Anti-Parkinsonian drugs and neuroleptics Flashcards
How is dopamine synthesised?
L-tyrosine → L-DOPA → dopamine (DA).
Tyrosine hydroxylase catalyses the conversion of L-tyrosine to L-DOPA.
DOPA decarboxylase catalyses the conversion of L-DOPA to dopamine (DA).
How is dopamine metabolised?
Dopamine is removed from the synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET).
3 enzymes metabolise dopamine:
- monoamine oxidase A (MAO-A) metabolises DA, NE and 5-HT
- MAO-B metabolises DA
- catechol-O-methyl transferase (COMT)- wide distribution, metabolises all catecholamines.
What 3 enzymes metabolise dopamine?
Monoamine oxidase A (MAO-A) metabolises DA, NE and 5-HT.
MAO-B metabolises DA.
Catechol-O-methyl transferase (COMT)- wide distribution, metabolises all catecholamines.
What are the major dopaminergic pathways?
Nigrostriatal pathway
Mesolimbic pathway
Mesocortical pathway
Tuberoinfundibular pathway
What is the nigrostriatal pathway?
Substantia nigra pars compacta (SNc) to the striatum
What does inhibition of the nigrostriatal pathway result in?
Movement disorders.
What is the mesolimbic pathway?
Ventral tegmental area (VTA) to the nucleus accumbens (NAcc).
Brain reward pathway.
What does inhibition of the mesolimbic pathway result in?
Associated with negative schizophrenia symptoms.
What is the mesocortical pathway?
Ventral tegmental area to the cerebrum.
Important in executive functions and complex behavioural patterns.
What does inhibition of the mesocortical pathway result in?
Associated with positive schizophrenia symptoms.
What is the tuberoinfundibular pathway?
Arcuate nucleus to the median eminence.
What does inhibition of the tubuloinfundibular pathway result in?
Hyperprolactinaemia.
What percentage of individuals over 60 years old have Parkinson’s disease?
1-2%.
What percentage of Parkinson’s disease cases are due to mutations in certain genes, e.g. SNCA, LRRK2?
Around 5%.
Describe the pathophysiology of Parkinson’s disease.
Severe loss of dopaminergic projection cells in SNc.
Lewy bodies and neurites → found respectively within neuronal cell bodies and axons.
Consist of abnormally phosphorylated neurofilaments, ubiquitin and alpha-synuclein.
What is the clinical presentation of Parkinson’s disease?
Motor symptoms: resting tremor, bradykinesia, rigidity, postural instability (cardinal symptoms).
Autonomic nervous system effects → olfactory deficits, orthostatic hypotension, constipation.
Neuropsychiatric → sleep disorders, memory deficits, depression, irritability.
What are the cardinal motor symptoms of Parkinson’s disease?
Resting tremor, bradykinesia, rigidity, postural instability.
What is the rate-limiting enzyme in dopamine metabolism?
Tyrosine hydroxylase.
What are the different treatment options for Parkinson’s disease?
Dopamine replacement.
Dopamine receptor agonists.
Monoamine oxidase B (MAO-B) inhibitors.
How can dopamine replacement be used to treat Parkinson’s disease?
Levodopa (L-DOPA):
- rapidly converted to DA by DOPA decarboxylase (DOPA-D)
- can cross blood-brain barrier
- peripheral breakdown by DOPA-D leads to nausea and vomiting
- long-term side effects: dyskinesias and ‘on-off’ effects, not disease-modifying
Need to be given with adjuncts:
- DOPA decarboxylase inhibitors: carbidopa and benserazide
- do no cross BBB → prevent peripheral breakdown of levodopa
- reduce required levodopa dosage
COMT inhibitors: entacapone and tolcapone increase the amount of levodopa in the brain.
What are the 2 types of dopamine receptor agonists and how can they be used to treat Parkinson’s disease?
Ergot derivatives- bromocriptine and pergolide:
- act as potent agonists of D2 receptors
- associated with cardiac fibrosis
Non-Ergot derivatives- ropinirole and rotigotine:
- ropinirole also available as extended-release formulation
- rotigotine also available as a patch
How can monoamine oxidase B (MAO-B) inhibitors be used to treat Parkinson’s disease?
Selegiline (deprenyl) and rasagiline.
Reduce the dosage of L-DOPA required.
Can increase the amount of time before levodopa treatment is required.
What are the limitations of anti-Parkinsonian drugs?
Not disease-modifying.
Discuss the epidemiology of schizophrenia.
Affects around 1% of the population and has genetic influence.
Onset of symptoms- between 15-35 years.
Higher incidence in ethnic minorities, e.g. Afro-Caribbean immigrants.
Patients’ life expectancy is 20-30 years lower than average due to drug abuse.
What are the positive symptoms of schizophrenia?
Increased mesolimbic dopaminergic activity
Hallucinations- auditory and visual
Delusions- paranoia
Thought disorder- denial about oneself
What are the negative symptoms of schizophrenia?
Decrease mesocortical dopaminergic activity
Affective flattening- lack of emotion
Alogia- lack of speech
Avolition/apathy- loss of motivation
What is chlorpromazine?
First generation anti-psychotic.
Discovered whilst developing new antihistamines.
Primary mechanism of action- possibly D2 receptor antagonism.
Side effects:
-high incidence- anticholinergic, especially sedation
-low incidence- extrapyramidal side effects (EPS)
What is haloperidol?
First generation anti-psychotic.
Very potent D2 antagonist (~50x more potent than chlorpromazine).
Therapeutic effects develop over 6-8 weeks.
Little impact on negative symptoms.
Side effects: high incidence of extrapyramidal side effects (EPS).
What is clozapine?
Most effective antipsychotic, second generation.
Very potent antagonist of 5-HT2A receptors.
Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms.
Side effects: can cause potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain.
What is risperidone?
Second generation anti-psychotic.
Very potent antagonist of 5-HT2A and D2 receptors.
Side effects: more extrapyramidal side effects (EPS) and hyperprolactinaemia than other atypical antipsychotics.
What is quetiapine?
Second generation anti-psychotic.
Very potent antagonist of H1 receptors.
Side effects: lower incidence of extrapyramidal side effects (EPS) than other antipsychotics.
What is aripiprazole?
Partial agonist of D2 and 5-HT1A receptors.
No more efficacious than typical antipsychotics.
Side effects: reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics.
What are the principle neurotransmitter defects in schizophrenia?
Increased dopamine in mesolimbic pathway: positive symptoms- hallucinations.
Reduced dopamine in mesocortical pathway: negative symptoms- affective flattening.
