Local Anaesthetics - NAS Lecture 9 PDF

**Local anaesthetics -- NAS Lecture 9\ 20/10/2023** Local anaesthetics are drugs which cause reversible nerve block by blocking voltage-gated sodium channels in high concentrations, preventing the generation of action potentials. They do not cause a loss of consciousness, as opposed to general anae...

**Local anaesthetics -- NAS Lecture 9\ 20/10/2023** Local anaesthetics are drugs which cause reversible nerve block by blocking voltage-gated sodium channels in high concentrations, preventing the generation of action potentials. They do not cause a loss of consciousness, as opposed to general anaesthetics. **The sensation of pain** Pain is caused by **nociceptors** which detect if something damaging is occurring, such as tissue injury or extreme temperatures. In response to the noxious stimulus, an action potential is generated which is transmitted to the brain. **Structure of local anaesthetics** The general structure of a local anaesthetic comprises an aromatic region and a basic amine side chain, joined by an ester bond or an amide bond. The molecules are weak bases with a pK~a~ in the range of 8-9. In basic environments the molecules are not ionised, however they become ionised in acidic environments to form +ve ions (cations). Ester bonds are more readily metabolised by enzymes, and therefore anaesthetics with ester bonds generally have shorter half-lives, they are therefore considered short acting.  **Mechanism of action** - - The anaesthetic molecules block the voltage-gated sodium channels by plugging into the pores of the channels. In order to reach the pores, they must either take the hydrophobic or hydrophilic pathway. - - Because entry of anaesthetic into cell through the hydrophobic pathway requires the molecule to be unionised, the optimal condition for this process is a **basic** extracellular pH. This allows the molecules to remain in their unionised state. This is of concern in inflamed tissues, which have relatively **acidic** environments and therefore the effectiveness of anaesthetics in these regions is reduced. Once inside the pores, it is the ionised state of the anaesthetic that is able to interact with and block the channel. Anaesthetic molecules have a greater affinity to the voltage-gated sodium channels in their **open** and **inactive** states (during action potential) as opposed to their closed state (when there is no action potential). Therefore, these molecules exhibit a **use-dependent** selectivity, where they associate more with those channels that are frequently opening and inactivating to generate an action potential, and inhibit them more. This explains why pain receptors are blocked more effectively by anaesthetic molecules than other sensory receptors. Pain receptors generate high frequency action potentials, therefore the sodium channels are rapidly cycling through the open and inactivated states, making anaesthetic molecules more likely to bind to them. Local anaesthetics block **smaller** neurones more readily than large fibres, as small neurones (such as pain sensory neurones) are **more sensitive** to the action of local anaesthetics than larger neurones (such as motor neurones). To **prolong the effect** of local anaesthetics, they may be administered with **vasoconstrictors** such as **adrenaline**. **Unwanted side effects** Local anaesthetics cause unwanted side effects when they seep into the general circulation, this affects systems such as the CNS and the cardiovascular system. **Cardiovascular system:** reduction of myocardial contractility, heart block, dysrhythmia, vasodilation. **CNS:** Depressive at low concentrations and very high concentrations. Very high concentrations can lead to death due to respiratory depression. At medium concentrations, they have stimulatory effects such as restlessness, tremors, agitation. Different local anaesthetics have unique side effect profiles due to their structural differences. For example, bupivacaine is the most cardiotoxic. **Modes of administration** As a general rule, the more proximally an anaesthetic is administered, the greater the area that is anaesthetised. **Surface anaesthesia** - - **Infiltration anaesthesia** - - - **Intravenous regional anaesthesia** - - - **Nerve block anaesthesia** - - - **Regional Anaesthesia** - -  **Spinal anaesthesia** - - - - **Epidural anaesthesia** - - - -