29. ANTI-PARKINSONIAN DRUGS AND NEUROLEPTICS

Question 1

Parkinsons Clinical Features

Answer 1

-------Motor symptoms 
resting tremor
bradykinesia
rigidity
postural instability 

———ANS effects
olfactory deficits
orthostatic hypotension
constipation

----------Neuropsychiatric  
sleep disorders
memory deficits
depression
irritability

Question 2

neuropathology of parkinsons

Answer 2

Severe loss of dopaminergic projection cells in Substantia Negra pars Compacta

Lewy bodies & neurites

Found respectively within neuronal cell bodies & axons

Consist of abnormally phosphorylated neurofilaments, ubiquitin & -synuclein

Nigrostriatal pathway degenerates = substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders

Question 3

Dopaminergic Pathways

Answer 3

NIGROSTRIATAL PATHWAY
susbstantia nigra pars compacta
–> striatum
inhibition = movement disorders

MESOLIMBIC PATHWAY 
ventral tegmental area
--> nucleus accumbens
brain reward pathway 
activation = positive schizophrenia symptoms 

MESOCORTICAL PATHWAY
ventral tegmental area
–> cerebrum
Important in executive functions and complex behavioural patterns
inhibition = negative schizophrenia symptoms

TUBEROINFUNDIBULAR PATHWAY
arcuate nucleus –> median eminence
inhibition = hyperprolactinaemia

Question 4

Parkinson’s drug treatments

Answer 4

DOPAMINE REPLACEMENT
Levodopa - DA precursor

D2-RECEPTOR AGONIST
ropinirole / bromocritine

MAOB-INHIBITORS:
selegiline - reduces dosage of L-DOPA required,

COMT INHIBITORS
entacapone, adjunct, increases amount of levodopa in the brain

DOPA DECARBOXYLASE INHIBITORS
carbidopa -> don’t cross BBB - only work peripherally - adjunct

bromocriptine = ergot derivative = potent d2 agonist associated with cardiac fibrosis

ropinirole = non ergot derivative

Question 5

Dopamine synthesis and metabolism

Answer 5

L-tyrosine
(tyrosine hydroxylase)
L-DOPA
(DOPA-decarboxylase)
Dopamine = DA

DAT (dopamine transporter) 
and
NET (noradrenaline transporter) 
removes DA from synaptic cleft 
(into the presynaptic neurone or glial cell via DAT)

3 enzymes metabolise DA:

MAO-A = Monoamine oxidase A
metabolises DA, NE & 5-HT

MAO-B: metabolises DA

Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines

Question 6

Long-term side-effects associated with levodopa

Answer 6

Dyskinesias & on-off symptoms

Question 7

Limitations of PD treatments

Answer 7

not disease-modifying

Question 8

Negative Schizophrenia Symptoms

Answer 8

decreased mesocortiyal dopaminergic activity

affective flattening: lack of emotion

alogia: lack of speech

abolition / apathy: loss of motivation

Question 9

Positive Schizophrenia Symptoms

Answer 9

increased mesolimbic dopaminergic activity

auditory and visual hallucinations

paranoia - delusions

denial about oneself - thought disorder

Question 10

explain how drugs targeting the dopaminergic system are utilized in the treatment of schizophrenia, which symptoms they treat

Chlorpromazine: 
Haloperidol: 
Clozapine: 
Risperidone
Quetiapine
Aripiprazole:

Answer 10

FIRST GENERATION ANTIPSYCHOTIC

Chlorpromazine:
phenothiazine causing antimuscarinic side-effects
sedative

Haloperidol:
potent D2 antagonist causing extrapyramidal side-effects

SECOND GENERATIION ANTIPSYCHOTIC

Clozapine:
very effective but causes agranulocytosis
resistant schizophrenia

Risperidone:
effective but associated with weight gain & EPS

Quetiapine:
low incidence of EPS
H1 antagonist

Aripiprazole:
partial D2 agonist, low incidence of hyperprolactinaemia

Question 11

levodopa = l-dopa

Answer 11

Rapidly converted to DA by DOPA decarboxylase (DOPA-D)

Can cross blood-brain barrier (BBB)

Peripheral breakdown by DOPA-D Leads to nausea & vomiting

Long-term side-effects: dyskinesias & ‘on-off’ effects. NOT disease-modifying