Anti-Parkinson drugs & Neuroleptics Flashcards
describe the synthesis of dopamine
L-tyrosine –> converted to L-DOPA (via Tyrosine hydroxylase)
–> which is then converted to Dopamine (DA) (via DOPA decarboxylase)
Describe the metabolism of dopamine
method 1 :
DA = removed from synaptic cleft by dopamine transporter (DAT) + noradrenaline transporter (NET)
method 2: enzyme metabolism (3)
- Monoamine oxidase A (MAO-A): –> metabolises DA, NE & 5-HT
- MAO-B: metabolises DA
- Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
What is the rate limiting step/ enzymes in the synthesis of dopamine
Tyrosine hydroxylase)
Where are the 4 major locations of the dopaminergic pathways?
Nigrostriatal pathway
- -> from susbstantia nigra pars compacta (SNc) to the striatum.
- -> Inhibition results in movement disorders
Mesolimbic pathway
- -> from ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc).
- -> Brain reward pathway.
Mesocortical pathway
- -> from VTA to the cerebrum.
- -> Important in executive functions & complex behavioural patterns.
Tuberoinfundibular pathway
- -> arcuate nucleus to the median eminence.
- -> Inhibition results in hyperprolactinaemia
5% of Parkinson’ disease cases = due to mutations in certain genes:
- SNCA
- LRRK2
Describe the pathophysiology of parkinson’s disease
- there is Severe loss of dopaminergic projection cells in SNc
- -> Lewy bodies & neurites = Found respectively within neuronal cell bodies & axons
–> Consist of abnormally phosphorylated neurofilaments, ubiquitin & a-synuclein
What are 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
sequence = ANS effects –> Motor symptoms –> Neuropsychiatric
What are methods to treat parkinson’s disease
- Dopamine replacement (gold standard)
- e.g Levodopa (L-DOPA)
- -> converted to DA by DOPA decarboxylase
- - acts on D2receptor
- -> crosses BBB - dopamine receptor agonists
a) Ergot Derivatives:
e.g Bromocriptine & Pergolide
Act as potent agonists of D2 receptors
–> Associated with cardiac fibrosis
b) Non-ergot derivatives:
e. g Ropinirole & Rotigotine
- -> Ropinirole also available as extended-release formulation
- -> Rotigotine also available as a patch
- -> non associated with cardiac fibrosis
- Monoamine oxidase B (MAOb) inhibitors
e. g Selegiline
- -> Reduces dosage of L-DOPA required
- -> Can increase the amount of time before levodopa treatment is required
What are long term side effects of L-DOPA?
- Dyskinesias + On&off effects
- -> not disease modifying
–> there is peripheral breakdown by DOPA-D - triggers Chemoreceptor trigger zones
(can cause nausea + vomiting)
L-DOPA can cause nausea + vomiting, how is this overcome?
via adjuncts
a) DOPA decarboxylase inhibitors: Carbidopa & Benserazide
- Do not cross BBB –> prevent peripheral breakdown of levodopa
- Reduce required levodopa dosage
b) COMT inhibitors: Entacapone & Tolcapone
increase amount of levodopa in the brain
a) + b) –> increases effect of levodopa
what receptors can dopamine act on?
D1,5 (Gs linked)
D2-4 (Gi linked)
What are symptoms of schizophrenia?
a) Positive symptoms
b) Negative symptoms
Positive symptoms
- increase in Mesolimbic dopaminergic activity
- Hallucinations: Auditory & visual
- Delusions: Paranoia
- Thought disorder: Denial about oneself
Negative symptoms
- decrease in Mesocortical dopaminergic activity
- Affective flattening: lack of emotion
- Alogia: lack of speech
- Avolition/ apathy: loss of motivation
Neuronal pathways
Nigrostriatal pathway: inhibition results in =
Mesolimbic pathway: activation associated with =
Mesocortical pathway: inhibition associated with =
Tuberoinfundibular pathway: inhibition results in =
Neuronal pathways
- Nigrostriatal pathway: inhibition results in movement disorders
- Mesolimbic pathway: activation associated with positive schizophrenia symptoms
- Mesocortical pathway: inhibition associated with negative schizophrenia symptoms
- Tuberoinfundibular pathway: inhibition results in hyperprolactinaemia
NOTE:
Disease probability of schizophrenia increases with the presence of one person in family with the disease
-
Onset age of schizophrenia =
15 - 35 years
NOTE schizophrenic patients –> deaths = more linked to drug use to alleviate symptoms
-
What are the drugs used to treat schizophrenia?
6 types
- give an overview of how each work
a) chlorpromazine
–> possibly D2 receptor antagonism
Side Effect =
- High incidence : anti-cholinergic, especially sedation
- Low incidence : extrapyramidal side-effects (EPS)
b) Haloperidol
–> potent D2 antagonist
Side Effect =
High incidence - EPS
c) Clozapine
–> most effective antipsychotic
–> potent antagonist of 5-HT2A receptors
Side Effect = can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain
d) Risperidone
–> potent antagonist of 5-HT2A & D2 receptors
SIDE Effect = More EPS & hyperprolactinaemia than other atypical antipsychotics
e) Quetiapine
–> potent antagonist of H1 receptors
Side Effect = Lower incidence of EPS than other antipsychotics
f) Aripiprazole
–> Partial agonist of D2 & 5-HT1A receptors
Side Effects = Reduces incidences of hyperprolactinaemia & weight gain than other antipsychotics
Increased DA in mesolimbic pathway:
Reduced DA in mesocortical pathway:
Increased DA in mesolimbic pathway: Positive symptoms –> hallucinations
Reduced DA in mesocortical pathway: Negative symptoms –> affective flattening
give a brief overview of how chlorpromazine works? on schz
Chlorpromazine: phenothiazine causing antimuscarinic side-effects
give a brief overview of how haloperidol works? on schz
Haloperidol: potent D2 antagonist causing extrapyramidal side-effects
give a brief overview of how clozapine works ? on schz
Clozapine: very effective but causes agranulocytosis
give a brief overview of how risperidone works? on schz
Risperidone: effective but associated with weight gain & EPS
give a brief overview of how quetiapine works ? on schz
Quetiapine: low incidence of EPS
give a brief overview of how Aripiprazole works? on schz
Aripiprazole: partial agonist, low incidence of hyperprolactinaemia
PD: L-DOPA & carbidopa & selegiline - used in conjunction to
- used in conjunction to reduce side-effects & required dosage
