Flashcards in CPTP 3.22 Neuropharmacology 7 Local Anaesthetics Deck (33)
Recall the three possible confirmations of sodium channels
There is also a number of intermediate states
Why are sodium channels impermeable in the resting confirmation?
The S4 regions (which are positive) are aligned along the middle of the channel by the 'lumen' when in the resting confirmation, repelling Na+ ions
How do sodium ion channels become inactivated?
Once sodium travels through, it induces a change in confirmation whereby a 'linker region' moves to block the lumen of the sodium channel (IMG 18)
Where do local anaesthetics target? How do they work
They REVERSIBLY bind to the intracellular side of the Na+ channels thus preventing sodium influx. Can do this by either:
• Physically blocking the lumen
• Stabilising the channel in the inactive confirmations
In which confirmations do local anaesthetics bind to sodium channels?
(NB: NOT resting)
What is needed for local anaesthetics to be effective?
• They must be able to diffuse across the nerve cell membrane to the intracellular side
• Bind to the LA target site
Describe the chemical structure of lidocaine. Which properties does each component influence?
• Aromatic group - affects hydrophobicity of the drug
• Linker region (ester or amide bond) - affects metabolism of drug
• Amine group - influences the charge of the drug
What are the central 'linker regions' in older and newer local anaesthetics structure?
Describe the metabolism of anaesthetics with different linker regions.
Affects how the drug is metabolised:
• Ester: Short half life - 3 mins, rapidly metabolised by plasma cholinesterases
• Amide: 3 hour half life, metabolised by liver P450 enzymes
Describe the hydrophobicity of anaesthetics with different aromatic groups.
Adding functional groups onto the aromatic ring INCREASES hydrophobicity
Describe the how hydrophobicity affects the drug pharmacology of local anaesthetics
The drug needs to be hydrophobic enough to be able to enter the lipid bi-layer and therefore cross into the neurone, but cannot be too hydrophobic or it will become trapped in the lipid bilayer (IMG 20)
The LA binding sire on Na+ channels contains hydrophobic residues, so more hydrophobic LAs bind more tightly to it and thus have greater potency
Therefore for an effective drug which can still get into the neurone = MODERATELY hydrophobic is ideal
Describe the pH of local anaesthetics
• Weak bases (proton acceptors)
What does the proportion of the drug which is ionised depend on?
What conditions are needed for 50% of the drug to be ionised?
• pH of the solution
• pKa of the drug
pH = pKa
What range of pKa's of local anaesthetics lie within?
Recall physiological pH?
Thus, determine if there are more ionised or unionised forms of local anaesthetics in the equilibrium at physiological pH
7.6 to 9
More in the ionised form (IMG 21)
How does increasing or decreasing the pKa of a weak base drug affect the amount of that drug which is ionised?
Increasing pKa: more is ionised
Decreasing pKa: less is ionised (more is in its neutral form)
What form of the local anaesthetic:
1) Passes through the hydrophobic lipid bi-layer?
2) Binds to the sodium ion channel?
1) Un-ionised form
2) Ionised form
Describe how the hydrophobicity of local anaesthetics is distributed within their molecule
They are amphiphilic
How does the pKa affect the onset time of a local anaesthetic?
Lower pKa = faster onset
• Lower pKa means more un-ionised drug
• More can cross the lipid bi-layer
• Therefore faster action
Recall the effect of hydrophobicity on:
2) Duration of action
1) More hydrophobic = greater potency
2) More hydrophobic = longer duration of action
How does hydrophobicity affect the duration of action?
Hydrophobic drugs are more likely to be sequested in fat and therefore
• Are less available for metabolisation
• Are less available to be removed by the blood stream
How is duration of action of local anaesthetics boosted in clinical practise?
What second benefit does this have
They are administered with a vasoconstrictor such as epinephrine to localise the anaesthetic
This reduces toxicity as it inhibits absorption into the systemic circulation
In which cases should a vasoconstrictor not be used in conjunction with local anaesthetics?
In terminal vasculature (e.g. fingers)
In which case will local anaesthetics not be effective and why?
What must be done to compensate for this?
In inflamed tissue
• Inflammation causes tissue acidosis
• Lower pH causes an increased proportion of the weak acid LA drug to be ionised
• Therefore the ionised drug cannot enter the neurones and inhibit the Na+ channels from inside
Increase the dose
What effect does the nerve type have on local anaesthetics? Why?
Small diameter fibres with little myelination are most readily blocked (A-δ, B and C-fibres)
This is because the local anaesthetic needs to diffuse into the neurone through the cell membrane. Increased thickness hinders this diffusion
Why can patients often still feel touch sensations regardless of local anaesthesia?
A-α, A-β and A-Ɣ fibres all have myelination and so hinder diffusion of LA into the neurone
What effect does ionisation have on water solubility?
How does this affect injection-able preparations?
Ionised drug is more water soluble
They are formulated as HCl salts, to ionise the weak base as much as possible
In which ways can LAs be administered?
• An oily vehicle is used
• Slow onset
• LA is injected intra-dermally or subcutaneously
• Fast onset
Peripheral nerve block anaesthesia
• Injection of LA around a nerve trunk
• Blocks all inputs which would be passing through this nerve trunk
• (e.g. brachial plexus block will anaesthetise a whole arm)
Central nerve block anaesthesia, can be:
• SPINAL ANAESTHESIA -Anaesthesia is injected into the subarachnoid space
• EPIDURAL ANAESTHESIA - Anaesthesia is injected into the epidural space
• Produces anaesthesia above AND below the site of injection
Intravenous regional anaesthesia:
• LA is injected into a limb after application of a tourniquet
What level must spinal anaesthesia be used below to avoid damage to the spinal cord?
What is intravenous regional anaesthesia used for?
What is the risk of this administration method?
Manipulation of fractures and minor surgical procedures
Toxicity - you must wait 20 mins before removing the tourniquet