Regional Anesthesia, History And Pharmacology

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1855- Cocaine was isolated from the coca plant.

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Same yr. needle and syringe 1st used for hypodermic med

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Heinrick Quinke

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1891
performed a lumbar puncture for hydrocephalus.

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1898

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August Bier, administered spinal anesthetic using 3 ml of 0.5% cocaine intrathecally for surgical anesthesia & published his results

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1904-

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Alfred Einhorn, synthesized Procaine (Novacaine) (big deal, this is when LA anes really starts)

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1940’s

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Lofgren and Lundquist introduce Lidocaine!!

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Today’s local anesthetics are descendents of cocaine which is:

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Poorly H2O soluble
Weak base
Benzoic acid derivative joined by an ester linkage to a tertiary amine

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Hydrophilic chain
Lipophilic portion

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Hydrophilic chain (tertiary amine
Lipophilic portion (aromatic ring)
By
An ester or amide linkage (hydrocarbon chain)

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HOW ARE LA COMMERCIALLY PREPARED?

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Commercially prepared as H2O soluble HCL salts
Thus, making them acidic with pH range of 4-7
This acidity is important for 2 reasons:
At this pH they are highly ionized, it is this portion that is H2O soluble
Epi (if added) needs an acidic pH as it is unstable in alkaline environments
NaHCO3 is often added to HASTEN onset

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The specific receptor for the LA’s is the

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Na channel (test question)

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Mechanism of action

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base form (unionized) diffuses across the nerve membrane
Once in the axoplasm; the base and the cationic (ionized) form “re”equilibrate

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It is believed that

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More affinity for LA’s in open and inactivated state than resting state
The base form keeps the Na channel in a closed inactive state
The ionized form sneaks in after an action potential has passed (and Na channels are open) attaches to a receptor site inside the Na channel and blocks it

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Cm: “minimum concentration

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The minimum amount of drug needed to produce a block
Influenced by:
Potency of local anesthetic
Nerve diameter
Myelination or lack of myelination
“frequency dependent blockade priniciple”
Position of nerve in nerve bundle

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To successfully block myelinated fibers;

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LA’s must generally inhibit 3 successive nodes of ranvier

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Unmyelinated fibers

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Usually conduct more slowly
Often relatively resistant to LA’s despite smaller size
Na channels more dispersed throughout membrane

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Frequency dependent blockade” or “Use dependence”

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The more action potentials that occur the more likely the local will encounter the Na channel in the open or inactive state
Because of the “dual action” of the locals, working in the un and ionized form

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“Locals will block smaller fibers at lower concentrations than are required

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by larger fibers of same type”
BUT….
As a group unmyelinated fibers are more resistant to LA’s compared with some larger myelinated fibers

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A fibers

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motor efferent conduction

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A-alpha

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innervate skeletal muscle motor/proprioception

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A-beta

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sensations of touch/pressure

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A-gamma

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skeletal muscles for muscle tone

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A-delta

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sensations of pain (1st;fast), temp., touch
A fibers are all myelinated

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B-fibers

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PREganglionic autonomic nerve fibers
Myelinated, frequently firing (bat out of hell) B fibers
The B fibers being blocked first explains why your sympathetic block is higher than your sensory.

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C-fibers

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pain (slow) or 2nd pain, reflex responses, POSTganglionic autonomic (chronic pain, visceral pain, etc. )
Unmyelinated, small fibers

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Nerve block recovery

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A-alpha
A-beta
A-gamma
C and A-delta
Beta (B fibers)
*OPPOSITE OF HOW THEY BLOCK

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S T P T P M V P

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Sympathetic (b fibers)
Temperature
Pain (A delta and C fibers)
Touch
Pressure
Motor
Vibration
Proprioception

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Lipid solubility
Related to potency

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Protein binding
Related to duration of action

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PKa
Related to onset

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All current clinically used locals have PKa’s higher than body pH
So less nonionized fraction at normal body pH
A lower PKa will give you more nonionized drug
Less than 50% of every LA we use is in the unionized form. A lower pKa will give you more unionized form.

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pKa & onset time

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The pH of the tissue becomes relevant in conditions of infection or inflammation, in which the pH may be more acidic. This acidity results in a greater proportion of the ionized (charged) form of the anesthetic, thereby delaying or preventing the onset of action.

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Epinephrine

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Now also thought to exert presynaptic adrenergic receptor activity that contributes to analgesia (specifically alpha 2)

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Dual mechanism, both forms have functions and mechanism of actions

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the unionized form blocks the channel, just not by binding. The ionized form binds to the alpha subunit, and blocks the channel. Primary reason to add epi is that it adds to the duration of action. Now they believe that the epi also helps to block the transmission of pain as well. Epinephrine makes it more acidic and increases the shelf life. The max with these is more because less is taken up in the blood over time, so it won’t be toxic with the higher dose

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Sodium Bicarbonate

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Used clinically to HASTEN onset of block
Increases amount of “nonionized” form available to cross membrane
Inconsistent (more effective with epi containing locals)
May see more effect with epinephrine containing locals

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Opioids

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Used with central blocks
Improves perioperative analgesia (and post op)
Opiods also improve the sensory block with the locals.

