Anti-parkinsonian drugs and neuroleptics Flashcards
What are 4 major dopaminergic pathways in the brain
Nigrostriatal - MOST IMPORTANT for PD
Mesolimbic
Mesocortical
Tuberoinfundibular
What is the nigrostriatal pathway and what is it important in? What condition is this impacted in
Substantia nigra zona compacta -> striatum
Important in initiating, fine tuning and ending movement control
Impacted in parkinsons
What is the mesolimbic pathway and what is it important in? What condition is this impacted in
VTA -> NAcc (nucleus accumbens), frontal cortex, limbic cortex, olfactory tubercle
Involved in emotion, and is brain reward pathway
Impacted in schizophrenia
What is the mesocortical system and what is it important in
VTA (ventral tegmental area) -> cerebrum
Important in executive functions and complex behavioural patterns
What is the difference in the amount of men and women affected by parkinsons
4x as many men as women
What are causes of parkinsons
Familial cases are 8% of cases
Idiopathic is 92% of cases
What are the 4 cardial motor symptoms of parkinsons?
Resting tremor
Rigidity
Bradykinesia
Postural instability
What are ANS effects of parkinson’s disease
Olfactory deficits, orthostatic hypotension, constipation
What is the main affected area in PD
Substantia nigra (pars compacta) which projects into the caudate and putamen
What does the substantia nigra lose in PD
Loss of dopaminergic projection cells in SNc and neuro melanin pigment (the function of this is unknown)
What are lewy bodies and neurites, where are they found and what do they consist of?
Aggregations of proteins in neuronal cell bodies and axons respectively, and consist of abnormally phosphorylated neurofilaments; ubiquitin and alpha-synuclein
What are the different stages of parkinson’s and what happens in them
Stages 1 & 2 – Synuclein deposition in the DM, RN and LC – pre-symptomatic.
Stages 3 – Synuclein deposition in SN – onset of motor deficits.
Stage 4, 5, 6 – deposition in the amygdala and cortical areas.
Synthesis of dopamine
L-Tyrosine -> L-DOPA (via tyrosine hyroxylase - rate limiting) -> Dopamine (via DOPA decarboxylase) in the neurone and stored in the neurone vesicle
Dopamine metabolism
Different ways
- DA removed from synaptic cleft via dopamine transporter and noradrenaline transporter and sends it back to neuronal cell - recycles dopamine
- enzymatic metabolism with different enzymes:
- MAO-A breaks down DA, NE and 5HT, MAO-B breaks down DA, COMT breaks down all catecholamines
What is the tuberoinfundibular pathway and what is it involved in
Acuate nucleus -> median eminance
Endocrine pathway where inhibition leads to hyperprolactinaemia - not really targeted for PD/Schizophrenia drugs but can account for some side effects
What are neuropsychiatric symptoms of PD
Sleep disorders
Memory deficits
Depression
Irritability
PD treatment options:
- dopamine replacement
2. receptor activation via dopamine receptor activation
What drug is given for dopamine replacement and why is dopamine not given directly
Give L-DOPA aka levodopa because tyrosine hyroxylase making L-DOPA is the rate limiting step so you skip that step but dopamine not given directly because it causes effects in the periphery before reaching the CNS
Body can convert L-DOPA into DOPA decarboxylase
Why does dopamine replacement work as an effective treatment for PD symptoms
Because the dopamine D2 receptors in the brain still exist, it is only the dopamine forming cells in the nigrostriatal tract that are degenerating, therefore giving dopamine replacement makes the cells that still are there work overtime to make enough dopamine
Side effect of Levodopa
Can cause induced dyskinesias (sudden uncontrolled movement due to too much dopamine) and on/off effects as dopamine can just run out - doesn’t mimic natural dopamine release.
