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

 

List:

·     Intro: LAST

·     Thresholds

·     Drug: factors increasing potency/toxicity

·     Kinetics: factors ↑ plasma concentration

·     Dynamics: factors ↑CNS and CNS sensitivity

 

Intro:

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

 

Amide thresholds:

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

 

1.Factors increasing drug potency:

↑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)

 

2.Kinetics: factors increasing peak plasma concentration

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)

·  ↓VDSS (e.g. cachexia, elderly)

Metabolism

·  ↓Intrinsic metabolism (e.g. bupivacaine slowest, t1/2β 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)

 

3.Dynamics: factors increasing sensitivity:

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+