Pharmacokinetics and toxicity of local anesthetics

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 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 W A K E F O R E S T U N I V E R S I T Y  LA toxicity  CNS  CV system  Allergy  Neurotoxicity  Additives  Treatment  Summary S C H O O L O F M E D I C I N E Local anesthetic concentrations in blood  Know your units!  1 g lidocaine HCl•H20 = 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 1972;37:277 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Epinephrine reduces local anesthetic concentrations after intercostal blocks  Patients received 20 7 ml of 2% lidocaine 6 (n=33) or 2% 5 prilocaine (n=39) 4 plain or with epi  Epi significantly (p< mg/L 3 .01) LA Cmax 2 1 0 Li Pr 0 Scott. Br J Anaesth 1972;44:1040-9 W A K E F O R E S T U N I V E R S I T Y S C H O O L 5 12.5 Epi (g/ml) O F M E D I C I N E 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  1:300,000 epinephrine  Continuous ECG  No group differences in HR or arrhythmias W A K E F O R E S T U N I V E R S I T Y Cmax (ng/ml) 1500 1000 500 0 0.5 0.25 Bupivacaine % S C H O O L O F M E D I C I N E * Plain Epi *p<.05 Harwood. J Cardiothorac Vasc Anesth 1999;13:703-6 Protein binding of LAs  Erroneously over-emphasized in relation to LA duration of action  All LAs are lipid soluble, so all are proteinbound to some extent  1-acid glycoprotein  albumin  In blood a greater fraction of more potent LAs is protein bound (than less potent LAs) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Factors influencing LA protein binding  Increased binding  Major trauma  Major surgery  Tobacco smoking  Chronic inflammation  Chronic pain  Uremia  Cancer W A K E F O R E S T U N I V E R S I T Y  Decreased binding  Pregnancy  Oral contraceptive pills  Newborn status S C H O O L O F M E D I C I N E Protein binding of lidocaine (2 g/ml) decreases during pregnancy Fragneto et al. Anesth Analg 1994;79:295-7 57 55 53 % 51 49 47 Control W A K E F O R E S T 1st U N I V E R S I T Y 2nd Trimester S C H O O L O F 3rd M E D I C I N E 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) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Rapid hydrolysis yields brief half-lives 5 4 3 2 1 0 Tetra Pro 2-CP Foldes. Clin Pharmacol Ther 1965;6:328-35; O’Brien. J Pharm Sci 1979;68:75-8; DuSouich. Clin Pharmacol Ther 1977;21:101-2 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E half-life 21 sec half-life 43 sec 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 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Li Et O F Me Bu Arthur. Handbook of Exp Pharmacol 1987 W A K E F O R E S T U N I V E R S I T Y S C H O O L M E D I C I N E Pharmacokinetic parameters for lidocaine series of LAs 3 2.5 2 1.5 1 0.5 0 Lid W A K E F O R E S T Cl (L/min) t1/2 (h) Pri U N I V E R S I T Y Eti S C H O O L O F M E D I C I N E Tucker, Mather 1975, 1979; Arthur 1979 Pharmacokinetic parameters for pipecoloxylidide local anesthetics 3 2.5 2 1.5 1 0.5 0 Mepiv W A K E F O R E S T Cl (L/min) t1/2 (h) Bupiv U N I V E R S I T Y Ropiv Tucker, Mather 1975, 1979; PDR 2002 S C H O O L O F M E D I C I N E 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: orthotoluidine; met hemoglobinemia  Mepivacaine, ropivacaine, bupivacaine: 2,6 PPX (pipecoloxylidide) S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effect of disease states on lidocaine pharmacokinetics 14 12 10 8 6 4 2 0 Normal CHF W A K E F O R E S T t1/2(h) Vd (l/kg) Cl (ml/kg/min) LVR CRI S C H O O L Thompson. Ann Int Med 1973;78:499 O F M E D I C I N E U N I V E R S I T Y 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 W A K E F O R E S T U N I V E R S I T Y  LA toxicity  CNS  CV system  Allergy  Neurotoxicity  Additives  Treatment  Summary S C H O O L O F M E D I C I N E 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 W A K E F O R E S T  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 U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 W A K E F O R E S T  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 U N I V E R S I T Y S C H O O L O F M E D I C I N E Convulsant doses and arterial concentrations of LAs in monkeys 25 20 15 10 5 0 Mep W A K E Dose (mg/kg) Con (mcg/ml) Pri Lid Bup Eti S C H O O L O F M E D I C I N E Munson. Anesthesiology 1975;42:471-8 F O R E S T U N I V E R S I T Y LA doses and blood concentrations with convulsions in sheep (45 kg) 120 100 80 60 40 20 0 LID W A K E F O R E S T Dose (mg) Conc (mg/L) ROP U N I V E R S I T Y BUP Rutten. Anesth Analg 1989;69:291-9 S C H O O L O F M E D I C I N E Acidosis and hypercarbia reduce the convulsive dose of lidocaine in cats Englesson & Grevsten. Acta Anaesthesiol Scand 1974; 18:88-103 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Lethal vs. convulsive LA doses in anesthetized dogs Liu et al Reg Anesth 1982;7:14-9 & Anesth Analg 1982;61:317-22 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Cardiovascular toxicity from 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? W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency 120 100 μg/mL 80 60 40 20 0 Bup Levo U N I V E R S I T Y Free Total Rop S C H O O L Lid O F M E D I C I N E Groban et al Anesth Analg 2000;91:1103-11 W A K E F O R E S T Bupivacaine more toxic than levo or ropivacane in rats  Rats infused LA at 2 mg/kg/min  Asystole treated with epi .01 mg/kg + CPR  Resuscitation success: SAP >100 mmHg  B more potent than LB or