Applied Neuropharmacology Flashcards
Describe the general sequence of events that occur during
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 (ie Ca2+ comes in and vesicle lets neurotransmitters out
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 - Ach inactivated by enzymatic breakdown
Transmitter is metabolised within cells
how could you block synaptic transmission? (7)
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. Lots of examples of that.
Activate those presynaptic inhibitory receptors.
Inhibit synthesis and packaging of transmitter.
Or if you need to potentiate the action of a transmitter, what would you do?
How could you increase synaptic transmission
Increase synthesis by flooding the cells with the appropriate precursors.
Potentiate effects of transmitter on receptor (eg increase channel open time)
Block breakdown of transmitter
block uptake of transmitter
List some common neurotransmitters
Ach
Monoamines:-
- NA
- Dopamine
- Serotonin
Amino acids:-
- Glutamate
- GABA
- Glycine
Purines:-
- ATP
- Adenosine
Neuropeptides:-
- CCK
- Endorphins
- Substance P
Nitric Oxide
Neurotransmitters often act in the brain and in the PNS which is separated by what?
the blood brain barrier
What happens with Parkinson’s disease
Degeneration of dopamine cells in the substantia nigra
also a dopamine deficiency in the basal ganglia
Which physiological functions is dopamine involved with?
voluntary movement
emotions/reward
vomiting
Where is dopamine found in the brain?
brain stem
basal ganglia
limbic system and frontal cortex
Dopamine synthesis
Glycine - alanine -others Tyrosine - DOPA - Dopamine
How is dopamine synthesis modulated in vivo?
can pharmacologically block the conversion of DOPA to Dopamine
Tyrosine can be lost through degeneration so that it doesn’t turn into DOPA
There are no ionotropic dopamine receptors - what does this mean?
so dopamine cannot evoke fast EPSPs or IPSPs
What are the key enzymes involved in dopamine breakdown?
MAO-B - selegiline, rasagiline
COMT - entacapone, opicapone
Symptoms associated with parkinson’s disease
stiffness
slow movements
change in posture
tremor
Dopaminergic drugs
precursor - Levodopa (L’DOPA) - its supplementation can increase dopamine levels in the body
agonists:-
Ergots - Bromocriptine, perfolide
Non-Ergots - ropinirole, pramipexole
Apomorphine
These drugs improve some symptoms of PD
How do peripheral Aromatic L-amino acid decarboxylase (AAAD) inhibitors work
they inhibit the synthesis of dopamine by the AAAD enzyme
decrease peripheral side-effects of levodopa and allows a greater
proportion of the oral dose to reach the CNS
Give 2 examples of peripheral AAAD inhibitors
carbidopa
benserazide
How do MAOB and COMT inhibitors work?
decrease metabolism of dopamine and so increase effectiveness of levodopa
Dopaminergic drug pros and cons
pros - improve some motor features of Parkinson’s - limb rigidity and bradykinesia (slow movement), tremor
cons - worsen or cause nausea, vomiting, psychosis, impulsivity/abnormal behaviour
What do dopaminergic drugs fail to help? (3)
dysathria - speech articulation
balance
cognition
Dopamine antagonists (block dopamine receptors) pros and cons
improve nausea, vomiting, psychosis
worsen or cause Parkinsonism
what is Parkinsonism?
a clinical syndrome characterised by tremor, bradykinesia (slow!), rigidity, and postural instability. It is found in Parkinson’s disease
what type of drug should generally not be used in people with Parkinson’s disease
dopamine antagonist antiemetics (anti-sickness) as these worsen parkinson’s disease
what is the area postrema and where is it found?
vomiting centre
functionally found outside the BBB
Name a Dopamine antagonist that does not cross the BBB
domperidone
What is domperidone?
an anti-emetic that doesn’t cross the BBB
has no antipsychotic properties
relatively safe to use in Parkinson’s disease
What is dyskinesias
abnormal involuntary movements
which type of drug may cause dyskinesias?
dopaminergic drugs (too much movement)
GABA agonists are what type of drugs?
anti-epilepsy drugs
also anti-anxiety
