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)	Speed of metabolism (1 is fastest)	Comment
Ester LA
Procaine	1	8.9	3%	0.6	0.02		6%	65 L	2
Chloroprocaine	4	8.7	5%		0.14			35 L	1	Rapid onset despite high pK, due to the high concentration used (3%)
Amethocaine	16	8.5	7%	80	4.1		76%		3	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%	91 L	2
Etidocaine	4	7.7	33%	141	141	39	94%	133 L	3
Prilocaine	1	7.9	24%	0.9	0.9		55%	191 L	1
Mepivacaine	1	7.6	39%	1	0.8		77%	84 L	2
Bupivacaine	4	8.1	17%	28	27.5 [SS3]	10	95%	73 L	3
Levobupivacaine	4	8.1	17%				>97%	55 L
Ropivacaine	4	8.1	17%		2.9 [SS3] (probably wrong)	2.9	94%	59 L	3

 

NB:

• Protein-binding tend to parallel lipid solubility

 

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