Anti-Parkinson's drugs and neuroleptics (A)

Question 1

Why might Levodopa be an unsuitable drug to treat PD in some cases? What class of drugs are used in these cases?

Answer 1

PD may be so progressed as for DOPA-D to no longer be present for L-DOPA conversion to DA/ not enough dopaminergic neurones for you to act on.
Use DA receptor agonists in this case

Question 2

Recall the MOA of clozapine

Answer 2

2nd generation neuroleptic - inhibits the 5HT2A receptor

Question 3

Recall the MOA of risperidone

Answer 3

Very potent antagonist of 5-HT2A & D2 receptors

Question 4

Recall the side effects of risperidone and where each of them originates

Answer 4

Extra-pyramidal: eg crooked neck - due to D2 antagonism

Hyperprolactinaemia: due to interference with tuberoinfundibular pathway

Question 5

Recall the target of 1st generation neuroleptics

Answer 5

D2 receptors

Question 6

What is avolition?

Answer 6

Lack of motivation

Question 7

What is the main function of the mesolimbic pathway?

Answer 7

Reward

Question 8

Recall the side effects of clozapine

Answer 8

(SWAMP)
Side effects:
Weight gain
Agranulocytosis
Myocarditis
Potentially fatal neutropenia

Question 9

What is the rationale behind using COMT inhibitors as an adjunctive therapy to L-DOPA?

Answer 9

Increase the amount of DA delivered to the brain by reducing peripheral breakdown

Question 10

Recall the re-uptake transporters of DA

Answer 10

On pre-synaptic terminal: DAT and NET transporters

On glia: DAT

Question 11

Recall the 4 major neuroanatomical sites of dopaminergic neurons and which regions they run between

Answer 11

1. Nigrostriatal tract = Substantia nigra to striatum (most important in PD)
2. Mesolimbic pathway = VTA to NA
3. Mesocortical area = VTA to cerebrum
4. Tuberoinfundibular= arcuate nucleus to the median eminence.

Question 12

Recall the causes of the positive and negative symptoms of schizophrenia

Answer 12

Positive: increased activity in the mesolimbic dopaminergic pathway
Negative: decreased activity in the mesocortical dopaminergic pathway

Question 13

What adjuncts can be given with L-DOPA to reduce peripheral metabolism and which of these is most common?

Answer 13

DOPA-D (eg Carbidopa)/ COMT (eg Entacapone) inhibitors.

Question 14

Inhibition of which dopaminergic pathway in the brain causes the motor symptoms of PD?

Answer 14

Nigrostriatal

Question 15

Why is L-DOPA given in PD instead of tyrosine?

Answer 15

TH is a rate-limiting enzyme

Question 16

Recall the cardinal symptoms of Parkinson’s disease

Answer 16

Cardinal symptoms = motor symptoms
Resting tremor
Bradykinesia
Rigidity
Postural instability (stooping)

Question 17

Describe the efficacy of clozapine at treating schizophrenia

Answer 17

Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms (ONLY drug that has shown evidence in which it can treat the negative symptoms of schizophrenia)

Question 18

What do Lewy bodies consist of?

Answer 18

abnormally phosphorylated:
neurofilaments
ubiquitin
alpha-synuclein

Build up of lewy bodies are thought to contribute to death of the dopaminergic neurons in Parkinsons

Question 19

Recall the name of a MAO-B-inhibiting drug

Answer 19

selegiline

Question 20

Recall 2 gene loci associated with Parkinson’s disease development

Answer 20

SNCA

LRRK2

Question 21

Recall the synthesis pathway of DA

Answer 21

Occurs in synaptic bouton
Tyrosine –> L-DOPA (tyrosine hydroxylase, rate limiting enzyme)
L-DOPA –> DA (DOPA-decarboxylase)

Question 22

Compare the high-incidence side effects of first generation neuroleptic drug options

Answer 22

chlorpromazine has anti-MUSCARINIC effects, especially causing sedation
Haloperidol has EXTRA-PYRAMIDAL side effects - especially a crooked neck and muscle disorders

Question 23

Recall the indications for clozapine treatment

Answer 23

Must be treatment-resistant schizophrenia as side-effect profile is significant

Question 24

Recall the names of 2 COMT-inhibiting drugs

Answer 24

Entacapone

Tolecapone

Question 25

What is the rationale behind using MAO-B inhibitors as an adjunctive therapy to L-DOPA?

Answer 25

Reduce the dose of Levodopa (synthetic L-DOPA)_ required

Can increase the amount of time before levodopa treatment is required. Levodopa comes with long term side effects after long term use. Therefore, if you can use this drug before Levodopa, it means that the patient will start levodopa LATER and so get a longer period of symptom control.

Question 26

Recall the histological changes that occur PD in the SNc

Answer 26

Lewy bodies and neurites will be present

Question 27

Recall thepossible sites of metabolism of DA, and the specificities of the enzymes involved

Answer 27

May be metabolised by:
MAO-A (specific for DA, NA and 5HT)
MAO-B (specific for DA only)
COMT (metabolises all catecholamines)