3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.4. Local anaesthetics
 3.1.3.4.2. Pharmacokinetics of local anaesthetics 

Pharmacokinetics of local anaesthetics

[SH4:p183-188]

Physicochemical properties

[SH4:p181, table 7-1]

 

 

Physicochemical properties
Potency pK

Nonionised

fraction

at pH 7.4

Lipid solubility Heptane:buffer
partition coefficient
[Mark Finnis]

Heptane:buffer ratio

[BJA 1976 Vol 58(3)]

Protein-binding Vd (L/kg) Toxic Dose Comment
Ester LA
Procaine 1 8.9

3%

0.6 0.02 6% 0.9 L/kg
Chloroprocaine 4 8.7 5% 0.14 0.5 L/kg Rapid onset despite high pK, due to the high concentration used (3%)

Amethocaine

16 8.5 7% 80 4.1 76%

High potency, slow metabolism

Used topically on eyes

Benzocaine 3.5 Very low pK, almost entirely non-ionised at physiological pH
Cocaine ?8.5
Amide LA
Lignocaine 1 7.9 25% 2.9 2.9 1 70% 1.3 L/kg 4 mg/kg
OR
7 mg/kg with adrenaline
Etidocaine 4 7.7 33% 141 141 39 94% 1.9 L/kg

Prilocaine

1 7.9 24% 0.9 0.9 55% 2.7 L/kg 6 mg/kg
Mepivacaine 1 7.6 39% 1 0.8 77% 1.2 L/kg
Bupivacaine 4 8.1 17% 28 27.5 [SS3] 10 95% 1.0 L/kg 2 mg/kg
Levobupivacaine 4 8.1 17% >97% 0.8 L/kg
Ropivacaine 4 8.1 17%

2.9 [SS3]

(probably wrong)

2.9 94% 0.85 L/kg 3 mg/kg

 

NB:

  • Protein-binding tend to parallel lipid solubility
  • Vd is estimated by using Vd figures in Stoelting and assume 70kg body weight

 

Heptane:buffer partition coefficient

[SS3, Mark Finnis notes]

 

 

[British Journal of Anaesthesia, 1986, Vol 58 (3) p310-314]

  • The relative n-heptane/buffer (37C) partitioning of bupivacaine: etidocaine: lignocaine: ropivacaine was 10: 39: 1: 2.9

Relationship between pH and pK

Local anaesthetics are

  • Weak bases
  • pK value a little higher than physiological pH
    --> <50% are nonionized at physiological pH

 

Thus,

  • Acidosis
    --> Fraction of non-ionised LA reduced
    --> Poor penetration into cells
    --> Slower onset and poorer quality of anaesthesia
  • LA with lower pK (i.e. closer to physiological pH)
    --> Higher non-ionised fraction
    --> Faster onset

Intrinsic vasoactive property

  • Intrinsic vasodilatory activity also affect onset and duration of action
    * e.g. lignocaine has shorter duration and greater systemic absorption than mepivacaine, due to the intrinsic vasodilation effect of lignocaine

Potency

Potency is proportional to lipid solubility
* High lipid solubility --> Greater penetration into the nerve
* [???] [James']

 

Absorption and distribution

Systemic absorption of LA is influenced by

  • Site of injection
    * Tissue blood flow
  • Dosage
  • Use of epinephrine
  • Individual characteristics of LA
    * Intrinsic vasodilation or vasoconstriction
    * Lipid solubility
    * Protein-binding (usually parallels lipid solubility)
  • Cardiac output

Plasma level of LA is influenced by:

  • Absorption (as per above)
  • Redistribution
    * Lung extraction
    * Uptake by vessel-rich group (brain, heart, and kidneys)
  • Clearance

Lung extraction

  • The lungs are capable of extracting LA from circulation
    * e.g. lignocaine, bupivacaine, and prilocaine
  • Lung extraction of bupivacaine is dose-related
    --> Uptake process becomes saturated at higher doses

