Local Anaesthetics Flashcards
Define and classify local anaesthetics
Definition: Compounds which produce temporary blockade of neuronal transmission when applied to a nerve fibre.
Esters ( -CO.O- )
- Procaine
- Amethocaine
- Cocaine
Amides ( -NH.CO- )
- Lidocaine
- Bupivacaine (also levobupivacaine)
- Ropivacaine
- Prilocaine
- Dibucaine
Describe the Vaughn-Williams classification of anti-arrhythmics.
Class 1 - Na channel blockers
> 1A: Quinidine and procainamide (Moderate Na block + Increased ERP)
> 1B:Lignocaine (Mild Na block + decreased ERP)
> 1C: Flecainide (Strong Na block + no change ERP)
Class 2 - Beta blockers
Class 3 - K channel blockers
Class 4 - Ca channel blockers
Draw the general chemical structure of local anaesthetics. Draw the basic structure of esters and amides and explain the difference.
Draw Lidocaine, bupivacaine and ropivacaine
Aromatic ring (lipophilic)
Link
Amine (Hydrophilic)
Page 157 Peck and Hill
What are the differences between esters and amides
Divided into structural and functional
STRUCTURAL
Chemistry of the link between aromatic ring and amine
COO - ester
NHCO - amide
FUNCTIONAL
Esters:
1. Unstable in solution (cocaine powder)
2. Distribution: minimal protein bound
3. Metabolism: Fast hydrolysis by plasma chilnesterase –> short T half life
4. Higher incidence of allergy (associated with metabolite para-aminobenzoate)
Amides
- Stable in solution 2 years (all ampoules at work)
- Distribution: protein bound
- Metabolism: Slower in the liver by amidases –> may accumulate in hepatic dysfunction
- Lower incidence allergy
How do local anaesthetics work?
Enter neuron –> block inward sodium current –> at voltage gated Na channels in the cell membrane –> depolarisation prevented –> stops action potential propagation.
In what state is the affinity of local anaesthetics for sodium channels the highest?
Open or inactivated state rather than the resting state.
The voltage gated Na channels are blocked from inside of the neuron. Why is this relevant and how does it relate to acid base
All local anaesthetics are weak bases which means that they are ionized at pH below their pKa and UNIONIZED at pH above their pKa.
Local anaesthetics are therefore mostly ionized at physiological pH as their pKa is above 7.4 (physiological pH). The unionized proportion depends on the pKa of the particular agent –> the lower the pKa the more unionized drug present.
UNIONIZED drug is lipid soluble and can cross phospholipid neuronal cell membrane –> is protonated and ionized and is then preferentially bound to inactive/open voltage gated sodium channels –> blocking these channels.
What is pKa
The dissociation constant.
It is the pH at which 50% of molecules are ionized and 50% are unionized in solution. i.e. there is equilibrium between the ionized and unionized drug molecules.
The pKa is not related to whether that drug is an acid or a base but rather is solely determined by the molecular structure of that drug.
Why is it important to know which drugs are acids and which drugs are bases?
Acids ionize at pH ABOVE pKa
Bases ionize at pH BELOW pKa
This means that acids are more unionized at pH below pKa
This means that bases are more unionized at pH above pKa
What is the henderson hasselbach equation
An equation that describes the relationship between the pH, the pKa and the concentration of ionized or unionized acid or base.
pH = pKa + log [HCO3-}/[PCO2]
What is pH
pH is the measure of acidity of an aqueous solution and depends on the concentration of H ions
pH = -log[H]
What is the significance of lipid solubility
Lipid solubility is closely related to potency. Higher lipid solubility –> higher potency.
However, other factors like vasodilatation and tissue distribution impact how much of the drug is available at the site of action and therefore these factors also affect the potency of a local anaesthetic.
What is the significance of protein binding
Protein binding is associated with the duration of action of local anaesthetic agents. Highly protein bound agents have a longer duration of action.
