27. Anti-Parkinsonian drugs and neuroleptics Flashcards
how is dopamine synthesised and which enzymes are involved?
- Tyrosine hydroxylase (rate-limiting enzyme) converts L-tyrosine –> L-DOPA
- DOPA decarboxylase converts L-DOPA –> dopamine
how is dopamine metabolised?
- removed from the synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET)
- metabolised by MAO-A, MAO-B and COMT
what is the difference between MAO and COMT?
- MAO enzymes are intracellular so only break down dopamine once it has been taken up into the presynaptic knob
- MAO-A metabolises dopamine, NE and 5-HT
- MAO-B metabolises dopamine only
- COMT is found in the mitochondria and post-synaptic enzymes
- COMT is widely distributed and metabolises all catecholamines
what is the nigrostriatal pathway?
The cell bodies of the nerve are present within the substantia nigra pars compacta (SNc), and the nerves project up to the striatum. Inhibition of these neurones results in movement disorders
IMPORTANT IN PARKINSONS DISEASE
what is the mesolimbic pathway (reward pathway)?
cell bodies are located in the ventral tegmental area (VTA) and the axons project up to the Nucleus Accumbens
IMPORTANT IN SCHIZOPHRENIA
what is the mesocortical pathway?
cell bodies start in the VTA but this time project to the cerebrum
important in executive functions and complex behavioural patterns
IMPORTANT IN SCHIZOPHRENIA
what is the tuberoinfundibular pathway
cell bodies in the arcuate nucleus –> projection to the median eminence
regulates prolactin secretion
what is the pathophysiology of parkinson’s?
- severe loss of dopaminergic projecton cells in nigrostriatal tract
- 80% of dopaminergic cells are lost before symptoms arise
- lewy bodies and neurites are found within neuronal cell bodies and axons
what is the clinical presentation of parkinson’s?
- motor symptoms: resting tremor, bradykinesia, rigidity, postural instability
- ANS effects: olfactory deficits, orthostatic hypotension, constipation
- neuropsychiatric sign: sleep disorders, memory deficits, depression, irritability
what are lewy bodies and neurites?
- lewy bodies are located within cell bodies of the nerves
- lewy neurites are located within the axons and dendrites
- they consist of abnormally phosphorylated neurofilaments, ubiquitin and a-synuclein
- a-synuclein plaques are thought to be responsible for neurodegeneration of neurones in the nigrostriatal tract
how is dopamine replacement used to treat parkinson’s?
levodopa (L-DOPA) treatment:
- is converted to dopamine by DOPA decarboxylase
- can cross the BBB
why is dopamine not given?
dopamine will enter the periphery –> peripheral breakdown by DOPA decarboxylase –> act on CTZ –> nausea and vomiting
why is L-DOPA given with DOPA decarboxylase inhibitors?
- DOPA decarboxylase enzyme can be found in the systemic circulation
- L-DOPA can therefore be converted to dopamine in the periphery –> nausea
- DOPA decarboxylase inhibitors (carbidopa and benserazide) prevent this and do not cross the BBB so conversion of L-DOPA in the CNS can still occur
what do COMT inhibitors do? give examples of COMT inhibitors
increase amounts of L-DOPA in the brain, so can be given with L-DOPA
e.g. entacapone and tolcapone
how are dopamine receptor agonists used to treat parkinson’s?
instead of increasing levels of dopamine, we can activate the dopamine receptors via ergot derivatives and non-ergot derivatives
