Parkinsons, schitz

Question 1

Summarise synthesis of dopamine

Answer 1

L-tyrosine to L-DOPA by tyrosine hydroxylase

L-DOPA to dopamine by DOPA decarboxylase

Question 2

How is dopamine metabolised?

Answer 2

Dopamine is taken up by pre-synaptic neuron and glial cell by NET/DAT and NET respectively.
Within presynaptic cell can be broken down by MAO - A/B
Within glial cell can be broken down by MAO-A or COMT (catechol-O-methyl transferase)
COMT is also present on the post-synaptic membrane

Question 3

Describe the selectivity of DAT and NET

Answer 3

DAT = dopamine transporter
NET = noradrenaline transporter

Question 4

Describe the selectivity of MAO - A/B and COMT

Answer 4

MAO - A: Metabolises noradrenaline, serotonin and dopamine
MAO - B: Dopamine
COMT - all neurotransmitters

Question 5

What are the 4 major dopaminergic pathways and what does inhibition cause in each?

Answer 5

Nigrostriatal - substantia nigra pars compacta to the striatum, controls movement, inhibition related to movement disorders
Mesolimbic - ventral tegmental area (midbrain) to the nucleus accumbens, reward pathway
Mesocortical - VTA to cerebrum, executive functions and behavioural control.
Tuberoinfundibular - Goes from arcuate nucleus of the hypothalamus to the median eminence and pituitary gland, regulates hormone secretion. Inhibition causes hyperprolactinaemia.

Question 6

Summarise the basic epidemiology of Parkinsons’

Answer 6

4:1 male predominant
1-2% individuals above 60
Around 5% due to gene mutations e.g. LRRK2/SNCA

Question 7

Describe the pathophysiology of parkinsons’

Answer 7

Loss of dopaminergic neurons from substantia nigra (80-85%), loss of nigrostriatal tract doesn’t mean we lose the neurons that they are projecting to.
Formation of lewy bodies and neurites in cell bodies and axons respectively. Lewy bodies are rich in alpha-synuclein, abnormally phosphorylated neurofilaments, ubiquitin

Question 8

What are the motor clinical presentations of Parkinson’s

Answer 8

Resting tremor
bradykinesia
Rigidity
Postural instability
KNOWN AS CARDINAL SYMPTOMS

Question 9

What are effects on the autonomic nervous system of Parkinson’s?

Answer 9

olfactory deficits, taste deficit, orthostatic hypotension(decreased of more than 20 systolic or more than 10 diastolic), constipation

Question 10

What are the neuropyschiatric presentations of Parkinson’s?

Answer 10

Sleep disorders
Memory deficits
Depression
Irritability

Question 11

What is the rate limiting enzyme in dopamine sysnthesis?

Answer 11

tyrosine hydroxylase

Question 12

What are the 3 types of Parkinson’s treatment

Answer 12

Dopamine replacement
Dopamine receptor agonists
MAO-B inhibitors

Question 13

How does dopamine replacement work?

Answer 13

Levodopa is given
Levodopa bypasses the rate limiting enzyme
Can cross BBB but there is a lot of peripheral breakdown hence you give cabidopa as an adjunct. These do not cross the BBB but prevent metabolism by DOPA-D

Question 14

What are the two types of adjuncts that can be given with levodopa to prevent peripheral breakdown?

Answer 14

DOPA-D inhibitors - carbidopa, allows to reduce levodopa dosage and also doesn’t cross BBB
COMT inhibitors - Entacapone/Tolacapone which increase the amount of levodopa in the brain

Question 15

What are the long term side-effects of levodopa

Answer 15

Dyskinesias (disordered voluntary movements), ON/OFF effects

This is not disease-modifying NOT A CURE

Question 16

Which receptors can dopamine act on?

Answer 16

D1-5

D1, 5 (Gs linked) D2-4 (Gi linked)

Question 17

How do dopamine receptor agonists work?

Answer 17

Ergot derivatives - Bromocriptine and Pergolide
These are potent D2 activators
Non ergot derivatives - Ropinirole (available as exteded release formation)

Question 18

What detrimental factor is associated with ergot derivatives?

Answer 18

Cardiac fibrosis

Question 19

What is the basic epidemiology of Schitzophrenia?

Answer 19

1% of pop, genetic influence
Onset of symptoms 15-35
Higher incidence in ethnic minorities
Patient’s life expectancy is 20-30 years reduced

Question 20

What are the positive symptoms?

Answer 20

Increased mesolimbic dopaminergic activity
Hallucinations - auditory/visual
Delusions - paranoia
Thought disorder - denial about oneself

Question 21

What are the negative symptoms?

Answer 21

Reduced mesocortical activity
affective flattening - lack of emotion
alogia - lack of speech
avolition - loss of motivation

Question 22

What are the 2 first generation anti-psychotics?

Answer 22

Chlorpromazine - possible D2 antagonism

Haloperidol - potent D2 antagonist, therapeutic effects develop over 6-8 weeks, little impact on negative effects?

Question 23

What are the side effects of chlorpromazine?

Answer 23

high incidence of anti-cholinergic side effects especially sedation
Low incidence of extrapyramidal side effects

Question 24

What are side effects of Haloperidol?

Answer 24

High EPS

Question 25

Name the 3 second gen anti-psychotics

Answer 25

Clozapine - most effective, 5-HT2a receptor antagonist, shows efficacy in treatment resistance and negative symptoms ONLY ONE Risperidone - potent 5-HT2a and D2 receptor antagonist Quetiapine - potent H1 receptor antagonist

Question 26

What are side effects of Clozapine(5-HT2a anta)?

Answer 26

Fatal neutropenia, agranulocytosis, myocarditis, weight gain

Question 27

What are side effects of risperidone(5ht2a and d2 anta)

Answer 27

More EPS than other, hyperprolactinaemia than other anti-psychotics

Question 28

What are side effects of quetiapine(h1 anta)?

Answer 28

lower incidence of EPS than others

Question 29

What are some extra pyramidal side effects?

Answer 29

Physical symptoms, including tremor, slurred speech, akathesia(inner restlessness physical disorder), dystonia, anxiety, distress, paranoia, and bradyphrenia

Question 30

What is aripiprazole?

Answer 30

Partial D2 and 5ht-2a agonist Not more efficacious than typical used now SEs = reduced hyperprolactinaemia and weight gain compared to others