Ho do local anaesthetics influence vascular tone
Low concentrations –> vasodilation
High concentration –> vasoconstriction
Exception: cocaine –> vasoconstriction and high and low concentrations (used ENT)
Compare the relative lipid solubility of lidocaine to bupivacaine. What does this mean and what are the toxic plasma concentrations for this drugs
Bupivacaine relative lipid solubility is 1000
Bupivacaine toxic [plasma] = 1.5 ug/mL
Bupivacaine toxic dose = 2 mg/kg (± adrenalin)
Lidocaine relative lipid solubility is 150
Lidocaine toxic [plasma] = 5 ug/ml
Lidocaine toxic dose 3 (without) and 7(with adrenalin) mg/kg
Bupivacaine is therefore 8 x potent (from relative lipid solubility)
Why does bupivacaine have a longer duration of action than lidocaine?
Bupivacaine protein binding = 95%
Bupivacaine elim half life = 160 minutes
Lidocaine protein binding = 70%
Lidocaine elim half life = 100 minutes
Therefore bupivacaine lasts longer
Why is the onset of action of lidocaine faster than bupivacaine
Bupivacaine and lidocaine are weak bases
Bases ionize at pH below their pKa
As lidocaine has pKa closer to physological pH, less of it is ionized at physiological pH
Bupivacaine pKa = 8.1
% unionized at pH 7.4 = 15%
Lidocaine pKa = 7.9
% unionized at pH 7.4 = 25%
Compare ropivacaine to bupivaciane and lidocaine
Bupivacaine
- Racemic: R and S enantiomer
Ropivacaine
- S enantioner
- Potency: intermediate between lido and bup
- Onset: similar to bup
- Low lipid solubility –> slower penetration of larger myelinated nerve fibres producing a more discriminative block –> this means:
- Slower onset, shorter duration and less dense motor block compared to bupivacaine
- Much less cardiotoxic.
- Toxic plasma concentration is 4 ug /ml
- Toxic dose: 3mg/kg
Compare the toxic doses of lidocaine, bupivacaine and ropivacaine, Prilocaine
Bupivacaine 2 mg/kg Lidocaine 3mg/kg without adrenalin Lidocaine 7mg/kg with adrenalin Ropivacaine 3 mg/kg Prilocaine 6mg/kg without adrenalin Prilocaine 9 mg/kg with adrenalin
Describe relative effects on the myocardium of lidocaine, bupivacaine and ropivacaine. Which drugs has the highest cardiotoxic effect and why
All 3
- postpone phase 0 arriving at threshold by blocking sodium channels
- Prolong refractory period –> PR and QRS prolonged
- All suppress the myocardium
Bupivacaine = most cardiotoxic
- takes 10 times longer to diffuse away from the sodium channels vs. lidocaine and ropivacaine
- this can lead to arrhythmias and VF.
What is heavy macaine and when is it used
Bupivacaine in solution with glucose 80mg/mL (8%).
Glucose is added to intrathecal blocks to increase the predictability of the blocks.
- Glucose increases the density of the solution relative to csf so gravity can be used to reliably manipulate the level of the block
What are the features of local anaesthetic toxicity
Neurological (occur first usually)
- Peri-oral numbness/paraesthesia
- light head
- Dizziness
- Visual and auditory
- Confusion
- Twitching and tremors
- Convulsion
- Coma
CVS
- Dysrhthmia
- VF and CA
What factors can predispose the patient to Local anaesthetic toxicity
Pharmacological factors
- Dose
- -> Rate of rise of plasma concentration and peak concentration NB - not just total dose
- -> Total dose - Choice agent (bupivacaine lower CC/CNS ratio)
- Site administration: Closer to large vessels / hyperaemic site/epidural)
- Coadministration of vasconstrictor (slows systemic absorption)
- Slower dissociation from sodium channels (bupivacaine)
- Drug interations
- -> Displacement from protein binding (Phenyotin)
- -> Decreased metabolism (Cimetidine)
Patient Risk factors
- Acidosis (Decreased PB. Increased availability of active ionized molecule )
- Old age (Slower clearance and cardiofragile)
- Young age (Lower alpha1 - acid glycoprotein with higher free fraction)
- Pregnant: (Lower alpha 1 - acid glycoprotein and better perfusion of blocked tissue)
- Hyperkalaemia (decreased toxic dose of agent)
What is EMLA
EMLA stands for Eutectic Mixture of Local Anaesthetic
A Eutectic mixture is when two compounds mix to produce a substance that behaves with a single set of characteristics.
