2011A01 Describe the factors which increase the risk of systemic toxicity with
 amide local anaesthetic agents.

LAST features

·   CNS: excitatory (e.g. seizure) -> inhibitory (coma)

·   CVS: conduction delay, re-entrant arrhythmia, arrest

Determinants of toxicity

1.    ↑Drug potency

2.    ↑Peak plasma concentration

3.    ↑CNS and CV sensitivity

Determinants of CC:CNS ratio

(safety margin)

·   Dynamics: ↑Cardiac:CNS isoform affinity ratio for VDNaC

o e.g. D-bupiv > L-bupiv

·   Kinetics (e.g. ↓lipid solubility): less important

Order of ↓toxicity

CNS toxicity (mcg/mL)

CC:CNS ratio

(∝ VDNaC isoform affinity ratio)

Lignocaine

5

~7:1

Ropivacaine

4

~5:1

Bupivacaine

1.5

~3:1

↑VDNaC affinity

·   ↑dwell time

·   e.g. bupivacaine has very high affinity, especially for the cardiac isoform

↑Lipid solubility

·   e.g. bupivacaine 1000x cf. lignocaine 150x (ref: procaine)

Stereochemistry

·   e.g. R-ropiv less potent, not toxic (only available S-enantiopure)

·   e.g. L-bupiv less toxic (often given enantiopure in children)

Administration

·   ↑Dose

·   ↑Rate of admin (bolus > infusion)

Absorption

·   ↓Tissue protein binding -> ↑release into circulation

·   ↑Tissue blood flow rate:

o Intrinsic: tracheal > intercostal > caudal > paracervical > epidural > plexus > nerve

o Global: pregnant, neonate

o Drug effect: absence of vasoconstriction (e.g. bupiv cf. ropiv)

Distribution

·   ↑Unbound drug

o Low intrinsic binding (e.g. prilocaine 55%)

o AAG (e.g. neonate, elderly, obese)
(important if highly bound and low HER e.g. bupiv)

·   ↓pH: ↑more active ionised fraction in ICF

o Ion trapping in acidaemic foetal blood

·   ↓Blood volume (e.g. shock)

·   ↓V_DSS (e.g. cachexia, elderly)

Metabolism

·   ↓Intrinsic metabolism (e.g. bupivacaine slowest, t_1/2β 160 mins)

·   Active metabolites (e.g. MEGX 80% as active, xylidide 10% as active)

·   Liver failure -> ↓phase 1 reactions -> ↓metabolism-dependent clearance

o If low extraction ratio (e.g. bupivacaine (but lignocaine also affected)

·   Hepatic hypoperfusion -> ↓flow-dependent clearance

o If high extraction ratio (e.g. lignocaine)

Excretion

·   Renal failure -> accumulation of active metabolites (e.g. MEGX, xylidide)

CNS

·   Pregnancy -> ↑sensitivity

·   Altered seizure threshold: epilepsy

·   Drug interactions: tramadol, cocaine, antiarrhythmics.

·   ↑PaCO₂ (↑CBF), ↓PaO₂, ↓pH

CVS

·   Cardiovascular disease e.g. ischaemia

·   Drug interactions: antiarrhythmics (esp. class 1 drugs)

·   ↑Heart rate -> ↑channel cycling rate

·   ↓PaO₂, ↓pH, ↑K⁺