Eisenberg – Local Anesthetics – NS Exam 2
Introduction to use:
General uses
 agents produce loss of pain sensation in a localized area
o -For surgery or manipulation
o -Diagnosis, obstetrics & other localized trauma
 nerve conduction is blocked by direct application to axon
 action involves sodium channel blockade & blockade of axonal
conduction
 effect is completely reversible
Properties of local anesthetics
 diffusion and absorption occur when the drug is in the un-ionized form
 activity in the axoplasm occurs when the drug is in the ionized form
 degradation occurs only after tissue metabolism or absorption into the
circulation
 vasoconstrictors may be required to increase duration of action
 threshold for excitation is elevated - conduction is impaired or blocked (more
you give, the more conduction is blocked)
 high frequency nerve fibers are the most sensitive (pain fibers are most
sensitive)
 rate and degree of penetration is inversely related to the thickness of the
myelin sheath
Type of use
 topical
 infiltration (or field) block - diagnostic or therapeutic block
 conduction (nerve) block
 subarachnoid (spinal) block - modification: epidural
 autonomic nerve block or ganglion block
 treatment of cardiac dysrhythmias: also depresses cardiac muscle discharge - Na channels here too
o ex: lidocaine used in treatment of cardiac disease
Categorized by structure
 3 components - fyi
o aromatic ring (lipophilic/hydrophobic region)
o ester or amide linkage
o tertiary amine (hydrophilic region)
 Ester type
o Cocaine - ‘Snow’ – used in respiratory tract – don’t inject or sniff - vasoconstrictor
o Procaine – used in dentistry
o Tetracaine – 4 hr+ duration (for surgery)
 Amide type
o Lidocaine
o Melpvacaine
 Generalizations on structure/activity
o Three components determine net properties of drugs
 aromatic ring (lipophilic/hydrophobic region)
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Lipophilicity determines the affinity for the Na channel receptor and to cross the axon
membrane into the axoplasm
 ester or amide linkage - determines the route of metabolism
 tertiary amine (hydrophilic region)
 Determines the ability to move through the axoplasm to reach the receptor on the inner portion
of the sodium channel..
Receptor affinity is proportional to lipophilicity; axoplasmic movement is proportional to hydrophilicity
 Tetracaine and bupivcaine are lipophilic, highly potent, slower onset, longer acting.
 Procaine and lidocaine are hydrophilic, less potent, faster onset, shorter acting
Potency, and duration of action are related to (pKa) - determines the proportion in the ionized (charged)
form
Mechanism of local anesthesia
 Sodium channel - membrane effects
o Interference with voltage-gated sodium channels (locks them up)
 threshold for depolarization 
 the magnitude of the action potential gradually declines after dosing
o Sodium channels can exist in three states:
 Resting
 Activated
 Inactivated
o High frequency nerves are more sensitive – pain fibers
 Open channels have greater receptor affinity for the drug in the axoplasm
 Sm amt of local anesthetic may enter externally through the channel
o Un-ionized local anesthetics - poorly soluble
 Used topically - benzocaine and benzyl alcohol may disrupt the membrane externally and distort
the Na channel
o Ionized toxins – don’t cross membrane b/c of their charge (might ‘cap’ the Na channel)
 tetrodotoxin and saxitoxin may are potent and may bind to the external surface of the channel
o Biologic toxins
 bind to channel receptors and prevent inactivation – channel stays open: free flow
 Significance of pH and ionization
o Drug in the un-ionized form enters the nerve membrane- concentration gradient
o Drug in the ionized form binds to the channel receptor
 pH determines the relative proportion
 remember that there is the same ratio of ionized:un-ionized drug in the axoplasm (same pH
normally)
o Infected tissue has an acidic pH so local is less effective (v. little in un-ionized form)
 More of the drug remains in the extracellular space to be taken up in the circulation causing
toxic reactions,
 vasodilation exists in infected tissue which shortens the duration of action - re-application of
drug increases
 Differential nerve block
o All nerve fibers can be blocked by local anesthetics depending on the dose used
o Small nerve fibers (sensory) are more sensitive than motor
 higher frequency of discharge - open Na channels allow for ionized drug
 higher surface area: volume ratio allows for more rapid diffusion into the nerve
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Potency and duration
 Low potency and short duration (30 min)
o Procaine
 Intermediate potency/ duration (90min)
o Lidocaine
o Mepivacaine
 High Potency/ Long Duration (4+ hrs):
o Tetracaine
Uptake, absorption, metabolism
 Uptake to the site of action
o injection is localized so uptake to the site of action is not a factor
o for topical anesthetics the rate of diffusion to the site is important - from the skin surface to nerves
 Absorption and distribution away from the site terminates activity
o rate of uptake away from the site of injection into the circulation influences the duration of action and
the potential for toxic reactions
 Metabolism
