LOCAL ANAESTHETICS Dr. Sanjita Das

1. LOCAL ANAESTHETICSDr. Sanjita Das

2. Local anesthetics are the agents which on topical application or local injection cause reversible loss of sensory perception, especially pain in a localized area of the body. • Local anesthesia is any technique to render part of the body insensitive to pain without affecting consciousness. • These cause loss of sensory as well as motor impulses. • No local damage to the neurons. • In many situations, such as cesarean section, it is safer and therefore superior to general anesthesia. • It is also used for relief of non-surgical pain and to enable diagnosis of the cause of some chronic pain conditions. • Anesthetists sometimes combine both general and local anesthesia techniques.

3. Techniques • Surface anesthesia- application of local anesthetic spray, solution or cream to the skin or a mucous membrane. The effect is short lasting and is limited to the area of contact. • Infiltration anesthesia - injection of local anesthetic into the tissue to be anesthetized. Surface and infiltration anesthesia are collectively topical anesthesia. • Field block - subcutaneous injection of a local anesthetic in an area bordering on the field to be anesthetized. • Peripheral nerve block - injection of local anesthetic in the vicinity of a peripheral nerve to anesthetize that nerve's area of innervation. • Plexus anesthesia- injection of local anesthetic in the vicinity of a nerve plexus, often inside a tissue compartment that limits the diffusion of the drug away from the intended site of action. The anesthetic effect extends to the innervation areas of several or all nerves stemming from the plexus. • Epidural anesthesia- a local anesthetic is injected into the epidural space where it acts primarily on the spinal nerve roots. Depending on the site of injection and the volume injected, the anesthetized area varies from limited areas of the abdomen or chest to large regions of the body. • Spinal anesthesia - a local anesthetic is injected into the cerebrospinal fluid, usually at the lumbar spine (in the lower back), where it acts on spinal nerve roots and part of the spinal cord. The resulting anesthesia usually extends from the legs to the abdomen or chest. • Intravenous regional anesthesia (Bier's block) - blood circulation of a limb is interrupted using a tourniquet (a device similar to a blood pressure cuff), then a large volume of local anesthetic is injected into a peripheral vein. \ • Local anesthesia of body cavities (e.g. intrapleural anesthesia, intraarticular anesthesia)

4. Channels Na Ca (multiple types) K Enzymes Adenylyl cyclase Guanylyl cyclase Lipases Receptors Nicotinic acetylcholine NMDA β2-adrenergic Important for spinal, epidural, or systemic effects? LAs bind and inhibit many differing receptors and channels Anesthesiology 1990; 72:711-34

5. Mechanism of action • The mechanism of local anesthetics connects with the ion channels, nerve, and depolarization. • Block the conduction in peripheral nerves that inhibited the nerve to excited and created anesthesia. • The anesthetic is a reversible reaction. It binds and activates the sodium channels. • The sodium influx through these channels and depolarizes the nerve cell membranes. It also created high impulses along the way. • As a result, the nerve loses depolarization and the capacity to create the impulse, the patient loses sensation in the area supplied by the nerve.

7. History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, CaCO3, or ash; first example of “free basing” Erythroxylon coca

8. History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, CaCO3, or ash; first example of “free basing” • Monardes brings coca leaves back to Europe (1580); fail to achieve instant popularity of tobacco Chewing coca From: cocamuseum.com

9. History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, CaCO3, or ash; first example of “free basing” • Monardes brings coca leaves back to Europe (1580); fail to achieve instant popularity of tobacco Fresh coca leaves From Andy Graham of hobotraveler.com

10. History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, CaCO3, or ash; first example of “free basing” • Monardes brings coca leaves back to Europe (1580); fail to achieve instant popularity of tobacco Cocain HCl Powder Cocaine HCl isolated by Albert Niemann (1860

11. Articaine Hydrochloride (Septocaine) • Old new drug • Thiophene-based amide • Metabolized by plasma carboxyesterase • Low maximum dosage; low accumulation with repeated dosing • 4% solution more effective than 2% lidocaine, both with epinephrine? • Increased incidence of nerve damage

12. CH CH 3 3 H H 3 3 Articaine (Septocaine, Zorcaine): a thiophene derivative O O H H NHC CH N NHC CH N S C H C H 3 7 3 7 C C COOCH 3 Articaine Prilocaine

13. Mean Sensory Voltage: First Premolar 300 F B F B F 250 F B F F B B A B B A J A F F J F A J F J F E J E A B E F J J B E J A A A J A F E 200 E J B J F J F J E E J J J A B B B J J E B F E A E A B B B A ∆ Voltage (V) F A A A E E 150 A E Lid-2%-H E A E F E B B E Ult-2%-L E 100 Ult-2%-H J Ult-4%-L A 50 Ult-4%-H F 0 E A F B J 0 10 20 30 40 50 60 70 80 90 Time (min)

