pharmacology of local anesthetics
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All about Local anestheticsTRANSCRIPT
Pharmacology of Local Anesthetics
Pharmacokinetics of Local AnestheticsFactors:
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 Anestheticsall 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 Plasma
Amides
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 plasmaProcaine (Novocaine) appears in the urine as 90% PABA
and 2% unchanged 10% of Cocaine is found unchanged in the urinepatients 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 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 mildeffects of sedation and/or drowsiness
-Shivering, slurred speech, muscular twitching, visual/auditory disturbances,
dizziness, drowsiness, disorientation andtremor
Convulsive Phaseo 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”