Salute Vivamus 2023 | Central Philippine University | College of Medicine

Anesthesiology: S02L08
Local Anesthetics
Dr. Jenny Sisnorio-Chan| 05-17-2022 | T | 5:30-7:30 PM

OUTLINE  interest in identification of an alternative local anesthetic

I. Introduction X. Prevention of Toxicity has been generated
II. History XI. Clinical Applications  Cocaine`s systemic toxicity, its irritant properties when placed
III. 2 Types of Linkages A. Surface Anesthesia topically or around nerves, and however its substantial
A. Aminoesters B. Infiltration Anesthesia potential for physical and psychological dependence
B. Aminoamides C. Nerve Block generated interest in identification of an alternative local
IV. Mechanism of Action D. Spinal Anesthesia anesthetic.
V. Physicochemical E. Epidural and Caudal
Properties Anesthesia PROCAINE
VI. Physiochemical XII.Adverse Effects  First useful injectable local anesthetic
Properties XIII.Computations  Prototype esters
VII.Factors that Affect XIV. References
 Derived from aromatic acid and an amino acid alcohol
Potency XV. Appendix
 The first useful injectable local anesthetic, procaine, can be
VIII. Order of Blockade
considered the prototype on which all commonly used local
IX. Selective
anesthetics are based.
Pharmacological
Properties
A. Bupivacaine LIDOCAINE
B. Ropivacaine  Introduce in 1948
C. Lidocaine  Prototype amide
 Derived from an aromatic amine (xylidine) and an amino acid
I. INTRODUCTION  Amide bond
 Averts allergic reactions
 Drugs which produce a transient and reversible loss of  First amide with less allergies
sensation in a circumscribed region without loss of
consciousness LAS- WEAK BASES (PKA:7.5-9)

