Local anaesthetics Flashcards
Local anaesthetics
Reversibly block nerve conduction when applied to a restricted area of the body to enable a procedure to be carried out without loss of consciousness. They are used to prevent the sensation of pain (nociception) by targeted voltage-gated Na+ channels.
Chemical structure of local anaesthetics
They consist of an aromatic ring, a linkage group, and a basic amine group.
Linkage group
This is an amide or ester group, which serves as the site of metabolism of the drug. Different groups are metabolised at different rates, and may be broken down into potentially toxic metabolites.
Aromatic ring
This non-polar arrangement of carbon atoms is lipid soluble, allowing the drug to pass through the phospholipid cell membrane.
Amine group
This basic group can be either uncharged (-NH2) or charged (-NH2+), influencing the drug’s ability to be absorbed.
Local anaesthetics: acidic or basic?
Local anaesthetics are all weak bases, so they will all accept a proton (H+) to become positively charged. They do not completely dissociate in solution, and the level of ionisation is determined by pH.
Level of ionisation
B + H20 –> B+ + OH-
In acidic conditions, the forward reaction is favoured. In alkaline conditions, the reverse reaction is favoured. At physiological pH B < B+.
Mechanism of action
Outside the cell, unionised and ionised local anaesthetic molecules are in equilibrium. Unionised molecules can pass through the cell membrane, where some then ionise within the cell. The ionised drug can block open Na+ channels from the inside (use-dependent).
Factors affecting effectiveness
Tissue pH- determines ionisation state
-acidic conditions caused by inflammation or infection increase the number of ionised molecules, reducing the drug’s ability to cross the cell membrane
Different neurones- axon diameter determines sensitivity
- smaller neurones (ie. nociceptive) have high sensitivity
- larger neurones (ie. motor) have low sensitivity
- myelination also affects effectiveness
Anaesthetised area
The more proximal the site of administration of a local anaesthetic to the CNS, the greater the anaesthetised area.
Routes of administration
- topical anaesthesia; applied to a surface, not very effective as it is hard to penetrate through the skin
- infiltration anaesthesia; injected into the skin, sometimes at multiple sites
- nerve block anaesthesia; injected more proximally, targeting a mixed nerve
- epidural anaesthesia; injected into the epidural space within the vertebrae but outside of the spinal cord, local anaesthetic bathes nerve roots
- spinal anaesthesia; injected into the cerebrospinal fluid to anaesthetise a large area of the body
- regional anaesthesia; injected intravenously into a limb, must be very specific
Side effects of local anaesthetics
Non-specific side effects include hypersensitivity (allergic) reactions to additives administered with the drug ie. preservatives. Specific side effects may arise from high doses or the wrong route of administration, where the local anaesthetic can block the Na+ channels of any excitable tissue within the body.
Other drugs administered with local anaesthetics
Vasoconstrictors prevent the entry of the local anaesthetic into the circulation, reducing unwanted side effects and increasing the duration of action.
Properties of good local anaesthetics
- reversible
- block nerve conduction in nociceptive neurones
- effective for the time of a procedure
- low toxicity
Suxamethonium
A highly potent agonist of nicotinic receptors that cannot be metabolised by acetylcholinesterase, resulting in prolonged stimulation of the effector muscle. It is metabolised by an enzyme in the blood called plasma cholinesterase, and it’s effects can be antagonised by an anti-cholinergenic agent.
