Local Anesthetics (LAs)
By: Seyoum Gizachew (B. Pharm., MSc.)
• 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
• Local anesthetics potentially can produce deleterious side
– Proper choice and care in its use are the primary
determinants in avoiding toxicity.
• 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
– amide linkage from an aromatic amine and an amino acid.
Figure: Model Structure of local anesthetics showing aromatic portion,
intermediate chain, and amine portion.
• 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.
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).
Mechanism of action cont…
Figure: Sodium channel
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
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.
Metabolism of LAs
• Depends on the linkage a LA has (either an ester or an
• Esters are extensively and rapidly metabolized in plasma by
pseudocholinesterase, whereas the amide linkage is resistant
• Rate of LA hydrolysis is important,
– slow biotransformation may lead to drug accumulation and
• 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.
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
• Regional Block
• Spinal Anesthesia (subarachnoid block)
• Epidural Anesthesia
• Caudal Anesthesia
Control of Cardiac Arrhythmias
• Procainamide and lidocaine are two of the primary drugs for treating
• 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:
– Lidocaine 1-1.5 mg/kg I.V. can be repeated with in 3 min to a
maximum of 3mg/kg.
• 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%.
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.
• By far the most commonly employed.
• precaution is needed when LAs containing this amine are
given to a patient with hypertension or an irritable
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
– Continued exposure to high concentrations results in
general CNS depression; death occurs from respiratory
– Treatment requires ventilatory assistance and drugs to
control the seizures (ultra-short acting barbiturates,
• CNS manifestations generally occur before cardiopulmonary
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).
• 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.
• 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)