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M&M Chapter 14

Local AnestheticsOctober 18, 2010

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Theories of Local Anesthetic Action

Most local anesthetics block voltage-gated

Na+ channels preventing subsequentchannel activation and interfering with large

Na+ influx that causes membrane

depolarization.

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Theories of Local Anesthetic Action As channels are blocked impulse

conduction slows, magnitude of action

potential decreases, threshold for excitationis increased until.

Action potential can no longer be generated

Impulse propagation is abolished

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Structure Activity Relationships As a general rule of thumb, the greater the

diameter of the nerve fiber, the greater the

concentration of LA

required to produceconduction blockade. Small unmyelinated fibers

are more vunerable to blockade than large

myelinated fibres.

There is a progressive loss of function, forexample with epidural anaesthesia, as the dose of

the LA is increased in the following order:

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Type of nerve Function Effect

C Pain &Temperature

B Pre-Ganglionic

Autonomic

Warm limb

A-delta Pain &Temperature

Loss of painsensation

A-gamma Proprioception Loss

A-beta Touch and

pressure

Loss

A-alpha Motor Paralysis

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Structure Activity Relationships Typical structure of LA consists of a

hydrophillic=lipophobic group (tertiary

amine) separated from a hydrophobic =lipophillic group (benzene ring) by a an

intermediate chain that includes either an

ester or amide linkage

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Structure Activity Relationships LAs are usually weak bases that carry a

positive charge at the tertiary amine group

at physiological pH

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Structure Activity Relationships Potency correlates with lipid solubility the

ability of the local anesthetic molecule to

penetrate hydrophobic membranes Highly lipid soluble drugs readily cross

membranes, the higher lipid partition

coefficient, the more potent and longerDOA of the drug eg. Prilocaine 0.9,

Lignocaine 2.9, Bupivicaine 28.

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Structure Activity Relationships The pKa is the pH at which the drug is 50% ionized and 50%

unionized. Ionized drugs are poorly lipid soluble (e.g.morphine compared to fentanyl - the former has a muchslower time of onset of action).

The closer the pKa is to local tissue pH (usually 7.4), themore unionized the drug is, or, the higher the pKa, the moreionized. Because all local anaesthetics are weak bases,those with a pKa near physiological pH (7.4) will have moremolecules in the unionized lipid soluble form (e.g. lignocaine)-> more rapid onset of action.

Importance: lower pKa -> better absorption into nerve tissue

higher pKa -> more effective blockade within nerve

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Structure Activity Relationships Onset of action depends on many factors,

including lipid solubility and the relative

concentration of non-ionized lipid-solubleform (B) and the ionized water-soluble form(BH+). LAs pass through nerve membranein B form then when they are within the

nerve axoplasm they equilibrate into anionic form that is active within the Na+channel

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Structure Activity Relationships LAs with pKa closest to physiological pH

will have a higher concentration of non-

ionized base that can pass through thenerve cell membrane and generally a more

rapid onset.

True in isolated nerves but not always in vivo

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Structure Activity Relationships LAs are produced as water-soluble

hydrochloride salts (pH 6-7). Because

epinephrine is unstable in alkalineenvironments, epi-containing solutions are

made even more acidic (pH 4-5) so have

less free base and therefore have slower

onset of action. Why add epi at time of

administration.

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Structure Activity Relationships Extracellular base to cation ratio is

decreased by infection and onset is

delayed or otherwise impaired wheninjected into acidic (infected) tissues.

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Structure Activity Relationships The more highly protein bound the drug,

the longer the duration of action. More

highly bound drugs probably bind for longerto neuronal membrane proteins. The

protein probably provides a depot for

maintenance of neural blockade.

