Neuropharmacology – 2009John Schriefer, Ph.D.

LOCAL ANESTHETICSObjectives:

The student shall be able to:

1. indicate which one of the following is most likely to be cardiotoxic; which is most widely used clinically; which is most likely to cause CNS sedation; which is limited to surface or topical anesthesia only; which is most likely to produce vasoconstrictor effects.

cocaine benzocaine procaine tetracaine lidocaine mepivacaine bupivacaine

2. describe the nature of ‘differential nerve sensitivities’ to local anesthetics.

3. describe the site and proposed mechanism(s) of action of local anesthetics.

4. indicate the clinical significance of distinguishing between the two general chemical classes of local anesthetics in respect to elimination processes, duration of action, and allergic phenomenon.

5. indicate which drug characteristics best correlates with rate of onset of local anesthesia. Indicate the relationship between local duration of anesthesia and vasodilation. Explain how local inflammation my adversely influence the effectiveness of local anesthetics.

6. explain the rationale for inclusion of vasoconstrictors in local anesthetic preparations and the potential risks associated with this drug combination.

7. indicate which system is most sensitive to systemic effect of local anesthetics and which system is second most sensitive.

8. indicate in what ways cocaine differs from most local anesthetics with regards to CNS and vascular effects.

9. compare procaine, lidocaine, bupivacaine, and tetracaine regarding onset and duration of action, lipid solubility, and chemical classification.

10. list two agents that are not classified as local anesthetics but have local anesthetic properties.

11. indicate which local anesthetic is almost 100% uncharged at physiological pH and used in many OTC preparations as a surface anesthetic.

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I. Local Anesthetics

A. Definition

1. Drugs which produce a reversible loss of sensation in a localized part of the body when applied directly onto nerve tissues or mucous membranes

2. Local anesthetics are local only because of how they are administered (selectivity).

B. Desirable Characteristics

1. rapid onset of action

2. brief, reversible block of nerve conduction

3. low degree of systemic toxicity

4. soluble in water and stable in solution

5. effective on all parts of the nervous system, all types of nerve fibers, and muscle fibers

None totally meets these completely yet.

C. Mechanism of action

1. Block activation of voltage-gated sodium channels in neuronal membranes.

a. bind to specific receptors at the intracellular end of the voltage gated sodium channel

b. prevent axonal conduction by a functional blockade

2. LA have greatest affinity for sodium channel in inactivated state and interfere with its reversion to the resting state.

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+ +

- -

+ +

--

- -

+ + + +

- -

Na+

+ ++ +

- - - -

Resting (Closed**)

Open

(brief)inactivated

Very slow repolarization in presence of LA

LA receptor

LA have highest affi nity for the inactivated form

Ref ractory period

**Closed state may exist in various forms as it moves from resting to open. LA have a high affinity for the different closed forms and may prevent them from opening.

3. action is voltage dependent

a. this may be due to

i. voltage changes induce changes in form on Na+ channels

ii. LA have a higher affinity for Na+ channel in

- some closed forms of the channel preventing them from opening

- the inactivated state; their binding slows the return to resting form

iii. increased entry into neuron through opened Na channel (myocardium)

4. action is also frequency dependent

a. because high affinity forms of Na+ channel (e.g., inactivated) are more frequently presented in neurons that are firing more frequently

b. this provides a degree of LA selectivity

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i. frequent firing pain neurons more affected than slow firing motoneurons

5. LA are weak bases and access to receptor site is dependent on

a. pKa

b. lipid solubility

c. molecular size and level of neuronal activity

6. LA act in cationic form (charged)

7. An effective LA must enter, pass through and leave the cell membrane and bind to receptor; compounds most likely to do this are moderately lipophilic/moderately hydrophobic.

Differential sensitivity of neurons to LAs

++++0.7 – 2.3None0.3 – 1.3postganglionic, (e.g. vasomotor)sympathetic

++++0.5 – 2.3None0.4 – 1.22nd pain, temperature

Type C

Dorsal root

++++3 – 15Light<3preganglioniicautonomic,(e.g.

vasomotor)

Type B

+++12 – 30Heavy2 – 51st pain, temperature

Delta

++15 – 30Heavy3 – 6muscle toneGamma

++30 – 70Heavy5 – 12touch, pressureBeta

+70 – 120Heavy12 – 20

proprioception, motor

Type A

Alpha

Sensitivity to LA block

Conduction velocity

(m/s)

Myelination

Diameter (μM)

FunctionFiber type

D. Factors influencing LA action – lipid solubility (LS)

1. potency and systemic toxicity directly correlate with LS

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2. local duration positively correlated with LS and inversely related to vasodilation