14. The efficacy question • No proof of increased effectiveness in double-blind clinical trials using standard injections • No clinical trial with sufficient power to distinguish small differences • If 97.5% versus 95% efficacy and 40 patients per week, • one less failure per week

15. Local anesthesia use in Germany (1996) 2% 3% Articaine 4% 91% Lidocaine Mepivacaine Others

16. Local anesthesia use in Canada (1999) Articaine 12% Prilocaine 46% 32% Lidocaine Mepivacaine 6% 4% Bupivacaine

17. Effect of lidocaine on intracellular Ca2+ Johnson: Anesthesiology 97:1466-76, 2002

18. Effect of lidocaine on neuronal survival Johnson: Anesthesiology 97:1466-76, 2002

19. Kishimoto T, Bollen AW, Drasner K: Comparative spinal neurotoxicity of prilocaine and lidocaine. Anesthesiology 97:1250-3, 2002. • Rats received intrathecal infusions of 2.5% prilocaine, 2.5% lidocaine, or normal saline (n=30/group) • Tail-flick test day 4 • Histopathologic examination day 7

20. Comparative spinal neurotoxicity of prilocaine and lidocaine Kishimoto et al: Anesthesiology 97:1250-3, 2002

21. Postulated mechanism for nerve injury

23. Summary of findings • Statistical association of 4% local anesthetic solutions with higher incidence of damage • Local anesthetics are neurotoxic in clinical concentrations • Neurotoxicity is concentration dependent • Clinically used local anesthetics show similar inherent neurotoxicity • The perineurium serves as a barrier to local anesthetic distribution • Intrafascicular injection appears to be required for damage • The lingual nerve has as few as 1 fascicle

24. Local Anesthetic Metabolism Role of cytochrome P450 enzymes

25. Principal drug metabolizing enzymes

26. Lidocaine metabolism

27. Lidocaine pharmacokinetics • CYP1A2 is the major determinant of lidocaine metabolism in patients with normal liver function • Liver disease reduces CYP1A2 activity • Fluvoxamine (Luvox) inhibits oxidative metabolism of lidocaine, MEGX, and GX by 60% Orlando et al. Clin Pharmacol Ther 2004;75:80-8.

28. Lidocaine pharmacokinetics (2) • CYP3A4 is normally a minor determinant of lidocaine metabolism in patients with normal liver function • Liver disease may not significantly reduce CYP3A4 activity • Erythromycin inhibits lidocaine metabolism by 15%-20% Orlando et al. Br J Clin Pharmacol 2003;55:86-93.

29. Conclusion

30. Safety Issues Related to Local Anesthetics • Related to • Drug • Dose • Site of administration • Condition of the patient

31. CNS Toxicity Tends to occur first (relative to CVS toxicity) See excitatory signs and symptoms first Followed by depressant signs Circumoral and tongue numbness Lightheadedness and tinnitus Visual disturbance Muscle twitching Convulsions COMA Respiratory arrest CVS depression

32. CVS Toxicity Alteration in the excitatory mechanism slower depolarization decreased HR prolonged PR interval widened QRS Arrythmias bradycardia ectopic beats ventricular fibrillation Decreased cardiac output on the basis of HR contractility OTHER Toxicities Lack of anesthetic effect due to infectious pus such as an abscess.

33. Additives and modifiersof LA activity • Increasing dose: ↓latency of onset; ↑duration, ↑block success, ↑[LA] • Vasoconstrictors: ↑duration, ↑block success, ↓[LA] • α2 agonists: ↑duration,↑[LA] • Opioids: ↑duration; permit ↓LA dose • Alkalinization (usually NaHCO3): ↓latency of onset, ↑potency • Cimetidine, Propranolol: ↑First-pass metabolisation of lignocain and amide type local anaesthetics. ↓[LA] • Phenobarbitone: ↓ First-pass metabolisation of lignocain and amide type local anaesthetics. ↑[LA] • Pregnancy: ↑dermatomal spread, ↑LA potency, ↑free blood [LA] • Procaine interferes with antibacterial action of sulphonamides. • Lignocaine potentiates succinylcholine action.

