Lecture 42 Applied Neurological-Pharmacology Flashcards
Describe the sequence of events in 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
Pharmacological manipulation to 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. Lots of examples of that.
- 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.
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.
Describe 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.
Each neurotransmitter has
- Its own anatomical distribution
- Its own rage of receptors it acts on
- Its own range of functions in different regions
What is the anatomical distribution in the brain of dopamine
- Brain stem
- Basal ganglia
- Limbic system and frontal cortex
What physiological functions are affected by dopamine
- Voluntary movement
- Emotions/reward
- Vomiting
Describe Parkinson’s disease
- Degeneration of DA cells in the substantia nigra (nigrostriatal)
- DA deficiency in the basal ganglia
- Stiffness, slow movements, change in posture, tremor
Describe Dopamine synthesis
Glycine–> Alanine–>Phenylalanine–>Tyrosine–>DOPA—>Dopamine
What enzymes are involved in the synthesis of dopamine
Tyrosine
Hydroxylase
Aromatic aa
Decarboxylase
How many subtypes are there of dopamine receptors
5 Metabotropic (protein coupled) Dopamine cannot evoke fast EPSPs or IPSPs
Name enzymes involved in Dopamine Metabolic Breakdown
MOAD
COMT
What is dopamine breakdown product
Homovanillic acid
Name a precursor that is a Dopaminergic drugs
Levodopa
Name DA agonists
Ergots- Bromocriptine
Non-ergots- Ropinirole
Apomorphine
Improve symptoms of PD
