Anti-Parkinsonian drugs and neuroleptics Flashcards
Describe the synthesis of dopamine
L-tyrosine–> (i) –> L-DOPA –> (ii) –> Dopamine (DA)
This process utilises the enzymes:
(i) Tyrosine hydroxylase = rate limiting enzyme
(ii) DOPA decarboxylase
Describe the metabolism of dopamine
Dopamine is removed from synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET). Reuptake can be back into the nuerone or into surrounding glial cells
Three enzymes metabolise DA:
1) Monoamine oxidase A (MAO-A): metabolises DA, NE and 5-HT
2) MAO-B: metabolises DA
3) Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
MAO - Dopaminergic neurone
COMT - Glial cells
Where are the major locations of the dopaminergic pathways?
Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders - Parkinsons
Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway. More associated with positive symptoms of Schizophrenia
Mesocortical pathway - VTA to the cerebrum. Important in executive functions and complex behavioural patterns. More associated with negative symptoms of Schizophrenia
Tuberoinfundibular pathway - arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia
Describe the epidemiology of Parkinson’s
1-2% of individuals over 60 years old
Around 5% of cases are due to mutations in certain genes (e.g. SNCA, LRRK2) = this is the rarer early onset form.
Describe the pathophysiology of Parkinson’s
- Neurone degeneration disorder
- Severe loss of dopaminergic projection cells in SNc
- Lewy bodies and lewy neurites –> Found respectively within neuronal cell bodies and axons
- Consist of abnormally phosphorylated neurofilaments, ubiquitin and alpha-synuclein
- They are thought to be involved in the neurodegenerative disorders
What are the clinical presentations of parkinsons?
1) Motor symptoms (cardinal symptoms) –> resting tremor, bradykinesia, rigidity (stiff), postural instability (stopping)
2) Autonomic nervous system effects –> olfactory deficits, orthostatic (postural) hypotension, constipation
3) Neuropsychiatric –> sleep disorders, memory deficits, depression, irritability
Autonomic nervous system effects –> Motor symptoms –> Neuropsychiatric. This is order in which Parkinson’s develops
What is the different treatment methods for parkinsons?
- Dopamine replacement
- Dopamine receptor agonists
- Monoamine oxidase B (MAO B) inhibitors
Describe dopamine replacement and give examples of the drugs
L-tyrosine (TYR) –> dopamine (DA)
Rate-limiting enzyme: Tyrosine hydroxylase (TH)
Levodopa (L-DOPA) - synthetic version of L-DOPA
- Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
- Can cross blood-brain barrier (BBB)
- A problem would be the peripheral breakdown by DOPA-D –> Leads to nausea and vomiting - Dopamine acts on D2 receptor in the CTZ. See anti-emetics lecture
- Long-term side-effects: dyskinesias and ‘on-off’ effects. NOT disease-modifying
To tackle the nausea and vomiting:
DOPA decarboxylase inhibitors: Carbidopa and Benserazide
- *Do not cross BBB –> prevent peripheral breakdown of levodopa so prevent nausea and vomiting
- Reduce required levodopa dosage = reduce peripheral side effects of DA
COMT inhibitors: Entacapone and Tolcapone
- increase amount of levodopa in the brain
Describe dopamine receptor activation?
- If you don’t have enough dopaminergic neurones; you can use dopamine agonists
- Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
- DA is re-uptaken by the dopamine transporter (DAT) and metabolised by monoamine oxidase (MAO) enzymes
Describe dopamine receptor agonists and give examples
Ergot derivatives: Bromocriptine and Pergolide
- Act as potent agonists of D2 receptors
- Associated with cardiac fibrosis
Non-ergot derivatives: Ropinirole and Rotigotine
- Ropinirole also available as extended-release formulation
- Rotigotine also available as a patch
- Not associated with cardiac fibrosis
Describe MAO B inhibitors and give examples
Selegiline (deprenyl) [MAO-B inhibitor] and Rasagiline
- Reduce the dosage of L-DOPA required
- Can increase the amount of time before levodopa treatment is required. These drugs stop working with prolonged use - levodopa is effective for 7 years. These drugs are NOT DISEASE MODIFYING
Describe the epidemiology of schizophrenia
Neuroaffective disorder not neurodegenerative
- Affects = 1% of population and has genetic influence
- Onset of symptoms: between 15-35 years. Onset tends to happen early on in life
- Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
- Patients’ life expectancy - 20-30 years lower than average. This will mostly be caused by drug abuse to try and alleviate the symptoms of schizophrenia
- Increased mesolimbic activity + Decreased mesocortical activity
What are the positive symptoms of schizophrenia?
- Increased mesolimbic dopaminergic activity
- Hallucinations: Auditory and visual
- Delusions: Paranoia
- Thought disorder: Denial about oneself
Most of the drugs for S are used to treat the positive symptoms because society is afraid of the the positive symptoms.
What are the negative symptoms of schizophrenia?
- decreased mesocortical dopaminergic activity
- Affective flattening: lack of emotion. Anhedonia
- Alogia: lack of speech
- Avolition/ apathy: loss of motivation
List two first generation antipsychotics and describe them.
Remember antipychotics based on their side effects
Chlorpromazine
- Primary mechanism of action – possibly D2 receptor antagonism
Side effects: anti-muscarinic side effects
- High incidence - anti-cholinergic (anti-muscarinic), especially sedation
- Low incidence - extrapyramidal side-effects (EPS)
Haloperidol
- Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
- Therapeutic effects develop over 6-8 weeks
- Little impact on negative symptoms
Side effects - Extra-pyramidal side effects
- High incidence - EPS
