Anti-parkinsonian drugs and neuroleptics Flashcards
Mesocortical pathway
Dopaminergic pathway
- ventral tegmental area to the cerebrum
- important in executive functions and complex behavioural patterns
- inhibition associated with negative schizophrenia symptoms (stimulation has opposite effect with positive)
Mesolimbic pathway
Dopaminergic pathway
- ventral tegmental area to the nucleus accumbens
- ‘the brain reward pathway’
- involved in emotion
- activation associated with positive schizophrenia symptoms (inhibition has opposite effect with negative)
Nigrostriatal pathway
Dopaminergic pathway
- substantia nigra pars compacta to the striatum
- inhibition results in movement disorders (involved in movement regulation)
- degenerates to give Parkinson’s disease
Tuberoinfundibular pathway
Dopaminergic pathway
- arcuate nucleus of the hypothalamus to the median eminence
- inhibition leads to hyperprolactinaemia (prolactin release regulation from the anterior pituitary gland)
L-DOPA adjuncts
Increases efficacy and safety of L-DOPA by preventing peripheral breakdown
DOPA-D inhibitors (eg: Carbidopa, Benserazide)
-inhibition of peripheral DOPA-D only to prevent peripheral L-DOPA breakdown
-can’t cross the blood brain barrier
-reduces required L-DOPA dosage
COMT inhibitors (eg: Entacapone, Tolcapone)
-increases L-DOPA levels reaching the brain by inhibiting peripheral metabolism
-reduces ‘on-off’ long term side effect
L-DOPA limitations
Peripheral breakdown by DOPA-D
-poor efficacy (low DOPA-D levels reach the brain)
-peripheral L-DOPA breakdown by DOPA-D=stimulate the chemoreceptor trigger zone (N&V)
Long-term side effects
-dyskinesias
-on-off effects (depends on plasma L-DOPA levels)
Dopamine receptor agonist examples
- Ergot derivatives
- Non-ergot derivatives
Ergot derivatives
- Act as potent agonists of Dopamine D2 receptors
- Associated with cardiac fibrosis
- Eg: Bromocriptine and Pergolide
Non-ergot derivatives
- Eg: Ropinirole and Rotigotine
- Ropinirole also available as extended-release formulation
- Rotigotine also available as patch
Monoamine oxidase B inhibitors
- Eg: Selegiline (Deprenyl) and Rasagiline
- reduces the dosage of L-DOPA required
- Can increase the amount of time before Levodopa (L-DOPA) treatment is required
First generation antipsychotics
- Chlorpromazine
- Haloperidol
Second generation antipsychotics
- Clozapine
- Risperidone
- Quetiapine
- Aripiprazole
Chlorpromazine
First generation antipsychotic
Haloperidol
First generation antipsychotic
Schizophrenia positive symptoms
Increased mesolimbic dopaminergic activity associated with positive symptoms
- hallucinations (auditory and visual)
- delusions (paranoia)
- thought disorder (denial about oneself)
Schizophrenia negative symptoms
Decreased mesocortical dopaminergic activity associated with negative symptoms
- affective flattening (lack of emotion)
- alogia (lack of speech)
- avolition/apathy (loss of motivation)
Quetiapine
Second generation antipsychotic
Aripiprazole
Second generation antipsychotic
Chlorpromazine
First generation antipsychotic
-discovered during new antihistamine development
Side effects:
- High incidence= of anti-cholinergic, especially sedation
- Low incidence of extrapyramidal symptoms
Haloperidol
First generation antipsychotic
- very potent dopamine D2 receptor antagonist (~50 times more potent than Chlorpromazine)
- Therapeutic effects develop over 6-8 weeks
- Little impact on negative symptoms
Side effects:
-High incidence of extrapyramidal symptoms
Clozapine
Second generation antipsychotic
- Most effective antipsychotic
- Very potent 5-HT2A receptor antagonist
- Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms
Side effects:
-potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain
Risperidone
Second generation antipsychotic
-Very potent 5-HT2A receptor and dopamine D2 receptor antagonist
Side effects:
-More extrapyramidal symptoms and hyperprolactinaemia than other atypical antipsychotics
Quetiapine
Second generation antipsychotic
-Very potent H1 receptor antagonist
Side effects:
-Lower extrapyramidal symptom incidence compared to other antipsychotics
Aripiprazole
Second generation antipsychotic
- Partial dopamine D2 receptor and 5-HT2A receptor agonist
- No more effective than typical antipsychotics
Side effects:
-reduced incidences of hyperprolactinaemia and weight gain compared to other antipsychotics
Dopamine synthesis
1) L-tyrosine converted to L-DOPA by Tyrosine hydroxylase
2) L-DOPA converted to Dopamine by DOPA decarboxylase
OCCURS IN THE NEURONE
Dopamine metabolism
-dopamine removed from synaptic cleft by dopamine transporter and noradrenaline transporter
3 enzymes metabolising dopamine:
1) Monoamine oxidase A (MAO-A) metabolises dopamine, NE, and 5-HT
2) Monoamine oxidase B (MAO-B) metabolises dopamine
3) Catechol-O methyl transferase (COMT)=wide distribution and metabolises all catecholamines
Parkinson’s disease epidemiology
- 1 to2% of individuals over 60 years old
- around 5% of cases are due to mutations in certain genes (eg: SNCA, LRRK2)
Parkinson’s disease pathophysiology
- severe loss of dopaminergic projection cells in substantia nigra pars compacta
- Lewy bodies and Lewy neurites=found respectively within neuronal cell bodies and axons
- neurofilaments and proteins (ubiquitin and alpha-synuclein) become abnormally phosphorylated, aggregating within Lewy bodies and Lewy neurites
Parkinson’s disease clinical presentation
MOTOR (BEFORE NON-MOTOR/COGNITIVE SYMPTOMS) -resting tremor -bradykinesia -rigidity -postural instability -stooped, shuffling gait -loss of arm swing -hypomimia -micrographia NON-MOTOR (AUTONOMIC) -anosmia (olfactory deficits) -orthostatic hypotension -constipation -erectile dysfunction -urinary incontinence -hypersalivation NON-MOTOR (NEUROPSYCHIATRIC) -insomnia (sleep disorders) -cognitive decline -dementia (memory deficits) -depression -anxiety -irritability
Schizophrenia epidemiology
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Receptor activation in Parkinson’s disease
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Dopamine replacement
L-tyrosine converted to dopamine
-rate limiting enzyme is tyrosine hydroxylase
