Chapter 7:Local Anesthetics

JC Gerancher MD

Associate Professor/ RAAPM Section Head

Chapter Review

• Structure• Mechanism of Action• Nerve Sensitivity• Pharmacokinetics• Side Effects:

– CNS toxicity– CV toxicity

– Allergy

Structure of Local Anesthetics

• Lipophilic benzene ring• Hydrophilic tertiary amide

(proton accepting weak base)

• Linkage by an ester or amide bond

• Mepivacaine, bupivacaine, and ropivacaine have chiral centers

Mechanism of Action

• Bind sodium channels in inactivated-closed state

• Slowing rate of depolarization

• Produce block of conduction (propogation of action potential)

LAs bind and inhibit many differing receptors and channels

• Channels– Na– Ca (multiple types)– K

• Enzymes– Adenylyl cyclase– Guanylyl cyclase– Lipases

• Receptors– Nicotinic

acetylcholine– NMDA

– β2-adrenergic

Anesthesiology 1990; 72:711-34

Factors responsible for nerve Sensitivity

• Anatomy, anatomy, anatomy • Myelination increase conduction velocity and

makes nerves more susceptable to local anesthetics

• Small unmylenated fibers are not especially susceptable just because they are small.

• Use dependant blockade (muscle activity, tachycardia)

PNB effect is predictable

• Onset:– Superficial fibers =

proximal and motor– Deep fibers = distal

and sensory

• Recovery:– Deep vessels clear

deep fibers first– Hard to obtain

‘differential’ blockade-Winnie 1977

Local Anesthesia for PNB: Pharmacokinectics

Manufacturer’s Recommended Maximum Dose

(mg)

Mean Latency to Surgical Anesthesia (minutes)

Mean Durationof SurgicalAnesthesia

(hours)

Mean Duration of Postoperative

Analgesia (hours)

2-chloroprocaine(Nesacaine)

980 5-15 1-2 2-3

Lidocaine(Xylocaine)

490 7-15 2-3 3-5

Mepivacaine(Polocaine,Carbocaine)

400 10-15 3-4 4-6

Bupivacaine (Marcaine)

225 15-40 6-10 12-17

Ropivacaine(Naropin)

250 15-40 5-9 8-14

Local Anesthesia for PNB: No Free Lunch

Manufacturer’s Recommended Maximum Dose

(mg)

Mean Latency to Surgical Anesthesia (minutes)

Mean Durationof SurgicalAnesthesia

(hours)

Mean Duration of Postoperative

Analgesia (hours)

2-chloroprocaine(Nesacaine)

980 5-15 1-2 2-3

Lidocaine(Xylocaine)

490 7-15 2-3 3-5

Mepivacaine(Polocaine,Carbocaine)

400 10-15 3-4 4-6

Bupivacaine (Marcaine)

225 15-40 6-10 12-17

Ropivacaine(Naropin)

250 15-40 5-9 8-14

Quotes from the PDR

• “maximal recommended dose” of 4.5 to 7 mg/kg• “maximum single recommended dose” of 11mg to

14mg/kg• “175 to 225 mg” and “more or less drug may be used

depending on individualization of each case” • “expected average dose of 175 to 250 mg” and “a

cumulative dose of 770 mg over 24 hours.”• “400 mg” with higher doses “not recommended”

Dose and Arterial Plasma Levels

-Brown 1996

Local Anesthetic Levels: site

- McClean 1988

35ml 1.5% Plain Prilocaine

Positive effects– Prolongs duration

– Increases intensity

– Reduces toxicity

– Test dose

Epinephrine

Local Anesthetic Levels: Epi

- Pihlajamaki 1987

40ml 1% Bupivacaine +/- Epi

•Epi→↓circulating levels with lido, mepi, Bupiv, Prilo, and Etidocaine

(vs epidural)

•5 mcg/ml may be max

•May delay peak level

33ml 0.5% Ropivacaine +/- Epi

- Hickey 1990

•Epi→no change in levels achieved with ropivacaine

•ropivacaine itself a vasoconstrictor

Local Anesthetic Levels: Epi

Epinephrine• Decreased nerve

blood flow• At risk:

– Diabetes

– Atherosclerosis

– Intraneural injection

-Myers 1989

AlkalinizationLOCAL

ANESTHETICS– Exists at basic pKa– Formulated at acidic

pH– Non-ionized form

diffuses– Protonated form is

active

-Brown 1996

Patterns of LA toxicity

• CNS

• CV system

• Allergy

• Treatment

CNS toxicity from LAs• Progression of signs &

symptoms with ↑LA– Vertigo– Tinnitus

– Ominous feelings

– Circumoral numbness– Garrulousness– Tremors– Myoclonic jerks

– Convulsions

– CNS 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

CNS toxicity from LAs• Progression of signs &

symptoms with ↑LA– Vertigo– Tinnitus

– Ominous feelings

– Circumoral numbness– Garrulousness– Tremors– Myoclonic jerks

– Convulsions

– CNS 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

LA doses and blood concentrations producing convulsions in sheep: similar rank order as for potency

0

20

40

60

80

100

120

LID ROP BUP

Dose (mg)Conc (mg/L)

Rutten. Anesth Analg 1989;69:291-9

Multiple LA actions on the cardiovascular system

• Electrophysiologic– Bupivacaine vs. lidocaine: faster binding, delayed

unbinding from cardiac Na channels – Antiarrhythmic and proarrhythmic effects– Inhibit conduction system

• Negative inotropic • Vascular

– Vasoconstrict (low concentrations)– Vasodilate (high concentrations)

• LA in CNS can have CV results• Interfere with resuscitation

LAs bind and inhibit many differing receptors and channels

• Channels– Na– Ca (multiple types)– K

• Enzymes– Adenylyl cyclase– Guanylyl cyclase– Lipases

• Receptors– Nicotinic

acetylcholine– NMDA

– β2-adrenergic

Anesthesiology 1990; 72:711-34

LAs bind and inhibit many differing receptors and channels

Do not assume LA toxic side effects arise from Na channel inhibition!

Anesthesiology 1990; 72:711-34

LA blood concentrations producing cardiac arrest in dogs: similar rank

order as for potency

0

20

40

60

80

100

120

Bup Levo Rop Lid

FreeTotal

Groban et al Anesth Analg 2000;91:1103-11

μg

/mL

Allergy to LAs• Common misdiagnosis after

accidental IV injections

• True allergy more common with esters (particularly those related to PABA) than amides

• Avoid PABA in sunscreens• Possible cross reaction

between PABA and methylparaben (preservative in some amide LAs)

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

0

20

40

60

80

100

+ - + -

Anaph(N=14)Others(N=76)

1:100 Undiluted

deShazo. J All Clin Immunol 1979;63:387-94

%

Treatment of local anesthetic toxicity

Apparent allergy• Steroids• Histamine (H1) blockers• With severe reactions

– Intravenous fluid– Epinephrine

CNS toxicity• Don’t treat minor

reactions• Seizures: maintain

airway, provide O2

– Terminate seizure with thiopental, midazolam, or propofol

– Intubate patients with full stomachs

Treatment of local anesthetic toxicity

Apparent allergy• Steroids• Histamine (H1) blockers• With severe reactions

– Intravenous fluid– Epinephrine

CNS toxicity• Don’t treat minor

reactions• Seizures: maintain

airway, provide O2

– Terminate seizure with thiopental, midazolam, or propofol

– Intubate patients with full stomachs

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

Polarized Light Images: Lidocaine or St Pauli Girl Beer