Anti-Parkinson's Drugs and Neuroleptics Flashcards
describe the dopamine synthesis
L-tyrosine –> L-DOPA by tyrosine hydroxylase (RLS)
L-DOPA –> dopamine by DOPA decarboxylase
describe dopamine reuptake
- DA removed from synaptic cleft by dopamine transporter (DAT) and NA transporter (NAT)
- taken back into neurone via NET + DAT
- taken back into glial cell via DAT
what are the 3 enzymes that metabolise DA?
- MAO-A: metabolises DA, NA, 5HT
- MAO-B: metabolises DA
- COMT: wide distribution, metabolises all catecholamines
state the 4 dopaminergic pathways
- nigrostriatal pathway
- mesolimbic pathway
- mesocorticol pathway
- tubero-infundibular system
describe the nigrostriatal pathway
- substantia nigra pars compacta (SNc) to striatum
- control of movement
- inhibition results in movement disorders
- impacted in Parkinsons
describe the mesolimbic pathway
- ventral tegmental area to nucleus accumbens
- brain reward pathway
- involved in emotion
- impacted in schizophrenia
describe the mesocortical pathway
- VTA to cerebrum
- important in executive functions and complex behavioural pathways
describe the tubero-infundibular system
- short neurones
- arcuate nucleus of hypothalamus –> medial eminence and pit gland
- regulate hormone secretion
what are the 2 families of DA receptors?
- D1 family: D1, 5
- D2 family: D2, D3, D4
is there a genetic link to Parkinson’s?
- SNCA, LRRK2
- genetics responsible for early onset
- 5% of cases
what is the pathophysiology?
- severe loss of dopaminergic projection cells in SNc
- Lewy body (within cell bodies), lewy neurite (wihtin axons)
- these are abnormally phosphorylated neurofilaments (ubiquitin and synuclein)
what is the clinical presentation of PD?
- motor symptoms: resting tremor, bradykinesia, rigidity, postural instability
- ANS effects: olfactory deficits, orthostatic hypotension, constipation
- neuropsychiatric: sleep disorders, memory deficits, depression
describe the staging in Parkinson’s
- 1+2: synuclein deposition in DM, RN, LC (pre-symptomatic)
- 3: synuclein deposition in SN (onset of motor deficits)
- 4,5,6: deposition in amygdala and cortical areas
describe dopamine replacement as a treatment
- levodopa
- peripheral breakdown by DOPA-decarboxylase into dopa can activate CTZ = nausea
- co-administer DOPA decarboxylase inhibitor
- can also give COMT inhibitors
- effectiveness dec. with time
what are the side effects of L-Dopa?
- Acute: nausea, hypotension
- Chronic: dyskinesias (abnormal movement of limbs/face)
what are the 2 groups of dopamine receptor agonists?
- D2 receptor agonist
- Ergot derivatives: bromocriptine, pergolide
- non-ergot derivatives: ropininole, rotigotine
what is the problem with ergot derivatives?
associated with cardiac fibrosis
what is the problem of non-ergot derivatives?
can cause addictive behaviours
how do MAOb inhibitors work?
- selegiline, resagiline
- reduce dosage of L-DOPA needed
what is a good thing about MAOb inhibitors?
can inc. amount of time before levodopa required
- levodopa only effetive for 7 years
- can give MAOb inhibitors for 2 years before
what us the epidemiology of schizophrenia?
- 1% of pop
- genetic influence
- pt life expectancy 20-30 years lower than average
- ass/ w. mesolimbic and mesocortical pathways
what are the positive symptoms?
- inc. mesolimbic dopaminergic activity
- hallucinations: auditory/ visual
- delusions
- thought disorder (denial about onself)
TREAT THESE - less scary to public
what are the negative symptoms?
- dec. mesocortical dopaminergic activity
- affective flattening (lack of emotion)
- alogia (lack of speech)
- avolution/ apathy (loss of motivation)
name 2 1st generation antipsychotics (typical)
- chlorpromazine
- haloperidol
what are 1st generation antipsychotics?
D2 antagonists
describe the side effects of chlorpromazine
- anti-muscarinic side effects (MRA)
- extra-pyramidal side effects
describe haloperidol
- little impact on -ve symptoms
- high incidence of EPS (block dopamine receptors –> motor system dysfunction)
state 4 second generation antipsychotics (atypical)
- different MoA (not D2)
- clozapine
- risperidone
- quetiapine
- amipiprazole
describe clozapine
- most effective anti-psychotic
- very potent antagonist of 5HT2a receptors
- only antipsychotic that is licensed and treats +ve and -ve symptoms
- last resort treatment
what is clozapine last resort?
problematic side effects:
- potentially fatal neutropenia
- agranulocytosis
- mycarditis
- weight gain
what is unique about risperidone?
- 2nd gen but behaves 1st gen
- very potent antagonist of 5-HT2a and D2 receptors
- side effects more EPS and hyperprolactinaemia
describe quetiapine
- very potent antagonist of H1
- side effects: lower incidence of EPS
why was it thought that Aripiprazole would be successful?
- partial agonist of D2 and 5-HT1a receptors
- partial agonist: too much activity = inhibitory, antagonist, not enough activity = agonist
- good because want to reduce DA in mesolimbic but not mesocortical
- no more efficacious than typical antipsychotic
what are the side effects of Ariprazole?
- reduced incidence of hyperprolactinaemia
- weight gain