Crystalline bases of:
1. Lidocaine 2.5%
2. Prilocaine 2.5%
White oil:water emulsion.
Eutectic because: at room temp the mixture is an OIL while the individual components would be crystalline solids at the same temperature
It is presented in an emulsion containing 5 or 30 grams and is applied to skin under a sticky plastic dressing for at least 60 minutes.
It is used to anaesthetize skin prior to cannulating in paeds and prior to harvesting skin grafts.
When should EMLA be avoided and what are the cautions with its use
EMLA should be avoided in MetHb or patients taking drugs that can induce Methaemoglobinaemia such as sulfonamides or phenytoin
One of the metabolites of prilocaine is otoludine which can cause Met Hb
Not on mucous membranes –> absorption too rapid systemically
Care required in patients using class 1 anti-arrhythmic drugs as toxic effects can be additive and synergistic
Rank the injection locations from highest to lowest risk for high systemic absorption and hance toxicity of LA
Highest to lowest
- Intercostal
- Caudal
- Epidural
- Brachial plexus
- Subcutaneous
Which have more significant protein binding esters or amides
Amides (a Acid glycoprotein and albumin)
Which crosses the placenta more esters or amides and why
Amides. Esters are usually rapidly metabolized by plasma esterases.
Does lidocaine or bupivacaine cross the placenta in greater qunatities and why
Lidocaine.
Bupivacaine is more protein bound so less free drug available to transit across the placenta.
What happens if the fetus becomes acidotic in the presence of local anaesthetic
Ion trapping due to increased ionized form.
Discuss ester metabolism and relevant complications
Rapid metabolism by plasma cholinesterases and other esterases to inactive compounds.
Para-aminobenzoate is one of the main metabolites and has been associated with hypersensitivity reactions especially in the atopic patient.
Cocaine is the exception –> undegoes hepatic hydrolysis to water soluble metabolites that are excreted in urine
Discuss amide metabolism
Hepatic metabolism by amidases. Much slower the ester hydrolysis. More prone to accumulation when administered in a continuous infusion.
Reduced hepatic blood flow and hepatic dysfunction can decrease amide metabolism
Compare: Relative potency| Relative lipid solubility | Toxic [Plasma} (ug/ml) for:
Amethocaine Cocaine Lidocaine Procaine Bupivacaine Ropivacaine
Compare: Relative potency| Relative lipid solubility | Toxic [Plasma} (ug/ml) for:
Amethocaine 8 | 200 | ? Cocaine ? | ? | 0.5 Lidocaine 2 | 150 | >5 Procaine 2 | 50 | > 5 Bupivacaine 8 | 1000 | 1.5 Ropivacaine 8 | 120 | 4
Compare: Onset | pKa | % unionized at pH 7.4 for:
Amethocaine Cocaine Lidocaine Procaine Bupivacaine Ropivacaine
Compare: Onset | pKa | % unionized at pH 7.4 for:
Amethocaine Slow | 8.5 | 7 % Cocaine Fast | 8.6 | 5% (but causes vasoconstriction) Lidocaine Mod | 7.9 | 25% Procaine Mod | 7.7 | 33% Bupivacaine Slow | 8.1 | 15% Ropivacaine Slow | 8.1 | 15%
Compare: Protein binding | duration of action for:
Amethocaine Cocaine Lidocaine Procaine Bupivacaine Ropivacaine
Compare: Protein binding | duration of action for:
Amethocaine 75% | Long Cocaine 95% | Short (anomaly) Lidocaine 70% | Moderate Procaine 55% | Moderate Bupivacaine 95% | Long Ropivacaine 94% | Long
Compare the elimination half life for
Amethocaine Cocaine Lidocaine Procaine Bupivacaine Ropivacaine
T 1/2 (mins)
Amethocaine 80 Cocaine 100 Lidocaine 100 Procaine 100 Bupivacaine 160 Ropivacaine 120
What are the physiological consequences of some of the lidocaine metabolites
Some might have anti-arrhythmic properties
Some may potentiate lidocaine-induced seizures
Define specific gravity, Density and Baricity
Compare the BARICITY of CSF , plain and heavy macaine
Density: Ratio of the mass of a substance to its volume at a specific temperature. Units: kg/m^3
Specific gravity: the ratio of the density of a substance to a standard (e.g. pure water). It is usual to relate anaesthetic solutions at 20 deg C to pure water at 4 deg C. Units: none (ratio)
Baricity: Analagous to specific gravity, but expressed as a ratio of the densities of local anaesthetic and CSF, both at 37 deg C. Units: none (ratio)
BARICITY
CSF = 1.000
Plain macaine = 1.000 (isobaric) with 10ug (0.2ml) fentanyl
Heavy macaine = 1.019 (hyperbaric) with 10 ug (0.2 ml) fentanyl.
