Pharm 28 - Anti Parkinsons-Disease drugs and Neuroleptics Flashcards
Explain how DA is synthesised
Synthesised in the neurone
- L-tyrosine —> L-DOPA (by Tyrosine hydroxylase)
- L-DOPA —> DA (by DOPA-decarboxylase)
Tyrosine hydroxylase is the rate limiting enzyme
In the metabolism of DA, what are the 2 means by which DA is removed from the synaptic cleft?
- Via DAT (Dopamine Transporter)
2. Via NET (noradrenaline transporter)
Which 3 enzymes metabolise DA?
- MAO-A (monoamine oxidase A)
- MAO-B - metabolises DA only
- COMT - metabolises all catecholamines, on postsynaptic membranes or in glial cells
Aside from DA, what other monoamines does MAO-A metabolise?
Noradrenaline, and 5-HT
What are MAO-A and MAO-B associated with?
Mitochondria
What are the 4 main dopaminergic pathways
- Nigrostriatal pathway - substantia nigra pars compacta (SNc) to striatum. Inhibition of this pathway result in movement disorders
- Mesolimbic pathway - VTA to NAcc. Brain reward pathway
- Mesocortical pathway - VTA to cerebrum. Important in executive functions and complex behavioural patterns.
- Tuberoinfundibular pathway - arcuate nucleus to median eminence - inhibition results in hyperprolactinaemia
Activation of which dopaminergic pathway is associated with positive schizophrenia symptoms?
Mesolimbic pathway
Activation of which dopaminergic pathway is associated with negative schizophrenia symptoms?
Mesocortical pathway
What is the main risk factor for Parkinson’s disease (PD)
Age
5% of early onset can be caused by genetic mutations. These includes?
SNCA, LRRK2
What is the pathophysiology behind PD
Severe loss of dopaminergic projection cells in SNc - Lewy bodies (neuronal cell bodies) and neuritis (axons) contain abnormally phosphorylated neurofilaments - ubiquitin and a-synuclein. This causes degeneration of neurones in the Nigrostriatal tract
What are the symptoms of PD
Motor symptoms - resting tremor, bradykinesia, rigidity, postural instability (cardinal symptoms)
ANS - Olfactory deficits, postural hypotension, constipation
Neuropsychiatric - sleep disorders, memory deficits, depression, irritability
(ANS and sleep affected before motor, dementia after motor affected)
What are the 3 general ways to treat PD
- Dopamine replacement + adjuncts
- DA receptor agonists
- MAO-B inhibitors
What drug can be given as dopamine replacement?
What is the good thing about this drug
L-DOPA (not L-Tyr as Tyrosine hydroxylase is rate limiting enzyme) - aka levodopa
Good thing about L-DOPA is that it crosses BBB and rapidly converted into DA by DOPA decarboxylase
What is the problem with giving L-DOPA as dopamine replacement?
It can also be broken down peripherally by DOPA-decarboxylase - the DA that is formed can activate the CTZ (outside BBB) - which causes nausea and vomiting
Does MAO or COMT break down most of the DA?
MAO
What are the long term side effects of L-dopa?
- Dyskinesias
- “On-off” effects - i.e. works for a few hours then doesn’t
L-DOPA is not disease modifying, simply treats the symptoms
Why are adjuncts given with L-DOPA?
Which Adjuncts are given
To prevent peripheral breakdown of DOPA
Adjuncts given =
1. DOPA-decarboxlase inhibitors - Carbidopa and Benserazide. These don’t cross BBB so prevent peripheral breakdown of L-dopa and reduce the dosage of L-dopa required
- COMT-inhibitors - Entacapone and Tolcapone. These increase the amount of L-dopa in the brain (helps treat on/off effects of DA)
Which receptors can DA act on?
- D1, D5 = Gs linked
2. D2-4 = Gi linked receptors
What are the 2 types of DA receptor agonists that can be given
- Ergot derivatives - Bromocriptine and Pergolide. These act as potent agonists of D2 receptors.
Ergot derivatives = associated with cardiac fibrosis
- Non-ergot derivatives - Ropinirole and Rotigotine.
- (Ropinirole also available as extended-release formulation)
- Rotigotine available as a patch
What are MAO-B inhibitors that can be used to treat PD
- Selegiline (deprenyl)
- Rasagiline
MAO-B inhibitors reduce dosage of L-DOPA required. They may also increase the time before L-dopa treatment is needed.
Schizophrenia (SP) affects about what percent of the population? What is the age of onset commonly?
1% of population affected - 15-35 common
Higher incidence in ethnic minorities, lower life expectancy by 20-30 years (lower LE due to drugs of abuse, not actual disorder)
What are the positive symptoms of SP
- Hallucinations - auditory and visual
- Delusions: paranoia
- Thought disorder - denial about oneself
Positive SP symptoms caused by increased Mesolimbic DAergic activity (Increased VTA –> NAcc)
What are the negative symptoms associated with SP
- Affective flattening - lack of emotion
- Alogia - lack of speech
- Avolition/apathy - loss of motivation
Negative symptoms caused by decreased mesocortical DAergic activity (VTA —> cerebrum)
Name and describe the actions of 2 first generation/typical anti-psychotic (neuroleptic) drugs
- Chlorpromazine - possible D2 receptor antagonism
- Haloperidol - potent D2 receptor antagonist (50x more potent than chlorpromazine). Therapeutic effects take 6-8 weeks. Has little impact on negative SP symptoms
What are the side effects of Chlorpromazine
- Anti-cholinergic - especially sedation (high incidence)
2. Extrapyramidal side effects (movement)
What are the side effects of Haloperidol?
Extrapyramidal side effects (affects movement) - (high incidence)
Extrapyramidal system modifies pyramidal system
Name some 2nd generation/atypical antipsychotic (neuroleptic) drugs
- Clozapine - most effective antipsychotic as it is the only licensed antipsychotic that has evidence of reducing negative symptoms. Only drug efficacious at treatment-resistant SP
It is a very potent antagonist of 5-HT2A receptors.
- Risperidone - very potent antagonist of 5-HT2A and D2 receptors
- Quetiapine - very potent agonist of H1 receptors
What are the side effects of Clozapine
Can cause:
1. Potentially fatal neutropenia, agranulocytosis, myocarditis, weight gain
Hence used as a last resort
What are the side effects of Risperidone
- Extrapyramidal side effects
- Hyperprolactinaemia
- Weight gain
Out of 2nd generation/atypical antipsychotics, Risperidone causes the most of these side effects.
What are the side effects of Quetiapine
Lower incidence of Extrapyramidal side effects than other antipsychotics
Apiprazole is a 2nd generation/atypical antipsychotic. It is the newest discovered antipsychotic. Describe it
Apiprazole = partial agonist of D2 receptors and 5-HT1A receptors
But no more efficacious than typical antipsychotics
Side effects include: Reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics.
Which drug do you give for resistant SP
Clozapine
