Pharmacokinetics and toxicity of local anesthetics

1
Pharmacokinetics and toxicity of local anesthetics

• John Butterworth, MD
• Professor Head
• Section on Cardiothoracic Anesthesiology
• Wake Forest University School of Medicine
• Winston-Salem, North Carolina

2
Pharmacokinetics and toxicity of local anesthetics

• LA pharmacokinetics
• Units of measure
• LAs vs other drugs
• Vasoconstrictors
• Protein binding
• Metabolism
• PK values
• Disease states and pregnancy

• LA toxicity
• CNS
• CV system
• Allergy
• Neurotoxicity
• Additives
• Treatment
• Summary

3
Local anestheticconcentrations in blood

• Know your units!
• 1 g lidocaine HClH20 0.94 g lidocaine HCl
  0.81 lidocaine base
• Blood concentrations are usually given in terms
  of the base
• Concentrations may refer either to plasma or
  whole blood
• Administered doses are usually given in terms of
  the HCl salt

4
LAs compared with other drugs

• LAs lack efficacy unless administered on or near
  site of action
• CNS and CV toxicity arise from absorption and
  systemic distribution
• Other drugs (not LAs) delivered by blood stream
  to their site of action
• Appropriate local or regional doses produce
  marked toxicity if given at another site or
  intravascularly

5
Mepivacaine concentrations in blood after
injection of the same dose at different sites

• Greatest to Least
• Intercostal
• Caudal
• Lumbar epidural
• Brachial plexus
• Sciatic-femoral

Anesthesiology 197237277
6
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7
Epinephrine reduces local anesthetic
concentrations after intercostal blocks

• Patients received 20 ml of 2 lidocaine (n33) or
  2 prilocaine (n39) plain or with epi
• Epi significantly (plt .01) ?LA Cmax

mg/L
Epi (?g/ml)
Scott. Br J Anaesth 1972441040-9
8
Bupivacaine ? epinephrine for superficial
cervical plexus block

• 40 patients having carotid TEA received 0.5 ml/kg
  (max 30 ml) 0.25 or 0.5 bupivacaine ? 1300,000
  epinephrine
• Continuous ECG
• No group differences in HR or arrhythmias

Cmax (ng/ml)

plt.05
Bupivacaine
Harwood. J Cardiothorac Vasc Anesth 199913703-6
9
Protein binding of LAs

• Erroneously over-emphasized in relation to LA
  duration of action
• All LAs are lipid soluble, so all are
  protein-bound to some extent
• ?1-acid glycoprotein
• albumin
• In blood a greater fraction of more potent LAs is
  protein bound (than less potent LAs)

10
Factors influencingLA protein binding

• Increased binding
• Major trauma
• Major surgery
• Tobacco smoking
• Chronic inflammation
• Chronic pain
• Uremia
• Cancer

• Decreased binding
• Pregnancy
• Oral contraceptive pills
• Newborn status

11
Protein binding of lidocaine (2 ?g/ml) decreases
during pregnancyFragneto et al. Anesth Analg
199479295-7

Trimester
12
LA metabolism

• Esters (half-lives in seconds to minutes)
• Hydrolyzed by nonspecific esterases
• Clearance independent of liver flow function
• p-aminobenzoic acid (PABA) and allergy with
  procaine or benzocaine
• Amides (half-lives in hours)
• N-dealkylation or hydroxylation (CYP450)
• Clearance dependent on liver blood flow
  function
• Active metabolites (prilocaine ? o-toluidine can
  produce methemoglobinemia)

13
Lung uptake of LAs

• 40-60 of bolus iv dose of lidocaine is absorbed
  during first pass through lung
• Drug is released rapidly after initial uptake
• Effect of lung uptake reduced as dose increases
• Nortriptyline and bupivacaine will displace
  lidocaine from lung tissue
• Increased toxicity of lidocaine in presence of
  right to left cardiac shunt

14
Rapid hydrolysis yields brief half-lives
half-life 21 sec
?M/h
half-life 43 sec
Foldes. Clin Pharmacol Ther 19656328-35 OBrien
. J Pharm Sci 19796875-8 DuSouich. Clin
Pharmacol Ther 197721101-2
15
Hepatic extraction ratios of LAs
Hepatic extraction ratio

• Most LA molecules entering liver are metabolized
• Extraction ratio and hepatic blood flow define
  clearance of amide LAs

Arthur. Handbook of Exp Pharmacol 1987
16
Pharmacokinetic parameters for lidocaine series
of LAs
Tucker, Mather 1975, 1979 Arthur 1979
17
Pharmacokinetic parameters for pipecoloxylidide
local anesthetics
Tucker, Mather 1975, 1979 PDR 2002
18
Important LA metabolites

