anti parkinsonian drugs and neuroleptics Flashcards
how is dopamine synthesised?
within the dopaminergic presynaptic neurone
tyrosine –> L-DOPA (via tyrosine hydroxylase)
-rate limiting step.
L-DOPA–> dopamine (via DOPA decarboxylase)
describe the metabolism of dopamine
removed from cleft by dopamine transporter & noradrenaline transporter and recycled back into the dopaminergic presynaptic neurone
metabolised by 3 enzymes
1) monoamine oxidase A metabolises dopamine, NA and serotonin (5HT)
2) monoamine oxidase B metabolises dopamine
3) catechol-O-methyl transferase- metabolises all catechlamines
where are the major locations of dopaminergic pathways
1) nigrostriatal pathway (most important in terms of parkinsons)
- substantia nigra pars compacta to striatum
2) mesolimbic pathway
- ventral trigeminal area to nucleus accumbens
3) mesocortical pathway
VTA to cerebrum
4) tuberoinfundibular pathway
- arcuate nucleus to median eminance (not a target in terms of pharmacology)
what is the major risk factors of parkinsons
age
genetic component - mutations is SNCA, LRRK2 genes predispose to early onset parkinsons
what is the pathophysiology of parkinsons
severe loss of dopaminergic projection cells in the nigrostriatal tract– which is responsible for fine tuning of motor actions
lewy bodys
what is the clinical presentatiojn
motor symptoms: -resting tremor (early onset) bradykinesia -rigidity (later onset) -postural instability
ANS effects:
- olfactory deficits (loss of smell)
- orthostatic hypotension
- constipation
neuropsychiatris:
- sleep disorders
- memory deficits
- depression
- irritability
how is parkinsons treated?
1) dopamine replacement
- LEVODOPA (L-DOPA)
- Rapidly converted to dopamine via DOPA decarboxylase
- requires intact dopaminergic presynaptic neurones
targets symptoms- does not prolong life
2) receptor activation
- dopamine receptor agonists
- dont require dopaminergic neurones. bypass presynaptic neurone component
what are the side effects of levodopa
dyskinesias and on-off effects when drug runs out
nausea and vomiting -dopa decarboxylase effects in peripheries
-carbidopa & benserazide prevent peripheral breakdown of levodopa
give examples of some adjuncts given with levodopa
DOPA decarboxylase inhibitors:
carbidopa & benserazide- reduce nausea and vommiting by shutteling levodopa to CNS
COMT inhibitors:
entacapone & tolcapone
- increase amount of levodopa in brain
what are some examples of dopamine receptor agonists
Ergot derivatives (natural) eg. Bromocriptine & pergolide
SE: associated with cardiac fibrosis
non- ergot derivatives
eg. ropinirole
SE: hallucinations, compulsive gambling diorder (effect on mesolimbic reward pathway)
what is the pathophysiology of schizophrina
over activation of dopaminergic pathways
what are the risk factors of schizophrenia
onset of symptoms 15-35 years
some genetic influence
higher incidence in ethnic minorites
what are the symptoms of schizophrenia?
positive symptoms (target of pharmacological drugs):
- increased dopaminergic activity in mesolimbic system
- hallucoinations (auditory and visual)
- paranoia
- denial about oneself
negative symptoms
- decreased mesocortical sopaminergic activity
- lack of emotion (affective flattening)
- lack of speech (alogia)
- loss of motivation (avolution/apathy)
what are some treatments for schizophrenia?
first generation antipsychotics
chlorpromazine (1950s)
- D2 receptor antagonist
- SE: anticholinergic effects
haloperidol (1960s)
- very potent D2 antagonist
- SE: extra pyramidal side effects (motor)
what are some
second generation antipsychotis drugs
clozapine (1970s)
- very potent antagonist of 5-HT2A receptors
- only drug that treats some of the negative symptoms
- SE: can cause potential fatal degranulization of WBCs and weight gain
risperidone
- very potent agonist of 5-HT2A and D2 receptors
- SE; EPS and hyperprolactinaemia
quetiapine
- very potent H1 histamine receptors
- SE:
