Local Anesthetics

CRNA Pharmacology
Art Hupka, Ph.D. 2008

Local Anesthetics Common exposure to LAs

For pain and itching associated with sunburn, poison ivy, etc.
Solarcaine (benzocaine) Mediquik (lidocaine) Rauli Spray (benzocaine)

For sore throat

Cepacol (benzocaine)

Local Anesthetics Common exposure to LAs

For pain of toothache, baby teething, sores on gums, etc.
Benzodent (benzocaine) Numzit (benzocaine) Ambesol (benzocaine) Orabase B (benzocaine)

To prolong sexual experience

Prolong (benzocaine)

Local Anesthetics DEFINITION

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

Local anesthetics are local ONLY because of how they are administered! (Selectivity)

Local Anesthetics DESIRABLE CHARACTERISTICS

Rapid onset of action

Brief, reversible block of nerve conduction

Low degree of systemic toxicity*** Soluble in water and stable in solution Effective on all parts of the nervous

system, all types of nerve fibers and muscle fibers NONE totally meets these optimally yet!!

LAs are Weak Bases

Intermediate chain Aromatic portion

O C O ESTER O NH C AMIDE R R N

Amine portion

R N R

LIPOPHILIC

HYDROPHILIC

Two types of linkages give rise to 2 chemical classes of local anesthetics.

ESTER LINKAGE AMIDE LINKAGE (2 EYES!!)

PROCAINE procaine (Novocaine) tetracaine (Pontocaine) benzocaine cocaine

LIDOCAINE lidocaine (Xylocaine) mepivacaine (Carbocaine) bupivacaine (Marcaine) etidocaine (Duranest) ropivacaine (Naropin)

Clinical Significance of chemical classification

Local Anesthetics

Cross sensitivity (allergy)

Occurs with drugs in the same chemical class Esters are metabolized to common metabolite PABA Allergy rarely occurs with amide linkage class

Biotransformation/duration of action

ESTERS are rapidly metabolized in the plasma by a cholinesterase AMIDES are more slowly destroyed by liver microsomal P450 enzymes.

Local Anesthetics MECHANISM OF ACTION (specific & non-specific)

Specific (No effect on RMP)

bind to specific receptors at the INTRACELLULAR end of the voltage gated sodium channel prevent axonal conduction by a functional blockade

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

LA receptor

Na+

++ --

++ --

-++

-++

--

--

++

++

Resting (Closed**)

Open (brief)

inactivated

Very slow repolarization in presence of LA

LA have highest affinity for the inactivated form

Refractory 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.

Local Anesthetics MECHANISM OF ACTION (specific)

action is voltage dependent

This may be due to
Voltage changes induce changes in form of Na+ channels LA have a higher affinity for Na+ channel in
Some closed forms of the channel preventing them from opening higher affinity for channel in inactivated state slowing return to resting form (prolonged refractory
period)

Increased entry into neuron through opened Na channel

Local Anesthetics MECHANISM OF ACTION (specific)

action is also frequency dependent

Because high affinity forms of Na+ channel (e.g. inactivated) are more frequently presented in neurons that are firing more frequently (increased binding and effect) This provides a degree of LA selectivity
Frequent firing pain neurons more affected than slow firing motoneurons

Local Anesthetics MECHANISM OF ACTION (specific)

LA are WEAK BASES and access to receptor site is dependent on:

pKa lipid solubility molecular size and level of neuronal activity

LA ACT IN CATIONIC FORM (charged)

Local Anesthetics MECHANISM OF ACTION (Non-specific)

LA have some non-specific actions

Appear to dissolve in the membrane Distorting the membrane and altering function
Benzocaine (pKa
~ almost 100% in nonionized form)

Most LA are in this form at pH 7.4

B+H+ B+H+ B

BH+ BH+

pH = 7.4
Nerve sheath

pH = 7.4 Specific action pH = 6.9 axoplasm

B+H

Non-specific action

BH+

(active form)

Differential sensitivity
Fiber type Function Diameter (M)
12 20 proprioception, motor touch, pressure 5 12

of neurons to Local anesthetics

Myelination Conduction velocity (m/s)
70 120

Sensitivity to LA block
+

Type A Alpha Beta

Heavy

Heavy

30 70

++

Gamma

muscle tone

36

Heavy

15 30

++

Delta

1st pain, temperature preganglioniic autonomic,(e.g. vasomotor) 2nd pain, temperature postganglionic, (e.g. vasomotor)

