Pharmacology of Local Anesthetics

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					Pharmacology of Local Anesthetics
Pharmacokinetics of Local Anesthetics
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
  the rate of hydrolysis is related to the degree of
  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
       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
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
If the local anesthetic has two “i”s in its
            name; it’s an amide

Esters   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
 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 tonic-
 clonic 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
    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
 -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
                       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

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

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
Handbook of Local Anesthesia. Malamed, Stanley. 5th Edition. 2004 “”