Pharmacology - Local Anaesthetics

Question 1

What is the structure of a local anaesthetic molecule, and what are the two classes?

Answer 1

Aromatic hydrocarbon group attached to an amine group via a linkage - either an ester or an amide link

The amine group is usually tertiary
Primary amines have low activity & are irritant
Secondary amines have good activity but are arritant
Quaternary amines have good activity, but very poor tissue penetration

Amides
Two ‘i’s in the name
Lidocaine, prilocaine, bupivacaine, ropivacaine
Intermediate duration
Rapid onset
Good tissue penetration
Metabolised by hepatic microsomal enzymes
Less allergy-inducing
May cause methaemoglobinaemia (prilocaine)

Esters
One ‘i’ in the name
Cocaine, amethocaine, procaine
Short duration
Slower onset
Poor tissue penetration
Metabolised by plasma cholinesterases
May causae allergies due to PABA breakdown product

Question 2

What is the mechanism of action of local anaesthetics?

Answer 2

Reversible inhibition of the voltage gated sodium channel - preventing action potential transmission in nerves in a use-dependent fashion, affecting smallest nerves first, and larger nerves more slowly.

Dull pain first (smallest C-fibres)
Temperature and sharp pain
Light touch
Pressure
Motor neurones last (largest alpha fibres)

To a lesser extent, they also bind to potassium and calcium channels, and G-protein coupled receptors - which might play a role in dextrobupivacaine’s cardiotoxicity.

A second theory is that local anaesthetics cause membrane expansion, infiltrating the phospholipid bilayer and altering the interface between the sodium channel and the membrane itself, to inactivate the channel

Question 3

What pH and ionisation changes are seen when local anaesthetic is injected?

Answer 3

Local anaesthetics are basic compounds, with pKas between 7.9 and 8.1
At physiological pH 7.4, more than 50% is ionised

Only unionised molecules can enter the axon across the phospholipid bilayer, before becoming ionised in the more acidic cytoplasm (pH 7.0-7.4)

They then reversibly bind to the voltage gated sodium channel, preventing depolarisation and therefore AP transduction

Question 4

List the pKa, speed of onset, lipid solubility, and protein binding of amide local anaesthetics

Answer 4

Prilocaine
7.9 | Fast | 50 | 50-55%

Lidocaine
7.9 | Fast | 150 | 70%

Ropivacaine
8.1 | Medium | 300 | 94%

(Levo) Bupivacaine
8.1 | Medium | 1000 | 95%

pKa, speed of onset, relative lipid solubility, protein binding

Protein binding relates to duration of action - as it prevents systemic spread & breakdown of the LA agent

pKa and lipid solubility have more of an effect on the speed of onset.

Question 5

Discuss the pharmacokinetics of local anaesthetics

Answer 5

Absorption
Rapid first-pass metabolism if given orally. Usually given SC, neuraxially, or IV
Rate of systemic absorption depends on site of injection - from highest systemic absorption to lowest:
Intercostal > Caudal > Epidural > Brachial plexus > Subcutaneous

Distribution
Protein binding
Bupivacaine >95%
Ropivacaine 94%
Lidocaine 70% (Mostly to albumin & alpha-1-acid glycoproteinm, which has higher affinity but is far less abundant than albumin)
Prilocaine 50%
Esters are significantly less protein bound than the amides

Metabolism
Esters generally undergo plasma hydrolysis, aside from cocaine which does so in the liver. May produce PABA (Para-aminobenzoate) as a byproduct.

Amides undergo slower hepatic metabolism - 90% of lidocaine undergoes hepatic metabolism by CYP3A4 and CYP1A2, with an active metabolite MEGX (Monoethylglycinexylide)

Excretion
Renal

Question 6

What factors influence the speed of onset and duration of actiony of local anaesthetics?