25

Heavy

12 30

+++

Type B

<3

Light

3 15

++++

Type C Dorsal root sympathetic

0.4 1.2 0.3 1.3

None None

0.5 2.3 0.7 2.3

++++ ++++

FACTORS INFLUENCING LA ACTION

~ LIPID SOLUBILITY ~

Potency and systemic toxicity directly correlate with LS Local duration positively correlated with LS and inversely related to vasodilation

FACTORS INFLUENCING LA ACTION

~ Hydrogen ion concentration ~

LA are tertiary amines and WEAK BASES with pKa ~ 8-9

C2H5 R-CH2-NH+ C2H5 Quaternary amine (ACTIVE FORM) R-CH2-N

C2H5 + H+ C2H5

Tertiary amine (LIPID SOLUBLE)

FACTORS INFLUENCING LA ACTION

~ Hydrogen ion concentration ~

at pH 7.4 80 - 90% is ionized and cant enter cells

non-ionized (lipid-soluble) form needed for penetration cationic form required for binding to receptor rate of ONSET is related to pKa (because it determines the % of LA in a LS form)

FACTORS INFLUENCING LA ACTION

~ Hydrogen ion concentration ~

LA are more ionized dont penetrate very well decreased ability of LA to produce effects

inflammation tends to produce lower pH in tissues therefore

For over 100 years, LA solutions have been alkalinized to hasten onset of neural block Limit to how much can alkalinize before ppt LA Limited increase of % in unionized form (~10% increase) Value of alkalinization of LA appears debatable as means to improve anesthesia

RATE LIMITING FACTOR for LA onset is the time to penetrate nerve sheath and permeate cell membrane

FACTORS INFLUENCING LA ACTION

Central neuraxial coadministration of LA and opioids to prolong and intensify analgesia and anesthesia
LA act to decrease propagation of pain sensation Opioids act to diminish pain by decreasing NT from afferent neurons

Alpha 2 agonists (e.g. clonidine) enhance intrathecal and epidural nerve blocks by acting on alpha 2 receptors to decrease NT release

FACTORS INFLUENCING LA ACTION

Tachyphylaxis of LA effect
Decreased effect of LA Observed after central neuraxial and peripheral nerve blocks with different LA Mechanism not clear Interestingly, if dosing intervals are not short enough for pain to occur, tachyphylaxis is avoided

Local Anesthetics ~ PHARMACOKINETICS ~

ABSORPTION
LA generally have good absorption from mucous membranes and intradermal injection sites. (into tissues) Systemic absorption terminates local action (out of tissues). (Not local metabolism!!!)

Local Anesthetics ~ PHARMACOKINETICS ~

ABSORPTION
Factors influencing peak PLASMA concentration:
Site of injection (vascularity) Total dose Specific drug characteristics
tendency to produce vasodilation

Presence of vasoconstrictor (e.g., epinephrine, phenylephrine)

Local Anesthetics ~ PHARMACOKINETICS ~

ABSORPTION
Effects of vasoconstrictors Decrease rate of systemic absorption and decrease systemic toxicity
Increase local drug concentration and increase neuronal uptake of LA Increase local duration of action (e.g. lidocaines duration my increase two fold with epi) Epinephrine or alpha 2 agonists may enhance and prolong spinal anesthesia by acting on alpha 2 receptors to reduce substance P release

Local Anesthetics ~ PHARMACOKINETICS ~

ABSORPTION
Potential adverse effects of vasoconstrictors
DONT use in areas of toes, fingers, ear lobes, penis (ischemia) May produce tissue necrosis May produce systemic toxicity (cardiovasc)

Local Anesthetics ~ PHARMACOKINETICS ~

DISTRIBUTION
LA can be widely distributed to all parts of the body including CNS Distribution is a means of terminating local drug action ........ not metabolism!!