II. HISTORY

YEAR DRUG
3000 B.C. Cocaine  The first local
1905 Procaine anesthetic introduced
1932 Tetracaine into medical practice
Cocaine, was isolated
1943 Lidocaine from Coca leaves by
1957 Mepivacaine Albert Niemann in
1960 Prilocaine Germany in the 1860s
1963 Bupivacaine  The very first clinical
1972 Etidocaine use of Cocaine was
1884 by Sigmund
1996 Ropivacaine Figure 1. Structure of Local Anesthetics
Freud who used it to
wean a patient from
morphine addiction  Local anesthetics consist of a lipid soluble, aromatic
benzene ring linked to an amine group (tertiary or quaternary
 Freud had his
depending on pKa and pH) via either an amide or an ester
colleague Karl Kollar
linkage.
first noticed its
1999 Levobupivacaine anesthetic effect  This type of linkage separates the local anesthetics into either
and introduced it to aminoamides (metabolized in the liver) or aminoesters
clinical (metabolized by plasma cholinesterases)
ophthalmology as a
topical ocular III.TWO TYPES OF LINKAGES GIVE RISE TO
anesthetic 2 CHEMICAL CLASSES OF LOCAL
Table 1. History of Local Anesthetics
ANESTHETIC
COCAINE A. AMINOESTERS
 First local anesthetic (late 19th century)
 Promoted the feeling of well-being  C13H19CIN202.HCl
 Physical and psychological dependence  Procaine
  Procaine (Novocaine)
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  Tetracaine (Pontocaine)
 Benzocaine
 Cocaine
 Have a significant metabolite called PABA (P-aminobenzoic
acid) a known allergen, therefore not used nowadays.
A. AMINOAMIDES
 C14H22N20.HCl
 Lidocaine
 Lidocaine (Xylocaine)
 Mepivacaine (Carbocaine)
 Bupivacaine (Marcaine)
 Etidocaine (Duranest)
 Ropivacaine (Naropin)
IV. MECHANISM OF ACTION
 Block the transmission of action potential by inhibition of
voltage- gated sodium ion channels.
 Reversibly binding to and inactivating sodium channels
Figure 2. Membrane Potential.
 Under normal or resting circumstances, the neural membrane
is characterized by a negative potential of roughly -70 to -90
mV (the potential inside the nerve fiber is negative to the
extracellular fluid). This negative potential is created by active
outward transport of sodium and inward transport of potassium
ions, combined with a membrane that is relatively permeable to
potassium and relatively impermeable to sodium ions.
 With excitation of the nerve, there is an increase in the
membrane permeability to sodium ions, causing a decrease in
the transmembrane potential.
 If a critical potential is reached (threshold potential), there is
a rapid and self- sustaining influx of sodium ions resulting to
depolarization, after which the resting membrane potential is
reestablished
 Local anesthetics block the conduction of neural
transmission by decreasing the rate of depolarization in
response to excitation thus preventing achievement of
threshold potential.
 They do not alter the resting transmembrane potential and
have little effect on threshold potential.
 Since they are weak bases, they are present in unionized form,
so they enter cell membrane of neuron and block the voltage-
gated sodium channels by physically plugging the
transmembrane pore from inside. There will be no entry of
sodium ions into cell, therefore no depolarization.
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 Local anesthetic blocks the transmission of the action potential
by inhibition of voltage- gated sodium ion channel
 Variation of affinity by local anesthetics to sodium channels
o Open or activated state
o Inactivated state
o Resting states
 Ionized forms determine the action of local anesthetics
 Primary target of LA is the open state, bind more readily to
these channels; onset of neuronal blockage is faster in rapidly
firing neurons
 Local anesthetics bind to the activated and inactivated states
more readily than the resting state, attenuating conformation
change.
V. PHYSICOCHEMICAL PROPERTIES
LIPID SOLUBILITY
 Potency
 Potency reflects the ability of local anesthetic molecules to
permeate lipid membranes
 The more lipid soluble the drug is, the more potent it becomes
PROTEIN BINDING
 Duration of action
 Degree of binding also affects activity of local anesthetics, as
only the unbound form is free for pharmacologic activity.
 In general, the more lipid soluble and longer acting agents
have increased protein binding.
PKA (IONIZATION CONSTANT)
 Speed of onset
 Local Anesthetic with lower pH have more rapid onset of
action because more unchanged form result.
 pKa is the pH at which the fraction of ionized and nonionized
drug is equal.
 The pKa provides a useful way to describe the propensity of
local anesthetic to exist in a charged or an uncharged state.
 The lower the pKa, the greater is the percent of unionized
fraction at a given pH, this result to more rapid diffusion to the
cytoplasmic side of the Na channel therefore increase speed
of onset.
VI. PHYSIOCHEMICAL PROPERTIES
(VIVA)
NEUTRAL BASE
 Permits the penetration to the nerve membrane to gain
access to the receptor
 Lipid soluble
CHARGED FORM
 Responsible for predominant action of local anesthetics
 Highly hydrophilic
 Relatively incapable of penetrating the nerve membrane to
reach its site of action
 All clinically used local anesthetics are weak bases that can
exists as either lipid-soluble, neutral, or as the charged
hydrophilic form
 The combination of pH of the environment and pKa, or
dissociation constant, of a local anesthetic determines how
much of the compound exist in each form
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  More cardiotoxic than other local anesthetics

VII. FACTORS THAT AFFECT POTENCY B. ROPIVACAINE

HYDROPHOBICITY  Enantiomer of Bupivacaine (S stereoisomer)

 More lipid soluble, more potent
HYDROGEN ION BALANCE
 Decrease hydrogen ion, the more basic, the more rapid onset
of action (sodium bicarbonate)
VASOCONSTRICTOR/VASODILATOR PROPERTIES
 Vasoconstrictor added in local anesthetics: Epinephrine
 Affects the rate of vascular uptake
 Vasoconstrictive effects prolong the LA block, increases block
intensity and decreased systemic absorption of LA
FIBER SIZE, TYPE, AND MYELINATION
 The thicker the fiber, the faster it could be blocked/ myelinated
nerve fibers are easily blocked than non-myelinated.
 No topical effectiveness
 Clinically equivalent to Bupivacaine
 Similar sensory versus motor selectivity as Bupivacaine with
significantly less cardiovascular toxicity
C. LIDOCAINE (XYLOCAINE)
 Effective by all routes
 Faster onset, more intense, longer lasting
 Good alternative for those allergic to ester type
 More potent than procaine but about equal toxicity
 More sedative effect than others