Answer 6

Speed of Onset
pKa - LAs are weak bases (unionised above their pKa) - a lower pKa means they will be more unionised at physiological pH, and therefore have a quicker onset of action.
Bupivacaine (pKa 8.1) is over 80% ionised in the plasma
Lidocaine (pKa 7.9) is only 75% ionised in the plasma (25% more availabile to cross membranes)

Concentration gradient - Drugs with lower potency are given in bigger doses - establishing a greater concentration gradient between the tissue and the axon.

For instance, chloroprocaine has a higher pKa (8.7), than lidocaine (7.9) so is significantly more ionised at physiological pH. But because it is less potent than lidocaine, up to 12mg/kg can be given, establishing a large concentration gradient, and this a much quicker onset

Duration of action
Protein binding - Mainly to alpha-1-acid glycoprotein and albumin - more binding increases duration with the bound fraction acting as a reservoir

Blood supply - Less blood supply means less redistribution and therefore longer duration

Lipid solubility More lipid solubility means that the LA is less like to leave the tissue and diffuse into the plasma, so therefore will redistribute less. This is largely related to the length of the alphatic (open carbon) chain on the compound itself.
Bupivacaine is 3x more lipid soluble than ropivacaine

Dose
Bigger dose results in a longer duration of action

Vasoconstrictor activity
Vasoconstriction prevents the drug being washed away by the blood

Question 7

What additives might be given with local anaesthetics, and why?

Answer 7

Adrenaline
Vasoconstriction to increase duration of action and reduce systemic spread/toxicity

Opioids
Synergistic increase in analgaesia and duration of block

Steroids
Increased duration of action and analgaesic effect

Clonidine
Increased analgaesic effect, may also be sedating

Bicarbonate
Increase speed of onset by increasing unionised fraction of LA

Question 8

What are the maximum safe doses of amide LA, with and without adrenaline?

Answer 8

Prilocaine
6mg/kg (9 with adrenaline)

Lidocaine
3mg/kg (7 with adrenaline)
Toxic plasma concentration 5mcg/ml

Ropicavaine
3.5mg/kg (3.5)

Bupivacaine
2mg/kg (2.5)
Toxic plasma concentration 4mcg/ml

Levobupivacaine
2.5mg/kg (3)

As bupivacaine is significantly more protein bound than lidocaine, adrenaline does not significantly reduce the amount of free drug, as compared with lidocaine.

Bupivacaine also has inherent vasoconstrictor activity, which adrenaline does not significantly increase.

Question 9

What are the cardiovascular effects of lidocaine and bupivacaine?

Answer 9

Lidocaine
Class IB antiarrhythmic agent - blocks cardiac sodium channels, decreasing the rate of phase 0 of the cardiac AP

Bupivacaine
Direct myocardial depression
Increases PR & QRS intervals, prolongs refractory period
Very slow to dissociate, meaning prolonged cardiac instability & refractory arrest if VF induced

Question 10

What CNS effects do LAs have?

Answer 10

LAs diffuse rapidly into the brain’s high lipid content, and have a two phase effect

Firstly inhibitory interneurones are blocked, causing excitation
Tingling around the mouth
Visual disturbance
Dizziness and tremor
Seizures

Then all neuron types are inhibited, leading to coma and apnoea

Question 11

Describe two topical local anaesthetics

Answer 11

EMLA
Eutectic mixture of local anaesthetics
Lidocaine 2.5mg/ml and prilocaine 2.5mg/ml
Prilocaine’s metabolite o-toluidine can trigger methaemoglobinaemia

Amethocaine
Ester LA
0.5-1% eye drops
Ametop 4% cream
Causes histamine release, and a useful vasodilation for cannulation. Faster onset than EMLA
Safe to use in methaemoglobinaemia

Eutectic means that both agents lower each other’s melting and freezing points to form a gel

Question 12

How is LA toxicity managed?

