Anti-Parkinsonian drugs and neuroleptics Flashcards
Explain the process of dopamine synthesis
L-tyrosine -> L-DOPA
Tyrosine hydroxylase (rate-limiting)
L-DOPA -> Dopamine
Dopamine decarboxylase
Explain the process of dopamine metabolism
Dopamine removed from the synaptic cleft by dopamine transport (DAT) and noradrenaline transporter (NET)
Monoamine oxidase A - MAO-A metabolises Dopamine, NEt and 5-HT
MAO-B - metabolises dopamine
COMT - metabolises all catecholamines, wide distribution
What are the major locations of the dopaminergic pathways
Nigrostriatal pathway
Mesolimbic pathway
Mesocortical pathway
Tuberofundibular pathway
Where is the nigrostriatla pathway and what does inhibition of it result in
Substantia nigra pars compacta (SNc) to the striatum.
Inhibition results in movement disorders
Where is the mesolimbic pathway
ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc).
Where is the mesocortical pathway and what is its function
VTA to the cerebrum.
Important in executive functions and complex behavioural patterns.
Where is the tuberoinfundibulnar pathway and what doe inhibition lead to
Arcuate nucleus to the median eminence.
Inhibition results in hyperprolactinaemia
Describe the epidemiology of Parkinson’s
1-2% of individuals over 60 years old
Around 5% of cases are due to mutations in certain genes (e.g. SNCA, LRRK2)
What is the pathophysiology of Parkinson’s
Severe loss of dopaminergic projection cells in Substantia nigra
Lewy bodies + neurites - Found respectively within neuronal cell bodies + axons
Consist of abnormally phosphorylated neurofilaments, ubiquitin + alpha-synuclein
How does Parkinsons disease clinically present
Motor symptoms (4 cardinal symptoms) - resting tremor, bradykinesia, rigidity, postural instability Autonomic nervous system effects - olfactory deficits, orthostatic hypotension, constipation Neuropsychiatric - sleep disorders, memory deficits, depression, irritability
How is levodopa used in Parkinsons treatment
Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
Can cross blood-brain barrier (BBB)
Peripheral breakdown by DOPA-D - Leads to nausea and vomiting
What are the long term side effects of levodopa
Dyskinesias + ‘on-off’ effects. NOT disease-modifying (same mortality)
Give example of adjuncts used in Parkinsons treatment
DOPA decarboxylase inhibitors: Carbidopa and Benserazide
COMT inhibitors: Entacapone and Tolcapone
Prevents peripheral breakdown of DOPA-D (nausea and vomiting)
Describe the pharmacokinetics of DOPA decarboxylase inhibitors
Carbidopa and Benserazide
Do not cross the BBB - prevents peripheral breakdown of levodopa
Reduce required levodopa dosage
How are COMT inhibitors used in Parkinsons treatment
Entacapone and Tolcapone
increase amount of levodopa in the brain
Which receptors can dopamine act on
D1,5(Gs linked) or D2-4 (Gi-linked) receptors
What are the types of dopamine receptor agonists and give examples of each
Ergot derivatives (bromocriptine and pergolide)
Non-ergot derivatives (Ropinirole)
Describe ergot derivative dopamine receptor agonists
Act as potent agonists of D2 receptors
Associated with cardiac fibrosis
What are non-ergot derivative dopamine receptor agonists available as (admin)
Ropinirole also available as extended-release formulation
Rotigotine also available as a patch
Give an example of Monoamine oxidase B (MAOB) inhibitors and describe its use
Selegiline (deprenyl) + Rasagiline
Reduce the dosage of L-DOPA required
Can increase the amount of time before levodopa treatment is required
Which types of drugs are used in Parkinsons treatment
Dopamine replacement (Levodopa) -DOPA decarboxylase inhibitors
Dopamine receptor agonists
MAO-B inhibitors
Describe the epidemiology of schizophrenia (proportion, onset of symptoms, countries with higher incidence, life expectancy)
Affects 1% of population and has genetic influence
Onset of symptoms: between 15-35 years
Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
Life expectancy - 20-30 years < average
What are the positive symptoms of schizophrenia
Increase in 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
Give examples of drugs used for schizophrenia treatment (separate by generations)
Chlorpromazine
Haloperidol
Clozapine
Risperidone
Quetiapine
Aripiprazole
What is the mechanism of action of chlorpromazine and its side effects
Primary mechanism of action – possibly D2 receptor antagonism
High incidence - anti-cholinergic, especially sedation
Low incidence - extrapyramidal side-effects (EPS)
What is the mechanism of action of haloperidol and its side effects
Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
Therapeutic effects develop over 6-8 weeks
Little impact on negative symptoms
High incidence - EPS
Describe clozapine
Most effective antipsychotic
Very potent antagonist of 5-HT2A receptors
Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms
What are the side effects of clozapine
Potentially fatal: Neutropenia Agranulocytosis Myocarditis Weight gain
What is the mechanism of action of risperidone and its side effects
Very potent antagonist of 5-HT2A and D2 receptors
More EPS and hyperprolactinaemia than other atypical antipsychotics
What is the mechanism of action of quetiapine and its side effects
Very potent antagonist of H1 receptors
Lower incidence of EPS than other antipsychotics
What is the mechanism of action of aripiprazole and its side effects
Partial agonist of D2 and 5-HT1A receptors
No more efficacious than typical antipsychotics
Reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics
What is the cause of the reduction in life expectancy in schizophrenic patients
due to lifestyle choices made by individuals who have schizophrenia. High rates of drug use, smoking and suicidal
