Local anesthetics work by blocking sodium channels in nerve fibers, preventing the generation of action potentials and conduction of nerve impulses. They typically contain a hydrophilic amine group, hydrophobic aromatic moiety, and intermediate ester or amide linkage. Esters are metabolized rapidly by plasma esterases while amides are metabolized more slowly by the liver. Common uses of local anesthetics include minor surgery, dental procedures, nerve blocks, epidurals and caudals. Adverse effects can include central nervous system toxicity, cardiac issues like arrhythmias or hypotension, and allergic reactions. Chloroprocaine and lidocaine are examples of commonly used local anesthetic agents.

1. Local Anesthetics (LAs)
By: Seyoum Gizachew (B. Pharm., MSc.)

2. Introduction
Defn.
• Local anesthesia is the loss of sensation in a body part
without the loss of consciousness or the impairment of central
control of vital functions.
• Two major advantages.
– physiological perturbations associated with general
anesthesia are avoided; and
– neurophysiological responses to pain and stress can be
modified beneficially.
• Local anesthetics potentially can produce deleterious side
effects.
– Proper choice and care in its use are the primary
determinants in avoiding toxicity.
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3. Chemistry
• The typical local anesthetics contain:
– hydrophilic and hydrophobic moieties that are separated
by an intermediate ester or amide linkage.
• Compounds containing these minimal structural features can
satisfy the requirements for action as local anesthetics.
• The hydrophilic group usually is a tertiary amine but also
may be a secondary amine.
• The hydrophobic moiety must be aromatic (benzene ring).
• The intermediate chain has either;
– ester linkage from an aromatic acid and an amino alcohol
or
– amide linkage from an aromatic amine and an amino acid.
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4. Chemistry cont…
Figure: Model Structure of local anesthetics showing aromatic portion,
intermediate chain, and amine portion.
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5. Chemistry cont…
• Can be classified as esters or amides,
– based on the structure of this intermediate chain.
• The nature of the linking group determines some of the
pharmacological properties of these agents.
• For example, local anesthetics with an ester link are
hydrolyzed readily by plasma esterases.
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6. Mechanism of Action
• Conduction of nerve impulses is mediated by action potential
(AP) generation along axon.
• Cationic form of local anesthetic binds at inner surface of
Na+ channel – preventing Na+ influx (rising phase of
membrane potential) which initiates AP → blockade of nerve
impulses (e.g., those mediating pain).
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7. Mechanism of action cont…
Figure: Sodium channel
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8. Mechanism of action
cont…
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9. Classification of LAs
Esters
• Cocaine, Butacaine, Tetracaine, Procaine, Benzocaine,
Chloroprocaine, Propoxycaine
Amides
• Articaine, Bupivacaine, Dibucaine, Etidocaine, Lidocaine,
Mepivacaine, Prilocaine, Ropivacaine
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10. Pharmacokinetic Properties
Absorption and Distribution
• Rate of absorption is affected by:
– The dose administered,
– The vascularity at the site of injection, and
– The specific physicochemical properties of the drug itself.
• All tissues will be exposed to LAs after absorption, but
concentration of LAs vary among tissues.
• Highly perfused organs (i.e., brain, kidney, and lung) will
have highest concentration.
• Degree of protein binding and lipid solubility also affect drug
distribution.
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11. Absorption and Dist. cont…
• Placental transfer is known to occur rapidly.
– fetal blood concentrations generally reflecting those
found in the mother.
• However, the quantity of drug crossing to the fetus is also
related to the time of exposure.
– i.e. from the time of injection to delivery (during labor).
• Rapidly hydrolyzed LAs (esters) such as chloroprocaine
used in obstetrics.
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12. Metabolism of LAs
• Depends on the linkage a LA has (either an ester or an
amide).
• Esters are extensively and rapidly metabolized in plasma by
pseudocholinesterase, whereas the amide linkage is resistant
to hydrolysis.
Esters
Amides
Plasma cholinesterases
CytP450
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13. Metabolism
cont…
• Rate of LA hydrolysis is important,
– slow biotransformation may lead to drug accumulation and
toxicity.
• Patients with atypical plasma cholinesterase,
– ester linked compounds (chloroprocaine, procaine and
tetracaine) increased potential for toxicity.
• Formation of paraaminobenzoic acid (PABA), from esterlinked LAs.
– known to be allergenic to some people.
• LA with an amide linkage are almost completely metabolized
by the liver before excretion.
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14. Clinical Uses of LAs
• LAs are extremely useful in a wide range of procedures,
varying from intravenous catheter insertion to extensive
surgery under regional block.
• For minor surgery, the patients can remain awake;
– an advantage in emergency surgery,
• Many operative procedures in the oral cavity.
– If surgery permits, the patient can return home.
• Topical Anesthesia
• Infiltration
• Regional Block
• Spinal Anesthesia (subarachnoid block)
• Epidural Anesthesia
• Caudal Anesthesia
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15. 15