Answer 12

As per AAGBI emergencies handbook

Recognise and announce problem, call for help
ABC assessment and treatment of reversible issues
Stop administration of LA where possible

If cardiac arrest, use mechanical CPR

Intralipid 20%
1.5ml/kg over 1 minute as a bolus
Start infusion at 15ml/kg/hr
Up to 2 repeat boluses 5 minutes apart
Can increase infusion rate to 30ml/kg/hr if CVS unstable
Not exceeding 12mg/kg total dose

Question 13

Discuss Lidocaine

Answer 13

Class and uses
Amide LA and class IB Vaughn Williams antiarrhythmic agent
Pain, local anaesthesia
Ventriclar tachyarrhythmias

Presentation
Topical
2% gel
0.5-10% spray for mucosal anaesthesia
4% nebuliser
Solution for injection - clear, colourless - 1% or 2%, with pH 6 to keep it ionised and therefore water soluble.

Dose
Safe dose 3mg/kg or 7mg/kg with adrenaline subcutaneously

Mechanism of action
Reversible, temporary, use-dependent blockade of voltage gated sodium channels

Effects & Side Effects
Neuro - Firstly inhibitory interneurones are blocked, causing excitation (perioral tingling, visual disturbance, dizziness & tremor, seizures). Then all neurones are inhibited (coma and apnoea)
Cardiovascular - Blocks cardiac sodium channels, decreasing the rate of phase 0 of the cardiac AP
Pharmacokinetics
Absorption - Rapid first pass metabolism PO, usually given subcutaneously, epidurally or IV.
Systempic absorption (highest to lowest) intercostal > caudal > epidural > brachial plexus > subcutaneous
Distribution - 70% protein bound (albumin and alpha-1-acid glycoprotein, which has higher affinity but is less abundant)
Metabolism - 90% undergoes hepatic metabolism (CYP3A4 and CYP1A2), with active metabolite MEGX (Monoethylglycinexylide)
Excretion - Renal

Question 14

Discuss Bupivacaine

Answer 14

Class and uses
Amide local anaesthetic

Used for regional anaesthesia

Presentation
Bupivacaine - Racemic mixture (brand name Marcaine)
Solution for injection 0.25 or 0.5%
Heavy Marcaine is hyperbaric, with 8% glucose

Levobupivacaine - Stereopure S-enantiomer (brand name Chirocaine) (0.25-0.75%)

Dose
Bupivacaine - up to 2mg/kg
Levobupivacaine - up to 2.5mg/kg

Mechanism of action
Reversible, temporary, use-dependent blockade of voltage gated sodium channels

Effects & Side Effects
Neuro - Firstly inhibitory interneurones are blocked, causing excitation (perioral tingling, visual disturbance, dizziness & tremor, seizures). Then all neurones are inhibited (coma and apnoea)
Cardiovascular - Direct myocardial depression, increase in PR/QRS intervals, prolonging refractory period.
Very slow to dissociate - prolonged cardiac instability and refractory arrest if VF induced
Pharmacokinetics
Absorption - Rapid first pass metabolism PO, usually given subcutaneously, epidurally or IV.
Systempic absorption (highest to lowest) intercostal > caudal > epidural > brachial plexus > subcutaneous
Distribution - Minimal change from adding adrenaline, as so heavily protein bound (up to 99%), with a smaller Vd than other LAs and longer duration of effect
Metabolism - Hepatic
Excretion - Renal

Question 15

What LA is most appropriate for day case surgery?

Answer 15

Prilocaine
Very fast onset, rapidly metabolised amide LA
Metabolised in kidneys and lungs as well as liver.

Large 6mg/kg safe dose contributes to speed of onset

Short duration of action means patients can go home the same day

Question 16

Discuss Cocaine as an LA

Answer 16

Ester LA used for topical anesthesia
Induces vasoconstriction

Maximum dose 1.5mg/kg or 100mg total dose

May trigger hypertension and arrhythmia via inhibition of MOA

Distribution - 95% protein bound
Metabolism - Hepatic hydrolysis
Excretion - Renal