Local anaesthetics Flashcards
What are anesthetics?
Dugs which are used to prevent pain for a limited period of time.
What are analgesics?
EG Morphine
Used to control pain
What are local anesthetics?
Prevent pain or nociception in a localised area (and also prevent tactile sensation)
Block electrical signalling in neurones.
Block voltage-gated Na+ channels
What are general anesthetics?
Prevent pain or nociception and loss of consciousness.
Two classes of anesthetics =
- Inhalation anesthetics (Halothane, nitrous oxide, enflurane, isoflurane)
- Intravenous anestetics (Thiopental, etomidate, propofol)
Mechanism of action - Two main theories
- Lipid theory:
Meyer Overton theory.
Strong relationship between anesthetic potency and lipid solubility.
Original hypothesis is largely discredited. - Ion channel theory:
Anesthetics target a number of ligand-gated ion channels, including GABAa and glycine NMDA.
Inhalation anesthetics physiochemical properties
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
Examples of Blood/Gas partition coefficient
Low (nitrous oxide) - Rapid induction, recovery
High (halothane) - Slow induction, recovery
Inhalation anesthetics
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.
Limited hepatic metabolism
Methoxyflurane: extensive (60%) hepatic metabolism resulting in nephrotoxic fluoride ion. Halothane 15% hepatotoxic Isoflurane 0.5% Desflurane 0.5% Sevoflurane 3% Nitrous oxide
Side effects common to inhaled anesthetics
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)
Examples of intravenous anesthetics
Thiopental sodium
Etomidate
Ketamine
Propofol
Thiopental sodium
Acts on GABAa receptor (on α1/β3 subunit interface)
Therapeutic index = 2.5
Etomidate
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
Propofol
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
Ketamine
NMDA receptor antagonist.
Less hypotension than Etomidate/Propofol.
Rarely used due to hallucinations and psychosis.
Does have some good analgesic effect.
Voltage-gated ion channels: Made up of 3 subunits - α, β1 and β2.
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.
Effect of local anesthetic of Voltage-gated ion channels
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)
Ideal local anesthetic
Unionised form gains access through nerve sheath and axon membrane.
Ionised form binds in channel
Most anesthetics are weak bases.
General structure of local anesthetics
Aromatic (lipophilic) group (left)
Ester or amide bond (middle)
Amine (basic) sidechain/group (right)
How can local anesthetics be manipulated?
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.
Do all nerves show similar susceptibility to local anesthetics?
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
Local anesthetics and dependent block
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.
Unwanted side effects of local anesthetics
CNS, confusion and agitation
Cardiovascular, hypotension
Inhibition of sympathetic activity
Inhibition of sodium conductance in cardiac tissue.
Limitation of local anesthetics
Not effective in infected/inflamed tissue
Factors that would affect local anesthetic activity
pKa of the local anaesthetic
Firing activity (rate) of the neurone
Lypophilicity of the local anaesthetic
pH of the tissue
