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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
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)
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
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
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
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
Esters
Plasma
Amides
-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
-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
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
Malignant Hyperthermia: pharmacogenic disorder in which a genetic variant alters the persons 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