Anti-Parkinson's drugs and neuroleptics Flashcards
Why might Levodopa be an unsuitable drug to treat PD in some cases? What class of drugs are used in these cases?
PD may be so progressed as for DOPA-D to no longer be present for L-DOPA conversion to DA
Use DA receptor agonists in this case
Recall the MOA of clozapine
2nd generation neuroleptic - inhibits the 5HT2A receptor
Recall the MOA of risperidone
Very potent antagonist of DA and 5HT receptors
Recall the side effects of risperidone and where each of them originates
Extra-pyramidal: eg crooked neck - due to D2 antagonism
Hyperprolactinaemia: due to interference with tuberoinfundibular pathway
Recall the target of 1st generation neuroleptics
D2 receptors
What is avolition?
Lack of motivation
What is the main function of the mesolimbic pathway?
Reward
Recall the side effects of clozapine
(SWAMP) Side effects: Weight gain Agranulocytosis Myocarditis Potentially fatal neutropenia
What is the rationale behind using COMT inhibitors as an adjunctive therapy to L-DOPA?
Increase the amount of DA delivered to the brain by reducing peripheral breakdown
Recall the re-uptake transporters of DA
On pre-synaptic terminal: DAT and NET transporters
On glia: DAT
Recall the 4 major neuroanatomical sites of dopaminergic neurons and which regions they run between
- Nigrostriatal tract = Substantia nigra to striatum (most important in PD)
- Mesolimbic pathway = VTA to NA
- Mesocortical area = VTA to cerebrum
- Tubuloinfundibular (endocrine)
Recall the causes of the positive and negative symptoms of schizophrenia
Positive: increased activity in the mesolimbic dopaminergic pathway
Negative: decreased activity in the mesocortical dopaminergic pathway
What adjuncts can be given with L-DOPA to reduce peripheral metabolism and which of these is most common?
DOPA-D (most common)/ COMT/ MAO-A inhibitors
Inhibition of which dopaminergic pathway in the brain causes the motor symptoms of PD?
Nigrostriatal
Why is L-DOPA given in PD instead of tyrosine?
TH is a rate-limiting enzyme
Recall the cardinal symptoms of Parkinson’s disease
Cardinal symptoms = motor symptoms Resting tremor Bradykinesia Rigidity Postural instability
Describe the efficacy of clozapine at treating schizophrenia
Good at treating positive symptoms, but 50 times less potent than haloperidol
What do Lewy bodies consist of?
Abnormally phosphoralated…:
neurofilaments
ubiquitin
alpha-synuclein
Recall the name of a MAO-B-inhibiting drug
selegiline
Recall 2 gene loci associated with Parkinson’s disease development
SNCA
LRRK2
Recall the synthesis pathway of DA
Occurs in synaptic bouton
Tyrosine –> L-DOPA (tyrosine hydroxylase, rate limiting enzyme)
L-DOPA –> DA (DOPA-decarboxylase)
Compare the high-incidence side effects of first generation neuroleptic drug options
Clozapine has anti-MUSCARINIC effects, especially causing sedation
Haloperidol has EXTRA-PYRAMIDAL side effects - especially a crooked neck and muscle disorders
Recall the indications for clozapine treatment
Must be treatment-resistant schizophrenia as side-effect profile is significant
Recall the names of 2 COMT-inhibiting drugs
Entacapone
Tolecapone
What is the rationale behind using MAO-B inhibitors as an adjunctive therapy to L-DOPA?
Reduce the dose required to produce the same effects by increasing the amount of L-DOPA delivered to the brain, therefore reducing the longterm effects
Recall the histological changes that occur PD in the SNc
Lewy bodies and neurites will be present
Recall thepossible sites of metabolism of DA, and the specificities of the enzymes involved
May be metabolised by:
MAO-A (specific for DA, NA and 5HT)
MAO-B (specific for DA only)
COMT (metabolises all catecholamines)
What is the result of inhibition of the tubuloinfundibular dopaminergic pathway in the brain?
Hyperprolactinaemia
Which of the non-motor symptoms of Parkinson’s disease are prodromal?
Sleep disturbance, anosmia, orthostatic hypotension, constipation
Where is the most significant loss of dopaminergic neurons suffered in PD?
Substantia nigra compacta
What is the main difference between ergot and non-ergot derivative dopamine receptor agonists
Ergot derivatives are associated with cardiac fibrosis
What is affective flattening?
Lack of emotion
What is the main difference between 1st and 2nd generation neuroleptics?
1st generation = DA receptor agonists
2nd generation = DA and 5HT receptor agonists
Recall the MOA of quetiapine
5HT antagonist, D2R antagonist, Potent H1 receptor antagonist
Recall where each of the enzymes involved in DA metabolism can be found
Pre-synaptic terminal: MAO-A+B
Glia: COMT and MAO-A
Post-synaptic terminal: COMT
Describe the side effects of apiprazole use
Less significant weight gain and hyperprolactinaemia than other neuroleptics
What is the other name for neuroleptic drugs?
Anti-psychotics
Recall examples of 2nd generation neuroleptics
Clozapine
Risperidone
Aripiprazole
Quetiaprine
What are the long-term side effects associated with L-DOPA administration?
Dyskinesias and on-off symptoms
Recall the non-motor symptoms of Parkinson’s disease
ANS: anosmia, orthostatic hypotension, constipation
Neuropsychiatric: sleep disorders, amnesia, depression, irritability
Describe the efficacy of haloperidol at treating schizophrenia
50 times more potent than clozapine at treating positive symptoms, but takes 6-8 weeks to become effective. Very little effect on negative symptoms
Recall examples of 1st generation neuroleptics
Chlorpromazine
Haloperidol
Describe the side effects of quetiapine
Lower incidence of EPS than other atypical neuroleptics
What is the rationale behind using DOPA-D inhibitors as an adjunctive therapy to L-DOPA?
Prevents peripheral breakdown of L-DOPA to reduce nausea and vomiting, ensure more un-changed L-DOPA is delivered to the brain
Recall the life expectancy reduction in schizophrenia and the reason for this
20-30 years
Due to use of drugs of abuse
Recall the prevalence of schizophrenia in the UK
Around 1%
What is alogia?
Lack of speech
Recall the names of 2 DOPA-D inhibitors
Carbidopa
Benserazide
Which of the dopaminergic pathways in the brain is most important in schizophrenia?
Mesolimbic
Which of the neuroleptic drugs is the most effective, out of all the 1st and 2nd generation drugs, and why?
Clozapine
Treats both positive and negative symptoms
What is the anatomical site of drug interference to produce a crooked neck as a side effect of drug use?
Extra-pyramidal
What is the MOA of apiprazole?
Partial agonist of 5HT2A and D2 receptors, so should moderate these receptors to control both pos and neg symptoms of schizophrenia (but is in reality not that effective)
Recall the coupling of D2 receptors and their immediate downstream signalling upon activation
Coupled to adenylate cyclase via a Gi protein
Adenylate cyclase linked to ATP–>cAMP, to increase [PKA]
Recall the symptoms of schizophrenia
Positive: Hallucinations, paranoia, thought disorder
Negative: affective flattening, alogia and avolition
What are the immediate side effects associated with L-DOPA metabolism peripherally
Activation of CTZ to produce nausea and vomiting
Recall the 2 classes of dopamine receptor agonists used in PD treatment and give examples
Ergot derivatives: bromocriptine and pergolide
Non-ergot derivatives: ropinirole