• Esters
• Procaine, Benzocaine PABA (para-aminobenzoic
  acid) allergy
• Cocaine methyl ecgonine, benzoyl ecgonine for
  prolonged detection of cocaine use

• Amides
• Lidocaine MEGX (methyl ethyl glycine xylidide),
  GX (glycine xylidide) active metabolites
• Prilocaine ortho-toluidine met hemoglobinemia
• Mepivacaine, ropivacaine, bupivacaine 2,6 PPX
  (pipecoloxylidide)

19
Effects of pregnancy, drugs, and organ failure on
LA kinetics

• Renal failure increases accumulation of
  metabolic products
• Hepatic failure increases amide Vd, decreases
  clearance, increases half-life
• Cardiac failure decreases amide clearance
• Cholinesterase deficiency or inhibition decrease
  ester clearance
• Pregnancy increases amide clearance decreases
  protein binding
• ? and H2 blockers decrease amide clearance

20
Effect of disease states on lidocaine
pharmacokinetics
Thompson. Ann Int Med 197378499
21
Pharmacokinetics and toxicity of local anesthetics

• LA pharmacokinetics
• Units of measure
• LAs vs other drugs
• Vasoconstrictors
• Protein binding
• Metabolism
• PK values
• Disease states and pregnancy

• LA toxicity
• CNS
• CV system
• Allergy
• Neurotoxicity
• Additives
• Treatment
• Summary

22
CNS toxicity from LAs

• Progression of signs symptoms with ?LA
• Vertigo
• Tinnitus
• Ominous feelings
• Circumoral numbness
• Garrulousness
• Tremors
• Myoclonic jerks
• Convulsions
• CNS depression
• CV depression

• Convulsive LA dose inversely related to LA
  potency
• Acidosis, hypercarbia ? convulsive dose
• Pregnancy lowers dose but not concentration
  producing convulsions
• CV toxicity requires greater LA doses and
  concentrations than CNS toxicity

23
CNS toxicity from LAs

• Progression of signs symptoms with ?LA
• Vertigo
• Tinnitus
• Ominous feelings
• Circumoral numbness
• Garrulousness
• Tremors
• Myoclonic jerks
• Convulsions
• CNS depression
• CV depression

• Convulsive LA dose inversely related to LA
  potency
• Acidosis, hypercarbia ? convulsive dose
• Pregnancy lowers dose but not concentration
  producing convulsions
• CV toxicity requires greater LA doses and
  concentrations than CNS toxicity

24
Convulsant doses and arterial concentrations of
LAs in monkeys
Munson. Anesthesiology 197542471-8
25
LA doses and blood concentrations with
convulsions in sheep (?45 kg)
Rutten. Anesth Analg 198969291-9
26
Acidosis and hypercarbia reduce the convulsive
dose of lidocaine in cats Englesson Grevsten.
Acta Anaesthesiol Scand 1974 1888-103
27
Lethal vs. convulsive LA doses in anesthetized
dogs Liu et al Reg Anesth 1982714-9 Anesth
Analg 198261317-22
28
Cardiovascular toxicityfrom LAs

• Cardiac arrest reported with bupivacaine
  etidocaine (Albright, 1979)
• S- isomers (levo-bupivacaine and ropivacaine)
  less potent at CV toxicity than R isomers or
  racemic mixes
• Toxicity related to LA size, potency, or
  stereoisomerism?

29
Multiple LA actions on the CV system

• Biochemical
• Inhibit cAMP formation
• Inhibit multiple enzyme systems
• Electrophysiologic
• Bupivacaine vs. lidocaine faster binding,
  delayed unbinding from cardiac Na channels
• LAs inhibit conduction system
• Negative inotropic (multiple Ca interactions)
• Vascular
• LAs vasoconstrict (low concentrations)
• LAs vasodilate (high concentrations)

30
LA blood concentrations producing cardiac arrest
in dogs similar rank order as for potency
µg/mL
Groban et al Anesth Analg 2000911103-11
31
Bupivacaine more toxic thanlevo or ropivacane in
rats

• Rats infused LA at 2 mg/kg/min
• Asystole treated with epi .01 mg/kg CPR
• Resuscitation success SAP gt100 mmHg
• B more potent than LB or R at sz, arr, asystole
• Less epi needed for ropiv than bup or levo

Cumulative dose mg/kg
Ohmura. Anesth Analg 200193743-8
32
Ventricular arrhythmias after supraconvulsant
(2x) doses of LAs
N
Feldman et al Anesth Analg 198969794-801
33
LA-induced arrhythmias, LV depression,
mortality in dogs

• LA infusion more inducible arrhythmias with B,
  LB than R,L
• When MAPlt45 mmHg, ACLS epi used to restore
  MAPgt55
• Continued epi more often needed for Li (86)
  than others
• More epi-induced VF (EpVF) death with B than R
  or Li

of animals
Groban. Anesth Analg 2000911103 Anesth Analg
20019237 RAPM 200227460
34
Is there one common mechanism for LA-induced
cardiac death?