NB:

  • Propranolol impairs pulmonary extraction of bupivacaine
  • Propranolol decrease plasma clearance of lignocaine and bupivacaine

Placental transfer

Protein-binding affects the rate and degree of LA diffusion into foetal circulation
--> Higher protein-binding --> Less available for diffusion

  • Bupivacaine
    * Highly protein-bound (about 95%)
    * Umbilical vein-maternal arterial concentration ratio = 0.32
  • Lignocaine
    * Protein-binding = 70%
    * Umbilical vein-maternal arterial concentration ratio = 0.73
  • Ester local anaesthetics
    * Rapid hydrolysis
    * Thus not able to cross placenta in significant amount

Ion trapping

  • Foetal acidosis
    --> Ion trapping
    --> Accumulation of LA in the foetus
  • Similar mechanism can lead to accumulation of weak basic drugs in gastric acid.
  • Examples of weak basic drugs include:
    * Opioids
    * Local anaesthetics

Protein binding

Ester LA

  • Procaine = 6%
  • Amethocaine = 76%

Amide LA

  • Lignocaine = 70%
  • Etidocaine = 94%
  • Prilocaine = 55%
  • Mepivacaine = 77%
  • Bupivacaine = 95%
  • Levobupivacaine = >97%
  • Ropivacaine = 94%

 

Metabolism of amide local anaesthetics

  • Metabolism via microsomal enzymes (mostly hepatic)
  • Speed of metabolism:
    * Prilocaine > Lidocaine and mepivacaine > Etidocaine, bupivacaine, ropivacaine
  • Compared to ester LA
    --> Metabolism of amide LA is more complex and slower
    --> Increased plasma concentration and systemic toxicity more likely with amide LA

NB:

  • Speed of metabolism seem to correspond to protein-binding
    * Low protein-binding --> Faster metabolism --> Shorter duration
    * e.g. Prilocaine (protein-binding = 55%) --> Duration 60-120 min
    * e.g. Mepivacaine (protein-binding = 77%) --> Duration 90-180 min
    * e.g. Bupivacaine (protein-binding = 95%) --> Duration 240-480 min

Lignocaine

  • Lidocaine
    ==> Monoethylglycinexylidide (via oxidative dealkylation in liver)
    ==> Xylidide (via hydrolysis)
  • Monoethylglycinexylidide
    * Approximately 80% of the antiarrhythmic property
    * Prolonged elimination half-time
  • Xylidide
    * Approximately 10% of the antiarrhythmic property
    * 75% are excreted in urine as 4-hydroxy-2,6-dimethylaniline
  • Reduced hepatic metabolism of lignocaine in:
    * Hepatic disease
    * Decreased hepatic blood flow (e.g. during anaesthesia)
    * Pregnancy-induced hypertension
  • Intrinsic vasodilation effect

Etidocaine

  • Small amount excreted in urine unchanged
    * i.e. Renal clearance does not play a big role
    --> Hepatic metabolism important

Prilocaine

  • Prilocaine
    ==> Orthotoluidine
  • Orthotoluidine
    * An oxidising compound
    * Cause formation of MetHb (when it oxidise haemoglobin)
  • When prilocaine > 600mg
    --> Methaemoglobinaemia can become significant
  • Dose-related methaemogloblinaemia limits its clinical usefulness
    --> Mostly used as IV regional anaesthesia
    * Useful because it is metabolised faster
  • Has less intrinisic vasodilation effect than other LAs
    --> Can be used without epinephrine

Mepivacaine

  • Mostly similar to lignocaine
    * Except duration is longer than lignocaine
  • Lacks vasodilator activity
    * Unlike lignocaine, which vasodilates
    --> Could be used as an alternative to lignocaine when epinephrine cannot be used