34. Special preparations www.aafp.org

35. Special preparations EMLA lidocaine 2.5% prilocaine 2.5% requires 45-60 application on intact skin TAC tetracaine 0.5% epi 1 in 2000 cocaine 10% application into wound maximum dose for kids 0.05ml/Kg toxicity due to cocaine Tumescent Anesthesia lidocaine dilute epi liposuction dose 35-55mg/Kg Peak levels 8-12h later

36. Topical Local anesthetics • Tetracaine, Adrenaline (Epinephrine), and Cocaine • Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent cocaine, was the first topical anesthetic mixture found to be effective for nonmucosal skin lacerations to the face and scalp.2 From 2 to 5 mL of solution is applied directly to the wound using a cotton-tipped applicator with firm pressure that is maintained for 20 to 40 minutes.2,3However, the use of TAC is no longer supported by the literature because of general concern about toxicity and expense, and federal regulatory issues involving medications containing cocaine. • Principles of Office Anesthesia: Part II. Topical Anesthesia • SURITI KUNDU, M.D.,

37. EMLA • Eutectic Mixture of Local Anesthetics • Most pure anesthetic agents exist as solids. Eutectic mixtures are liquids and melt at lower temperatures than any of their components, permitting higher concentrations of anesthetics.Eutectic mixture of local anesthetics (EMLA) represents the first major breakthrough for dermal anesthesia onintact skin.It consists of 25 mg per mL of lidocaine, 25 mg per mL of prilocaine, a thickener, an emulsifier, and distilled water adjusted to a pH level of 9.4.3 • Etymology: Greek eutEktos easily melted, from eu- + tEktos melted, from tEkein to melt -- more at THAW1of an alloy or solution: having the lowest melting point possible2: of or relating to a eutectic alloy or solution or its melting or freezing point • Principles of Office Anesthesia: Part II. Topical AnesthesiaSURITI KUNDU, M.D.,

38. Iontophoresis • Iontophoresis is a method of delivering a topical anesthetic with a mild electric current. Lidocaine-soaked sponges are applied to intact skin, and electrodes are placed on top of the anesthetic. A DC current is then applied to the skin (Figure 2). The anesthetic effect occurs within 10 minutes and lasts approximately 15 minutes. The depth of anesthesia can reach up to 1 to 2 cm.12 • Although the effectiveness of iontophoresis has been compared favorably to that of EMLA, it remains underused. Some patients find the mild electrical sensation uncomfortable. The apparatus is expensive and bulky, and cannot be used over large surface areas of the body.8 Other applications using iontophoresis are still being developed. • Principles of Office Anesthesia: Part II. Topical AnesthesiaSURITI KUNDU, M.D.,

39. Iontophoresis

40. Iontophoresis • Comparison of EMLA and lidocaine iontophoresis for cannulation analgesia.CONCLUSIONS: Although lidocaine iontophoresis is effective more quickly than the eutectic mixture of local anaesthetic cream, the superior quality of analgesia produced by the eutectic mixture in this study should be borne in mind if these treatments are used electively • Eur J Anaesthesiol. 2004 Mar;21(3):210-3. Moppett

41. Liposomes Liposomes are comprised of lipid layers surrounded by aqueous layers. They are able to penetrate the stratum corneum because they resemble the lipid bilayers of the cell membrane. A liposomal delivery system recently became available as an over-the-counter product called ELA-Max. It contains 4 percent lidocaine cream in a liposomal matrix and is FDA-approved for the temporary relief of pain resulting from minor cuts and abrasions. ELA-Max is applied to intact skin for 15 to 40 minutes without occlusion.15-17 In limited studies, ELA-Max has also proved effective in providing dermal analgesia before chemical peeling.18 The safety of its application to mucous membranes has not been evaluated.5 Despite a paucity of data and lack of an FDA indication, clinicians are be ginning to use ELA-Max for topical anesthesia before other dermatologic procedures.

42. Liposome www.bioteach.ubc.ca

45. Liposomal Bupivacaine A Novel Liposomal Bupivacaine Formulation to Produce Ultralong-Acting Analgesia • Conclusions: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain. • Anesthesiology: Volume 101(1) July 2004 pp 133-137 Grant,

46. Lidocaine and prilocaine periodontal gel (Oraqix)

47. Lidocaine and prilocaine periodontal gel 2.5%/2.5%(Oraqix) Eutectic mixture of local anesthetics Solution at room temperature; gel at body temperature First topical anesthetic specifically designed for scaling and root planing FDA approved December 19, 2003 http://www.oraqix.com

49. Lidocaine and prilocaine periodontal gel 2.5%/2.5%(Oraqix) Eutectic mixture of local anesthetics Solution at room temperature; gel at body temperature First topical anesthetic specifically designed for scaling and root planing FDA approved December 19, 2003

50. Oraqix delivery syringe