Anti-PD drugs & Neuroleptics Flashcards
What are the two dopamine removal mechanisms?
1) removal from synapse by transporters
2) enzymatic breakdown by dopamine
Outline the mechanism of removal of dopamine from the synapse
dopamine transporter/noradrenaline transporter
–> dopamine re-uptaken into neuronal glial cells
Which three enzymes break down dopamine in the synaptic cleft?
MAO-A
MAO-B (selective for dopamine)
COMT –> both intracellular + extracellular
acts both in the synaptic cleft + inside neuronal glial cells
How is dopamine produced?
L-tyrosine –> L-DOPA (enzyme = tyrosine hydroxylase)
L-DOPA –> Dopamine (enzyme = DOPA decarboxylase)
–> neuron activated –> dopamine released
What are the four main dopaminergic pathways and what pathologies are they involved in?
Nigrostriatal pathway: - SNc --> striatum (PD) Mesolimbic pathway: - VTA --> NAcc (schizophrenia) Mesocortical pathway: - VTA --> cerebellum (schizophrenia) Tuberoinfundibular pathway: - AN --> ME (inhibition = hyperprolactinaemia)
What genes are implicated in PD?
SNCA
LRK2
What is the pathophysiology of PD?
severe loss of dopaminergic projection cells in SNc
Lewy bodies + neurites
Abnormally phosphorylated neurofilaments, ubiquitin + a-synuclein
How does PD clinically present?
Motor symptoms –> resting tremor, bradykinesia, rigidity, postural instability
ANS effects –> olfactory deficits, hypotension, constipation
Neuropsychiatric effects –> sleep disorders, memory deficits, depression, iritability
What are the main ways PD is treated?
Dopamine replacement
Dopamine receptor agonists
MAO B inhibitors
How do you replace dopamine in PD?
give L-DOPA –> can cross BBB –> rapidly converted to DA (E= DOPA-Decarboxylase)
N.B. can’t give tyrosine as it won’t be converted, can’t give straight dopamine as it causes nausea + vomiting
What are the side effects of dopamine replacement therapy?
SE: dyskinesias + ON/OFF effects
How do you prevent nausea + vomiting in dopamine replacement therapy?
nause + vomiting caused by PERIPHERAL breakdown of L-DOPA –> give with adjuncts:
DOPA-Decarboxylase inhibitors –> Carbidopa + Benserazide
COMT inhibitors –> Entacapone + Tolacapone
can’t cross BBB, prevent peripheral breakdown of L-DOPA
What are the two types of dopamine receptor agonist? (+ examples of each)
Ergot derivatives –> Bromocriptidine + Pergotide
Non-ergot derivatives –> Ropinirole
Which type of dopamine receptor agonist is better + why?
non-ergots are better as they are not associated with cardiac fibrosis
Give an example of a MAO B inhibitor
Selegiline
What are the positive symptoms of schizophrenia?
upregulates mesolimbic dopaminergic pathway hallucinations delusions thought disorder (denial about oneself)
What are the negative symptoms of schizophrenia?
decreased mesocortical dopaminergic activity
affective flattening –> lack of emotion
alogia –> lack of speech
avolition/apathy –> loss of motivation
What is another name for an anti-psychotic?
neuroleptic
(1st gen AP = typical neuroleptic)
(2nd gen AP = atypical neuroleptic)
Give some examples of first generation anti-psychotics
Chlorpromazine
Haloperidol
How do first generation anti-psychotics work?
D2 receptor antagonists
What are their side effects?
Chlorpromazine –> anti-cholinergic, esp sedation, + extrapyramidal (EP)
Haloperidol –> EP
Give some examples of second generation anti-psychotics + their mechanisms of action
Clozapine –> 5HT2A receptor antagonist
Risperidone –> 5HT2A receptor antagonist
Quetiapine –> H1 agonist
Apipiprazole –> partial agonist of D2 + 5HT1A receptors
Which is the only drug to treat both the positive and negative symptoms of schizophrenia?
Clozapine
What are the side effects of the anti-psychotic drugs?
Chloropromazine –> anti-muscarinic side effects
Haloperidol –> EPS
Clozapine –> agranulocytosis
Risperidone –> weight gain + EPS
Quetiapine –> EPS (low)
Aripiprazole –> hyperprolactinaemia (low)