o ester types are quickly metabolized by plasma pseudocholinesterase
o amide types are metabolized in the liver
 Excretion
o all agents are weak bases and converted to water-soluble compounds
o Acidification of the urine (ammonium Cl) promotes drug ionization and excretion
 the charge on the molecule prevents reuptake from the renal collecting tubules into the
capillary circulation
 If you want to excrete a weak acid – you give bicarbonate to make fluids more basic and
weak acids are in charged form (can’t be reabsorbed)
Toxic reactions
 Factors
o kind of drug used: ester vs. amide
 ester: idiosyncrasy for plasma cholinesterase is a problem
 amide: hepatic dysfunction is a problem
o amount of drug administered - a linear relationship into the circulation
o characteristics of injections site - degree of vascularity
o vasoconstrictors
 prolongs the therapeutic effect
 epinephrine is particularly effective with procaine, lidocaine and mepivacaine, but less so with
the more lipid soluble drugs
o rate of injection – hydrostatic pressure
 the greater the pressure, the larger the field (lower concentration, less focus)
o premedication / drug interactions
 epinephrine to promote vasoconstriction
 seizure threshold lowered bu morphine, phenothiazines, tricyclic antidepressants, cortisol
 benzodiazepines if large doses are to be used
o coexisting conditions and diseases
 changes in local pH -inflamed tissue has a lower pH, more drug is in the ionized form - less
effective so more drug needed
 reduced hepatic blood flow (volatile anesthetic) and liver function
o Pregnancy
 cardiotoxity leading to death had resulted in racemic bupivacaine withdrawal from use
 levo-bupivacaine and ropivacaine have been substituted - less cardiotoxic
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increased sensitivity may be related to estrogen, progesterone or some other factor
CNS toxicity
o Initial events
 tinnitus, other auditory and visual disturbances
 lightheadedness, euphoria
 confusion, sleepiness
 circumoral numbness
o Apparent stimulation followed by depression
 cerebral cortex - nystagmus, shivering, tonic/clonic convulsions
 medulla - respiratory and vasomotor depression
Direct neurotoxicity
o During spinal anesthesia, high concentrations pooling in the cauda equina can produce transient
neuropathic symptoms
o May be due to interference with axonal transport
o Disruption of Ca++ may be a factor
Cardiovascular toxicity
o Initial effects
 hypertension and tachycardia
o Intermediate phase
 direct myocardial depression- may block Ca++ channels at high doses
 decreased cardiac output
 hypotension - direct action on arteriolar smooth muscle
o Unique toxicity from cocaine
 hypertension, arrhythmias, coronary artery spasm
 a particular problem in highly trained athletes
Other reactions
o Allergy
 usually to the ester type
 may be to the first metabolite - para-aminobenzoic acid
o Idiosyncrasy
 a metabolite of prilocaine (toluidine) may cause oxidation of hemoglobin to methemoglobin
 a problem with reduced methemoglobin reductase or sulfhemoglobinemia
Prevention of toxic reactions
o Proper premedication
o Smallest dose and volume
o Avoid rapid or intravascular injections
o Use a vasoconstrictor
o Obtain a good history of previous reactions
Symptomatic treatment
o Artificial or assisted respiration
o Control seizures - prevent hypoxemia
o Hypotensive episodes
o Allergic reactions
Special precautions
o Inflamed or highly vascular areas
 Urethra, bronchus, larynx, other mucous membranes
o Cocaine used only topically
o Adequate anticonvulsant premedication with large doses
o Potential for gangrene of digits, hands, and feet with epinephrine
 increased oxygen consumption, stimulated by epinephrine, may aggravate this
o hypoxia (due to vasoconstriction)
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Application
 Surface anesthesia - wounds, burns, diagnostic procedures
o tetracaine, lidocaine (2%), and cocaine (restricted to respiratory tract)
o cocaine has vasoconstrictor properties
o procaine is not very effective topically
 Infiltration - injection under the skin
o lidocaine, procaine and bupivacaine with epinephrine
o advantage - other functions (like motor control) are not disrupted
o disadvantage - large amounts of drug for a small area
 Field block
o injected proximal to the desired area
o blockade at a small trunk of a branching nerve
o a small amount of drug blocks a wide area
 Nerve block
o injection into or near a peripheral nerve or plexus
o wide area is blocked
 Intravenous regional anesthesia
o upper extremity is ensanguinated during i.v. application
o lidocaine is the drug of choice
 Spinal
o subarachnoid block - injected into the CSF, blockade from site of injection downward
o epidural block - injection outside of the dura providing segmental anesthesia - used in labor and delivery
linkage
type
metabolism route
lipophilic/hydrophilic
Procaine
ester
hydrolyzed by plasma
(pseudo)cholinterase to
PABA
hydrophilic = less potent,
faster onset, shorter acting
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Tetracaine
ester
detoxified by liver
lypophilic= highly potent,
slower onset, longer acting
16
ester
uniquely toxichypertension,
arrythmias, coronary
artery spasm (Len Bias)
Drug
Cocaine
relative
potency
use w/epi?
