Parkinsons Flashcards
What is parkinson’s disease
- progressive neurodegeneration of basal ganglia, and later the brain stem
- loss of 70-80& of neurones within substantia nigra
- corresponding loss of dopamine in the striatum
how does parkinson’s effect body chemistry and what are the effects?
- disorder of extrapyrimidal system involving basal ganglia - maintains posture and muscle tones, regulates voluntary smooth muscle activity
- loss of dopamine in nigro-striatal
- relative increase in Ach
- involuntarty muscle contractions interefere with voluntary movement
symptoms of parkinsons
- tremor
- rigidity
- slowness of movement
and more…
3 main dopaminergic pathways
- motor channel (nigrostriatal pathway)
- behaviour/emotion (mesocortical pathway)
- endocrine/secretion (tuberohyophyseal neurons)
what causes the motor symptoms in people with parkinsons?
overactivity of neurotransmitter Ach leads to motor symptoms such as tremor, rigidity.
What are the aims of drug treatment in parkinsons
Aims to treat symptoms not the cause of the neurodegeneration therefore improving the quality of life by minimizing deterioration and side effects
Role of dopaminergic drugs in parkinsons
- increase levels of dopamine in striatum
- deliver a precursor of dopamine thus preventing degredation of dopamine at the neurones
- stimulating dopamine receptors (D2, D3)
- improve bradykinesia and rigidity, less effective at controlling tremor
Dopamine replacemnt therapy
because dopamine cannot cross the BBB, a dopamine precursor is used called Levodopa
Role of Levodopa in parkinsons
- aleve symptoms of, bradykinesia, involuntary movement
- MOA: Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors
- Adverse effects: nausea, vomitting, hypotension, cardia arythmia, coloured urine, GI bleeding
Role of anti-cholonergics in treatment of parkinsons
- Aims to reduce tremour, no effect on slowness of movements
- used in treatment of drug-induced parkinsonian symptoms
examples of antimuscuranics in parkinsons
- Orphenadrine, benzhexol, benztropin, procyclidine
- reduce tremor, no offect on slowness of movement
- less effective than levodopa
- side effects: dry mouth, blurred vision, constipation, confusion, hallucimations, euphoria
How do the symptoms of parkinsons occur?
Loss of dopamine inhibition alters the output of the basal ganglia circuitry resulting in changed motor control producing the typical parkinson’s symptoms of rigidity, tremor, bradykinesia
What is a requirement for levodopa to work?
there must be dopa decarboxylase in remaining striatal neurones
Reducing side effects of levodopa
A dopa decarboxylase inhibitor (DDCI) is used to reduce the side effects of levodopa. reducing the amount of dopamine in the periphary reuces adverse affects.
examples include (carbiodopa and beserazide)
1st and 2nd line treatment early PD
1st line: Levodopa + DDCI
Oral/transdermal non-ergot dopamine agonist
mono-amine oxidase B inhibitors
2nd line: beta-adrenergic antagonists - postural tremour
Amantadine
anti-cholinergics - severe tremour,rigidity, young
Dopamine agonists
- D2 (ergot derived) receptor agonists:
- bromocriptine
- pergolide
- cabergoline
non ergot: - Ropinorole - D2 agonist
- pramipexole - D2,D3 agonist
- Apomorphine - D1,D2 agonist (injection)
side effects of dopamine agonists
- excessive daytime sleepiness (driving, operating machinery)
- peripheral oedema
- hallucinations
*
side effects - ergot derived dopamine agonists
- Risk of heart valve problems = NO due to moderate/severe cardiac valvulopathy
- seroasal fibrosis
- tests required: ECGs, bloods, echocardiogram, x-ray
What does the BBB consist of
specific cellular and etracellular proteins produced and influencing endothelia and pericyte function
Levodopa + Carbiodopa
MOA: Levodopa crosses the BBB and gets converted into Dopamine via Dopa-decarboxylase. however dopa-decarboxylase can also inhibit L.dopa before it crosses BBB, therefore Carbiodopa is a dopa decarboxylase inhibitor allowing more levodopa to cross the BBB.
COMT-I
Can be given to increase the effects of L.dopa
reduces breakdown of dopamine into 3-omd and 3-mt via COMT enzyme
side effects: hepatotoxicity, nausea, vomitting
MAO-B inhibitors
Reduces the breakdown of dopamine into inactive metabolite
Adjunct to L.dopa + carbiodopa
What causes Bradykinesia in Parkinson’s
Direct and indirect pathways responsible for increased voluntary/involuntary movement. Loss of dopamine results in loss of stimulation resulting in slowness of movement
adverse affects of increased dopamine
nausea, vomitting,hepatotoxicity
Amantadine
Dopamine agonist
Increases dopamine release and blocks dopamine reuptake allowing more dopamine to bind to receptor
