Local Anesthetics Flashcards
LOCAL ANESTHETICS: ACTIONS?
• Block nerve conduction of sensory impulses from
the periphery to the CNS.
• Abolish sensation (and in higher concentrations
motor activity) in a limited area of the body
without producing unconsciousness.
Relevant chemistry of local anesthetics?
• Local anesthetics consist of a lipophilic group (an aromatic ring) connected by an intermediate chain (ester or amide) to an ionizable group (usually a tertiary amine)
• Ester links (as in procaine) are more prone to hydrolysis than amide links, therefore esters usually have a shorter duration of action.
• Local anesthetics are weak bases with pK values around 8.0 – 9.0.
• Therefore the larger fraction in the body fluids at physiologic pH will be the cationic form.
• The cationic form is the most active form at the
receptor site.
• But the uncharged form is important for penetration of biologic membranes.
Actions of vasoconstrictors with anesthetics?
• Procedures that keep the drug at the nerve
prolong the period of anesthesia.
• Preparations of local anesthetics often contain a
vasoconstrictor, usually epinephrine.
• Vasoconstrictors reduce systemic absorption of
local anesthetics by decreasing blood flow.
• As a consequence neuronal uptake of the
drug is enhanced and systemic toxic effects
are reduced.
• Also, in spinal anesthesia, epinephrine acts on α2-adrenoceptors, which inhibit release of substance P.
AE of vasoconstrictors and note on how cocaine acts?
• The vasoconstrictor may cause adverse reactions: Delayed wound healing, tissue edema, or necrosis.
• Cocaine itself constricts blood vessels by potentiating the action of norepinephrine;
therefore, it prevents its own absorption.
METABOLISM AND EXCRETION of local anesthetics?
• Ester-linked local anesthetics are metabolized by tissue and plasma esterases (pseudocholinesterases).
• Amide-linked local anesthetics are in general
degraded by liver microsomal cytochrome P450.
MOA of local anesthetics?
MECHANISM OF ACTION
• Local anesthetics block voltage-gated sodium channels.
• Local anesthetics bind to receptors near the intracellular end of the channel and block the
channel.
• Sufficient concentrations of a local anesthetic applied to a nerve fiber abolish action potentials.
STRUCTURE-ACTIVITY CHARACTERISTICS
OF LOCAL ANESTHETICS? Describe liposolubility in regards to local anesthetics?
• Liposolubility correlates with both potency and
duration of action.
• Greater liposolubility also increases toxicity.
• The pKa correlates with the speed of onset of
action: the closer the pKa to the body pH, the
faster the onset.
Clinical Pharmacology of local anesthetics? Which are short, intermediate, and long acting?
• The choice of local anesthetics for a specific
procedure is usually based on the duration of action required.
• Procaine and chloroprocaine are short-acting
• Lidocaine, mepivacaine, and prilocaine are
intermediate-acting.
• Tetracaine, bupivacaine, etidocaine and ropivacaine are long-acting.
General toxicity of local anesthetics and the PNS?
• Ultimately, local anesthetics are absorbed from the site of administration.
• If blood levels rise too high, effects on several organs systems may be observed.
• At excessively high concentrations, all local
anesthetics can be toxic to nerve tissue.
Toxicity of local anesthetic and CNS?
• CNS stimulation: restlessness and tremor that
may proceed to clonic convulsions.
• CNS stimulation is followed by CNS depression.
Death is usually due to respiratory failure.
• More serious toxic reactions: due to convulsions from excessive blood levels.
• When large doses must be given, premedication with a benzodiazepine provides significant prophylaxis against seizures.
Toxicity of CV system with local anesthetics?
• Local anesthetics block sodium channels and thus depress cardiac pacemaker activity,
excitability and conduction.
• With the exception of cocaine they also depress
strength of cardiac contraction and cause
arteriolar dilation, leading to hypotension.
• Cocaine may cause vasoconstriction and
hypertension; also cardiac arrhythmias.
• Bupivacaine is more cardiotoxic than other
local anesthetics.
Local anesthetic systemic adverse effects? (from highest plasma concentration to lowest)
Cardiac arrest Respiratory arrest Coma Seizures Muscular spasms Tinnitus, auditory hallucinations Paresthesias in mouth and tongue Drowsiness
TOXICITY: BLOOD of local anesthetics?
• Large doses of prilocaine during regional anesthesia may lead to accumulation of the metabolite o-toluidine
• O-toluidine is an oxidizing agent capable of
converting hemoglobin to methemoglobin.
TOXICITY: ALLERGIC REACTIONS of local anesthetics?
• The ester type local anesthetics are metabolized
to p-aminobenzoic acid derivatives.
• These metabolites are responsible for allergic
reactions in a small percentage of the population.
• Amides are not metabolized to p aminobenzoic acid.
• Allergic reactions to agents of the amide group
are extremely rare.
Drug interactions of local anesthetics?
• Procaine is hydrolyzed in vivo to produce paraaminobenzoic acid (PABA), which inhibits
the action of sulfonamides.
• Large doses should not be administered to patients taking sulfonamide drugs.
INHIBITION OF TETRAHYDROFOLATE
SYNTHESIS BY SULFONAMIDES
Pteridine + PABA Dihydropteroic acid(Blocked by sulfonamides)
