Applied Neuro-Pharmacology Flashcards
What is the sequence of event sin synaptic transmission?
- 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
How can pharmacological manipulation reduce synaptic transmission?
Block the voltage gated Na+ channels - eg local anaesthetics, would block all action potentials, not too useful
Block the voltage gated Ca2+ channels - eg those clever spider toxins, would block all transmitter release, not too useful
Block the release machinery, eg botox, would block all transmitter release, not too useful
Block the postsynaptic receptors, eg receptor antagonists, competitive or non-competitive. Selectivity helps
Activate those presynaptic inhibitory receptors
Increase breakdown of transmitter (though I can’t think of an example of that)
Increase uptake of transmitter (though I can’t think of an example of that)
Inhibit synthesis and packaging of transmitter
What are pharmacological manipulation to increase synaptic transmission?
Increase synthesis by flooding the cells with the appropriate precursors
Use an agonist to activate the postsynaptic receptors - though that is not so useful because they get activated all the time – most of which is inappropriate
Better to use an allosteric drug that does activate the receptor on its own, but potentiates the effects of the endogenous transmitter, eg benzodiazepines and barbiturates on GABA receptors
Block break down of transmitter – eg anticholinesterases on Ach
Or block the uptake of transmitter
Do drugs act on just one receptor?
Likely it will have more than one effect and act on more than one receptor
WHat are examples of neurotransmitter?
(there isnt too many)
Acetylcholine
Monoamines - Noradrenaline, Dopamine, Serotonin (5-HT)
Amino acids - Glutamate, GABA, Glycine
Purines - ATP, Adenosine
Neuropeptides - Endorphins, CCK, Substance P
NO
Do neurotransmitters have just one function?
It should be no surprise that a single neurotransmitter has multiple functions in different regions
Often in the brain and in the peripheral nervous system - separated by the blood brain barrier
• Each neurotransmitter has:
- its own __________ distribution
- Its own range of _________ it acts on
- Its own range of _______ in different regions (some separated by the blood brain barrier)
• Each neurotransmitter has:
- its own anatomical distribution
- Its own range of receptors it acts on
- Its own range of functions in different regions (some separated by the blood brain barrier)
Where is dopamine (DA) distributed in the brain?
• Anatomical distribution in the brain
- Brain stem
- Basal ganglia
- Limbic system and frontal cortex
What are the functions of dopamine?
• Physiological functions affected:
- Voluntary movement
- Emotions/reward
- Vomiting
What are the different dopamine pathways in the brain?
What dopamine pathway is involved in parkinsons?
Nigrostriatal pathway
What is parkinsons disease?
- Degeneration of DA cells in the SN (nigrostriatal)
- DA deficiency in the basal ganglia
What is the process of dopamine synthesis?
Where does dopamine sythesis occur?
both inside and outside the brain
Can dopamine made in the periphery cross the BBB?
No but its precurssors, tyrosine and DOPA, can
What are blockages in the dopamine pathway which may occur?
May pharmacologically block dopamine in the periphary to make sure the DOPA crosses into the brain and it is made in the brain
What are the dopamine receptors like?
No ionotropic receptors (so dopamine cannot evoke fast EPSPs or IPSPs)
5 subtypes of metabotropic (ie g-protein coupled) receptor named D1-D5
Dopamine can produce many effects, and different effects in different brain regions, depending on which receptors are expressed
All drugs are non-specific on what ones they act on
What is the dopamine metabolic breakdown pathway?
2 stages and 2 different pathways
Can inhibit the enzymes to avoid breakdown of dopamine to enhance its effects
What are the 2 main enzymes involed in the metabolic breakdown of dopamine?
MAO-B and COMT are the key enzymes in dopamine breakdown
What does parkinsons disease result in (symptoms and signs)?
Stiffness, slow movements, change in posture, tremor
What are some dopaminergic drugs that can be used to improve some symptoms of parkinsons disease?
- DA precursor - Levodopa
- DA agonists
- Ergots:
Bromocriptine, pergolide, cabergoline
No longer used: 5-HT(2B) stimulation → fibrosis
- Non-ergots:
ropinirole, pramipexole, rotigotine
- Apomorphine
What enzyme inhibitors can be used?
Peripheral AAAD inhibitors eg carbidopa, benserazide
↓ peripheral side-effects of levodopa and allows a greater proportion of the oral dose to reach the CNS
MAOB inhibitors eg selegiline, rasagiline, safinamide
COMT inhibitors eg entacapone, opicapone
↓ metabolism of dopamine and so effectiveness of levodopa
What do dopaminergic drugs improve?
Some motor features of Parkinson’s
e.g. limb rigidity & bradykinesia, tremor
What do dopaminergic drugs worsen or cause?
- Nausea
- Vomiting
- Psychosis
- Impulsivity/abnormal behaviours
What do dopaminergic drugs fail to gelp?
“Midline” features
eg dysathria, balance, cognition
What do dopamine antagonists improve?
- Nausea
- Vomiting
- Psychosis
What do dopamine antagonists worsen or cause?
Parkinsonism - a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability
What are the effects of DA antagonist antiemetics?
DA antagonist antiemetics (effective against vomiting and nausea) will worsen parkinsons disease and generally should not be used in people with PD
Area postrema (vomiting centre) in the medulla is functionally OUTSIDE the BBB
If there was a DA antagonist that didn’t cross the BBB that would be ok
What is a drug that is a DA antagonist that doesnt cross the BBB?
Domperiodne
What is Domperidone?
DA antagonist
Anti-emetic
Does not cross the BBB
No antipsychotic properties
Relatively safe to use in PD
Has permitted the therapeutic use of apomorphine (which is a powerful emetic).
What is dyskinesias?
abnormal involuntary movements
Would dopaminergic drugs and DA antagonists cause dyskinesias or parkinsonism?
Dopaminergic drugs - May cause dyskinesias (eg chorea)
“too much movement”
DA antagonists - May cause parkinsonism
“not enough movement”
What are the effects of long term DA antagonist use?
Antipsychotics/anti-dizziness
Often cause parkinsonism e.g. receptor blockade in basal ganglia
Sometimes cause dyskinesias
Tardive dyskinesias (orofaciolingual) - Hard to explain: upregulation or increased sensitivity of certain DA receptors
What are some examples of other
neurotransmitter functions?
Noradrenaline:
- Reuptake blockers eg tricyclic drugs are antidepressants
- MAO inhibitors are antidepressants.
Serotonin; 5-HT:
- Selective serotonin reuptake inhibitors (SSRIs) are antidepressants
- Triptans (selective 5HT agonists) used for the treatment of migraine
GABA:
- GABA agonists are anti-epilepsy drugs
- They also have anti-anxiety properties
