LOCAL ANAESTHETICS Dr Sanjita Das Local anesthetics are

LOCAL ANAESTHETICS Dr. Sanjita Das

• 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.

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)

LAs bind and inhibit many differing receptors and channels • Channels – Na – Ca (multiple types) –K • Enzymes – Adenylyl cyclase – Guanylyl cyclase – Lipases • Receptors – Nicotinic acetylcholine – NMDA – β 2 -adrenergic • Important for spinal, epidural, or systemic effects? Anesthesiology 1990; 72: 711 -34

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.

History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500 s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, Ca. CO 3, or ash; first example of “free basing” Erythroxylon coca

History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500 s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, Ca. CO 3, 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

History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500 s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, Ca. CO 3, 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

History of local anesthesia-1 • Cocaine = natural product • Properties well-known to Incas • Chewed coca dripped on trepanning sites • 1500 s: Spaniards seize plantations & pay workers with coca paste • Mixed with corn starch, chewed with guano, Ca. CO 3, 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

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 • •

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

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

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

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

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

Effect of lidocaine on intracellular Ca 2+ Johnson: Anesthesiology 97: 1466 -76, 2002

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

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

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

Postulated mechanism for nerve injury

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

Local Anesthetic Metabolism Role of cytochrome P 450 enzymes

Principal drug metabolizing enzymes

Lidocaine metabolism

Lidocaine pharmacokinetics • CYP 1 A 2 is the major determinant of lidocaine metabolism in patients with normal liver function • Liver disease reduces CYP 1 A 2 activity • Fluvoxamine (Luvox) inhibits oxidative metabolism of lidocaine, MEGX, and GX by 60% Orlando et al. Clin Pharmacol Ther 2004; 75: 80 -8.

Lidocaine pharmacokinetics (2) • CYP 3 A 4 is normally a minor determinant of lidocaine metabolism in patients with normal liver function • Liver disease may not significantly reduce CYP 3 A 4 activity • Erythromycin inhibits lidocaine metabolism by 15%-20% Orlando et al. Br J Clin Pharmacol 2003; 55: 86 -93.

Conclusion Anesthetic p. Ka Onset Duration (with Max Dose Epinephrine) in (with minutes Epinephrine) Procaine 9. 1 Slow 45 - 90 8 mg/kg – 10 mg/kg Lidocaine 7. 9 Rapid 120 - 240 4. 5 mg/kg – 7 mg/kg Bupivacaine 8. 1 Slow 4 hours – 8 hours 2. 5 mg/kg – 3 mg/kg Prilocaine 7. 9 Medium 90 - 360 5 mg/kg – 7. 5 mg/kg Articaine 7. 8 Rapid 140 - 270 4. 0 mg/kg – 7 mg/kg

Safety Issues Related to Local Anesthetics Related to 1) Drug 2) Dose 3) Site of administration 4) Condition of the patient

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

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.

Additives and modifiers of LA activity • Increasing dose: ↓latency of onset; ↑duration, ↑block success, ↑[LA] • Vasoconstrictors: ↑duration, ↑block success, ↓[LA] • α 2 agonists: ↑duration, ↑[LA] • Opioids: ↑duration; permit ↓LA dose • Alkalinization (usually Na. HCO 3): ↓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.

Special preparations

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. 05 ml/Kg toxicity due to cocaine Tumescent Anesthesia lidocaine dilute liposuction dose 35 -55 mg/Kg Peak levels 8 -12 h later epi

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 m. L 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, 3 However, 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. ,

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 on intact skin. It consists of 25 mg per m. L of lidocaine, 25 mg per m. L of prilocaine, a thickener, an emulsifier, and distilled water adjusted to a p. H level of 9. 4. 3 • Etymology: Greek eut. Ektos easily melted, from eu- + t. Ektos melted, from t. Ekein to melt -- more at THAW 1 of an alloy or solution : having the lowest melting point possible 2 : of or relating to a eutectic alloy or solution or its melting or freezing point – Principles of Office Anesthesia: Part II. Topical Anesthesia. SURITI KUNDU, M. D. ,

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 Anesthesia. SURITI KUNDU, M. D. ,

Iontophoresis

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

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.

