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Local anesthetics 2


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Local anesthetics 2

  1. 1. Local Anesthetics (LAs) By: Seyoum Gizachew (B. Pharm., MSc.)
  2. 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. 2
  3. 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. 3
  4. 4. Chemistry cont… Figure: Model Structure of local anesthetics showing aromatic portion, intermediate chain, and amine portion. 4
  5. 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. 5
  6. 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). 6
  7. 7. Mechanism of action cont… Figure: Sodium channel 7
  8. 8. Mechanism of action cont… 8
  9. 9. Classification of LAs Esters • Cocaine, Butacaine, Tetracaine, Procaine, Benzocaine, Chloroprocaine, Propoxycaine Amides • Articaine, Bupivacaine, Dibucaine, Etidocaine, Lidocaine, Mepivacaine, Prilocaine, Ropivacaine 9
  10. 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. 10
  11. 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. 11
  12. 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 12
  13. 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. 13
  14. 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 14
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  18. 18. Epidural Anesthesia 18
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  23. 23. Caudal Anesthesia 23
  24. 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%. 24
  25. 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. 25
  26. 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. 26
  27. 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). 27
  28. 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. 28
  29. 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) 29