Applied Neuropharmacology Flashcards
What is the sequence of events in synaptic transmission? What is the exception?
- Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
- Na+ action potential invades terminal
- Activates voltage gated Ca2+ channels
- Triggers Ca2+ dependent exocytosis of pre packaged vesicles of transmitter
- Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
- Presynaptic autoreceptors inhibit further transmitter release
- Transmitter is (usually) inactivated by uptake into glia or neurones
- Or transmitter is (unusually) inactivated by extracellular breakdown
- Transmitter is metabolised within cells
ACH IS THE EXCEPTION
How is Ach inactivated?
By enzymatic breakdown in the synaptic cleft
How are most transmitters inactivated?
By high affinity uptake into the neurons and glia
Examples of pharmacological manipulation to reduce synaptic transmission
Block the voltage gated Na+ channels e.g. local anaesthetics would block the APs
Block the voltage gated Ca2+ channels e.g. toxins from spiders
Block the release machinery e.g. botox - blocks all transmitter release
Block the post synaptic receptors e.g. receptor antagonists, competitive or non competitive
Activate those presynaptic inhibitor receptors
Increase breakdown of transmitter
Increase uptake of transmitter
Inhibit synthesis and packaging of transmitter
Examples of pharmacological manipulation to increase synaptic transmission
Increase synthesis by flooding the cells with the appropriate precursors
Use an agonist to activate the post synaptic receptors - not that useful cause activated all of the time
Allosteric drug which potentiates the effects of endogenous transmitters e.g. benzodiazepines and barbituates on GABA receptors
Block break down of transmitter e.g. Anticholinesterases on GABA
Block the uptake of transmitter
Examples of neurotransmitters
Acetylcholine Monoamines - noradrenaline - dopamine - serotonin (5-HT) Amino acids - Glutamate - GABA - Glycine Purines - ATP - adenosine Neuropeptides - endorphins - CCK - Substance P NO
What is the brain and the PNS separated by?
BBB
What does BBB stand for?
Blood brain barrier
What does each neurotransmitter have?
Anatomical distribution
Own range of receptors it acts on
Own range of functions in different regions (some seperated by BBB)
Exploited by therapeutic uses
Where is dopamine found in the brain?
Brain stem
Basal ganglia
Limbic system and frontal cortex
What physiological functions are affected by dopamine?
Vomiting
Voluntary movement
Emotions/rewards
Where is the vomiting centre found?
Brainstem
What is the function of the basal ganglia?
Regulates movement
What is involved in the limbic system?
Behaviour
Reward
Pathology of Parkinson’s disease
Degeneration of DA cells in the SN
DA deficiency in the basal ganglia
Fairly selective degeneration of a certain type of neurones
Does dopamine cross the BBB?
No
What are tyrosine and DOPA and can these get into the BBB?
Precursors of dopamine - these can get through the BBB
Where is DOPA broken down into dopamine?
In the liver
What are the dopamine receptors? What types of receptors are these?
D1 D2 D3 D4 D5 These are all metabotropic
Does dopamine have ionotropic receptors? What does this mean?
No
Dopamine cannot evoke fast EPSPs or IPSPs
What is the only neurodegenerative disorder that can be manipulated?
Parkinson’s disease
What TYPES of drugs can be used to treat parkinsons disease?
DA precursor
DA agonists
Enzyme inhibitors
Example of a DA precursor
Levodopa
Examples of DA agonists
Ergots - bromocriptine - pergolife - cabergoline Non-ergots - Ropinirole - Pramipexole - Rotigotine Apomorphine
Examples of enzyme inhibitors
Peripheral AAAD inhibitors - carbidopa - benserazide MOAB inhibitors - selegiline - rasagiline - sanfinamide COMT inhibitors - entacapone - tolcapone
What do dopaminergic drugs improve?
Some motor features of Parkinson’s e.g. limb rigidity and bradykinesia, tremor
What do dopaminergic drugs worsen or cause?
Nausea
Vomiting
Pyschosis
Impulsivity/abnormal behaviours
How do dopaminergic drugs cause vomiting?
More dopamine working on the brainstem working areas which promotes vomiting
Examples of impulsivity / abnormal behaviours that dopaminergic drugs can cause
Impulsivity - gambling - hypersexuality Emotion - hallucinations etc
What do dopaminergic drugs fail to help?
“Midline” features
- dysarthria
- balance
- cognition
What do dopamine antagonists do? What would this induce?
Block the dopamine system
This would induce parkinsonian syndrome
What do dopamine antagonists improve?
Nausea
Vomiting
Psychosis
What do dopamine antagonists worsen or cause?
Parkinson’s
What is another name for the vomiting centre?
Area postrema
Where is the vomiting centre found in respect to the BBB?
Outside of the BBB
Features of doperidone
Does not go into the BBB
Reduces the nausea feeling
Does not make parkinsons worse
What type of drug is doperidone?
DA antagonist
Anti emetic
What type of drug is apomorphine?
A powerful emetic
What does AIM stand for?
Abnormal involuntary movements
Features of long term DA Antagonist use
Often cause parkinsonism
Sometimes cause dyskinesias
- tardive dyskinesiasis
Who needs to be on lifelong DA antagonists?
Antipsychotics and schizophrenia patients
What type of drug are MAO inhibitors?
Antidepressants
What type of drugs are SSRIs?
Antidepressants
What are triptans (selective 5HT agonists) used to treat?
Migraine
What type of drug are GABA agonists?
Anti epilepsy drugs
also have anti anxiety properties