Bupivacaine

  • Possible metabolic pathways include:
    * Aromatic hydroxylation
    * N-dealkylation
    * Amide hydrolysis
    * Conjugation
  • N-desbutylbupivacaine (a N-dealkylation metabolite) is the only one found in blood or urine after epidural or spinal anaesthetics
  • Alpha1-acid glycoprotein is the most important plasma protein binding site

Cardiotoxicity of bupivacaine

[RDM6:p594]

  • CC:CNS ratio = 3.7
    * Lignocaine = 7.1
    * i.e. Less safety margin
  • Pregnant patient may be more sensitive to the cardiotoxic effects of bupivacaine
  • Cardiac resuscitation is more difficult after bupivacaine-induced CVS collapse
  • Acidosis and hypoxia markedly potentiate the cardiotoxicity of bupivacaine

Ropivacaine

  • Ropivacaine
    ==> 2,6-pipecoloxylidide + 3-hydroxyropivacaine
    * ??? Unsure if these two metabolites are created concurrently or sequentially
  • The metabolites have weak actions
    * 2,6-pipecoloxylidide may accumulate in uraemic patients
  • Metabolism is by hepatic P450 enzyme
    * Renal excretion of unchanged drug very small
    * Adjustment usually unnecessary in renal impairment (except in uraemia)
  • Highly bound to alpha1-acid glycoprotein

Ropivacaine vs bupivacaine

  • Compared to bupivacaine, ropivacaine has:
    * Higher clearance
    * Shorter elimination half-time
    * Lipid solubility less than bupivacaine, but greater than lignocaine
    * [SH4:p186]
  • In addition, compared to bupivacaine, ropivacaine:
    * May be slightly less potent (studies are conflicting)
    * Less cardiac toxic at equipotent dose (but may simply due to chirality)
    * Resuscitation after cardiotoxicity is slightly more successful
    * [RDM6:p595-p596]

NB:

  • Text in [SH4:p186] says ropivacaine has higher clearance despite the table in [SH4:p181] says ropivacaine clearance is 0.44L/min and bupivacaine 0.47L/min

Dibucaine

  • A quinoline derivative
  • Metabolised in liver
  • Most slowly eliminated (among all amide LA)
  • Inhibits plasma cholinesterase
    --> Used to test atypical plasma cholinesterease

Metabolism of ester local anaesthetics

  • Metabolism of ester local anaesthetics is by hydrolysis by plasma cholinesterase
    * Mostly occurs in plasma
    * Some occur in the liver
    * Except for cocaine --> Significant hepatic metabolism 
  • Speed of hydrolysis:
    * Chloroprocaine > Procaine > Amethocaine
  • Metabolites are inactive
    * But para-aminobenzoic acid (a procaine metabolite) may be antigenic

Toxicity by ester LA

Also see [Esterases]

  • Systemic toxicity is inversely proportional to hydrolysis rate
  • Hydrolysis is decreased (with increased risk of toxicity) in:
    * Atypical plasma cholinesterease
    * Liver disease
    * Increased blood urea nitrogen concentration
    * Pregnancy and some chemotherapy drugs may decrease activity of plasma cholinesterase
  • Patients with atypical plasma cholinesterase
    --> Increased risk for toxic systemic concentration

Procaine

  • Procaine
    ==> Para-aminobenzoic acid and dimethylaminoethanol
    * (???) [SH(H)2:p191] (Unclear if both metabolites are produced concurrently, or alternatively)
  • Para-aminobenzoic acid is excreted unchanged in urine
  • Dimethylaminoethanol is 30% excreted in urine
    * Rest further metabolised
  • Overall, < 50% of procaine is excreted unchanged in urine

Chloroprocaine

  • Form by adding a chlorine atom to procaine
  • Increased hydrolysis by plasma cholinesterase compared to procaine
    * By 3.5 times

Amethocaine (aka Tetracaine)