FREQUENCY OF NERVE STIMULATION

PH
 acidic environment will antagonize the block (such as:
cellulitis in diabetic patient)

ELECTROLYTES CONCENTRATION
 Hypokalemia and hypercalcemia antagonize blockade

VIII. ORDER OF BLOCKADE

Figure 3. Systemic Toxicity of Local Anesthetics.
1. Autonomic (Sympathetic blockade: decrease BP. In the OR, we
monitor the BP frequently)  Table shows the dose dependent effects of local anesthetics
2. Pain  Toxicity involves the cardiovascular and CNS primarily
3. Temperature
4. Touch BLOOD
5. Deep Pressure LIDOCAINE
6. Motor SIGNS AND SYMPTOMS
LEVELS
(Recovery in Reverse Order) (ug/mL)
 Tinnitus
 Nerve fiber can be classified according to fiber diameter,  Lightheadedness
presence (type A and B) or absence (type c) of myelin, and 1-5  Circumoral numbness
function.  Diplopia
 Nerve fiber diameter influences conduction velocity: a larger  Metallic taste in the mouth
diameter correlates with a more rapid nerve conduction
 Nystagmus
 The presence of myelin also increases conduction velocity
 Slurred speech
 The observation that sensitivity to local anesthetics blockade 5-8
 Localized muscle twitching
is inversely related to nerve fiber diameter probably does not
reflect cause and effect.  Fine tremors
 Focal seizure activity
(See appendix, Table 2. Peripheral Nerve Fiber Classification) 8-12  May progress to tonic-clonic
seizures
IX. SELECTIVE PHARMACOLOGICAL  Respiratory depression which can
20-25
lead to coma
PROPERTIES  Cardiovascular depression
>25
 Irreversible
A. BUPIVACAINE (MARCAINE) Table 2. Signs and Symptoms of Lidocaine Toxicity

 No topical effectiveness  1-5 ug/ml plasma concentration, effect is only analgesia

 Slower onset and one of the 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
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 5-10 ug/ml plasma concentration, effect is circum-oral
numbness, tinnitus, skeletal muscle twitching, systemic
hypotension, and myocardial depression
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 10-15 ug/ml plasma concentration, effect is seizures and  Be cautious in patients with liver damage
unconsciousness  Cirrhotic patients have slow local anesthetic metabolism
 15-25 ug/ml plasma concentration, effect is apnea and coma which increases the risk of toxicity
 More than 25 ug/ml plasma concentration, effect is  Decreased clearance
cardiovascular depression  Amino-amides are metabolized in the liver
 CNS is the most affected, next is respiratory arrest, and  Amino-esters are metabolized by plasma cholinesterase
cardiovascular arrest  Proper site
 Systemic toxicity of local anesthetics results from excessive  Correct knowledge of nerve course
plasma concentrations of these drugs  Minimal effective dose usage
 Most often from accidental intravascular injection during  Avoid IV administration
performance of peripheral nerve blocks  Wait after injection
 Wait for reactions
LIDOCAINE TOXICITY (SAMS)  Give it in increments
 S – Slurred or difficult speech  Observe the face for any twitching, excitement, and pulse for
 Paresthesia tachycardia
 Numbness of lips/tongue  Observe post-op for allergic reactions
 A – Altered Central Nervous System  Avoid food intake at least 4 hours prior to anesthesia to
 Drowsiness prevent vomiting
 Dizziness
 Arrythmias XI. CLINICAL APPLICATIONS (VIVA)
 Restlessness
 Confusion A. SURFACE ANESTHESIA (TOPICAL)
 M – Muscle twitching
 Tremors  Ear, nose, mouth, bronchial tree, nasopharynx, cornea, GIT
 S – Seizures and urinary tracts
 Convulsions  Lidocaine, Tetracaine, Benzocaine
 Respiratory depression  EMLA cream (Eutectic Mixture of Local Anesthetics)
 Respiratory and cardiac arrest o Lidocaine 2.5% + prilocaine 2.5% permits anesthetic
penetration of keratinized layer of skin as deep as 5mm
producing localized numbness

