Pharmacology of Local Anesthetics
Pharmacokinetics of Local Anesthetics
Factors:
1) Uptake
2) Distribution
3) Metabolism (Biotransformation)
4) Excretion
Most drugs must enter the circulation to
attain therapeutic blood levels before they
can exert their clinical action
local anesthetics, on the other hand, cease
to provide any clinical effect once they
leave the site of administration and enter
into the blood stream
Uptake of Local Anesthetics
all local anesthetics possess some degree of vasoactivity;
most producing some level of vasodilation
ester local anesthetics are potent vasodilating drugs
Procaine (Novocaine) possesses tremendous vasodilating
abilities which are employed to halt arteriospasm
(accidental IA injection)
*Cocaine is the only local anesthetic that consistently
produces vasoconstriction  initial vasodilation 
intense vasoconstriction
vasodilation leads to an increased rate of
absorption of the local anesthetic into the
blood, thus decreasing the duration and
depth of pain control while increasing the
anesthetic blood concentration and
potential for overdose (toxic reaction)
Distribution of Local Anesthetics
• once in the blood, local anesthetics are
distributed to all tissues
• brain, head, liver, lungs, kidneys and spleen
have high levels of local anesthetics due to
their high level of perfusion
• skeletal muscle has the highest level because
it has the largest mass of tissue in the body
The blood level of local anesthetics is influenced by:
1) Rate at which the drug is absorbed into the
cardiovascular system
2) Rate of distribution from the vascular compartment
to the tissues
3) Elimination of the drug through metabolic or
excretory pathways
Elimination Half-Life:
the rate at which a local anesthetic is removed from
the blood; the time necessary for 50% reduction in the
blood level
One half life  50% reduction
Two half lives  75% reduction
Three half lives  87.5% reduction
Four half lives  94% reduction
Five half lives  97% reduction
Six half lives  98.5% reduction
All local anesthetics cross the blood brain barrier
All local anesthetics cross the placenta and enter the
blood stream of the developing fetus
PABA Metabolism
(ParaAminoBenzoic Acid)
Ester Local Anesthetics: plasma pseudocholinesterase
hydrolyzed in the plasma by the enzyme
pseudocholinesterase
the rate of hydrolysis is related to the degree of
toxicity
Tetracaine is hydrolyzed the slowest which makes it
16 times more toxic than Chloroprocaine which is
hydrolyzed the fastest
Slower Hydrolyzation = Toxicity
Metabolism of Local Anesthetics
2) Amide Local Anesthetics:
primary site of metabolism of amide local
anesthetics is the liver
virtually the entire metabolic process occurs in
the liver for Lidocaine, Mepivicaine,
Articaine, Bupivacaine and Etidocaine
Prilocaine is metabolized in the liver and lung
liver function and hepatic perfusion greatly affect
the rate of metabolism (biotransformation) of amide
local anesthetics
significant liver dysfunction (ASA IV/ASA V
patients) represents a relative contraindication to the
use of amide local anesthetics
Articaine has a shorter half-life than other amides
because a portion of its metabolism occurs in the
blood by plasma cholinesterase
Biotransformation of Local
Anesthetics
2) Amide Local Anesthetics
metabolism byproducts of amide local anesthetics
can possess clinical activity if allowed to
accumulate in the blood
All local anesthetics have the ability to cause
sedation
Example: large doses of Prilocaine can produce a
side effect called Methemoglobinemia;
orthotoluidine, a primary metabolite of Prilocaine,
induces the formation of methemoglobin
Example: large amounts of Lidocaine produce a
sedation effect which is due primarily to two
metabolites glycine xylidide and
monoethylglycinexylidide
If the local anesthetic has two “i”s in its
name; it’s an amide
Lidocaine
Prilocaine
Bupivacaine
Articaine
Mepivacaine
Esters
Amides
Plasma
Two Types of Contraindications to Drugs:
Relative Contraindication: the drug in question may
be given to the patient after carefully weighing the
risks and benefits
Absolute Contraindication: under no circumstance
should this drug be administered; toxicity likely
Excretion of Local Anesthetics
kidneys are the major excretory organs for both local
anesthetics
 esters appear in very small concentrations in the urine; this
is because they are almost completely hydrolyzed in plasma
 Procaine (Novocaine) appears in the urine as 90% PABA
and 2% unchanged
 10% of Cocaine is found unchanged in the urine
 patients undergoing dialysis are likely to be unable to