• Arrhythmias?
• Left-ventricular depression?
• Resuscitation drug failure?
• Probably depends on specific drug!

35
Neurotoxic effects of LAs

• 2-chloroprocaine
• Found when large doses accidentally injected in
  CSF
• Metabisulfite, low pH
• Disappeared when 2-CP reformulated
• Toxicity returns when generics using old
  formulation appear!

• Spinal lidocaine
• Deficits first linked to microcatheters later
  reported after single-shot spinals
• 5 lidocaine produces permanent nerve block
• Association between transient neurologic symptoms
  and arthroscopy, lithotomy position, lidocaine

36
Allergy to LAs

• Frequently a misdiagnosis of toxic reactions to
  LAs or epinephrine
• True allergy (including anaphylaxis) more common
  with esters (particularly those related to PABA)
  than amides
• Cross reaction between PABA and methylparaben (a
  preservative sometimes included with amide LAs)

37
Approach to patients with a history of LA
hypersensitivity

• 14 of 90 referrals had history consistent with
  anaphylactic or anaphylactoid rxn
• lt20 react to undiluted 11 LA
• 0 of 90 reacted to 1100 LAs
• Real (immune) LA allergy a rare condition

11 1100
deShazo. J All Clin Immunol 197963387-94
38
Toxicity of additives-1

• Vasoconstrictors epi and phenylephrine may
  ?blood flow no other likely toxicity
• Methylparaben antibacterial agents added to LAs
  may be metabolized to PABA
• Dextrose no clear evidence of toxic effects
• Metabisulfite added to ?stability and shelf
  life ? relationship to nerve injury
• NaHCO3 no evidence of toxicity

Rowlingson. Reg Anesth 199318453-60 Watson. Br
J Anaesth 199371422-5
39
Toxicity of additives-2

• Clonidine no toxicity ?sedation, ?BP
• Neostigmine no toxicity ?N ?V
• Hyaluronidase occasion anaphylaxis
• Opioids no toxicity respiratory depression, N,
  V, itching
• EDTA added to LAs to replace metabisulfite
  possibly neurotoxic in large doses

Rowlingson. Reg Anesth 199318453-60 Watson. Br
J Anaesth 199371422-5
40
Treatment of LA toxicity

• Depends on severity
• Allow minor reactions to IV LAs to dissipate
  spontaneously
• Seizures maintain airway provide O2
• May terminate seizure with thiopental or
  midazolam
• May need to intubate (succinylcholine?)
• Cardiac toxicity follow ACLS guidelines
• Allergy steroids, H1 blockers, epinephrine
  (depending on severity)

41
Pharmacokinetics and toxicity of local anesthetics

• LA pharmacokinetics
• LAs vs other drugs
• Units of measure
• Protein binding
• Metabolism
• PK values
• Disease states

• LA toxicity
• CNS
• CV system
• Allergy
• Neurotoxicity
• Additives
• Treatment
• Summary

42
Pharmacokinetics and toxicity of local anesthetics

• LA pharmacokinetics
• Units of measure
• LAs vs other drugs
• Vasoconstrictors
• Protein binding
• Metabolism
• PK values
• Disease states and pregnancy

• LA toxicity
• CNS
• CV system
• Allergy
• Neurotoxicity
• Additives
• Treatment
• Summary

43
Oxygen concentration and bupivacaine toxicity in
piglets
mg/kg
Heavner. Anesthesiology 199277142-7
FIO2
44
Local anesthetic pharmacokinetics

• Differences between LAs and other drugs
• Sites of injection and LA concentrations in blood
• Protein binding
• Metabolism
• Disease states and pregnancy

45
LAs are differentfrom other drugs

• LAs lack efficacy when not administered on or
  near site of action
• CNS and CV toxicity arise from absorption and
  systemic distribution
• Appropriate local or regional doses produce
  marked toxicity if given at another site or into
  a blood vessel

46
Mepivacaine concentrations in blood after
injection of the same dose in different sites

• Greatest to Least
• Intercostal
• Caudal
• Lumbar epidural
• Brachial plexus
• Sciatic-femoral

Anesthesiology 197237277
47
Protein binding of LAs

• All LAs are lipid soluble, so all are
  protein-bound to some extent
• ?1-acid glycoprotein
• albumin
• Greater fraction of more potent LAs protein bound
  than less potent LAs
• Protein binding declines during pregnancy (but
  not by much!)