Does a larger volume of injection cause a more extensive block if dose is kept constant
Very low volumes (1.5 - 2.0 mls) may reduce spread. Larger volumes (with same dose) don’t tend to change the extent of spread.
How does the temperature of the solution affect the spread of neuraxial local anaesthetic
PLAIN MACAINE
Density at Room temp (24 deg C) 1.0032 kg/m^3 –> hyperbaric
Density at Body temp (37 deg C) 0.9984 kg/m^3 –> hypobaric
Density decreases 2 minutes after injection. This accounts for the large variability of spread that occurs with plain bupicaine when injected at room temperature
What is levobupivacaine
It is the S - enantiomer of bupivacaine
Bupivacaine is a racemic mixture of S - and R - enantiomers
What is the toxic dose of bupivacaine per dose and over 24 hours
For an adult
No more than 2 mg/kg every 3 hours with a maximum dose over 24 hours of 400mg
What are the advantages of levobupivacaine over bupivacaine
- Levobupivacaine requires higher dose to produce myocardial depression (blocking K+ channels)
- Higher doses of levobupivacaine are required to cause excitatory CNS effects / convulsions
So less chance of CVS and CNS toxicity
Compare the presentations of bupivacaine, ropivacaine and lidocaine
Bupivacaine (Racemic with S - and R - )
- 0. 25% and 0.5% (with or without adrenalin)
Ropivacaine (S - enantiomer)
- 0.2% and 0.75% and 1%
Lidocaine
What are the main differences of ropivacaine from bupivacaine
- Pure enantiomeric preparation
- Improved toxic profile
- Lower lipid solubility (lower penetration of motor AB fibres –> more motor sparing): i.e. favourable sensory/motor block discrimination
What is Prilocaine most commonly used for and what is its toxic dose
Intravenous regional anaesthesia (Bier’s block)
6mg/kg without felypressin or adrenalin
9 mg/kg with adrenalin
What important side effect is characteristic of Prilocaine (Prilocaine is in EMLA
When given in large doses, a metabolite called o-toludine may precipitate methaemoglobinaemia which may require treatment with ascorbic acid or methylene blue (reducing agents)
What is Moffat’s solution and what is it used for
It is used during ENT procedures to cause local anaesthesia and vasoconstriction to prevent epistaxis during the procedure
Cocaine — 2ml 8%
NaHCO3 – 2ml 1%
Adrenalin - 1 ml 1:1000 (1 mg)
Total of 5 mls
Unfavourable side effect profile.
What is the maximum dose of cocaine
1.5 mg/kg or 100 mg
Describe the administration of intralipid in LAST
70 kg adult:
BOLUS 1
1.5 ml / kg = 100 mls over 1 minute
INFUSION 1
15 ml/ kg / hour = 1000 ml/hr
BOLUS 2 (5 minutes --> inadequate response) 1.5 ml/kg = 100 ml over 1 minute
INFUSION 2
30 ml / kg / hour = 2000 ml/hr
BOLUS 3 (further 5 minutes no response) 1.5 ml/kg = 100 ml over 1 minute
Maximum cumulative dose in 1 hour
12 ml/kg = 840 mls
But bolus x 3 gives 300 mls
If significant response at any stage reduce infusion to 1.5 ml/kg/hour = 100 ml/hour and monitor. If instability recurs –> increase to 15 ml/kg/hour = 1000ml/hour.
What are the uses of amethocaine
Used for topical anaesthesia
0.5% or 1% drops for use before local anaesthetic block in lens surgery (or as sole agent).
Initial burning sensation
4% cream can be used similar to EMLA
- faster than EMLA (30 vs 60 mins)
Effects last 4 - 6 hours