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Structure Activity Relationships -

Esters Procaine, Chloroprocaine, Tetracaine,

Cocaine

Undergo hydrolysis by pseudocholinesterasesfound in plasma

pKa is usually >8

A significant metabolite PABA can cause allergic

reaction

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Structure Activity Relationships -

Amides Lidocaine, Bupivacaine, Mepivacaine,

Etidocaine, Ropivacaine

They undergo metabolism by hepatic microsomalenzymes

The pKa is usually < 8

May contain antibacterial preservative

(methylparaben)

Allergic reactions less common

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Clinical Pharmacology - Absorption Rate of systemic absorption is

proportionate to the vascularity of the site

of injection as well as the presence ofvasoconstrictors

Intravenous > Tracheal > Intercostal >

Caudal > Paracervical > Epidural >

Brachial Plexus > Sciatic > Subcutaneous

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Clinical Pharmacology - Absorption Epinephrine causes vasoconstriction at the

site of administration@ decreased

absorption increases neuronal uptake,enhances quality of analgesia, prolongs

duration of action, and limits toxic side

effects

More pronounced effect with shorter acting

agents

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Clinical Pharmacology - Distribution Tissue Perfusion Highly perfused organs

(brain, lung, liver, kidney, and heart) are

responsible for the initial rapid uptake(alpha phase) which is followed by slower

redistribution (Beta phase) to moderately

perfused tissues (muscle, gut)

Lungs extract significant amount of LA

why threshold for tox

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Clinical Pharmacology - Distribution Tissue/blood partition coefficient strong

plasma binding tends to retain anesthetic in

blood whereas high lipid solubility facilitatestissue uptake

Tissue mass Muscle provides the

greatest reservoir for local anesthetic

agents because of its large mass

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Metabolism and Excretion Esters metabolized by plasmacholinesterases

Hydrolysis very rapid and metabolites excreted in

the urine CSF lacks esterase enzymes so termination of

action depends on absorption into blood stream

Pts with genetically abnormal

pseudocholinesterase are at increased risk oftoxic effects

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Metabolism and Excretion Amides metabolized by microsomal P-

450 enzymes in the liver

Rate of metabolism is agent specific andslower than ester hydrolysis

Decreased hepatic function (Cirrhosis) or

blood flow (C

HF) predispose to systemictoxicity

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Metabolism and Excretion Prilocaine, Benzocaine can lead to

methemoglobinemia

Tx with Methylene blue reducesmethemoglobin (Fe3+) to Hemoglobin

(Fe2+)

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Effects on OrganS

ystems Mixtures of local anesthetics should be

considered to have roughly additive side

effects. A solution containing 50% of thetoxic dose of lidocaine and 50% of the toxic

dose of bupivacaine will have roughly

100% of the toxic effects of either drug

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Effects on Organ Systems

Neurological Particularly vulnerable to LA toxicity and is the site

of premonitory signs of overdose in awake

patients

Early symptoms - circumoral numbness, tongue

paresthesia

Sensory complaints dizziness, tinnitus

blurred vision

Excitatory signs restlesness, agitation, nervousness,paranoia often precede cns depression slurred

speech, drowsiness, unconciousness

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Effects on Organ Systems

Neurological Muscle twitching heralds the onset of tonic-clonic

seizures. Respiratory arrest often follows

Excitatory reactions are the result of selectiveinhibition of inhibitory pathways

Benzodiazepines and hyperventilation decrease

cerebral blood flow, and drug exposure raising the

threshold for anesthetic-induced seizures

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Effects on Organ Systems

Respiratory Lidocaine depresses hypoxic drive (ventilatory

response to low PaO2)

Apnea from phrenic and/or intercostal nerveparalysis or direct contact of LA with medullary

respiratory center

IV lidocaine may be effective in blocking reflex

bronchoconstriction sometimes associated withintubation, but aerosolize lidocaine can lead to

bronchospasm in pts with RAD

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Effects on Organ Systems

Cardiovascular All local anesthetics depress myocardial

automaticity (spontaneous phase IV

depolarization) Myocardial contractility and conduction

velocity are also depressed at higher

concentrations. Due to cardiac Na+

channel blockade and inhibition of

autonomic nervous system

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Effects on Organ Systems

Cardiovascular R-isomer of bupivacaine avidly blocks

cardiac Na+ channels

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