parkinson's Disease & Myasthenia Gravis Flashcards
List some of the clinical features of Parkinsonism
Tremor
Rigidity
Bradykinesia
Postural instability
What is the difference between clasp-knife, lead-pipe and cog-wheel signs?
What type of neurological signs do each indicate?
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)
List some non motor manifestations of Parkinsonism
Mood changes
Pain
Cognitive change
Urinary symptoms
Sleep disorder
Sweating
Explain the prognosis of PD by using 15 year follow up %s
Dyskinesia- 94%
Cognitive Decline- 84%
Falls- 81% Somnolence- 80%
Difficulty swallowing- 50%
Severe speech problems- 27%
What features need to be present to diagnose idiopathic parkinsons disease?
Clinical features
Exclusion of other causes of Parkinsonism
Response to treatment
Structural neurology imaging is normal
Where are the cell bodies of dopaminergic neurones found?
In the substantia nigra of the basal ganglia
What effect does dopaminergic neurone stimulation have on the neostriatium in “normal” circumstances?
Inhibitory effect on ACh production
How does loss of dopaminergic neurons in the substantia nigra lead to impaired mobility (as in Parkinsonism)?
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
L-DOPA is generated from _________ by the enzyme, ______________
L-Tyrosine
Tyrosine hydroxylase
L-DOPA is converted to what by DOPA decarboxylase?
Dopamine
Dopamine is converted to what using dopamine B-hydroxlase?
This can then be converted by further enzymatic action to what?
Noradrenaline
Adrenaline
What are the 6 classes of drugs that can be used in the treatment of idopathic PD?
Levodopa
Dopamine receptor agonists
MAOI type B inhibitors COMT inibitors
Anticholinergics Amantidine
Why can we not just use dopamine in the treatment of IPD?
It does not cross the BBB whereas L-DOPA can cross via active transport
Why is treatment with L-DOPA less effective with advancing IPD?
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
How is Levodopa administered?
Orally
How is Levodopa absorbed?
By active transport
In competition with amino acids (no high protein meals with it)
What is the half life of Levodopa?
What does this mean in relation to administration?
2 hours
Should be given in short dose intervals
Fluctuations in blood levels and symptoms
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
Use in combination with a peripheral DOPA decarboxylase inhibitor
- Reduce the required dose of L-DOPA
- Reduced side effects
- Increased L-DOPA reaching the CNS
Give two examples of L-DOPA formulations that are used to treat IPD?
Co-careldopa (Sinemet)
Co-beneldopa (Madopar)
What are some advantages of L-DOPA over other classes of drugs used to treat IPD?
Highly efficacious
Low side effects
List some of the side effects of L-DOPA
Nausea
Anorexia
Hypotension
Psychosis
Tachycardia
Give some disadvantages of L-DOPA compared to other IPD therapy
It is a precursor- requires enzymatic conversion
In the long-term: loss of efficacy involuntary movements and motor complications
_______ increases peripheral breakdown of L-DOPA
Pyridoxine (Vitamin B6)
What is the risk when combining MAOIs with L-DOPA?
Hypertensive crisis
Dopamine receptor agonists can be separated into which categories?
Ergot derived
Non-ergot derived
Patches
Subcutaneous
Give some examples of ergot-derived dopamine receptor agonists
Bromocryptine
Pergolide
Cabergoline
Give some examples of non ergot-derived dopamine receptor agonists
Ropinirole
Pramipexole
List some advantages of Dopamine Receptor Agonists compared to other treatments for IPD
Direct acting
Less motor complications
Possible neuroprotection
List some disadvantages of Dopamine Receptor Agonists compared to other treatments for IPD
Less efficacy than L-DOPA
Impulse control disorders
More psychiatric side effects
Expensive
List some side effects of Dopamine Receptor Agonists
Sedation
Hallucinations
Confusion
Nausea
Hypotension
Impulse control disorders
What is the method of action of Monoamine oxidase B inhibitors?
MAOB inhibits the metabolism of dopamine to enhance the effects of dopamine
Give some examples of MAOB inhibitors
Selegiline
Rasaglaine
List some of the advantages of MAOB inhibitors for the treatment if IPD over other treatment methods
Can be used alone
Can be used with L-DOPA to prolong its action
Smooths out the motor response
May be neuroprotective
What is the mechanism of action of COMT inhibitors in the treatment of IPD?
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
What use to COMT inhibitors have in the treatment of IPD?
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”)
Give some disadvantages of Anticholinergics in the treatment of IPD
No effect on bradykinesia
Generally poorly tolerated
Side effects: confustion, drowsiness, anticholinergic side effects
Not much place for these in the treatment of PD
What is the mechanism of action of Amantadine?
When is it used in the treatmne if PD?
The mechanism of action is uncertain
Possible enhanced dopamine release
It isn’t!!!!! Used for fatigue in MS
Surgery can be of high value in selected cases of IPD, which patients would make good candidates for surgery?
Dopamine responsive patients
Significant side effects with L-DOPA
No psychiatric illness
What is Myasthenia Gravis?
An autoimmune condition in which antibodies are produced against ACh receptors at the neuromuscular junction
What is the main presenting symptom of myasthenia gravis?
Where is this most commonly seen?
Fluctuating, FATIGUABLE, weakness of skeletal muscle
Most common in the extraocular muscles: causing PTOSIS and DIPLOPIA
How might a patient with bulbar involvement myasthenia gravis present?
Dysphagia
Dysphonia
Dysarthria
Describe the pattern of limb weakness seen in myasthenia gravis
Proximal and symmetric
Which kind of drugs exacerbate myasthenia gravis?
Drugs affecting NMJ transmission:
Aminoglycosides, beta blockers, CCBs, ACE inhibitors, Magnesium
Give examples of some of the complications of myasthenia gravis
Acute exacerbation–> Myasthenic crisis
Overtreatment–> Cholinergic crisis (depolarising block)
What is the main way to therapeutically manage myasthenia gravis?
Give an example
How is this administered?
Acetylcholinerase inhibitors e.g. Pyridostigmine
Orally
What is the onset, peak and duration of Pyridostigmine?
What is the relevance of these in relation to timing of taking medication?
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)
What are the antimusclarinic side effects of acetylcholinesterase inhibitors?
What is the mneumonic used to remember these?
Salivation
Sweating
Lacrimation
Urinary incontinence
Diarrhoea
GI upset and hypermotility
Emesis
“SSLUDGE”
