Transcript
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)
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