Local anesthetics

Neuroaxial

Signal epidural and paravertebral anesthesia

Plexus block

Brachial and lumbar plexus

Peripheral nerve blocks

Dental, peripheral nerves, biers block

Facial plane blocks

Rectum, TAP

Other modern clinical applications

Airway topicalization, subcutaneous, IV infusion- ultrasound guided placement has been a game changer

Examples of ester local anesthetic

Cocaine, procaine

Examples of amide local anesthetic

Lidocaine, bupivacaine

Ionization

Have cationic and uncharged form

Use H-H equation to find ratio

Local anesthetics are weak base

Henderson-hasselbach equation

Log(cationic/uncharged)=pKa-pH

PH in plasma is 7.4 but can say 7 so simplicity sake

Increased pKa means less uncharged molecules available

Mechanism of action of LA

Interact it’s Na channels, increase threshold for depolarization, block conduction

-Unionized LA passes through phospholipid membrane, re-ionises and enters Na channel from inside, access to receptor enable by activation/opening of channel

Are LA always active?

No use-dependant, more active the nerve is the faster the block develops

Chirality

R vs S, R bupicacaine is more readily available to cardiac cells=more cardiotoxic=heartattack

Ropivacaine as well

What type of salts are LA

Water soluble salts of lipid soluble alkaloids

Lipid solubilty

Increasing length/quantitiy of hydrocarbons increases Lipophilicity

Larger more lipophilic LA permeate nerve membranes more readily and bind to Na channels with greater affinity

Protein binding

Bind to alph1-acid glycoprotein and albumin

More lipid soluble=more protein binding=longer duration of action

When do we see decreased binding? What is the effect

Hypoxia, hypercarbia, acidemia, younger than 6 months

Increased bioavailibility and toxicity

What is the pKa

pH at which the ionized and un-ionized forms are present in equal amounts

Rate of diffusion is related to the proportion of non-ionized drugs

low pKa=fast on set

What is the pKa of lidocaine? And bupivacaine

7.8, 8.1

PH change in inflamed tissue

More acidic- more ionized form of basic drugs

Why/when is bicarbonate used?

Raises pH, increase speed of onset of epidural anaesthesia

PKa of mepivacaine, procaine

8, 9

Can we give LA to septic patients

No, looks of inflamed and infected tissue- lower pH meaning more ionized drug=toxicity

What are the three main parameters and what affects them?

-Speed of onset: pKa and molecular weight

-Potency: lipid solubility

-Duration: protein binding (linked to lipid solubility)

What affects absorption

Site, rate (pressure), dose, vasoactivity of injectate(add epi)

Order of peak plasma concentration after a single dose

intrapleural>intercostal>lumbar epidural>brachial plexus>subcutaneous

Why would we add a vasoconstrictor (adrenaline)

-Limit systemic absorption

-Increas [LA] at some of actions

-Counteract tendency for LA to vasodilate (not needed for cocaine)

When would we not give a vasoconstrictor with LA?

ready ischemic distal appendages

Fingers, penis

Distribution of esters vs amide

Esters are less protein bound, alpha-1-acid glycoprotein has higher binding affinity but there is a lot more albumin so more is found bound to albumin

Metabolism of esters

Hydrolyzed rapidly by plasma cholinesterases to para-aminobenzoic acid (PABA)

Shower half life, prolonged with abnormal enzyme activity

PABA is known to cause allergic reactions

What is the exception to ester metabolism

Cocaine

Hepatic hydrolysis then renal excretion

Rapidly metabolized in the circulation by cholinesterases

Metabolism of amides

Aromatic hydroxyation, amide hydrolysis, N-dealkylation

Much slower process-higher accumulation in hepatic dysfunction (or reduced blood flo in post-op phase

Lower allergic reaction

Tachycardia at injection can be mistaken for an allergic reaction

Nerve fiber susceptibility

Small,unmyelinated are faster (C fibers)

C-fibers and A-gama are both involved in pain

Fire more=more effect

Broad spikes are active longer therefore more effect

how do we dissolve LA

1g in 100 mg so 2%=20mg/ml

What is the lowest safe dose and highest safe dose

Bupibacaine/ropivacaine- 3 mg/kg

Chloroprocaine- 12mg/kg

What two LA increase in the maximum safe dose when used with epinephrine

Lidocaine, mepivacaine

Intralipid rescue

Injecting intralipid to increased binding of drugs and lowering free concentration