FACTORS INFLUENCING LA ACTION~ Hydrogen ion concentration ~

LA are tertiary amines and WEAK BASESwith pKa ~ 8-9

R-CH2-NH+

C2H5

C2H5

R-CH2-N

C2H5

C2H5

+ H+

Quaternary amine

(ACTI VE FORM)

Tertiary amine(LIPID SOLUBLE)

1. at pH 7.4 80-90% is ionized and can’t enter cells

a. non-ionized (lipid soluble) form needed for penetration

b. cationic form required for binding to receptor

c. rate of onset is related to pKa

2. inflammation tends to produce lower pH in tissues therefore

a. LA are more ionized

b. don’t penetrate very well

c. decreased ability of LA to produce effects

3. rate limiting factor for LA onset is the time to penetrate nerve sheath and permeate cell membrane

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E. Chemical Classification

C

LAs are Weak Bases

C O

O

R N

R

R

NH

O

R N

R

R

Aromatic portion Amine portion

I ntermediate chain

ESTER

AMIDE

LIPOPHI LIC HYDROPHILI C

Two types of linkages give rise to 2 chemical classes of

LAs. ESTER LINKAGE AMIDE LINKAGE (2 EYES!!)

PROCAINE

procaine (Novocaine)

tetracaine (Pontocaine)

benzocaine

cocaine

LIDOCAINE

lidocaine (Xylocaine)

mepivacaine (Carbocaine)

bupivacaine (Marcaine)

etidocaine (Duranest)

ropivacaine (Naropin)

F. Clinical significance of chemical classification

1. Cross sensitivity (allergy)

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a. occurs with drugs in the same chemical class

b. esters are metabolized to common metabolite PABA

c. allergy rarely occurs with amide linkage class

2. Biotransformation/duration of action

a. esters are rapidly metabolized in the plasma by a cholinesterase

b. amides are more slowly destroyed by liver microsomal P450 enzymes

G. Pharmacokinetics

1. Absorption

a. LA generally have good absorption from mucous membranes and intradermal injection sites (into tissues)

b. Systemic absorption terminates local action (out of tissues) (Not local metabolism!)

c. Factors influencing peak plasma concentration

i. site of injection (vascularity)

ii. total dose

iii. specific drug characteristics

- tendency to produce vasodilation

iv. presence of vasoconstrictor (e.g., epinephrine, phenylephrine)

d. effects of vasoconstrictors

i. decrease rate of systemic absorption and decrease systemic toxicity

ii. increase local drug concentration and increase neuronal uptake of LA

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iii. increase local duration of action (e.g., lidocaine’s duration may increase twofold with EPI)

e. potential adverse effects of vasoconstrictors

i. don’t use in areas of toes, fingers, ear lobes, penis

ii. may produce tissue necrosis

iii. may produce systemic toxicity (CV)

2. Distribution

a. LA can be widely distributed to all parts of the body including CNS

b. distribution is a means of terminating local drug action…not metabolism

3. Metabolism

a. ester type LA

i. hydrolysis by cholinesterase in plasma to PABA derivatives

- pseudo cholinesterase or butyrylcholinesterase

ii. generally, short acting and low systemic toxicity

iii. prolonged effects seen with genetically determined deficiency or altered esterase (cholinesterase inhibitors)

b. amide type LA

i. hydrolyzed by liver microsomal enzymes (P450)

ii. longer acting and more systemic toxicity than esters

iii. caution with severely compromised hepatic function

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Comparison of LA characteristicsRelative lipid solubility

Relative potency

Onset pKa Local duration

Vasodilation Plasma protein binding

procaine 1 1 slow 8.9 short +++ 5%

lidocaine 4 4 rapid 7.9 moderate +++ 55%

tetracaline 80 16 slow 8.5 long + 75%

bupivacaine 130 16 slow 8.1 long + 90%

Plasma protein binding may be used as an indirect measure of tissue binding tendencies

H. Systemic Effects (toxicities)

1. extensions of pharmacological action

2. intensity is dependent on blood levels

3. toxic levels of LA in blood will not occur if absorption (into systemic blood) is slow or metabolism is rapid

4. CNS (more sensitive than CVS)

a. dose-related spectrum of effects and all effects are due to depression of neurons

i. first an apparent CNS stimulation (convulsions most serious)

ii. followed by CNS depression (death due to respire depression)

b. cocaine – euphoria (unique in its ability to stimulate CNS)

c. lidocaine – sedation even at non-toxic doses

5. cardiovascular system

a. hypotension: arteriolar dilation is a result of:

i. direct effect (procaine and lidocaine have most effect)

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ii. block of postganglionic sympathetic fiber function

iii. CNS depression

iv. avoid by adding vasoconstrictor to prep

NOTE:cocaine is exception: produces vasoconstriction, blocks NE reuptake.

