Last updated on January 9, 2019 at 22:16
Ester type local anaesthetics
Amide type local anaesthetics
Local anaesthetics are drugs that are used to prevent or eliminate pain, often during smaller surgical procedures. They stand in contrast to general anaesthetics, which work on the CNS and induces a state where the patient is unconscious and unable to feel pain.
Local anaesthetics work by reversibly blocking voltage-gated Na+ channels. These channels are responsible for the upstroke phase of the action potential in nerve fibres. By blocking them will there be no depolarization, so nociceptive nerve signals won’t be carried to the brain.
Pharmacodynamics of local anaesthetics
These drugs physically “plug” and therefore block voltage-gated Na+ channels. At high concentrations may they block other ion channels as well.
The degree to which the nerve fibre is myelinated is important for the effect of these drugs – thick myelinated fibres are less affected than thin fibres. Recall from neuroanatomy that we have A, B and C type nerve fibres. Nociceptors have two different types of axons, one Aδ and one C type. The Aδ fibres is responsible for the initial sharp pain, while the C fibres are responsible for the prolonged, less intense pain. From this can we understand that local anaesthetics work better against the slow pain than the immediate, sharp pain.
The sequence of loss of sensory modalities go like this. From first to last lost are:
- Motor function
All local anaesthetics are weak bases, meaning that they have pK between 7-9. This means that at physiological pH are most of the drug molecules ionised, i.e. in the form of “drug-H+”, or BH+, because they’re bases. If the pH is lower than normal are more drugs in the BH+ form, if the pH is higher than normal are more in the lipophilic B form.
These drugs bind to Na+ channels from the inside of the fibre, not from the outside. They must therefore diffuse across the lipid membrane of the axon to get to the inside in order to work. We know that charged molecules diffuse more poorly across the membrane, so the more drug molecules that are unionised (in the lipophilic B form, not the BH+ form), the better the diffusion.
Recall that the pH inside cells is more acidic than in the interstitium and plasma. Because of this will more drug molecules be ionised to the hydrophilic BH+ form, and it is this form that binds to and blocks the Na+ channel. The drug can enter and plug the Na+ channel by two pathways: the use-dependent pathway and the pathway that isn’t use-dependent. Let me explain.
During rest are voltage-gated Na+ channels closed from the inside of the cell (see the figure below), so the local anaesthetics can’t plug them. As soon as the action potential arrives and the channels opens will the drugs plug them before any Na+ can enter the cell. From this can we understand that more active fibres, fibres that fire more often, are more efficiently blocked. This means that we need a lower concentration of local anaesthetic to block fibres that work at higher rates. This phenomenon is called use-dependent block.
Drug molecules enter the Na+ channel even if they’re closed too, through another pathway that involves partially diffusing across the axonal membrane, as seen in the drawing above.
Anyway, there are three important things to gather from all this: First, the effect of local anaesthetics during inflammation is weaker, because in inflammation there is acidosis, meaning that fewer drug molecules are in the B form that can diffuse across the membrane. Second, highly active nerve fibres are blocked more efficiently than less active fibres. Third, the more lipophilic the drug the more suitable it is for surface anaesthesia.
There are many important uses for local anaesthetics:
- Surface anaesthesia – by applying directly to skin or mucous membrane
- Infiltration anaesthesia – by giving multiple injections targeting small nerve branches, as done at the dentist
- Nerve block anaesthesia – giving injections close to major nerve trunks, which anaesthetizes the entire are innervated by this trunk
- Spinal anaesthesia – by administering directly into the subarachnoid space, into the CSF
- Epidural anaesthesia – by administering directly into the epidural space
- IV regional anaesthesia – giving IV and applying a tourniquet to an extremity
When do local anaesthetics stop working? When they are absorbed from the tissue they’re applied to and to the plasma. From this can we gather that the higher the perfusion of the tissue, the shorter the duration of the drug. Applying vasoconstrictors together with the anaesthetic can therefore prolong the duration of action.
The systemic side effects also occur when the anaesthetics are taken up into the plasma. Therefore, the shorter the plasma half-life, the fewer systemic side effects. Amide type local anaesthetics bind more easily to plasma proteins than ester types, and therefore have fewer systemic side effects.
Esters are hydrolysed in the plasma and liver by pseudocholinesterase, and amides are metabolised in the liver by P450.
Voltage-gated Na+ channels are found everywhere, so when the local anaesthetics are absorbed into the plasma will channels all over the body be affected.
CNS side effects:
Cardiovascular side effects:
- Negative chronotropic, dromotropic, inotropic effects
Allergic reactions may occur, mostly to ester types, and can range from skin reactions to anaphylactic shock.
Spinal anaesthesia carries some risk. Not only sensory nerves travel in the spinal cord, but autonomic and motor nerves as well. The following effects may occur:
- Sympathetic block -> Bradycardia, hypotension
- Parasympathetic block -> urinary retention
- Paralysis of phrenic nerve
Ester type local anaesthetics
Cocaine is probably the most interesting drug you’ll read about today. It has an intermediate duration of action. It’s harvested from the coca plant. In addition to being a local anaesthetic does it inhibit the uptake-1 mechanism, which causes sympathetic overactivity. This also affects the CNS where you have psychomotor stimulation and euphoria. It also causes mucosal irritation and inflammation, but on the bright side it may work as a decongestant! It’s obviously rarely used medically these days.
Procaine has a short duration of action. It has poor tissue penetration and therefore can’t be used for surface anaesthesia. It frequently elicits allergic reactions but has low systemic toxicity because it’s rapidly metabolised.
Tetracaine has a long duration of action. It has good tissue penetration, and you may already have seen it been used for surface anaesthesia. It’s also used for nerve blocking and spinal anaesthesia. It’s metabolised very slowly, so it has more systemic side effects. It’s therefore often given with a vasoconstrictor.
Benzocaine is the weird kid in the block. It works in a different way than the others. It isn’t water soluble, so it’s given as a powder, ointment or suspension for surface anaesthesia.
Amine type local anaesthetics
Lidocaine is perhaps the most famous one. It has an intermediate duration of action and has good tissue penetration, so it’s good for surface anaesthesia. It can also be given IV as an antiarrhythmic drug.
Prilocaine also has an intermediate duration of action. It has a very special side effect – methaemoglobinaemia!
Mepivacaine is the last one to have an intermediate duration. It’s mostly used for nerve block and spinal anaesthesia, but not during delivery because of neonatal side effects.
Bupivacaine has a long duration of action. It has less motor fibre blocking than the others and is therefore preferred during delivery. It has an isomer, levobupivacaine, which has fewer side effects. It has cardiac toxicity like arrhythmia and impaired contractility.
Ropivacaine also has long duration of action and has even less motor fibre block and isn’t cardiotoxic.
Articaine is the last one to have long duration of action.
Tetrodotoxin (TTX) and saxitoxin (STX) are two toxins produced by fish. They are very potent and highly selective Na+ channel blockers and aren’t used clinically. They act from the extracellular side of the fibre, unlike the drugs. Tetrodotoxin does not affect Na+ channels in the heart or in nociceptive fibres.
Paralysis of the respiratory muscles is what kills you.
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