Local Anesthetics (LAs)

By: Seyoum Gizachew (B. Pharm., MSc.)

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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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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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Chemistry cont…

Figure: Model Structure of local anesthetics showing aromatic portion, intermediate chain, and amine portion.

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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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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).

7Figure: Sodium channel

Mechanism of action cont…

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Mechanism of action cont…

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Classification of LAs

Esters• Cocaine, Butacaine, Tetracaine, Procaine, Benzocaine,

Chloroprocaine, Propoxycaine

Amides • Articaine, Bupivacaine, Dibucaine, Etidocaine, Lidocaine,

Mepivacaine, Prilocaine, Ropivacaine

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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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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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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 Plasma cholinesterases

Amides CytP450

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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 ester-

linked 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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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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18Epidural Anesthesia

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23Caudal Anesthesia

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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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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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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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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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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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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)