b. arrhythmias: direct effect (more resistant than CNS)

i. decrease cardioexcitability and contractility

ii. decreased conduction rate

iii. increased refractory rate (bupivicaine)

iv. NOTE: cocaine is exception…it stimulates heart

v. all can cause arrhythmias if conc. is high enough

c. allergic reactions…fairly rare

i. mostly with ester types, rarely amides (procaine)

- esters metabolized to PABA which has allergenic properties

ii. cross-sensitivity within same chemical class of LA

iii. anaphylactic reactions are rare…diphenhydramine can be used to control minor reactions

iv. the preservative paraban in multidose vials may be responsible for some allergic phenomenon

d. neurotoxicity

i. LA can cause concentration-dependent nerve damage to central and peripheral NS

ii. mechanism(s) not clear

iii. permanent neurological injury is rare

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iv. may account for transient neurological symptoms after spinal anesthesia

- cauda equine syndrome

II. Selective pharmacological properties of some ester – type LA

A. cocaine (schedule II substance)

1. Medical use limited to surface or topical anesthesia (corneal or nasopharyngeal)

2. avoid epinephrine because cocaine already has vasoconstrictor properties. (exception)

3. a toxic action on heart may induce rapid and lethal cardiac failure

4. a marked pyrexia is associated with cocaine overdose.

B. benzocaine (Americaine)

1. pKa ~ 3, essentially all non-ionized (results in weak action)

2. available in many OTC preps for relief of pain and irritation

3. for surface anesthesia (topical) only…ointments, sprays, etc.

4. used to produce anesthesia of mucous membranes and to suppress gag reflex during endoscopy

C. procaine (Novocaine)

1. topically ineffective

2. used for infiltration because of low potency and short duration but most commonly used for spinal anesthesia

3. short local duration…produces significant vasodilation. Epinephrine used to prolong effect.

4. systemic toxicity negligible because rapidly destroyed in plasma

D. tetracaine (Pentocaine)

1. topical, infiltration, and spinal anesthesia

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a. frequently used for topical ophthalmogical anesthesia

2. slow onset and more prolonged effect than procaine (longest duration of the esters)

3. ~10X more toxic and more potent than procaine

III. Selective Pharmacological properties of some Amide – type LA

A. lidocaine (Xylocaine) most widely used LA

1. effective by all routes

2. faster onset, more intense, longer lasting than procaine

3. good alternative for those allergic to ester type

4. more potent than procaine but about equal toxicity

5. more sedative than others

6. prilocaine similar except has a vasoconstrictor action

B. mepivicaine (Carbocaine)

1. effective by all routes except topical

2. similar onset and duration as lidocaine

3. more toxic to neonates so not used in obstetrical anesthesia (fetus poorly metabolized mepivicaine)

C. bupivacaine (Marcaine)

1. no topical effect

2. slower onset and one of longer duration agents

3. unique property of sensory and motor dissociation and provide sensory analgesia with minimal motor block

a. has been popular drug for analgesia during labor

4. more cardiotoxic than other LA

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D. ropivacine (Naropin)

1. enantiomer of bupivacaine

2. no topical effectiveness

3. clinically ~ equivalent to bupivacaine

4. similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicity

IV. Clinical Applications

A. Surface anesthesia (topical)

1. nose, mouth, bronchial tree, cornea, urinary tract, skin

a. lidocaine, tetracaineb. EMLA – mixture of lidocaine and prilocaine

B. infiltration anesthesia

1. direct injection into tissues to reach nerve branches and terminals

2. used in minor surgery

3. immediate onset with variable duration

a. most LA’s used

C. nerve block or field block

1. interruption of nerve conduction upon injection into the region of nerve plexus or trunk

2. used for surgery, dentistry, analgesia

3. less anesthetic needed than for infiltration if a large area must be anesthetized

a. most LA’s used

D. spinal anesthesia

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1. injection into subarachnoid space below level of L2 vertebra to produce effect in spinal roots and spinal cord

2. use hyperbaric or hypobaric solutions depending on area of blockade

3. used for surgery to abdomen, pelvis, or leg when can’t use general anesthesia.

a. lidocaine, tetracaine

4. problems

a. spinal headache due to increased CSF

b. hypotension and bradycardia, respiratory depression

5. advantages over epidural

a. greater predictability

b. faster onset

c. shorter duration

E. epidural and caudal anesthesia

1. injection and epidural space usually at lumbar or sacral levels

2. used like spinal and also painless childbirth

3. unwanted effects similar to that of spinal except less likely because longitudinal spread is reduced.

a. lidocaine, bupivacaine, ropivacaine

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