Peripheral breakdown of DOPA-D can lead to nausea and vomiting
And it is not disease modifying - increases quality of life but doesn’t affect survival
What some commonly used DOPA decarboxylase inhibitors
Carbidopa and benserazide
What drugs are given with Levodopa to help with nausea and vomiting
DOPA decarboxylase inhibitors - they don’t cross BBB but protects the levodopa from breaking down peripherally, this can also allow you to reduce dose of levodopa as it is not lost in periphery
What drugs can be given with Levodopa to increase time that levodopa is effective in the brain
COMT inhibitors eg Entacapone and tolcapone as they prevent breakdown of dopamine it increases the amount in the brain. Reduces on/off effect
What are examples of dopamine receptor agonists
- Ergot derivative: Bromocriptine or pergolide that act as potent D2R agonists
- Non-ergot derivatives (synthetic):
Ropinirole and Rotigotine - MAO B inhibitors eg selegilinen and rasagiline (cheese reaction)
Why are dopamine receptor agonists good for treatment of PD
Don’t require intact presynaptic neurones and as they are disappearing in PD this is a good treatment
What is the problem of using ergot derivatives as treatment for PD
They are associated with cardiac fibrosis; cause fibrosis of cardiac valves - increase valve disorders
What are side effects of dopamine agonists
Hallucinations
Compulsive gambling
(affect mesolimbic+mesocortical pathways)
What is the cheese effect?
An acute attack of hypertension that can occur in a person taking a monoamine oxidase inhibitor (MAOI) drug who eats cheese, caused by an interaction of the MAOI with tyramine, formed in ripe cheese when bacteria provide an enzyme that reacts with the amino acid tyrosine in the cheese
Who does schizophrenia affect and what are environmental factors
Affects 1% of population and has genetic influence, onset of symptoms between 15-35 years and high incidence in ethnic minorities that migrate to other countries that don’t integrate into the larger society
What is the patient life expectancy of a patient with schizophrenia and what is it due to
20-30 years and this isn’t due to any schizophrenia based degeneration etc its more due to the lifestyle eg drinking and drugs that is associated with the condition
What are ‘positive’ symptoms of schizophrenia?
Increased mesolimbic dopaminergic activity leading to
hallucinations; auditory and visual,
delusions, paranoia,
thought disorder; denial about onset
What are ‘negative’ symptoms of schizophrenia
Decreased mesocortical dopaminergic activity leading to
Affective flattening: lack of emotion
alogia: lack of speech
Avolition/apathy: loss of motivation
What types of symptoms do drugs target in schizophrenia
positive symptoms, the negative ones are really hard to treat
What are the first generation antipsychotics aka ‘typical antipsychotic’
Chlorpromazine (developed as antihistamine as an antimuscarinic) - inhibits the D2R
Haloperidol - potent D2 receptor antagonist (50x more effective than chorpromazine)
What are the side effects of chlorpromazine
High incidence anticholinergic- especially sedation
Low incidence extrapyramidal side effects so mainly motor disorders
What are side effects of haloperidol
High incidence extrapyramidal side effects -> motor disorders
What are the second generatio nantipsychotics or ‘atypical antipsychotics’
Clozapine - potent 5HT antagonist and is most effective antipsychotic
Risperidone - potent 5HT an D2R antagonist
Quetiapine - potent H1 receptor antagonist
What are positives and negatives of Clozapine
+ve: is only drug that affects negative symptoms of schizophrenia
-ve: can cause fatal agranularcytosis so can cause degradation of white blood cells, neutropenia
Side effects of Clozapine
Potentially fatal neuropenia, agranulocytosis, myocarditis, and weight gain
Side effects of risperidone
EPS (motor) and hyperprolactinaemia
Side effects of quetiapine
Lower incidence of EPS than other antipsychotics
How does aripiprazole work to treat schizophrenia
Too much activity -> causes inhibition
Too little -> increase activity
What is one of the main problems with schizophrenia drugs
The side affects are all really bad and patients don’t want to deal with them so compliance is low
Side effects of aripiprazole compared to other antipsychotics
Hyperprolactinaemia and weight gain have reduced incidences compared to other antipsychotics