16. 16

17. 17

18. Epidural Anesthesia
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19. 19

20. 20

21. 21

22. 22

23. Caudal Anesthesia
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24. Control of Cardiac Arrhythmias
• Procainamide and lidocaine are two of the primary drugs for treating
cardiac arrhythmias.
• Since lidocaine has a short duration of action, it is common to
administer it by continuous infusion.
• Procainamide, because of its amide linkage, has longer action than
does its precursor, procaine.
Symptomatic ventricular tachycardia treatment.
• For Acute termination:
First line:
– Lidocaine 1-1.5 mg/kg I.V. can be repeated with in 3 min to a
maximum of 3mg/kg.
Alternative:
• Procainamide, 25-50 mg I.V. over one minute period then repeated
every 5 min until the arrhythmia is controlled, hypotension results, or
the QRS complex is prolonged more than 50%.
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25. Use of Vasoconstrictors
• Vasoconstrictors (commonly sympathomimetic drugs), are
often added to LA to delay absorption from the injection site.
• By slowing absorption, these drugs reduce the anesthetic’s
systemic toxicity and keep it in contact with nerve fibers
longer, thereby increasing the drug’s duration of action.
• Administration of lidocaine 1% with epinephrine results in
the same degree of blockade as that produced by lidocaine 2%
without the vasoconstrictor.
Epinephrine:
• By far the most commonly employed.
• precaution is needed when LAs containing this amine are
given to a patient with hypertension or an irritable
myocardium.
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26. Adverse Effects of LAs
• CNS and cardiopulmonary systems are most commonly
affected by high plasma levels of LAs.
• LAs given in initially high doses produce CNS stimulation:
– restlessness, disorientation, tremors, and at times clonic
convulsions.
– Continued exposure to high concentrations results in
general CNS depression; death occurs from respiratory
failure.
– Treatment requires ventilatory assistance and drugs to
control the seizures (ultra-short acting barbiturates,
benzodiazepines).
• CNS manifestations generally occur before cardiopulmonary
collapse.
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27. Adverse Effects cont…
• Cardiac toxicity:
– result of drug induced depression of cardiac conduction
(e.g., atrioventricular block, intraventricular conduction
block) and systemic vasodilation.
– may progress to severe hypotension and cardiac arrest.
• Allergic reactions:
– with the ester type local anesthetics (PABA).
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28. Esters
Chloroprocaine
• Obtained from addition of a chlorine atom to procaine,
– greater potency and less toxicity than procaine itself.
• Hydrolyzed very rapidly by cholinesterase
– short plasma half-life.
• commonly used in obstetrics.
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29. Amides
Lidocaine HCl
• The most commonly used local anesthetic.
• well tolerated
• Infiltration and regional nerve blocks.
• Also commonly used for spinal and topical anesthesia and as
an antiarrhythmic agent.
• Has a more rapidly occurring, more intense, and more
prolonged duration of action than does procaine.
• Metabolized by Liver (CYP 1A2, CYP 3A4)
• Dose: 5 to 10 ml of 2% lidocaine (max. 300 mg/dose)
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