2. EO 003.19 Local Anesthetics PA Course EO 003.19

3. Learning Objectives To understand the mechanism of action of local anesthetics To understand the mechanism of action of local anesthetics To understand indications, contraindications, and adverse effects of local anesthetics To understand indications, contraindications, and adverse effects of local anesthetics To be able to select an appropriate local anesthetic (practical applications will will covered in next lecture) To be able to select an appropriate local anesthetic (practical applications will will covered in next lecture)

4. EO 003.19 Local Anesthetics Work by blocking the generation and propagation of nerve impulses when applied locally in adequate concentrations. Work by blocking the generation and propagation of nerve impulses when applied locally in adequate concentrations. – Blocks sodium channels This block is reversible thus normal function returns to the nerve when the local anesthetic is removed by the blood stream. This block is reversible thus normal function returns to the nerve when the local anesthetic is removed by the blood stream.

5. EO 003.19

6. Nerve Impulse Transmission

7. EO 003.19

8. Ionized

9. Extracellular solution Intracellular Solution Local Anesthetics Binding Sites + + + Voltage sensor LA LA + H+H+ LA Hydrophobic Pathway LA LA + H+H+ -70 mV -15 mV LA + Hydrophilic Pathway

10. EO 003.19 pKa, pH and Why They Matter pKa = pH at which ionized and non-ionized base are equally present. LA’s are weak bases with pKa of 8- 9. pKa = pH at which ionized and non-ionized base are equally present. LA’s are weak bases with pKa of 8- 9. Onset of action related to amount of LA present as base form. Onset of action related to amount of LA present as base form. As environment becomes more acidic (lower pH/ more H + ), equilibrium shifts to the cationic form, which does not diffuse readily in to the nerve. As environment becomes more acidic (lower pH/ more H + ), equilibrium shifts to the cationic form, which does not diffuse readily in to the nerve.

11. EO 003.19 Pharmacologic Actions Order of blockade of nerves depends on Nerve size (from small to big: C, B, A , A ,A ,A  ) Nerve size (from small to big: C, B, A , A ,A ,A  ) Myelination Myelination Sequence of nerve loss Loss of pain Temperature Touch Proprioception Skeletal muscle tone

12. EO 003.19 Desirable Properties of Local Anesthetics Reversiblility Reversiblility Non-irritating to tissues Non-irritating to tissues Rapid onset of action Rapid onset of action Long duration of action (to facilitate procedures) Long duration of action (to facilitate procedures) High therapeutic index High therapeutic index Effective topically and by injection Effective topically and by injection Ideal physical properties (solubility and stability) Ideal physical properties (solubility and stability)

13. EO 003.19 General Anesthetic Structure hydrophobic hydrophilic 1 2 3

14. EO 003.19 Classification of Anesthetics esters amides

15. EO 003.19Esters Not very stable in solution; easily broken down by sunlight, heat Not very stable in solution; easily broken down by sunlight, heat Metabolized by cholinesterases in blood and skin. Para-aminobenzoic acid (PABA) is a by-product of metabolism Metabolized by cholinesterases in blood and skin. Para-aminobenzoic acid (PABA) is a by-product of metabolism Examples: benzocaine, cocaine, procaine, tetracaine Examples: benzocaine, cocaine, procaine, tetracaine

16. EO 003.19Amides Long duration of effect Long duration of effect Cleared from the site of anesthesia by local blood flow, then metabolized by liver to water soluble products which are removed by the kidney Cleared from the site of anesthesia by local blood flow, then metabolized by liver to water soluble products which are removed by the kidney Fairly stable in solution Fairly stable in solution Examples: articaine, bupivacaine, lidocaine, mepivacaine, prilocaine & ropivacaine. Examples: articaine, bupivacaine, lidocaine, mepivacaine, prilocaine & ropivacaine.

17. EO 003.19 Allergy to LA’s Esters may cause allergy due to para- aminobenzoic acid, which is a breakdown product of all these agents. Thus allergy to one ester means allergy to all esters. Esters may cause allergy due to para- aminobenzoic acid, which is a breakdown product of all these agents. Thus allergy to one ester means allergy to all esters. Allergy to an amide is very rare. Allergy to an amide is very rare. History of allergy to an ester or another amide does not rule out use of an amide. History of allergy to an ester or another amide does not rule out use of an amide. Most “allergy” to dental LA is psychogenic (anxiety reaction to dental procedure) Most “allergy” to dental LA is psychogenic (anxiety reaction to dental procedure)

18. EO 003.19 Physicochemical properties Determines potency, onset and duration of action 1. pKa, dissociation constant Proportion of ionized to non-ionized molecules Proportion of ionized to non-ionized molecules Correlates with onset Correlates with onset Equilibrium exists Equilibrium exists low pH = more in ionized state & unable to cross membrane low pH = more in ionized state & unable to cross membrane Sodium bicarbonate –  pH and non-ionized base = faster onset Sodium bicarbonate –  pH and non-ionized base = faster onset Acidic tissues (ie septic) -  ionized = slower entry Acidic tissues (ie septic) -  ionized = slower entry

19. EO 003.19 Physicochemical properties 2. Lipid solubility - Correlates with potency Higher solubility = more potent, thus can use smaller dose (more molecules penetrate into axioplasm) Higher solubility = more potent, thus can use smaller dose (more molecules penetrate into axioplasm) 3. Protein binding - Correlates with duration of action Increased binding = longer duration of action Increased binding = longer duration of action

20. EO 003.19 LA and Blood Flow Vasodilation: affects duration of action. At clinically useful concentrations, the LA’s (except cocaine) are vasodilators. Vasodilation: affects duration of action. At clinically useful concentrations, the LA’s (except cocaine) are vasodilators. Inhibiting blood flow increases duration of the block- done deliberately during IV regional anesthesia, or may be a result of circulatory impairment. Inhibiting blood flow increases duration of the block- done deliberately during IV regional anesthesia, or may be a result of circulatory impairment. Vasoconstrictors added to LA for this effect. Vasoconstrictors added to LA for this effect.

