Pharmacology 27 - Antiparkinson Drugs and Neuroleptics Flashcards
Describe dopamine synthesis
- L-tyrosine to L-dopa to Dopamine
- Tyrosine hydroxylase (step 1 - rate limiting enzyme)
- DOPA decarboxylase (step 2)
Describe metabolism of dopamine
- Dopamine removed from synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET)
- Present on presynaptic terminals and glial cells
Three enzymes metabolise dopamine:
- Monoamine oxidase A (MAO-A): metabolises dopamine, noradrenaline and seratonin (mitochondria)
- MAO-B: metabolises dopamine only (mitochondria)
- Catechol-O-methyl transferase (COMT): has a wide distribution, metabolises all catecholamines (glial cell and postsynaptic terminal)
List the major dopaminergic pathways
- Nigrostriatal pathway - susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders.
- Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway.
- Mesocortical pathway from the ventral tegmental area to the cerebrum. Important in executive functions and complex behavioural patterns.
- Tuberoinfundibular pathway - arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia
Describe epidemiology of Parkinsons
- 1-2% of individuals over 60 years old (age is most important risk factor)
- Around 5% of cases are due to mutations in certain genes, causing early onset form (e.g. SNCA, LRRK2)
Describe pathophysiology of Parkinsons
- Severe loss of dopaminergic projection cells in substantia nigra
- Lewy bodies and lewy neurites -> Found respectively within neuronal cell bodies and axons
- Lewy bodies/neurites consist of abnormally phosphorylated neurofilaments, ubiquitin and a-synuclein
Describe clinical presentation of Parkinsons 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
List drugs used in Parkinson’s treatment
- Dopamine replacement (levodopa)
- Adjuncts (DOPA decarboxylase inhibitors Carbidopa and Benserazide, and COMT inhibitors entacapone and tolcapone)
- Dopamine receptor agonists (Ergot and non-ergot derivatives, useful when presynaptic nerve is damaged)
- Monoamine oxidase B inhibitors (selegiline)
Describe levodopa use in Parkinsons Disease
- Rapidly converted to dopamine by DOPA decarboxylase (DOPA-D)
- Can cross blood-brain barrier (BBB)
- Peripheral breakdown by DOPA-D -> Leads to nausea and vomiting
- Long-term side-effects: dyskinesias and ‘on-off’ effects (large dose of dopamine which quickly wears off). Not disease-modifying
- Does not prolong life
Describe adjunct use in levodopa treatment
- DOPA decarboxylase inhibitors: Carbidopa and Benserazide
- Do not cross BBB, therefore prevent peripheral breakdown of levodopa
- Reduces required levodopa dosage
COMT inhibitors: Entacapone and Tolcapone
- Increases the amount of levodopa in the brain, by inhibiting breakdown of dopamine
Describe receptor activation of dopamine
- Dopamine (DA) can act on D1 and 5 (Gs linked) receptors or D2-4 (Gi-linked) receptors
- DA is re-uptaken by the dopamine transporter (DAT) and metabolised by monoamine oxidase (MAO) enzymes
Describe use of dopamine receptor agonists in parkinsons
Ergot derivatives: Bromocriptine and Pergolide
- Naturally occuring
- Act as potent agonists of D2 receptors
- Associated with cardiac fibrosis (cause fibrosis of the cardiac valves)
Non-ergot derivatives: Ropinirole and Rotigotine
- Synthetic (no fibrosis, though associated with hallucinations and gambling problems)
- Ropinirole also available as extended-release formulation
- Rotigotine also available as a patch
Describe monoamine oxidase B inhibitor use in parkinsons disease
- Selegiline (deprenyl) and Rasagiline
- Reduce the dosage of L-DOPA required
- Can increase the amount of time before levodopa treatment is required
Describe epidemiology of Schizophenia
- Affects 1% of population and has genetic influence (50% chance of monozygotic twin having schizophrenia)
- Onset of symptoms: between 15-35 years
- Higher incidence in ethnic minorities who are immigrants (eg. Afro-Caribbean immigrants)
- Patients’ life expectancy - 20-30 years lower than average
List positive symptoms of Schizophrenia
Increased mesolimbic dopaminergic activity
- Hallucinations: Auditory and visual delusions leading to paranoia
- Thought disorder: Denial about oneself
Targeted by pharmacological drugs
List negative symptoms of Schizophrenia
- Decreased Mesocortical dopaminergic activity
- Affective flattening: lack of emotion
- Alogia: lack of speech
- Avolition/ apathy: loss of motivation
Very difficult to treat
List first generation antipsychotics
- Chlorpromazine
- Haloperidol
Also called typical
Describe use of chlopromazine
- Used to treat schizophrenia
- Discovered whilst developing new antihistamines
- Primary mechanism of action – possibly D2 receptor antagonism (used to treat increased mesolimbic dopaminergic activity)
List side effects of chlopromazine
- High incidence - anti-cholinergic, especially sedation
- Low incidence - extrapyramidal side-effects (EPS), including motor side effects similar to Parkinsons
Describe use of haloperidol
- Treatment of scizophrenia
- Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
- Slight activity on 5HT2 receptors
- Therapeutic effects develop over 6-8 weeks
- Little impact on negative symptoms
List second generation antipsychotics
- Clozapine
- Risperidone
- Quetiapine
Describe use of clozapine
- Most effective antipsychotic
- Very potent antagonist of 5-HT2A receptors
- Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms (agranulocytosis)
List side effects of clozapine
Can cause potentially fatal
- Neutropenia
- Agranulocytosis
- Myocarditis
Can also cause weight gain
Describe use of risperidone
- Antipsychotic
- Potent antagonist of 5-HT2A and D2 receptors
List side effects of risperidone
- Extrapyramidal side effects (movement symptoms)
- Hyperprolactinaemia
- More than other antipsychotics
Describe use of Quetiapine
- Antipsychotic
- Antagonist of H1 receptor
Describe side effects of quetiapine
Lower incidence of extrapyramidal side effects than other antipsychotics
Describe use of aripiprazole
- Partial agonist of D2 5-HT1A receptors (when too much activity, it inhibits activity and when too little activity, it increases activity of dopamine)
- No more efficacious than typical antipsychotics
Describe side effects of arpiprazole
Reduced incidences of hyperprolactinamia and weight gain than other antipsychotics
Which pathway is associated with parkinsons?
Nigrostriatal pathway
Which pathways are associated with schizophrenia?
- Mesolimbic pathway (dopaminergic)
- Mesocortical pathway (serotonin)
List side effects of haloperidol
Side effects include high incidence extrapyramidal side effects (motor disorder side effects)
List extrapyramidal side effects
- Physical symptoms
- Tremor
- Slurred speech
- Akathesia (inability to stay still)
- Dystonia (repetitive muscle contractions)
- Anxiety
- Distress
- Paranoia
- Bradyphrenia (slowed thinking)
Which antipsychotics are used once extrapyramidal side effects occur?
- Clozipine (reduced D2 binding)
- Quetiapine (reduced D2 binding)
Why do dyskinesias and on-off symptoms occur in parkinsons?
- Usually effects elderly people
- Caused by long term use of levodopa
- Rapid on-off effects due to flutations in plasma L-DOPA and loss in the neurones ability to store dopamine