Local Anesthetics ~ PHARMACOKINETICS ~

METABOLISM
Ester type LA
Hydrolysis by cholinesterase in plasma to PABA derivatives
pseudo cholinesterase or butrylcholinesterase

Generally, short acting and low systemic toxicity** Prolonged effects seen with genetically determined deficiency or altered esterase (cholinesterase inhibitors)

Local Anesthetics ~ PHARMACOKINETICS ~

METABOLISM
Amide type LA
Hydrolyzed by liver microsomal enzymes (P450) Longer acting & more systemic toxicity than esters

Caution with severely compromised hepatic function

Comparison of LA characteristics
Relative lipid solubility procaine Relative potency onset pKa Local duration vasodilation Plasma protein binding

slow

8.9

short

+++

5%

lidocaine

rapid

7.9

moderate

+++

55%

tetracaine

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

Local Anesthetics Systemic Effects (toxicities)

Extensions of pharmacological action
Primarily related to blocking sodium channels

Intensity is dependent on blood levels Toxic levels of LA in blood will not occur if absorption (into systemic blood) is slow or metabolism is rapid

Local Anesthetics Systemic Effects (toxicities)

CNS (More sensitive than cardio)
Dose-related spectrum of effects and All effects are due to depression of neurons First an apparent CNS stimulation (convulsions
most serious) Followed by CNS depression (death due to respir depression) Premonitory signs include: ringing in ears, metalic taste, numbness around lips

Cocaine - euphoria (unique in its ability to stimulate CNS) Lidocaine - sedation even at non-toxic doses

Local Anesthetics Systemic Effects (toxicities)

Cardiovascular System
HYPOTENSION: Arteriolar dilation is a result of: Direct effect (procaine and lidocaine have most effect) Block of postganglionic sympathetic fiber function CNS depression Avoid by adding vasoconstrictor to prep
Note: cocaine is exception: produces vasoconstriction, blocks NE reuptake

Local Anesthetics Systemic Effects (toxicities)

Cardiovascular System
ARRHYTHMIAS: direct effect (More resistant than CNS)
Decrease cardioexcitability and contractility Decreased conduction rate Increased refractory rate (bupivicaine) Note: cocaine is exception......it stimulates heart ALL can cause arrhythmias if conc. is high enough

Local Anesthetics Systemic Effects (toxicities)

Methemoglobinemia
Some LA metabolites have significant oxidizing properties This may cause a significant conversion of hemoglobin to methemoglobin and compromize ability to carry oxygen May be a problem if cardiopulmonary reserve is limited Treat with oxygen and methylene blue (converts methemoglobin to hemoglobin)
prilocaine benzocaine lidocaine have been implicated

Local Anesthetics Systemic Effects (toxicities)

ALLERGIC REACTIONS ... fairly rare
Mostly with ester types; rarely amides (procaine) esters metabolized to PABA which has allergenic properties Cross-sensitivity within same chemical class of LA
Anaphylactic reactions are rare ..... diphenhydramine can be used to control minor reactions. The preservative paraban in multidose vials may be responsible for some allergic phenomenon

Local Anesthetics Systemic Effects (toxicities)

NEUROTOXICITY
LA can cause concentration-dependent nerve damage to central and peripheral NS Mechanism(s) not clear Permanent neurological injury is rare May account for transient neurological symptoms after spinal anesthesia
Cauda equina syndrome

Local Anesthetics ~ the drugs ~

1. Lots of drugs
No real qualitative differences

2. TIs are similar 3. Special side effects and kinetic differences

Local anesthetics

The esters

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

ESTER - type LA

Cocaine (Schedule II substance)

Medical use limited to surface or topical anesthesia (corneal or nasopharyngeal)
Avoid epinephrine because cocaine already has vasoconstrictor properties. (EXCEPTION!!!) A toxic action on heart may induce rapid and lethal cardiac failure. A marked pyrexia is associated with cocaine overdose.

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

ESTER - type LA

Benzocaine (Americaine)

pKa ~ 3, essentially all non-ionized.... mechanism may be non-specific Available in many OTC preps for relief of pain and irritation for surface anesthesia (topical) only ... ointments, sprays, etc. Used to produce anesthesia of mucous membranes and to suppress gag reflex during endoscopy methemoglobinemia

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

ESTER - type LA

Procaine (Novocaine)
Topically ineffective Used for infiltration because of low potency and short duration but most commonly used for spinal anesthesia Short local duration ......produces significant vasodilation. Epinephrine used to prolong effect systemic toxicity negligible because rapidly destroyed in plasma