Liposome www. bioteach. ubc. ca

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 dosedependent 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,

Lidocaine and prilocaine periodontal gel (Oraqix)

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

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

Oraqix delivery syringe

Oraqix cartridge contents • • • Lidocaine/prilocaine 2. 5%/2. 5% Poloxamers 188 and 407 HCl for p. H adjustment Purified water p. H 7. 5 -8. 0

Nanoparticles Scavenging Nanoparticles: An Emerging Treatment for Local Anesthetic Toxicity • The authors of the lipid-based studies speculated that four mechanisms may play a role in the success of resuscitation. In their primary hypothesis, the lipid infusion may create plasma lipid droplets capable of segregating uncharged bupivacaine molecules from plasma, which makes them unavailable for interaction at their target sites. The authors supported this theory by showing that bupivacaine molecules preferentially segregated from plasma to their lipid infusion in a 1: 12 ratio. In two of the other proposed mechanisms, the lipid acts within tissue. Here, lipid or its component fatty acids either interact in a clinically significant way with tissue bupivacaine molecules or directly overcome bupivacaine’s inhibitory effect on cellular metabolism by supplying substrate for cellular energy production. ] Finally, the lipid infusion may act on nitric oxide pathways and reverse bupivacaine’s inhibitory effects. Building on this work and assuming that sequestration of bupivacaine is an important aspect of resuscitation in the aforementioned lipid-based studies, some investigators have hypothesized even greater segregation of bupivacaine into lipid may occur with large reductions in particle size to the dimension of the nanometer. – Regional Anesthesia and. PMJuly - May, 2005 pp: 380 -384 Renehan,

Regional Anesthesia and. PMJuly - May, 2005 pp: 380 -384 Renehan ,

Regional Anesthesia and. PMJuly - May, 2005 pp: 380 -384 Renehan,

Encapsulation of mepivacaine • Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice. PURPOSE: Liposomal formulations of local anesthetics (LA) are able to control drug-delivery in biological systems, prolonging their anesthetic effect. This study aimed to prepare, characterize and evaluate in vivo drug-delivery systems, composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and mepivacaine (MVC). • CONCLUSION: MVC(LUV) provided a LA effect comparable to that of BVC. We propose MVC(LUV) drug delivery as a potentially new therapeutic option for the treatment of acute pain since the formulation enhances the duration of sensory blockade at lower concentrations than those of plain MVC. – Can J Anaesth. 2004 Jun-Jul; 51(6): 566 -72. de Araujo

Tumescent Anesthesia • Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia. Background: It is common today to use tumescent anaesthesia with large doses of lidocaine for liposuction. The purpose of the present study was to evaluate lidocaine plasma levels and objective and subjective symptoms during 20 h after tumescent anaesthesia with approximately 35 mg per kg bodyweight of lidocaine for abdominal liposuction. Methods: Three litres of buffered solution of 0. 08% lidocaine with epinephrine. Results: Lidocaine 33. 2 +/- 1. 8 mg/kg was given at rate of 116 +/- 11 ml/min. Peak plasma levels (2. 3 +/- 0. 63 microg/ml) of lidocaine occurred after 5 -17 h • Conclusion: Doses of lidocaine up to 35 mg/kg were sufficient for abdominal liposuction using the tumescent technique and gave no fluid overload or toxic symptoms in eight patients, but with this dose there is still a risk of subjective symptoms in association with the peak level of lidocaine that may appear after discharge. • Acta Anaesthesiol Scand. 2005 Nov; 49(10): 1487 -90. Nordstrom

