Session 11 - Parkinsons Flashcards
Give four motor symptoms which characterise parkinson’s disease
Tremor
Rigidity
Bradykinesia
Postural Instability
Describe the tremor which occurs in parkinsons - What is it caused by?
Low frequency rest tremor
Abolished by movement
Low dopamine and disturbance of other neurotransmitters
What two types of rigidity do you find in parkinsons?
Lead pipe rigiditiy/Cog-wheel
What type of rigidity do you not find in parkinsons and why?
Clasp knife
Sign of pyramidal disorder, which parkinsons is not.
What is rigidity caused by in parknson’s
Low dopamine and disturbance of other NTs
What is bradykinesia caused by in dopamine
Low dopamine
Give 6 non-motor manifestations of parkinson’s
o Mood changes o Pain o Cognitive change o Urinary symptoms o Sleep disorder o Sweating
What are two causes of parkinonism
o Idiopathic Parkinson’s Disease
o Dopamine blocking or depleting drugs
Particularly antipsychotics
How is parkinson’s disease taken up?
Pre-synaptically by dopaminergic neurones
What are the two main pathologies which come in parkinsons?
Presence of neuronal inclusion called lewy bodies
Loss of dopaminergic neurones from pars compacta of the substantia nigra in the midbrain that project to the striatum of the basal ganglia
What are lewy bodies and how do they progress?
Contain tangles of α-synuclein and ubiquitin
Gradually become more widespread as the condition progresses, spreading from lower brainstem Midbrain Cortex
When do parkinson’s symptoms occur?
Once there is 50% cell loss
Outline the metabolic path of dopamine (before it and after)
L-Tyrosine -> L-Dopa -> Dopamine -> Noradrenaline -> Adrenaline
What converts L-dopa to dopamine?
DOPA decarboxylase
What is the main pharmacokinetic properterial difference between L-Dopa and Dopamine
L-dopa can.. Wait for it.. Cross the BBB :D :D :D :D !!! :D :D :D !!! :D :D :D :D
Name 6 drugs used in Parkinson’s treatment
Levodopa (L-DOPA) o Dopamine receptor agonists o MAOI Type B inhibitors o COMT inhibitors o Anticholinergics o Amantadine
What is the route of admine of L-Dopa?
Oral
How much of an L-Dopa dosa reaches the brain
1%
What are indications for L-DOPA (1)
Parknsons
What is the mechanism of action for L-dopa
L-DOPA is the immediate precursor of Dopamine and is able to penetrate the blood brain barrier to replenish the dopamine lost in the Neostriatum
Name four ADRs for L-dopa
Nausea and vomiting
Psychiatric side effects (Schizophrenia-like symptoms)
Cardiovascular effects (hypotension)
Dyskinesia
What kind of drug is L-dopa usually given with and why?
peripheral DOPA decarboxylase inhibitor (Sinemet, Madopar), reducing necessary dose, side effects and increase the amount of L-DOPA reaching the brain
Name a pharamocologically active substance which would increease breakdown of L-dopa
Vitamin B6
What is the risk of using monoamine oxidase inhibitors as L-dopa adjuvants
Hypotensive crisis
What do anti-psychotics do in parkinsons?
block dopamine receptors and parkinsonism is a side-effect
Why do large doses of L-dopa have to be given?
Extensive peripheral metabolism of L-DOPA means that large doses have to be given to produce therapeutic effects. These large doses are more likely to bring about adverse effects.
What inhibits absorption of L-dopa
Large protein meals (compete with amino acids)
How is L-dopa metabolised in the body?
90% inactivated in intestinal wall by MAO and DOPA decarboxylase
9% converted to dopamine in peripheral tissues
1% crosses BBB to enter the CNS (competes with amino acids)
Give two advantages of L-dopa
Highly efficacious
Low side effects
Give two disadvantages of L-dopa
Precursor, needs enzyme conversion
- Long term loss of efficacy and development of involuntary movements
Why would you use a dopamine receptor agonist?