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

ESTER - type LA

Tetracaine (Pentocaine)
topical, infiltration and spinal anesthesia
Frequently used for topical ophthalomogical anesthesia

slow onset and more prolonged effect than procaine (longest duration of the esters) ~10X more toxic and more potent than procaine

Local anesthetics

The AMIDES

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

AMIDE - type LA

LIDOCAINE (Xylocaine) Most widely used LA

Effective by all routes. Faster onset, more intense, longer lasting, than procaine. Good alternative for those allergic to ester type More potent than procaine but about equal toxicity More sedative than others

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

AMIDE - type LA

Mepivicaine (Carbocaine)
Effective by all routes except topical
Similar onset and duration as lidocaine More toxic to neonates so not used in obstetrical anesthesia (fetus poorly metabolizes
mepivicaine)

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

AMIDE - type LA

Bupivacaine (Marcaine)
No topical effect Slower onset and one of longer duration agents Unique property of sensory and motor dissociation can provide sensory analgesia with minimal motor block
has been popular drug for analgesia during labor

More cardiotoxic than other LA

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

AMIDE - type LA

Ropivacaine
Enantiomer of bupivacaine (S stereoisomer) No topical effectiveness Clinically ~ equivalent to bupivacaine Similar sensory versus motor selectivity as bupivacaine with significantly less CV toxicity (allegedly)

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME

AMIDE - type LA

Prilocaine
Similar clinical profile to that of lidocaine Does cause significantly less vasodilation than lidocaine
Less vasoconstrictor need be added

Most popular clinical application is for topical anesthesia as in combo with lidocaine in a eutectic mixture Because of rapid systemic metabolism considered least toxic of amide LA

Combination product EMLA

EMLA = eutectic mixture of local anesthetics
Eutectic = two solid substances mixed together in equal quanitites by weight form a eutectic mixture the melting point of the mixture is lower than the melting points of the individual components

EMLA = lidocaine and prilocaine becomes an oily mixture

EMLA
lidocaine/prilocaine combination is indicated for dermal anaesthesia
Specifically it is applied to prevent pain associated with intravenous catheter insertion, blood sampling, superficial surgical procedures; and topical anaesthesia of leg ulcers for cleansing or debridement it can also be used to numb the skin before tattooing. EMLA cream is also used in the treatment of premature ejaculation It is applied 20 minutes prior to sex

Other drugs with LA activity

A few drugs not generally used for local anesthesia have LA effects May be substituted if patient is allergic to both esters and amide types.
propranolol diphenhydramine chlorpromazine corticosteroids

Local anesthetics THINGS TO REMEMBER

Give smallest volume and dose Make injections slowly to avoid inadvertent IV

Have drugs available to manage adverse effects

Dont take food or liquids < 60 minutes after oral topical application .... gag, swallow, cough reflexes may be not working

Local anesthetics FOR YOUR INFORMATION

Description of administration of LA and examples of LA often used

Sites of LA administration

CLINICAL APPLICATIONS
SURFACE ANESTHESIA (Topical)
Nose, mouth, bronchial tree, cornea and urinary tracts
Lidocaine, tetracaine

Clinical Applications
INFILTRATION ANESTHESIA
Direct injection into tissues to reach nerve branches and terminals. Used in minor surgery. Immediate onset with variable duration.

Most LAs used

Clinical Applications
NERVE BLOCK or FIELD BLOCK
Interruption of nerve conduction upon injection into the region of nerve plexus or trunk. Used for surgery, dentistry, analgesia. Less anesthetic needed than for infiltration

Most LAs used

Clinical Applications
SPINAL ANESTHESIA
Injection into subarachnoid space below level of L2 vertebra to produce effect in spinal roots and spinal cord. Use hyperbaric or hypobaric solutions depending on area of blockade. Used for surgery to abdomen, pelvis or leg when cant use general anesthesia.
Lidocaine, tetracaine

Spinal Anesthesia PROBLEMS

Spinal headache due to increased CSF Hypotension and bradycardia, respiratory depression

Spinal anesthesia ADVANTAGES OVER EPIDURAL

greater predictability faster onset shorter duration

Clinical Applications
EPIDURAL AND CAUDAL ANESTHESIA
Injection into epidural space usually at lumbar or sacral levels. Used like spinal and also painless childbirth. Unwanted effects similar to that of spinal except less likely because longitudinal spread is reduced.
Lidocaine, bupivacaine, ropivacaine