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Pharmacology for Anaesthetists > Local Anaesthetics > Flashcards

Local Anaesthetics Flashcards

1
Q

Define and classify local anaesthetics

A

Definition: Compounds which produce temporary blockade of neuronal transmission when applied to a nerve fibre.

Esters ( -CO.O- )

  1. Procaine
  2. Amethocaine
  3. Cocaine

Amides ( -NH.CO- )

  1. Lidocaine
  2. Bupivacaine (also levobupivacaine)
  3. Ropivacaine
  4. Prilocaine
  5. Dibucaine
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2
Q

Describe the Vaughn-Williams classification of anti-arrhythmics.

A

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

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3
Q

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

A

Aromatic ring (lipophilic)
Link
Amine (Hydrophilic)

Page 157 Peck and Hill

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4
Q

What are the differences between esters and amides

A

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

  1. Stable in solution 2 years (all ampoules at work)
  2. Distribution: protein bound
  3. Metabolism: Slower in the liver by amidases –> may accumulate in hepatic dysfunction
  4. Lower incidence allergy
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5
Q

How do local anaesthetics work?

A

Enter neuron –> block inward sodium current –> at voltage gated Na channels in the cell membrane –> depolarisation prevented –> stops action potential propagation.

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6
Q

In what state is the affinity of local anaesthetics for sodium channels the highest?

A

Open or inactivated state rather than the resting state.

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7
Q

The voltage gated Na channels are blocked from inside of the neuron. Why is this relevant and how does it relate to acid base

A

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.

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8
Q

What is pKa

A

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.

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9
Q

Why is it important to know which drugs are acids and which drugs are bases?

A

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

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10
Q

What is the henderson hasselbach equation

A

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]

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11
Q

What is pH

A

pH is the measure of acidity of an aqueous solution and depends on the concentration of H ions

pH = -log[H]

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12
Q

What is the significance of lipid solubility

A

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.

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13
Q

What is the significance of protein binding

A

Protein binding is associated with the duration of action of local anaesthetic agents. Highly protein bound agents have a longer duration of action.

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14
Q

Ho do local anaesthetics influence vascular tone

A

Low concentrations –> vasodilation

High concentration –> vasoconstriction

Exception: cocaine –> vasoconstriction and high and low concentrations (used ENT)

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15
Q

Compare the relative lipid solubility of lidocaine to bupivacaine. What does this mean and what are the toxic plasma concentrations for this drugs

A

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)

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16
Q

Why does bupivacaine have a longer duration of action than lidocaine?

A

Bupivacaine protein binding = 95%
Bupivacaine elim half life = 160 minutes

Lidocaine protein binding = 70%
Lidocaine elim half life = 100 minutes

Therefore bupivacaine lasts longer

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17
Q

Why is the onset of action of lidocaine faster than bupivacaine

A

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%

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18
Q

Compare ropivacaine to bupivaciane and lidocaine

A

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
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19
Q

Compare the toxic doses of lidocaine, bupivacaine and ropivacaine, Prilocaine

A 
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
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20
Q

Describe relative effects on the myocardium of lidocaine, bupivacaine and ropivacaine. Which drugs has the highest cardiotoxic effect and why

A

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.
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21
Q

What is heavy macaine and when is it used

A

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

22
Q

What are the features of local anaesthetic toxicity

A

Neurological (occur first usually)

  1. Peri-oral numbness/paraesthesia
  2. light head
  3. Dizziness
  4. Visual and auditory
  5. Confusion
  6. Twitching and tremors
  7. Convulsion
  8. Coma

CVS

  1. Dysrhthmia
  2. VF and CA
23
Q

What factors can predispose the patient to Local anaesthetic toxicity

A

Pharmacological factors

  1. Dose
    - -> Rate of rise of plasma concentration and peak concentration NB - not just total dose
    - -> Total dose
  2. Choice agent (bupivacaine lower CC/CNS ratio)
  3. Site administration: Closer to large vessels / hyperaemic site/epidural)
  4. Coadministration of vasconstrictor (slows systemic absorption)
  5. Slower dissociation from sodium channels (bupivacaine)
  6. Drug interations
    - -> Displacement from protein binding (Phenyotin)
    - -> Decreased metabolism (Cimetidine)

Patient Risk factors

  1. Acidosis (Decreased PB. Increased availability of active ionized molecule )
  2. Old age (Slower clearance and cardiofragile)
  3. Young age (Lower alpha1 - acid glycoprotein with higher free fraction)
  4. Pregnant: (Lower alpha 1 - acid glycoprotein and better perfusion of blocked tissue)
  5. Hyperkalaemia (decreased toxic dose of agent)
24
Q

What is EMLA

A

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.