yes
no, has own
vasoconstrictive
properties
Lidocaine
amide
detoxified by liver
hydrophilic = less potent,
faster onset, shorter acting
Mepivacaine
amide
detoxified by liver
lypophilic= highly potent,
slower onset, longer acting
allergies?
yes, 1st metabolite
para-aminobenzoic
acid
yes, 1st metabolite
para-aminobenzoic
acid
maybe b/c it's an ester
type
specific uses
infiltration
skin +
topical only
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yes
choice for IV
regional anesthesia,
Skin(2%), infiltration
2
yes
Not topical!
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Severson – Pelvic Anesthesia:
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Pudendal nerve anesthesia (block)
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Anesthetic agent injected near the ischial spine where the nerve enters Alcock’s canal
o
Anesthetizes S2-S4 dermatomes and lower ¼ of vagina
Spinal anesthesia (block) – Intrathecal block
o
Anesthetic agent introduced w/ needle into subarachnoic space at L3/L4 vertebral lvl
o
Anesthetizes basically everything below waist (T10), including limbs, perineum, pelvic floor & birth canal
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Sensation of uterine contractions are temporarily eliminated
Epidural anesthesia (block) – done in 70% of OB pts
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Anesthetic agent administered using an indwelling catheter in sacral canal
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Anesthetizes S2-S4 nerve fibers including the pain fibers from the uterine cervix & upper vagina, and the
afferent fibers of the pudendal nerve.
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Done for vaginal deliveries
Pain fibers from uterine body and fundus ascend to lower thoracic & lumbar lvls in the lumbar
splanchnic nerves (superior & inferior hypogastric plexus) – so mom is aware of uterine contractions
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Clinical correlation question - Answer on the next page!
A medical student decided to have his two impacted wisdom teeth extracted on an outpatient basis. Local
anesthesia was accomplished with several injections (local infiltrations, nerve blocks) of lidocaine hydrochloride
2% solution. However, the initial blocks were not entirely satisfactory and two more injections were required, for a
total volume of 15 ml. After the fourth injection, the student began to complain of lightheadedness, visual
problems, and restlessness. He then suddenly developed tonic-clonic seizures while in the chair. How much
lidocaine did he receive? How do you explain these symptoms and signs? How should they be treated? Is there
any way to slow the absorption of lidocaine or to prevent seizures if large doses must be given?
Clinical correlation answer
A 2% solution of lidocaine hydrochloride contains 2 g/100 ml, which equals 2,000 mg/100 ml or 20 mg/ml.
The student received a total of 15 ml, which is equivalent to 300 mg of the drug. This dose is comparable to the
usual intravenous dose of 100 to 200 mg given to control ventricular arrhythmias. Remember that the tissues in
the mouth, especially the tongue, are very vascular and lidocaine may be rapidly absorbed through the extensive
venous system. The signs and symptoms are typical of lidocaine toxicity, and they are caused by direct central
nervous system (CNS effects (CNS stimulation because of suppression of inhibitory neurons). The patient should
be treated with a rapidly acting CNS depressant drug that has anticonvulsant activity. A good choice would be
intravenous diazepam.
The dose of lidocaine can be kept restricted to the area where local anesthesia is desired by incorporating a
vasoconstrictor into the lidocaine solution. This will reduce blood flow to the area and reduce the rate of
absorption of lidocaine. Epinephrine is often used for this purpose. Occasionally, when large doses of lidocaine
are needed, the patient can also be sedated with diazepam, which has the added advantage of helping to
suppress potential seizures.
This "trick" of slowing lidocaine absorption by adding epinephrine is useful, but it must not be used in areas of
the body where the resultant vasoconstriction could cause serious problems. For example, lidocaine with
epinephrine must never be used in tissues such as the fingers, toes, ears, or nose.
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