local anaesthics Flashcards
locals anaesthetics what are they
drugs that relieve
Drugs that relieve pain in specific parts of the body without causing the loss of consciousness
•Drugs that reversibly block pain sensation by blocking nerve conduction
what is the history of local anaesthetics
clue
= coke
= procaine
Cocaine (first local anaesthetic)
•Albert Niemann isolated crystals from coca in 1880: found it had numbing effects on the mouth and tongue)
•Karl Koller
–Used cocaine in ophthalmology
•In 1905 procaine (first synthetic local anaesthetic developed).
what are the ideal properties of local anaesthetics
- irritant
- toxic
- fast
Specific and reversible action.
–Non-irritant with no permanent damage to tissues.
–No systemic toxicity
–Rapid onset and long duration
–Active Topically or by injection
what is in the general structure of local anaesthetics
- A
- e or am
- ionised a
The general structure of local anaesthetic molecules consists of i) an aromatic group (left) , ii) linked by an ester or amide group to iii) an ionisable amine group (right)
potency of local anaesthetics
- lipid
- pka
Two important properties of local anaesthetics determine their activity:
1)lipid solubility (increases with number of carbons on aromatic ring and/or amine group). Higher lipid solubility means can use lower dose and reduce toxicity risks
2)Ionization constant (pKa): determines the proportion of ionised and unionised anaesthetic in solution
Lipid solubility determines potency of LA.
Local anaesthetics with lower pKa values have faster onset of activity (greater amount of unionised form can diffuse across membrane)
what is the mechanism of action
Local anaesthetics reversibly bind to the voltage gated sodium channels (Nav channels) present on neurons
•Blocks sodium channel gating
•Blocks action potential propagation and thus nerve conduction
Both the ionised (BH+) and unionised form (B) of the local anaesthetic are necessary for activity
Local anaesthetics block the inner region of the Na+ channel and block sodium ion conduction
what part of the action potential does local anaesthetics affect
local anaesthetics block the depolarisation
the opening of the na+ channels
what are the pharmacological effects of locals anaesthetics
- nerves
- vascular smooth muscle
- cns
Nerves: decrease and abolish conductance of action potentials
•Vascular smooth muscle: vasodilation
•Cardiac muscle: decreased excitability. Prolong the effective refractory period
•CNS: increased excitability followed by depression
what is the summary of net eve fibres responses to local anaesthetics
unmyelinataed
Local anaesthetics preferentially block conduction in small diameter nerve fibres (Aδ fibres and C fibres).
•Better at blocking unmyelinated C-fibres
•Aδ fibres and C fibres mediate nociceptive impulses; therefore LA block pain sensation more readily than other sensory functions (e.g. touch, proprioception)
•BUT: other sensory modalities will be affected over increased exposure time
what is the selectivity of the local anaesthetics
- what it passes through
- the pka of the mits effective LA
Must first gain access to axon membrane
•Pass through myelin layers (ie lipid)
•Ionised form cannot penetrate myelin
•Therefore a compound pKa ~7.4 most effective
•E.g. pKa’s of some local anaesthetics
•bupivacaine (pKa 8.1)
•mepivacaine (pKa 7.6)
•Lidocaine (pka 7.8-7.9)
what do most injections contain
Most other injections contain adrenaline
–Remains in contact with nerve (prolongs actions of LA)
–Reduces systemic toxicity
–Danger of hypoxic damage to tissue (not to extremities)
–Beta2 action in muscle can increase systemic exposure to local anaesthetic
adrenaline preparation
Concentration of epinephrine (adrenaline) in preps can vary and is usually expressed in g/ ml. Above example 1: 200,000 = 1g : 200,000 ml (5ug: ml)
•Effect of adrenaline is to prolong local effect of local anaesthetic
bicarbonate preparations
Bicarbonate (0.15 ml of a 8.4% solution added to 10 ml of 0.5% bupivacaine).
•Bicarbonate increases the amount of unionised drug via raising pH of the environment drug administered in. Speed of onset of anaesthesia is increased.
glucose preparations
Glucose (80mg/ml)
•For intrathecal applications of LA. Glucose is added to bupivacaine in order to increase the baricity of the solution to greater than that of the CSF. This results in more controlled spread of solution within the intrathecal space.
•Other inclusions with LA include preservatives, fungicides
what is the metabolism of LA
- ester
- amide
where it’s metabolised
Esters (Metabolised in the plasma)
• Most ester-linked LA are quickly metabolized by non specific esterases in plasma
•Amides (Metabolised in the liver)
•Amide-linked LA are more stable with longer plasma half lives. Metabolized by oxidative dealkylation/oxygenation by monooxygenases and hydroxylation by carboxylesterase in the liver