25
Q

When should EMLA be avoided and what are the cautions with its use

A

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

26
Q

Rank the injection locations from highest to lowest risk for high systemic absorption and hance toxicity of LA

A

Highest to lowest

  1. Intercostal
  2. Caudal
  3. Epidural
  4. Brachial plexus
  5. Subcutaneous
27
Q

Which have more significant protein binding esters or amides

A

Amides (a Acid glycoprotein and albumin)

28
Q

Which crosses the placenta more esters or amides and why

A

Amides. Esters are usually rapidly metabolized by plasma esterases.

29
Q

Does lidocaine or bupivacaine cross the placenta in greater qunatities and why

A

Lidocaine.

Bupivacaine is more protein bound so less free drug available to transit across the placenta.

30
Q

What happens if the fetus becomes acidotic in the presence of local anaesthetic

A

Ion trapping due to increased ionized form.

31
Q

Discuss ester metabolism and relevant complications

A

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

32
Q

Discuss amide metabolism

A

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

33
Q

Compare: Relative potency| Relative lipid solubility | Toxic [Plasma} (ug/ml) for:

Amethocaine
Cocaine
Lidocaine
Procaine
Bupivacaine
Ropivacaine
A

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
34
Q

Compare: Onset | pKa | % unionized at pH 7.4 for:

Amethocaine
Cocaine
Lidocaine
Procaine
Bupivacaine
Ropivacaine
A

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%
35
Q

Compare: Protein binding | duration of action for:

Amethocaine
Cocaine
Lidocaine
Procaine
Bupivacaine
Ropivacaine
A

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
36
Q

Compare the elimination half life for

Amethocaine
Cocaine
Lidocaine
Procaine
Bupivacaine
Ropivacaine
A

T 1/2 (mins)

Amethocaine 80 
Cocaine 100
Lidocaine 100
Procaine 100
Bupivacaine 160
Ropivacaine 120
37
Q

What are the physiological consequences of some of the lidocaine metabolites

A

Some might have anti-arrhythmic properties

Some may potentiate lidocaine-induced seizures

38
Q

Define specific gravity, Density and Baricity

Compare the BARICITY of CSF , plain and heavy macaine

A

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.

39
Q

Does a larger volume of injection cause a more extensive block if dose is kept constant

A

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.

40
Q

How does the temperature of the solution affect the spread of neuraxial local anaesthetic

A

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

41
Q

What is levobupivacaine

A

It is the S - enantiomer of bupivacaine

Bupivacaine is a racemic mixture of S - and R - enantiomers

42
Q

What is the toxic dose of bupivacaine per dose and over 24 hours

A

For an adult

No more than 2 mg/kg every 3 hours with a maximum dose over 24 hours of 400mg

43
Q

What are the advantages of levobupivacaine over bupivacaine

A
  1. Levobupivacaine requires higher dose to produce myocardial depression (blocking K+ channels)
  2. Higher doses of levobupivacaine are required to cause excitatory CNS effects / convulsions

So less chance of CVS and CNS toxicity

44
Q

Compare the presentations of bupivacaine, ropivacaine and lidocaine

A

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

45
Q

What are the main differences of ropivacaine from bupivacaine

A
  1. Pure enantiomeric preparation
  2. Improved toxic profile
  3. Lower lipid solubility (lower penetration of motor AB fibres –> more motor sparing): i.e. favourable sensory/motor block discrimination
46
Q

What is Prilocaine most commonly used for and what is its toxic dose

A

Intravenous regional anaesthesia (Bier’s block)

6mg/kg without felypressin or adrenalin

9 mg/kg with adrenalin

47
Q

What important side effect is characteristic of Prilocaine (Prilocaine is in EMLA

A

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)

48
Q

What is Moffat’s solution and what is it used for

A

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.

49
Q

What is the maximum dose of cocaine

A

1.5 mg/kg or 100 mg

50
Q

Describe the administration of intralipid in LAST

A

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.

51
Q

What are the uses of amethocaine

A

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

Pharmacology for Anaesthetists (37 decks)

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