B. INFILTRATION ANESTHESIA

 Direct injection into tissues to reach nerve branches and

terminals
 Can be superficial as well as deep
 Used in minor surgery
 Immediate onset with variable duration
 This type involves skin region as deep as intraabdominal
tissue

C. NERVE BLOCK OR FIELD BLOCK

 Interruption of nerve conduction upon injection into the region

of nerve plexus or trunk
 Used for surgery, dentistry, analgesia
 Given with specific nerve area such as brachial plexus, within
intercostal nerves, abdominal nerves are targeted, cervical
plexus when neck region is targeted

D. SPINAL ANESTHESIA

 Injection into subarachnoid space below level of L2 vertebra

Figure 4. Compendium of Regional Anesthesia: Symptoms, diagnosis, and
treatment of local anesthetic systemic toxicity infographic.
X. PREVENTION OF TOXICITY
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 can’t use
general anesthesia

 Inquire about history of allergy E. EPIDURAL AND CAUDAL ANESTHESIA

 Amino-amides are commonly used now not amino-esters
because of the allergy history  Injection into epidural space usually at lumbar or sacral levels
 Caution in presence of liver/ myocardial damage or near dura matter where nearly most nerves pass closely

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 Lower part of the body
 For painless childbirth

XII. ADVERSE EFFECTS (VIVA)

 LAST- Local Anesthetic Systemic Toxicity
 CNS (1st stimulation, then depression)
 Local Neurotoxicity (cauda equina syndrome associated with
continuous spinal anesthesia- CSA)
 CVS (Bupivacaine as the most cardiotoxic)
 Motor paralysis
 Hematological effects
 Hypersensitivity reactions

XIII. COMPUTATION FOR LOCAL

ANESTHETICS
 Recommended dose:
 Lidocaine: 5mg/kg (2%- 0.02 in 20ml)
 Lidocaine + Epinephrine: 7mg/kg
o Vasoconstrictor to increase seizure threshold of patient
to prevent LAST
 Sample computation
 Lidocaine ONLY
 Patient 20 kgs, maximum dose is 5ml
o 20kgs x 5mg/kg = 100mg
o Lidocaine preparation: 2% (20mg/mL)/ 50mL
 100 mg divided by 20mg/mL = 5ml (Maximum)
 In cases of peripheral wound sutures, long laceration, or big
wounds:
 Stick with Lidocaine but lower the concentration to 1% by
adding 5ml NSS to the solution
 Lidocaine as low as 0.5-1% is still effective
 You can increase it to 7 mg/kg but need to add
epinephrine with it.

XIV. REFERENCES
 Dr. Jenny Sisnorio-Chan’s Lecture Recordings and
PowerPoint Presentation
 VIVA Trans

XV. APPENDIX

FIBER MYELINATION CONDUCTION LA SENSITIVITY

FUNCTION DIAMETER
TYPE VELOCITY
Largest Fastest
Aα Motor, proprioception ↓
↓ Yes +
Aβ Touch, pressure, proprioception ↓ Yes ↓ ++
Aγ Muscle spindle ↓ Yes ↓ ++
Aẟ Pain, touch, temperature ↓ Yes ↓ +++
B Preganglionic autonomic ↓ Yes ↓ ++++
Pain, temperature, postganglionic ↓ No ↓ +++
C
sympathetic Smallest Slowest
Table 3. Peripheral Nerve Fiber Classification

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