Anti-Parkinson's Drugs and Neuroleptics

Question 1

describe the dopamine synthesis

Answer 1

L-tyrosine –> L-DOPA by tyrosine hydroxylase (RLS)

L-DOPA –> dopamine by DOPA decarboxylase

Question 2

describe dopamine reuptake

Answer 2

• 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

Question 3

what are the 3 enzymes that metabolise DA?

Answer 3

• MAO-A: metabolises DA, NA, 5HT
• MAO-B: metabolises DA
• COMT: wide distribution, metabolises all catecholamines

Question 4

state the 4 dopaminergic pathways

Answer 4

• nigrostriatal pathway
• mesolimbic pathway
• mesocorticol pathway
• tubero-infundibular system

Question 5

describe the nigrostriatal pathway

Answer 5

• substantia nigra pars compacta (SNc) to striatum
• control of movement
• inhibition results in movement disorders
• impacted in Parkinsons

Question 6

describe the mesolimbic pathway

Answer 6

• ventral tegmental area to nucleus accumbens
• brain reward pathway
• involved in emotion
• impacted in schizophrenia

Question 7

describe the mesocortical pathway

Answer 7

• VTA to cerebrum

- important in executive functions and complex behavioural pathways

Question 8

describe the tubero-infundibular system

Answer 8

• short neurones
• arcuate nucleus of hypothalamus –> medial eminence and pit gland
• regulate hormone secretion

Question 9

what are the 2 families of DA receptors?

Answer 9

• D1 family: D1, 5

- D2 family: D2, D3, D4

Question 10

is there a genetic link to Parkinson’s?

Answer 10

• SNCA, LRRK2
• genetics responsible for early onset
• 5% of cases

Question 11

what is the pathophysiology?

Answer 11

• 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)

Question 12

what is the clinical presentation of PD?

Answer 12

• motor symptoms: resting tremor, bradykinesia, rigidity, postural instability
• ANS effects: olfactory deficits, orthostatic hypotension, constipation
• neuropsychiatric: sleep disorders, memory deficits, depression

Question 13

describe the staging in Parkinson’s

Answer 13

• 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

Question 14

describe dopamine replacement as a treatment

Answer 14

• 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

Question 15

what are the side effects of L-Dopa?

Answer 15

• Acute: nausea, hypotension

- Chronic: dyskinesias (abnormal movement of limbs/face)

Question 16

what are the 2 groups of dopamine receptor agonists?

Answer 16

• D2 receptor agonist
• Ergot derivatives: bromocriptine, pergolide
• non-ergot derivatives: ropininole, rotigotine

Question 17

what is the problem with ergot derivatives?

Answer 17

associated with cardiac fibrosis

Question 18

what is the problem of non-ergot derivatives?

Answer 18

can cause addictive behaviours

Question 19

how do MAOb inhibitors work?

Answer 19

• selegiline, resagiline

- reduce dosage of L-DOPA needed

Question 20

what is a good thing about MAOb inhibitors?

Answer 20

can inc. amount of time before levodopa required

• levodopa only effetive for 7 years
• can give MAOb inhibitors for 2 years before

Question 21

what us the epidemiology of schizophrenia?

Answer 21

• 1% of pop
• genetic influence
• pt life expectancy 20-30 years lower than average
• ass/ w. mesolimbic and mesocortical pathways

Question 22

what are the positive symptoms?

Answer 22

• inc. mesolimbic dopaminergic activity
• hallucinations: auditory/ visual
• delusions
• thought disorder (denial about onself)
  TREAT THESE - less scary to public

Question 23

what are the negative symptoms?

Answer 23

• dec. mesocortical dopaminergic activity
• affective flattening (lack of emotion)
• alogia (lack of speech)
• avolution/ apathy (loss of motivation)

Question 24

name 2 1st generation antipsychotics (typical)

Answer 24

• chlorpromazine

- haloperidol

Question 25

what are 1st generation antipsychotics?

Answer 25

D2 antagonists

Question 26

describe the side effects of chlorpromazine

Answer 26

• anti-muscarinic side effects (MRA)

- extra-pyramidal side effects

Question 27

describe haloperidol

Answer 27

• little impact on -ve symptoms

- high incidence of EPS (block dopamine receptors –> motor system dysfunction)

Question 28

state 4 second generation antipsychotics (atypical)

Answer 28

• different MoA (not D2)
• clozapine
• risperidone
• quetiapine
• amipiprazole

Question 29

describe clozapine

Answer 29

• most effective anti-psychotic
• very potent antagonist of 5HT2a receptors
• only antipsychotic that is licensed and treats +ve and -ve symptoms
• last resort treatment

Question 30

what is clozapine last resort?

Answer 30

problematic side effects:

• potentially fatal neutropenia
• agranulocytosis
• mycarditis
• weight gain

Question 31

what is unique about risperidone?

Answer 31

• 2nd gen but behaves 1st gen
• very potent antagonist of 5-HT2a and D2 receptors
• side effects more EPS and hyperprolactinaemia

Question 32

describe quetiapine

Answer 32

• very potent antagonist of H1

- side effects: lower incidence of EPS

Question 33

why was it thought that Aripiprazole would be successful?

Answer 33

• 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

Question 34

what are the side effects of Ariprazole?

Answer 34

• reduced incidence of hyperprolactinaemia

- weight gain