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Alpha-2 adrenergic agonists
Most commonly clonidine

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Enhances analgesia WITHOUT OPIOID SIDE EFFECT PROFILE Binds to a-2 receptors on primary AFFERENT fibers and SEVERAL BRAINSTEM NUCLEI Increases AcH and norepi in CSF and inhibits release of several neurotransmitters (that are responsible for nociception)

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Absorption of locals is dependent on many factors
Injection site:
Tissue blood flow: More vascular/ incr. absorption

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I'm In Trouble Cause Every Booty Smells Stinky
IV > Intercostal > trachael > caudal/paracervical > epidural > brachial plexus > spinal > sub Q
*****presence of epi will decrease absorption

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LIDOCAINE METABOLITE

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Has active metabolite mono ethyl glycine xylidide
Remember with liver dx ^ toxicity

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PRILOCAINE METABOLITE

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Metabolite ortho toluidine
Converts Hgb to meth Hgb
Tx?? Methemoglobinemia, methylene blue 1-2 mg/kg

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Toxicity

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Locals readily cross the BBB
CNS toxicity can occur with direct IV injection or systemic absorption
S/S dose dependent
Vertigo/Lightheadedness
“Tinnitus” Visual/auditory disturbances
Circumoral numbness (numbness funny taste in mouth)
Ominous feelings
Muscle twitching
Convulsions
unconsciousness
Coma
Resp collapse
CV collapse

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Prevention and treatment of toxicity:

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Choice of appropriate drug/dose
Frequent aspiration from catheter (epid)
Small “test doses”
Checking for systemic effects (talk to the patient)
Monitors
Slow injection

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TREATMENT FOR LA TOXICITY

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Dependent on severity
Stop injection
Know s/s
Minor rx’s may be allowed to spont terminate (example would be a bier block letting the cuff down close to 20min)
Maintain patent airway/O2 (ABC’s)
barbs/benzo’s
Tx CV s/s
Initially excitation
Tachy, hypertension (doesn’t last long)  collapse follows
Followed by depression
Decr CO, hypotension
Fluids, phenylephrine, ephedrine, norepi
Cardiac arrest
Amiodarone, vasopressin (in place of) vs. epi and lidocaine
Increased resuscitation time

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LIPID RESCUE PROTOCOL

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Administer 1.5 mL/kg as an initial bolus; the bolus can be repeated 1- 2 times for persistent asystole.
Start an infusion at 0.25 mL/kg/min for 30-60 minutes; increase infusion rate up to 0.50 mL/kg/min for refractory hypotension

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TOXIC LEVEL OF LIDO

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4mcg/ml (serum level of lido)
Tongue numbness, lightheadedness

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Pseudocholinesterase is

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an enzyme produced by the liver and circulates in the plasma. (liver dx may have problems metabolizing both kinds of locals)

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Ester local anesthetics are derivatives of

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benzoic acid.
Para-aminobenzoic acid (PABA) is a metabolic end product of ester local anesthetics.

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WHAT DOES DIBUCAINE DO?

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depresses the activity of pseudocholinesterase. (test question
Very potent, 15 times as toxic as procaine. (Not used in clinical practice)

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If pseudocholinesterase is normal
HETEROZYGOTE
HOMOZYGOTE ATYPICAL

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Dibucaine will depress it 80%- Dibucaine is 80 or 80% depr40% depressed. (20-40min block)
essed.
2 abnormal genes)= 20% depressed

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Dibucaine number

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percentage of inhibition of pseudocholinesterase.

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Methemoglobinemia

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Prilocaine may induce methemoglobinemia.
O-toluidine is a metabolite of liver metabolism of prilocaine which may cause methemoglobinemia.
Normal hemoglobin has iron in the ferrous state (Fe++) Met-Hb has iron in the ferric state (Fe+++) O2 carrying capability is poor. Tx. Methylene blue 1-2mg/kg over 5 minutes. (patients become hypoxic)

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Parabens are

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cytotoxic – do not use for spinal , epidural or intravenous regional anesthesia. (toxic to the nerves)
Needs to say Methylparaben Free or MPF or PF

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CV EFFECTS OF LA

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Generally depressant (exception cocaine)
Cardiac Na channel blockade
Inhibition of ANS

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RESPIRATORY EFFECTS OF LA

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Lidocaine depresses hypoxic drive
Relax bronchial smooth muscle (IV)
Apnea from phrenic nerve paralysis (this does not happen unless the level is high or they are hypotensive)

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NEURO EFFECTS FROM LA

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Lidocaine (IV) decreases cerebral blood flow
Attenuates the rise in ICP from laryngoscopy
IV can reduce MAC up to 40%
Cocaine stimulates CNS
Neurotoxicity
Chloroprocaine (associated) no spinal (preservatives)
Lidocaine 5% (cauda equina usually permanent)
Continuous subarachnoid, lithotomy, ischemia
TNS (transient neurologic symptoms)
Lido, litho, obesity, parasthesia

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IMMUNOLOGIC EFFECTS FROM LA

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Rare allergic rx
Uncommon to local
Usually preservative or rx to epi

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MUSCULOSKELETAL EFFECTS FROM LA

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Myonecrosis with direct injection

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HEMATOLOGIC EFFECTS FROM LA

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Decrease coagulation
Enhance fibrinolysis