excrete the unchanged portion of the esters or amides thus
increasing toxicity
Systemic Actions of Local Anesthetics
the pharmacological action of local anesthetics on
the CNS is depression
at high levels, local anesthetics will produce tonicclonic convulsions
Procaine, Lidocaine, Mepivacaine, Prilocaine and
Cocaine generally produce anti-convulsant
properties; this occurs at a blood level considerably
below that at which the same drugs cause seizures
-Procaine, Lidocaine and Mepivacaine have
been used therapeutically to terminate or
decrease the duration of both grand mal and
petit mal seizures; anti-convulsant levels
(.5 to 4 micrograms/ml)
-The depressant action of local anesthetics raise
the seizure threshold by decreasing the
excitability of cortical neurons in epileptic
patients
Preconvulsive Signs and Symptoms
numbness of the tongue and circumoral regions
anesthetic has been transported to these areas by the
cardiovascular system rather than the local delivery
of the anesthetic
if excitation or sedation occurs in the first 5 to 10
minutes after local anesthetic delivery, it should
serve as a warning that convulsive activity could be
possible
-U.S. Air Force an U.S. Navy pilots are
grounded for 24 hours following
administration of Lidocaine due to its mild
effects of sedation and/or drowsiness
-Shivering, slurred speech, muscular
twitching, visual/auditory disturbances,
dizziness, drowsiness, disorientation and
tremor
Convulsive Phase
o duration of seizures is related to blood level of anesthetic and
inversely related to arterial pCO2 levels
o at a normal pCO2, a Lidocaine blood level between 7.5 and 10
micrograms/ml usually result in a convulsive episode
o when CO2 levels are increased, the blood level of local
anesthetic necessary for seizures decreases while the duration of
the seizure increases
o seizures usually last less than or equal to one minute
o cerebral blood flow and cerebral metabolism increase during a
seizure
o increased blood flow to the brain leads to an increase in the
volume of local anesthetic being delivered to the brain causing a
longer seizure
Convulsive Phase
-increased cerebral metabolism leads to acidosis which
prolongs the seizure activity even in the presence of
declining local anesthetic levels in the blood
-seizures gradually subside  generalized CNS
depression respiratory depression  respiratory
arrest  death
How do seizures happen since local anesthetics produce
depressant actions on excitable membranes?
Answer: local anesthetics produce CNS excitation through a
selective blockade of inhibitory pathways in the cerebral
cortex; inhibition of inhibition is a pre-synaptic event that
follows local anesthetic blockade of impulses traveling
along inhibitory pathways; the local anesthetic depresses
the action of the inhibitory neurons thus tipping the
balance in favor of excessive excitatory input 
tremor, agitation, seizure and death
Convulsive stage
CNS depression
Cardiovascular Effects of
Local Anesthetics
local anesthetics have a direct action of the
myocardium and peripheral vasculature
CVS is more resistant to the effects local anesthetics
than the CNS
increased local anesthetic blood levels result in
decreased myocardial depolarization, however, no
change in resting membrane potential and no
prolongation of the stages of repolarization
local anesthetics decrease myocardial excitation,
decrease conduction rate and decrease the force of
contraction
Lidocaine is used therapeutically for pre-ventricular
contractions (PVCs) and ventricular tachycardia
local anesthetics cause hypotension from the direct
relaxant action on vascular smooth muscle
Lung Toxicity
local anesthetics have a direct relaxant
action on bronchial smooth muscle
generally, respiratory function is
unaffected by local anesthetics until
near overdose levels are achieved
Local Tissue Toxicity
• skeletal muscle will heal within two weeks of
being injected with local anesthetic
• longer acting local anesthetics (Bupivacaine)
produce more damage to skeletal muscle than
do shorter acting agents
Malignant Hyperthermia: pharmacogenic disorder in
which a genetic variant alters the person’s response to
certain drugs. Tachycardia, tachypnea (rapid breathing),
unstable blood pressure, cyanosis, fever muscle rigidity and
death; 68% mortality rate.
Malignant Hyperthermia Association of the U.S. determined
that there are no documented cases in Dental or Medical
literature supporting the concept of amide local anesthetics
triggering malignant hyperthermia
References
Handbook of Local Anesthesia. Malamed, Stanley. 5th Edition. 2004 “www.mhaus.org”