  • Also undergoes hydrolysis by plasma cholinesterase

Benzocaine

  • Benzocaine = ethyl aminobeonzoate
  • Unique because of its low pK (pK 3.5)
    --> Almost all nonionised at physiological pH
  • Suited for topical anaesthesia of mucous membranes prior to intubation, endoscopy, etc
  • Onset rapid
  • Last 30-60min
  • Methaemoglobinaemia is a rare complication
    * May occur with dose exceeding 200-300mg
  • Spray concentration: 20%

NB:

  • [SH4:p187] Benzocaine is said to be a weak acid, with low pKa, and thus all non-ionised at physiological pH. This cannot be correct because
    * Acid with pKa of 3.5 will be very much ionised
    * Benzocaine (a tertiary amine) can only take a proton (i.e. base), not give a proton
    * I think Stoelting is wrong in confusing that a low pKa makes a substance acid. It does not.

Cocaine

  • Metabolised by plasma and liver cholinesterase
    --> Metabolites are water-soluble
    --> Urine test available for detecting cocaine use

Elimination

Renal elimination

  • LA has poor water solubility (i.e. high lipid solubility)
    --> High renal tubule resorption
    --> Less than 5% excreted unchanged in urine
  • Exception: cocaine
    --> 10-12% of cocaine is excreted unchanged in urine
  • Metabolites are generally readily excreted in urine

Clearance and elimination half-time

  • For amide LA
    --> Influenced by hepatic metabolism
    * Renal excretion of unchanged drug is minimal
  • For ester LA
    * Limited data, probably not dependent on hepatic metabolism
    * Short elimination half-time due to rapid hydrolysis in plasma and liver

Action profile

[SH4:p181, table 7-1]

Action profiles of local anaesthetics
Onset Duration of action Elimination half-time Clearance Protein-binding
Ester LA
Procaine Slow 45 - 60 min 9 min 6%
Chloroprocaine Rapid 30 - 35 min 7 min
Amethocaine Slow 60 - 180 min 76%
Amide LA
Lignocaine Rapid 60 - 120 min 96 min (1.6 hours) 0.95 L/min 70%
Etidocaine Slow 240 - 480 min 156 min (2.6 hours) 1.22 L/min 94%
Prilocaine Slow 60 - 120 min 96 min (1.6 hours) 55%
Mepivacaine Slow 90 - 180 min 114 min (1.9 hours) 9.78 L/min 77%
Bupivacaine Slow 240 - 480 min 210 min (3.5 hours) 0.47 L/min 95%
Levobupivacaine Slow 240 - 480 min 156 min (2.6 hours) >97%
Ropivacaine Slow 240 -480 min 108 min (1.8 hours) 0.44 L/min 94%

NB:

  • High protein-binding
    --> Lower fraction of free drug
    --> Slower hepatic metabolism
    --> Longer duration
  • [James] [???] Clearance (mL/kg/min)
    * Lignocaine = 9
    * Bupivacaine = 7
    * Ropivacaine = 11 (???) --> May be contrary to the table in [SH4:p181], but consistent with the text in [SH4:p186]

 

Other considerations

Use of vasoconstrictors

  • Epinephrine may be added to produce vasoconstrction
    --> Limits systemic absorption and maintains local concentration
    * Prolong the duration of action of local anaesthetics
    * Systemic toxicity also less likely
    * No effect on time of onset
    * Dose used = 1:200,000 (i.e. 5 microgram/mL) --> Decrease systemic absorption by 1/3
  • Epinephrine also has alpha-adrenergic action
    --> Associated with some analgesic action
    --> May contribute to conduction blockade
  • Epinephrine may also enhance blockade by increasing LA uptake
  • Addition of epinephrine has less effect on bupivacaine and etidocaine
    * Due to high lipid solubility --> Greater systemic absorption
  • Low MW dextran may also be used for prolonging the duration of action of LA

Intrinsic vasodilatory effect

The following LA have less or lack of vasodilatory effect

  • Prilocaine (less) [SH4:p186]
  • Mepivacaine (absence) [SH4:p186]
  • Ropivacaine (absence) [SH4:p187]
    * ??? vasoconstriction with ropivacaine