regulating neuronal excitability Flashcards
motor neurons receive excitatory and inhibitor output. In the case of epilepsy, there is an excess of […] input, with inordinate amounts of NT […] released on the post synaptic motor neuron.
excitatory
glutamate.
one tx option for epilepsy would be to enhance GABA receptor activity on the motor nerve, accomplished through [….] type drugs
benzodiazepines
epilepsy may be tx by specifically limiting the excessively firing nerves releasing glutamate, with drugs such as […].
OR inhibiting T-type calcium channels in these excessively firing nerves, with drugs such as […]
OR by inhibiting the NMDA receptor for glutamate on the post synaptic motor nerve., with drugs such as […]
phenytoin
Ethosuximide
Felbemate
analgesics target the […] and […] pathways
pain and sensory (regulate the pain rather than stopping sensation all together like local anaesthetics
[….] induce regional inhibition of pain/sensory pathways. They DO NOT cause loss of consciousness.
local anaesthetics
[….] depress cortical processing of pain/sensory signal. Causes loss of consciousness, with widespread, not regionalized effect.
general anaesthetics
cocaine was an early local anaesthetic, works by inhibiting […] reuptake. it is a cns [….]
NA
stimulator
local anaesthetics agents are drugs that [….] block conduction of nerve impulses at the [….].
the clinically used agents tend to be […] bases with differing onset, duration and toxicity.
reversibly
axonal membrane
weak bases.
aminoesters are [….] acting local anaesthetics, and undergo hydrolysis by [….].
A common drug is […]
short
esterases
procaine.
aminoamides are [….] acting local anaesthetics, and undergo metabolism by [….].
common drugs are [….]
long
hepatic metabolism
lignocaine
bupivicaine
ropivicaine
local anaesthetics are safe/effective when they remain in the periphery due to selectine […] channel binding, reversible binding without nerve damage, blanket effect on all nerves and [….].
Na+
excitable tissues.
Depending on dose/systemic absorption In the CNS, local anaesthetics can cause [….] in the heart, [….] on autonomic nerves. and [….] peripheral nerves.
anti-dysrhythmic function, but cardiac arrest in excess.
causes hypotension, but CNS convulsion/coma in excess.
causes sensory loss, but paralysis in excess.
NB: how they’re used and who uses them makes them safe!
In epidural injection of local anaesthetic, for the same dose of anaesthetic sensory fibres are blocked […] % while motor fibres will be blocked [….] %.
This is because local anaesthetics only bind [……]
—-> favouring [….] fibres more.
Conversely, toxins bind [….] causing blanket effects.
100
25
intracellular portion of transmembrane domain receptor (S6 in domain IV).
sensory fibres more.
extracellular portion of channel, causing blanket sensory and motor suppression.
how do local anaesthetics interact with the Na+ channel membrane?
(two mechanisms)
1) fast, and non-use dependant path …..
Which drugs use this path?
2) slow, use dependant…..
Which drugs use this path?
With this in mind, what limits the rate of onset of these drugs?
1) hydrophobic but lipophilic drug, so can diffuse through membrane to reach intracellular channel binding site.
This is fast, and non-use dependant (independent of nerve firing).
Benzocaine.
2) Slow path, use dependant. Depends on use of Na+ channels to slip through and reach intracellular membrane binding site (ie lignocaine is 65% protonated at normal pH 7.4, more than half wont be able to cross membrane).
All the aminoesterases and aminoamides can use this path.
Rate of onset limited by diffusion accross membrane and use-dependance of the Na channels.
which pathway of local anaesthetic channel inhibition is most potent? (hydrophobic vs hydrophilic)
hydrophobic/lipophilic pathway crosses membrane independant of use, however binds weakly to Na channel, only physically obstructing the channel.
Hydrophilic/lipophobic pathway is most potent! Although limited by slow-onset.
Half the drug is not protonated at normal pH, and crosses the membrane. The other half crosses when the Na channel opens. They combine on the intracellular side, revert to charged form, and exert a much stronger effect on blocking influx of Na+ through its channel.