48
Protein binding of lidocaine (2 ?g/ml) decreases
during pregnancyFragneto et al. Anesth Analg
199479295-7

Trimester
49
LA metabolism

• Esters (half-lives in seconds to minutes)
• Hydrolyzed by nonspecific esterases
• Clearance independent of liver flow function
• Active metabolites (p-aminobenzoic acid (PABA)
  and allergy with procaine or benzocaine)
• Amides (half-lives in hours)
• N-dealkylation or hydroxylation (CYP450)
• Clearance depends on liver blood flow, function
• Active metabolite (prilocaine ? o-toluidine and
  methemoglobinemia)

50
Effects of pregnancy, drugs, and organ failure on
LA kinetics

• Left-ventricular depression?
• Resuscitation drug failure?
• Probably depends on specific drug!

• Renal failure ?Vd ?accumulation of metabolic
  products
• Hepatic failure ?amide Vd, ?amide clearance
• Cardiac failure ß and H2 blockers ?hepatic
  blood flow and ?amide clearance
• Cholinesterase deficiency or inhibition ?ester
  clearance
• Pregnancy ?hepatic blood flow ?amide clearance
  ?protein binding

51
Neurotoxic effects of LAs

• 2-chloroprocaine
• Large doses injected accidentally in CSF produce
  cauda equina syndrome
• Metabisulfite, low pH
• Toxicity disappeared when 2-CP reformulated
• Toxicity returns when generic manufacturers use
  old formulation!
• 2-CP used for spinals

• Spinal lidocaine
• Deficits first linked to microcatheters later
  reported after single-shot spinal anesthetics
• 5 lidocaine (not other spinal LAs) in vitro
  produces irreversible nerve block
• Transient neurologic symptoms linked with
  arthroscopy, lithotomy position, and lidocaine
  spinal anesthesia

52
Neurotoxic effects of LAs

• 2-chloroprocaine
• Large doses injected accidentally in CSF produce
  cauda equina syndrome
• Metabisulfite, low pH
• Toxicity disappeared when 2-CP reformulated
• Toxicity returns when generic manufacturers use
  old formulation!

• Spinal lidocaine
• Deficits first linked to microcatheters later
  reported after single-shot spinal anesthetics
• 5 lidocaine (not other spinal LAs) in vitro
  produces irreversible nerve block
• Transient neurologic symptoms linked with
  arthroscopy, lithotomy position, and lidocaine
  spinal anesthesia

53
Allergy to LAs

• Misdiagnosis of toxic reactions to LAs or
  epinephrine?
• True allergy (including anaphylaxis) more common
  with ester Las (particularly those related to
  PABA) than amide LAs
• Avoid PABA in sunscreens
• Cross reactions between PABA and methylparaben
  (preservative sometimes added to amide LAs)

54
None of 90 patients referred for LA reactions
have allergy!

• 0 of 90 reacted to 1100 LA dilutions!
• Few respond to undiluted LA even among 14
  referred after anaphylactoid reactions
• Thus, almost no patients had real LA allergy

1100 Undiluted
deShazo. J All Clin Immunol 197963387-94
55
Treatment of LA CNS toxicity

• Let minor LA reactions dissipate spontaneously
• Seizures maintain airway, provide O2
• May end seizure with thiopental, midazolam, or
  propofol
• May need to intubate if patient has a full stomach

56
Treatment of LA CV toxicity

• Follow ACLS guidelines
• Substitute amiodarone for lidocaine
• Substitute vasopressin for epinephrine
• Consider cardiopulmonary bypass or lipid infusion
  if standard drugs fail

57
Intravenous lipid counteracts bupivacaine cardiac
toxicity

• Pretreatment with lipid emulsion increases toxic
  dose of bupivacaine
• Animals not resuscitated using ACLS recovered
  when given lipid emulsion
• Lipid may draw bupivacaine into plasma from
  binding site(s) in the heart
• Could lipid in propofol serve same purpose?

Weinberg. Anesthesiology 1998881071-5 Weinberg.
Reg Anesth Pain Med 200328 (in press)
58
Treatment of LA allergy

• Steroids
• H1 blockers
• With severe reactions
• Volume resuscitation
• Epinephrine

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60
Cardiovascular toxicity from LAs

• CV toxicity usually requires larger dose or
  concentration than CNS toxicity
• Bupivacaine vs. lidocaine more avid binding,
  delayed unbinding from cardiac Na channels
• S- isomers (levo-bupivacaine and ropivacaine)
  less potent at CV toxicity than R isomers or
  racemic mixes
• LAs inhibit conduction system
• LAs inhibit cAMP formation
• LAs vasoconstrict (low dose) dilate (high dose)
• LA-induced cardiac arrest from arrhythmias, LV
  failure, or resuscitation drug failure?