Anti-PD drugs and neuroleptics Flashcards
Describe the synthesis of dopamine?
L-tyrosine (1)L-DOPA (2) Dopamine (DA)
This process utilises the enzymes:
(1) Tyrosine hydroxylase
(2) DOPA decarboxylase
Describe the metabolism of dopamine?
DA removed from synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET)
Three enzymes metabolise DA:
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 4 dopaminergic pathways?
Nigrostriatal pathway - susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders
Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway.
Mesocortical pathway - VTA to the cerebrum. Important in executive functions & complex behavioural patterns.
Tuberoinfundibular pathway - arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia
What is 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 synuclein
What is the clinical presentation of PD?
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
How is dopamine replacement used to treat PD?
Give Levadopa (L-DOPA). You skip tyrosine hydroxylase as its rate imiting
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
Long-term side-effects: dyskinesias and ‘on-off’ effects. NOT disease-modifying
What adjuncts do you give with it?
DOPA decarboxylase inhibitors: Carbidopa and Benserazide
Do not cross BBB prevent peripheral breakdown of levodopa so reduce required levodopa dosage
COMT inhibitors: Entacapone & Tolcapone
Increase amount of levodopa in the brain
How can you classify the dopamine receptor types?
Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
Describe use of 2 types of dopamine receptor agonists to treat PD?
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
Describe the use of Monoamine oxidase B inhibitors in treating PD?
Selegiline (deprenyl) and Rasagiline
Reduce the dosage of L-DOPA required
Can increase the amount of time before levodopa treatment is required
How can you classify the symptoms of schizophrenia?
Positive symptoms
Hallucinations: Auditory and visual
Delusions: Paranoia
Thought disorder: Denial about oneself
Negative symptoms
Affective flattening: lack of emotion
Alogia: lack of speech
Avolition/ apathy: loss of motivation
What are the correlates of these classifications?
Positive symptoms: increased mesolimbic dopinamergic activity
Negative symptoms: Dereased mesocortical dopinamergic activity
Describe 2 first generation anti-psychotics?
Chlorpromazine
Primary mechanism of action: possibly D2 receptor antagonism
Side effects:
High incidence - anti-cholinergic, especially sedation through muscarinic antagonism
Low incidence - extrapyramidal side-effects (EPS)
Haloperidol Very potent D2 antagonist Therapeutic effects develop over 6-8 weeks Little impact on negative symptoms Side effects: High incidence - EPS
Describe 3 second generation anti-psychotics?
Clozapine
Most effective antipsychotic
Very potent antagonist of 5-HT2A receptors
Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms
Side effects: fatal neutropenia, agranulocytosis, myocarditis & weight gain
Risperidone
Very potent antagonist of 5-HT2A & D2 receptors
Side effects: More EPS & hyperprolactinaemia than other atypical antipsychotics
Quetiapine
Very potent antagonist of H1 receptors
Side effects: Lower incidence of EPS than other antipsychotics
Describe a partial D2 agonist used in treating schizophrenia
Partial agonists theroised in leveliing out increased mesolimbic and decreased mesocortical so treat both sets of symptoms.
Aripiprazole
No more efficacious than typical antipsychotics
Side effects: Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics
