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Physical properties of drugs with regard to their use as local and general anaesthetic agents- Their adverse effects.

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  1. Introduction
  2. The clinical use of anesthetics
  3. Local anaesthetics
  4. Local anaesthetic activity
  5. Adverse effects
  6. Four stages associated with the onset of action of general anaesthetics
  7. Conclusion

Local anaesthetics now have many clinical uses and can be applied in a number of ways; they vary in their pharmacological properties, and as such are used in various techniques of anesthesia. Infiltration anesthesia sees the direct injection of local anesthetic into tissues to reach nerve branches and nerve terminals, and is mainly used in minor surgeries. In Intravenous regional anaesthesia, the local anaesthesia is injected distal to a pressure cuff, and remains effective until circulation is restored, this process is used for limb surgery. In nerve block anesthesia local anesthetic is injected close to nerve trunks to produce a loss of sensation peripheral, and is used in surgery and dentistry. In spinal anesthesia, local anaesthesia is injected into the subarachnoid space to act on the spinal roots and spinal cord, this is used for surgery to the abdomen, pelvis, or leg, mainly when general anesthesia cannot be used. In epidural anesthesia, local anesthetic is injected into the epidural space, blocking spinal roots, and is used for a painless child birth.

Local anesthetics are weak bases and are usually formulated as the hydrochloride salt to render them water-soluble. They consist of an aromatic part linked by an ester or amide bond to a basic side chain. Thus they contain hydrophobic region and a basic region, accounting for their weak basic nature. They have pka values mainly in the range 8-9, so that the majority, but not all, are ionised at physiological pH. This is important in the local anesthetic mechanism of action as they need to remain non-ionized when outside the cell to remain effective. Thus the majority of local anesthetics are tertiary amines, as quaternary amines are fully ionized irrespective of pH and as such are ineffective as local anesthetics.

[...] Single anaesthetics are rarely used on their own, it is more common for a mixture of drugs to be used throughout the anaesthetic process to increase control over the anaesthetic, and to remove the unwanted effects. The patient may be given pre-medication drugs before the operation, such as opioids like fentanyl or sedatives such as the benzodiazepine midazolam, to induce drowsiness of relaxation. Commonly, unconsciousness is produced rapidly with an initial dose of intravenous anaesthetic, such as propofol, and unconsciousness and analgesia is often maintained throughout the surgery by supplying one or more inhalation agents, such as nitrous oxide and halothane. [...]


[...] Sodium and hydrogen ions are constantly moving into and out of the sodium channel, even when it is closed and they do not pass through to the cytosol, and as such a passing hydrogen ion protonates the local anaesthetic at the binding site, creating the hydrostatic repulsion needed to block the channel. Thus it can be seen that local anaesthetic activity is strongly pH dependant, being increased at alkaline pH when there are less protonated molecules outside the cell and so more can diffuse into the cell, and being decreased at an acid pH when there is a high majority of protonated molecules outside the cell that cannot diffuse in. [...]


[...] This is important in the local anaesthetic mechanism of action as they need to remain non-ionised when outside the cell to remain effective. Thus the majority of local anaesthetics are tertiary amines, as quaternary amines are fully ionised irrespective of pH and as such are ineffective as local anaesthetics. The presence of the ester or amide bond within a local anaesthetic is important in determining the plasma half life of the drug due to the differences in susceptibility to metabolic hydrolysis. [...]

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