Tumescent Anesthesia • Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia. Background: It is common today to use tumescent anaesthesia with large doses of lidocaine for liposuction. The purpose of the present study was to evaluate lidocaine plasma levels and objective and subjective symptoms during 20 h after tumescent anaesthesia with approximately 35 mg per kg bodyweight of lidocaine for abdominal liposuction. Methods: Three litres of buffered solution of 0. 08% lidocaine with epinephrine. Results: Lidocaine 33. 2 +/- 1. 8 mg/kg was given at rate of 116 +/- 11 ml/min. Peak plasma levels (2. 3 +/- 0. 63 microg/ml) of lidocaine occurred after 5 -17 h • Conclusion: Doses of lidocaine up to 35 mg/kg were sufficient for abdominal liposuction using the tumescent technique and gave no fluid overload or toxic symptoms in eight patients, but with this dose there is still a risk of subjective symptoms in association with the peak level of lidocaine that may appear after discharge. • Acta Anaesthesiol Scand. 2005 Nov; 49(10): 1487 -90. Nordstrom

Newer Local anesthetics • bupivacaine, • levobupivacaine and • ropivacaine. • All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity • Br J Pharmacol. 2001 Feb; 132(3): 649 -58. Chang DH,

Ropivacaine depts. washington. edu/anesth/ regional/ropivacainetext. html • Pharmacokinetic parameters Ropivacaine is 2 -3 times less lipid soluble and has a smaller volume of distribution, greater clearance, and shorter elimination half-life than bupivacaine in humans. 3 The two drugs have a similar p. Ka and plasma protein binding

Ropivacaine depts. washington. edu/anesth/ regional/ropivacainetext. html • Ropivacaine is slightly less potent than bupivacaine. When used for spinal anesthesia, 0. 75% ropivacaine produces less intense sensory and motor block than 0. 5% bupivacaine. 5 However, multiple clinical trials comparing the two local anesthetics in epidural and axillary block demonstrate similar potency of bupivacaine and ropivacaine with respect to the intensity of sensory anesthesia.

Ropivacaine depts. washington. edu/anesth/ regional/ropivacainetext. html • Epinephrine does not prolong the duration of ropivacaine block. The addition of epinephrine does not prolong the duration of ropivacaine in subclavian brachial plexus 17, 18 or epidural 19 block. Low concentrations of ropivaciane may produce clinically significant vasoconstriction, which is not increased further by the addition of epinephrine.

• Conclusions Ropivacaine is slightly less potent than bupivacaine, but multiple studies show that it can provide adequate surgical anesthesia when used in similar concentrations. Ropivacaine is half as potent as bupivacaine in its direct negative inotropic effect and slowing of ventricular conduction. A potential for sudden ventricular arrhythmias still exists with systemic ropivacaine toxicity. Any slight advantage ropivacaine has over bupivacaine may be eliminated if higher concentrations of ropivacaine are used.

Ropivacaine

Ropivacaine Related Articles, Links Arterial and Venous Pharmacokinetics of Ropivacaine with and without Epinephrine after Thoracic Paravertebral Block. The absorption of ropivacaine after thoracic paravertebral block is described by rapid and slow absorption phases. The rapid phase approximates the speed of intravenous administration and accounts for nearly half of ropivacaine absorption. The addition of 5 mug/ml epinephrine to ropivacaine significantly delays its systemic absorption and reduces the peak plasma concentration. Anesthesiology. 2005 Oct; 103(4): 704 -711. Karmakar *.

Ropivacaine • Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? • Slightly different anaesthetic potency, bupivacaine>levobupivacaine>ropivacaine. • However, the reduced toxic potential of the two pure leftisomers supports their use in those clinical situations in which the risk of systemic toxicity related to either overdosing or unwanted intravascular injection is high, such as during epidural or peripheral nerve blocks • Best Pract Res Clin Anaesthesiol. 2005 Jun; 19(2): 247 -68. Casati.

Levobupivacaine The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. In healthy volunteers. Levobupivacaine and ropivacaine produced similar central nervous system and cardiovascular effects when infused IV at equal concentrations, milligram doses, and infusion rates. • Anesth Analg. 2003 Aug; 97(2): 412 -6, Stewart

Limitations of Local Anesthetics Amount and complexity of the work to be done Patient Area to be anesthetized Duration of procedure Immobility