R at sz, arr, asystole  Less epi needed for ropiv than bup or levo Ohmura. Anesth Analg 2001;93:743-8 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Cumulative dose mg/kg 120 100 80 60 40 20 0 Sz Arr Asy B LB Ro Ventricular arrhythmias after supraconvulsant (2x) doses of LAs 6 5 4 N 3 2 1 0 Bup Rop Lido V arr No V arr Feldman et al Anesth Analg 1989;69:794-801 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA-induced arrhythmias, LV depression, & mortality in dogs  LA infusion: more % of animals inducible arrhythmias 50 with B, LB than R,L 40  When MAP<45 mmHg, ACLS + epi used to 30 restore MAP>55 Death 20  Continued epi more EpVF often needed for Li 10 (86%) than others 0  More epi-induced VF B R LB Li (EpVF) & death with B than R or Li Groban. Anesth Analg 2000;91:1103; Anesth Analg 2001;92:37; RAPM 2002;27:460 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Is there one common mechanism for LA-induced cardiac death?     Arrhythmias? Left-ventricular depression? Resuscitation drug failure? Probably depends on specific drug! W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Neurotoxic effects of LAs 2-chloroprocaine Spinal lidocaine  Found when large  Deficits first linked to doses accidentally microcatheters; later injected in CSF reported after singleshot spinals  Metabisulfite, low pH  Disappeared when 2-  5% lidocaine produces permanent nerve block CP reformulated  Toxicity returns when  Association between transient neurologic generics using “old” symptoms and formulation appear! arthroscopy, lithotomy position, lidocaine W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Approach to patients with a history of LA hypersensitivity  14 of 90 referrals had 100 history consistent 80 with anaphylactic or anaphylactoid rxn 60  <20% react to % undiluted 1:1 LA 40  0 of 90 reacted to 20 1:100 LAs  “Real” (immune) LA 0 allergy a rare + - + 1:1 1:100 condition W A K E F O R E S T U N I V E R S I T Y S C H O O L O F Hyper (N=14) Others (N=76) deShazo. J All Clin Immunol 1979;63:387-94 M E D I C I N E 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 1993;18:453-60 Watson. Br J Anaesth 1993;71:422-5 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 1993;18:453-60 Watson. Br J Anaesth 1993;71:422-5 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 W A K E F O R E S T U N I V E R S I T Y  LA toxicity  CNS  CV system  Allergy  Neurotoxicity  Additives  Treatment  Summary S C H O O L O F M E D I C I N E Oxygen concentration and bupivacaine toxicity in piglets 35 30 25 20 mg/kg 15 10 5 0 0.1 0.15 0.3 Heavner. Anesthesiology 1992;77:142-7 S C H O O L O F M E D I C I N E CD100 VArr AS FIO2 W A K E F O R E S T U N I V E R S I T Y Local anesthetic pharmacokinetics  Differences between LAs and other drugs  Sites of injection and LA concentrations in blood  Protein binding  Metabolism  Disease states and pregnancy W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs are different from 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 1972;37:277 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Protein binding of LAs  All LAs are lipid soluble, so all are proteinbound 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!) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Protein binding of lidocaine (2 g/ml) decreases during pregnancy Fragneto et al. Anesth Analg 1994;79:295-7 58 56 54 % 52 50 48 46 Control 1st U N I V E R S I T Y 2nd Trimester S C H O O L O F 3rd M E D I C I N E W A K E F O R E S T 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) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E  Left-ventricular depression?  Renal failure: ↑Vd; ↑accumulation of metabolic  products Resuscitation drug failure? Probably depends on specific clearance  Hepatic failure: ↑amide Vd, ↓amidedrug!  Cardiac failure; β and H2 blockers: ↓hepatic blood flow and ↓amide clearance  Cholinesterase deficiency or inhibition: ↓ester clearance  Pregnancy: ↑hepatic blood flow; ↑amide clearance; ↓protein binding W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effects of pregnancy, drugs, and organ failure on LA kinetics 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 S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y 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 S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y 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) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E None of 90 patients referred for LA reactions have allergy!  0 of 90 reacted to 1:100 LA dilutions!  Few respond to undiluted LA even among 14 referred after anaphylactoid reactions  Thus, almost no patients had “real” LA allergy W A K E F O R E S T 100 80 60 % Hyper (N=14) Others (N=76) 40 20 0 + - + 1:100 Undiluted O F deShazo. J All Clin Immunol 1979;63:387-94 U N I V E R S I T Y S C H O O L M E D I C I N E 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E  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 1998;88:1071-5 Weinberg. Reg Anesth Pain Med 2003;28 (in press) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Intravenous lipid counteracts bupivacaine cardiac toxicity Treatment of LA allergy  Steroids  H1 blockers  With severe reactions  “Volume” resuscitation  Epinephrine W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E 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? W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E