Used in combination with L-DOPA in an attempt to reduce it’s late adverse effects, or when it does not control symptoms
Give three ADRs for dopamine agonists
Sedation, hallucination, confusion
Nausea
Hypotension
Psychiatric symptoms
What is the most commonly used dopamine receptor agonist?
Bromocriptine is most used
What are the main psychiatric side-effects of dopamine receptor agonists
impulse control disorder – pathological gambling, compulsive shopping - Basically due to shit high dopamine
Why is mech of action of monoamine oxidase inhibitor useful in parko?
Selegiline selectively inhibits the MAOB enzyme in the brain that is normally responsible for the breakdown of dopamine. By inhibiting breakdown, the dose of L-DOPA is prolonged.
Give three ADRs of MOA
Selegiline selectively inhibits the MAOB enzyme in the brain that is normally responsible for the breakdown of dopamine. By inhibiting breakdown, the dose of L-DOPA is prolonged.
What is a Catechol-O-methyl Transferase Inhibitors used for
Adjunct to L-DOPA therapy to reduce end-dose ADRs
Give a contra-indication for COMT?
Phaeochromcytoma - Can’t break down dat noradrenaline any more! So much adrenaline! Ahh!
What is the mechanism of action of COMT
Inhibits the enzyme COMT, which degrades L-dopa in the periphery. No therapeutic effect alone.
Potentiates effects of L-dopa
Give three ADRs for COMT
Nausea and Vomiting
Abdominal pain
Diarrhoea
What is the mech of action of anti-cholinergics in parko
Antagonists at the muscarinic receptors that mediate striatal cholinergic excitation
Acetylcholine -> Antagonistic effect on dopamine
Main action in treatment of Parkinson’s disease is to reduce excessive striatal cholinergic activity
What are the main ADRs of anti-cholinergics?
Alzheimers effects!
CNS effects – Mild memory loss, acute confusional states
Dry mouth and blurred vision (less common)
Give two therapeutic notes for anticholinergics, in respect to withdrawal of therapy
Termination of anticholinergic treatment should be gradual, as parkinsonism can worsen when these drugs are withdrawn
Good for treating tremor, however has no effect on bradykinesia
What does amatadine do and when is it used?
Synergistic effect when used in conjunction with L-DOPA
Stimulates neuronal dopamine release and inhibition of its reuptake
Additional muscarinic blocking actions
Give three ADRs of amantadine
Anorexia
Nausea
Hallucinations
How do you reduce side-effects of parkinsons?
Reduce L-dopa dose and add an adjuvant
What is surgery used for in parko?
To remove lesions causing tremor and globus pallidus dysfunction
What can you do to the subthalamic nucleus to treat parko?
Deep brain stim to relieve symptoms
HOw does parko get worse
Over 15 year period
o Dyskinesia – 94% (writhing movement due to L-DOPA treatment)
o Falls – 81%
o Cognitive Decline – 84% (50% have hallucinations)
o Somnolence – 80%
o Swallowing Difficulty – 50%
o Severe Speech Problems – 27%
What is myasthenia gravis? (3 main pathological things + bit that causes death)
o An autoimmune destruction of the end-plate ACh receptors
o Loss of junctional folds at the end-plate
o A widening of the synaptic cleft
The crisis point is when it affects respiratory muscles
Give three presenting symptoms of myasthenia gravis
o Drooping eyelids
o Fatigability and sudden falling due to reduced ACh release
o Double vision
When are symptoms of myasthenia gravis worse?
Effected by general state of health and emotion
What is treatment for myasthenia gravis?
o Acetylcholinesterase inhibitors (e.g. Pyridostigmine)
Prevent breakdown of Ach in synaptic cleft
What are side-effects of Acetylcholinesterase inhibitors?
Can cause muscarinic side effects (parallel those effects seen with excessive release of Ach)
Miosis
SSLUDGE Syndrome
What is plasmapheresis used for in myasthenia gravis?
o Plasmapheresis
Removes AchR antibodies and gives short term improvement
Immunosupression for long term treatment
What is SSLUDGE syndrome?
Muscarinic side effects o Salivation o Sweating o Lacrimation o Urinary Incontinence o Diarrhoea o GI upset and hypermotility o Emesis
