analgesia and anaesthesia Flashcards
local anaesthetics: explain the cellular mechanisms of action of local anaesthetics, their pharmacokinetic profiles and adverse effects
define local anaesthetic
drug which reversibly blocks neuronal conduction when applied locally
describe process of generation of neuronal action potential (“all or nothing” response in 10-15ms)
depolarisation (from -70mV) -> resting voltage-sensitive Na+ channels open -> Na+ enters cell -> Na+ channels close (inactivation), K+ channels open (start at depolarisation but take longer) -> K+ leaves cell -> Na+ channels restored to resting state, but K+ channels still open, so cell refractory (can create new depolarisation if greater stimulus) -> Na+ and K+ channels restored to resting state, so cell will respond normally to further depolarising stimuli
5 examples of local anaesthetics
procaine, cocaine, lidocaine, bupivacaine, benzocaine (doesn’t have amine side-chain so surface anaesthetic as weak but more lipid soluble)
what is structure of local anaesthetic important for
mechanism of action, pharmacokinetics
3 main areas of structure of local anaesthetics
aromatic region, ester or amide bond, basic amine side-chain
example of local anaesthetic with ester bond
cocaine
example of local anaesthetic with amide bond
lidocaine
mechanism of action of local anaesthetics with Na+ channels of sensory neurone: hydrophilic pathway (main)
applied close to trunk -> ionised and unionised form reach equilibrium -> unionised form crosses connective tissue sheath -> crosses neurone -> ionised and unionised form reach equilibrium -> ionised (cation) form binds inside voltage-sensitive Na+ channel (channel must be open, so if firing more rapidly, local anaesthetic has greater effect - use dependency so gives degree of selectivity) -> prevent Na+ influx
describe local anaesthetic effect in motor vs sensory neurones
block of motor neurone not as effective as sensory neurone (due to myelination)
mechanism of action of local anaesthetics with Na+ channels of sensory neurone: hydrophobic pathway
increased lipid solubility: diffuse in membrane -> ionised and unionised form reach equilibrium -> ionised (cation) form binds inside voltage-gated Na+ channels (channels don’t need to be open) -> prevent Na+ influx
4 effects of local anaesthetics
prevent generation and conduction of action potentials, don’t influence resting membrane potential, may influence channel gating (e.g. binding preferentially to inactivated voltage-gated Na+ channels, increasing refractory period), selectively block small diameter (ad and C-fibres) and non-myelinated fibres (as well as firing rate)
what are local anaesthetics (acid or base), and effect on mechanism of action
weak bases (pKa 8-9), so mechanism of action is pH dependent
why is it more difficult to anaethetise infected tissue
tends to be more acidic, so more is ionised so less can enter neurone
6 routes of local anaesthetic administration
surface, infiltration, i.v. regional, nerve block, spinal, epidural
describe surface local anaesthetic administration (where, how and dose)
mucosal surface (mouth, bronchial tree) by spray (or powder), requiring high concentration
consequence of using high concentrations of surface local anaesthetic administration
systemic toxicity
describe infiltration local anaesthetic administration (where and when)
directly into tissues (sensory nerve terminals) for minor surgery
why does infiltration local anaesthetic require co-injection of adrenaline (not for extremities to avoid ischaemic tissue damage)
vasoconstrictor so limits distribution (lower dose, reduce risk of systemic toxicity)
describe i.v. regional local anaesthetic administration (where and when)
i.v. distal to pressure cuff for limb surgery
when can systemic toxicity occur with i.v. regional local anaesthetic administration
premature cuff release (leave it on for at least 20 minutes, so most diffused into tissue)
describe nerve block local anaesthetic administration (where, what does this require, dose, onset)
close to nerve trunks e.g. dental nerves, with vasoconstrictor co-injection, with low doses and slow onset (wait to diffuse across connective tissue)
describe spinal central anaesthetic administration (dose, where, and when)
low doses into CSF in sub-arachnoid space for spinal roots in abdominal, pelvic and lower limb surgery
2 consequences of spinal central anaesthetic
blood pressure drop (preganglionic SNS neurones are narrow diameter, so blocked as well), prolonged headache (CSF into brain or leakage)
why is glucose added to spinal central anaesthetic
increase specific gravity, so can move bolus around spinal cord to localise anaesthesia
describe epidural central anaesthetic administration (where, onset, dose)
into fatty tissue of epidural space to effect spinal roots, with slower onset so requires higher doses
when is epidural central anaesthetic administration used
same as spinal (spinal roots in abdominal, pelvic and lower limb surgery), and painless childbirth
why is systemic toxicity of epidural central anaesthetic less than spinal central anaesthetic
more restricted action as doesn’t diffuse into CSF (less effect on blood pressure drop)
location of injection of spinal or epidural anaesthesia
between L3 and L4 to avoid spinal cord
pharmacokinetics: absorption, distribution (plasma protein binding %), metabolism and plasma half life of lidocaine (amide)
good absorption, 70% plasma protein binding, hepatic metabolism (N-dealkylation), plasma half life of 2 hours (more stable)
pharmacokinetics: absorption, distribution (plasma protein binding %), metabolism and plasma half life of cocaine (ester)
good absorption, 90% plasma protein binding, liver and plasma metabolism (non-specific esterases), plasma half life of 1 hour (less stable)
bupivacaine duration of action and use
6 hours, so used for epidural anaesthesia
paradoxical CNS unwanted effects of lidocaine (more normal for local anaesthetics) due to GABA receptors (inhibition) being sensitive at low doses
stimulation, restlessness, confusion, tremor
CVS unwanted effects of lidocaine due to Na+ channel blockade on cardiac myocytes
myocardial depression, vasodilation, decreased blood pressure
2 CNS unwanted effects of cocaine (less normal for local anaesthetics) due to central sympathetic actions (blocks monoamine reuptake)
euphoria, excitation
3 CVS unwanted effects of cocaine due to central sympathetic actions (blocks monoamine reuptake)
increased cardiac output, vasoconstriction, increased blood pressure