W4: Pharmacology of Local Anaesthetics Flashcards
What is the chemical origin of cocaine?
From coca plant
Is an alkaloid
Contains a amine group (weak base) and an ester bond
What is the naming stem for local anaesthetics?-
Suffix caine.
What is the chemistry of most local anaesthetics?
Are amine - weak base linked to an aromatic group
Either contain an amide link such as lidocaine
Or an ester link such as procaine
How do local anaesthetics with an ester link vary from thoses with an amide link?
Ester link - shorter duration of action
Metabolised by plasma esterases.
What is the physiological effects of local anaesthetic?
Prevent the generation of an action potential and transmission of impulses along nerve fibres.
More effective as smaller diamater fibres such as A-delta and C fibres.
Therefore sensitivity varies among neurons, so higher concentration of LA can have other variable effects, as affects any neurons/tissue that have voltage gated Na+ channels
What tissue function is most sensative to the use of local anaesthetics?
MOST
Pain
Sensory
Autonomic neurons
Motor function
LEAST
How does the diameter of the nerve fibre effect its function and vulnerability to local anaesthetics?
Larger diameter - faster electrical impulses
Smaller diameter - more sensitive to local anaesthetics.
What is the basic pharmacology of local anaesthetic (cocaine)?
Targets voltage gated sodium ion channels, acts as a channel blocker.
What does the Hodgkin-Huxley model shown about membrane potential and membrane current?
Completed an experiment - looking at flow of sodium ions.
Shows that when a depolarisation (control value) is applied to the membrane (increased voltage), originally there is a rapid activation due to increased current (measured value), this then changes to become slower inactivation.
Inactivation will remain immediately afterwards even if the depolarising pulse is still present.
What are the two different gates present in the voltage gated sodium ion channel?
m gate or activation gate
h gate or inactivation gate
How are the different gates within the voltage gated sodium ion channel affected by resting membrane potential?
M gate - activation gate is closed at rest
H gate - inactivation gate is open at rest
The channel is at rest
How are the different gates within the voltage gated sodium ion channel affected by depolarisation?
Depolarisation causes rapid opening of m gate
Depolarisation causes slow closing of h gate. Now the channel is termed inactivated.
Interval between M opening and H closing allows sodium ions to flow across the channel and into the neuron contributing to further depolarisation. The channel is open.
Therefore both these gates are voltage sensitive.
What is the physiology undermining resting membrane potential?
Na+ K+ ATPase - 3Na+ out and 2K in - generates a Na+/K+ chemical gradient
Selective permeability to K+ allows K+ to move out down chemical gradient, however membrane is relatively impermeable to Na+ at rest
This generates an electrical gradient with more positive charge outside the neuron than inside.
The Em is around 70mV, this is near the Ek (electrical and chemical gradient near point of balance for K+)
The m gate is closed and the h gate is open CGNaC is closed or resting.
Explain what changes occur at the neuron membrane during action potential.
M gate opens rapidly in response to increased voltage
M gate and H gate are now open, VGNaC is open
Na+ influx further depolarised the neuron - action potential is generated around +30mV
Action potential is propagated along the neuron.
What changes happen in the neuron and VGNaC during repolarisation?
H gate closed slowly due to depolarisation
M gate is still open but the H gate is slowed = VGNaC is deemed inactivated
No Na+ current
K+ efflux down an electrochemical gradient causes repolarisation.
Describe how the VGNaC is reactivated after repolarisation.
m gate closes rapidly as voltage decreases
m gate is closed and h gate closed - VGNaC is closed but reactivating
H gate opens slowly in response to decreased voltage (same that closed m gate)
M gate is closed and H gate open - VGNaC is closed (resting)
Describe how the resting membrane potential is restored after an action potential generation.
VGNa+ channels are resting and activatable
Intra and extra-cellular concentration of Na+ and K+ do not change greatly during the action potential.
Na+ K+ pump preserves the chemical gradients and resting membrane potential is restored.
What does an inactivation curve show about the properties of voltage gated sodium ion channels?
When a channel is more depolarised before an action potential stimuli is applied there is less flow of current all channels were in inactivated state.
In contract when the channel is more hyperpolarised before an action potential is applied there is more flow of current as all channels are in resting state.
How do local anaesthetics acts preferentially based on channel state?
Why?
Different channel states have different channel structures - this alters the affinity for the drug
The affinity for LA is higher in the inactivated state
Preferentially act on inactivated state channels (when H gate is closed and M gate is open initially after action potential - during the repolarisation state)
What is the effect of local anaesthetics at the VGNaC level?
LA have a higher affinity for VGNaC in the inactivated state
As as a channel blocker
Increases the number of channels stuck in the refractory/inactivated state by stabilising the channel it binds to
This shift the inactivation curve to the left, as a greater proportion of VGNaC are inactivated at any voltage/
What factors influence the usefulness of local anaesthetics?
Are use dependent - influence channel state
pH dependent
Voltage dependent - influence channel state
Why are local anaesthetics described as use dependent?
Repeated stimulation of the neuron leads to increased inactivation state of channel for a longer period of time.
Leading to increased inhibitory effects of the local aneasthetic.
This is because the local aneasthetic is more effective when VGNaCs are opened then inactivated.
Why are local anaesthetics described as pH dependent?
Are weak bases
pKa of 8-9
Onset of block is slower at acidic pH - as LA acts as a base to accept H+ and becomes protonated/charged.
Low pH greater proportion HB+ than B.
When charged is more difficult to cross the cell membrane by hydrophilic method.
So is unable to effect the channel, as effects channel from the cytoplasmic side
This is clearly shown be lidocaine.
Why are local anaesthetics adapted to working at higher pH?
Are weak bases have a pKa of 8-9.
At a high pH there is a greater proportion of B to HB+.
This uncharged form finds it easier to cross the cell membrane by hydrophilic methods so is is able to act of the VGNaC from the cytoplasmic side.
This is cleary shown by lidocaine
