Local anaesthetics

Question 1

What are anesthetics?

Answer 1

Dugs which are used to prevent pain for a limited period of time.

Question 2

What are analgesics?

Answer 2

EG Morphine

Used to control pain

Question 3

What are local anesthetics?

Answer 3

Prevent pain or nociception in a localised area (and also prevent tactile sensation)
Block electrical signalling in neurones.
Block voltage-gated Na+ channels

Question 4

What are general anesthetics?

Answer 4

Prevent pain or nociception and loss of consciousness.

Question 5

Two classes of anesthetics =

Answer 5

1. Inhalation anesthetics (Halothane, nitrous oxide, enflurane, isoflurane)
2. Intravenous anestetics (Thiopental, etomidate, propofol)

Question 6

Mechanism of action - Two main theories

Answer 6

1. Lipid theory:
   Meyer Overton theory.
   Strong relationship between anesthetic potency and lipid solubility.
   Original hypothesis is largely discredited.
2. Ion channel theory:
   Anesthetics target a number of ligand-gated ion channels, including GABAa and glycine NMDA.

Question 7

Inhalation anesthetics physiochemical properties

Answer 7

Depth of anesthesia determined by concentration in the brain and spinal cord.
Blood/gas partition coefficient, measure of blood solubility.
Lower the solubility in the blood, faster the induction and recovery - less drug needs to be transferred via the lungs to produce equilibrium.
Oil:Gas partition coefficient, measure of lipid solubility.. Main factor that determines potency, since brain high lipophicity.
The lower Oil:Gas pc, the less potent the GA

Question 8

Examples of Blood/Gas partition coefficient

Answer 8

Low (nitrous oxide) - Rapid induction, recovery

High (halothane) - Slow induction, recovery

Question 9

Inhalation anesthetics

Answer 9

Vascularisation of tissue will determine tissue levels of anesthetic.
Brain good blood flow - High levels.
Body fat has poor blood flow so anesthetic doesn’t accumulate in body fat
Ventilation rate will effect rate of removal of the anesthetic but anesthetics cause respiratory depression and so require controlled ventilation.
Inhaled anesthetics mainly eliminated via lungs.

Question 10

Limited hepatic metabolism

Answer 10

Methoxyflurane: extensive (60%) hepatic metabolism resulting in nephrotoxic fluoride ion.
Halothane 15% hepatotoxic
Isoflurane 0.5%
Desflurane 0.5%
Sevoflurane 3%
Nitrous oxide

Question 11

Side effects common to inhaled anesthetics

Answer 11

Malignant hyperthermia (Hypermetabolism, muscle rigidity, muscle injury and increased sympathetic nervous system activity, hyperthermia).
Cardiovascular (Can cause hypotension - except nitrous oxide - Decreased output and decreased vascular resistance)
Respiration (Depressed respiration - Greater with the fluranes - Iso>Des>Sevo)
Hepatic toxicity (Mainly halothane)
Kidney (Depressed glomular filtration and urine output)

Question 12

Examples of intravenous anesthetics

Answer 12

Thiopental sodium
Etomidate
Ketamine
Propofol

Question 13

Thiopental sodium

Answer 13

Acts on GABAa receptor (on α1/β3 subunit interface)

Therapeutic index = 2.5

Question 14

Etomidate

Answer 14

Acts on GABAa receptor (on α1/β3 subunit interface)
Wider therapeutic window than Thiopental sodium.
Between anesthesia and respiratory depression.
More rapidly metabolized.
Therapeutic index = 26

Question 15

Propofol

Answer 15

Acts on GABAa receptor (on α1/β3 or β3/β3 subunit interface)
Very rapid metabolism
Extrahepatic, elimination via plasma (esterases) and lungs.
Rapid recovery.
No hangover
Day case surgery
Therapeutic index = 3

Question 16

Ketamine

Answer 16

NMDA receptor antagonist.
Less hypotension than Etomidate/Propofol.
Rarely used due to hallucinations and psychosis.
Does have some good analgesic effect.

Question 17

Voltage-gated ion channels: Made up of 3 subunits - α, β1 and β2.

Answer 17

The α-subunit is a single polypeptide. It contains extracellular domains, 4 transmembrane domains each comparing 6 α-helical regions. Also contains, in the hydrophobic domains, voltage sensors that change their orientation when voltage varies. Their orientation determines the configuration of the entire domain and controls opening and closing of the pore.

The β-subunits flank the α-subunit. The β2-subunit is linked covalently to the α-subunit, the β1-subunit is not linked. The two β-units anchor the α-subunit into the lipid membrane.

Question 18

Effect of local anesthetic of Voltage-gated ion channels

Answer 18

Local anesthetics are thought to interact with the α-subunit and physically ‘plug’ the transmembrane pore.
Local anesthetics bind in the ionised (hydrophilic) form.
The local anesthetic binding area is located in the inner end of the channel (drug needed to gain access intracellularly)

Question 19

Ideal local anesthetic

Answer 19

Unionised form gains access through nerve sheath and axon membrane.
Ionised form binds in channel
Most anesthetics are weak bases.

Question 20

General structure of local anesthetics

Answer 20

Aromatic (lipophilic) group (left)
Ester or amide bond (middle)
Amine (basic) sidechain/group (right)

Question 21

How can local anesthetics be manipulated?

Answer 21

Restrict site of action and prolong duration of action - Coadminister adrenaline (local vasoconstriction via α1 adrenoreceptors)
Accelerate the speed of onset of the anesthetic - Use slightly alkaline solution, this will assist in absorption of the anesthetic into the nerve tissue.

Question 22

Do all nerves show similar susceptibility to local anesthetics?

Answer 22

Different types of axons show different sensitivity to local anesthetics.
Block conduction in small diameter fibres more effectively than in large diameter fibres.
Small myelinated axons > non-myelinated axons > Large myelinated axons.
Nociceptive (pain) fibres are small diameter and particularly sensitive.
Motor axons have a large diameter and are less sensitive

Question 23

Local anesthetics and dependent block

Answer 23

In many cases the depth of block increases with an increase in action potential frequency.
Channels in 3 states - Resting, open, inactive.
Use dependent block occurs because the anesthetic gains access to and has a higher affinity for the channels more readily when it is open and/or innactive.

Question 24

Unwanted side effects of local anesthetics

Answer 24

CNS, confusion and agitation
Cardiovascular, hypotension
Inhibition of sympathetic activity
Inhibition of sodium conductance in cardiac tissue.

Question 25

Limitation of local anesthetics

Answer 25

Not effective in infected/inflamed tissue

Question 26

Factors that would affect local anesthetic activity

Answer 26

pKa of the local anaesthetic
Firing activity (rate) of the neurone
Lypophilicity of the local anaesthetic
pH of the tissue