21. EO 003.19Epinephrine Most common vasoconstrictor used with local anesthetics Most common vasoconstrictor used with local anesthetics Prolongs duration of anesthesia Prolongs duration of anesthesia Increases the intensity of blockade Increases the intensity of blockade Reduces systemic absorption of LA Reduces systemic absorption of LA Reduces surgical bleeding Reduces surgical bleeding

22. EO 003.19Epinephrine Solutions of epi nephrine containing 5 mcg/ml (1:200,000) appear to be optimal for the reduction of surgical bleeding and systemic absorption of local anesthetics Solutions of epi nephrine containing 5 mcg/ml (1:200,000) appear to be optimal for the reduction of surgical bleeding and systemic absorption of local anesthetics

23. EO 003.19Epinephrine Manifestations of systemic epinephrine absorption Increased heart rate. Increased heart rate. Increased cardiac output. Increased cardiac output. Decreased systemic vascular resistance – confusing, but small vessels in skin, mucosa and viscera are constricted, while vasculature of skeletal muscles relaxes Decreased systemic vascular resistance – confusing, but small vessels in skin, mucosa and viscera are constricted, while vasculature of skeletal muscles relaxes Warning Warning epinephrine is light and heat sensitive. It oxidizes easily: do not use if pinkish or brownish in color or if a precipitate is visible.

24. EO 003.19Epinephrine Contraindications to the addition of epinephrine Peripheral nerve blocks in areas that may lack collateral blood flow (penis, digits) Peripheral nerve blocks in areas that may lack collateral blood flow (penis, digits) Unstable angina Unstable angina Cardiac dysrhythmias Cardiac dysrhythmias Uncontrolled hypertension Uncontrolled hypertension Treatment with monoamine oxidase (MAO) inhibitors, tricyclic antidepressants or sympathomimetics Treatment with monoamine oxidase (MAO) inhibitors, tricyclic antidepressants or sympathomimetics Uteroplacental insufficiency Uteroplacental insufficiency Intravenous (IV) regional anesthesia Intravenous (IV) regional anesthesia

25. EO 003.19 Routes of Administration of LA Topical/surface Topical/surface – Skin, mucous membranes, eye, – ointments, drops, lozenges, gels, creams, sprays – Many OTC Injection Injection – Infiltration – Regional – Intrarticular – Epidural – Spinal – Intravenous

26. EO 003.19 Systemic absorption Rate of systemic absorption depends on route Rate of systemic absorption depends on route Intravenous Tracheal Intercostals Caudal Paracervical Epidural Brachial plexus Sciatic/femora Subcutaneous fast slow

27. EO 003.19 Clinical Uses Topical/Surface Used to relieve pain and itching of sunburn, insect bites, skin abrasions, hemorrhoids, needle sticks, teething etc. This type of use is not generally recommended, since there is risk of sensitization/ absorption, and other drug or non drug measures are available. Used to relieve pain and itching of sunburn, insect bites, skin abrasions, hemorrhoids, needle sticks, teething etc. This type of use is not generally recommended, since there is risk of sensitization/ absorption, and other drug or non drug measures are available. Numb area prior to dental procedures, other diagnostic procedures Numb area prior to dental procedures, other diagnostic procedures

28. EO 003.19 Clinical Uses Infiltration (used for superficial surgery) – Removal of moles, warts, sebaceous cysts Used for IV insertion Used for IV insertion Regional block Regional block Intravenous Intravenous Epidural Epidural Spinal Spinal

29. EO 003.19 Spinal Anesthesia These products contain NO ANTIMICROBIAL PRESERVATIVE. They are in single-dose vials. These products contain NO ANTIMICROBIAL PRESERVATIVE. They are in single-dose vials. spinal products are hyperbaric due to addition of dextrose. The patient is positioned so that anesthesia is achieved at the appropriate nerve roots spinal products are hyperbaric due to addition of dextrose. The patient is positioned so that anesthesia is achieved at the appropriate nerve roots

30. EO 003.19 Drug Interactions With topical or infiltration anesthesia, interactions are unlikely, since systemic absorption should be very low. With topical or infiltration anesthesia, interactions are unlikely, since systemic absorption should be very low. Inhalation anesthetics and general anesthetic pre- meds Inhalation anesthetics and general anesthetic pre- meds MAOI’s : increase risk of hypotension MAOI’s : increase risk of hypotension Neuromuscular blockers: LA may enhance/ prolong action Neuromuscular blockers: LA may enhance/ prolong action Cholinesterase inhibitors increase likelihood of toxicity with ester LA’s Cholinesterase inhibitors increase likelihood of toxicity with ester LA’s

31. EO 003.19 Adverse Effects of LA’s Hypersensitivity Hypersensitivity – Usually due to preservative or metabolite of ester – Skin rash, contact dermatitis, asthmatic attack, anaphylactic Musculoskeletal Musculoskeletal – Local anesthetics are myotoxic when injected directly into skeletal muscle Respiratory Respiratory – Lidocaine depresses the hypoxic drive – Apnea can result from phrenic and intercostal nerve paralysis or depression of medullary centre

32. EO 003.19 Central Nervous System ConcentrationToxicity Low Circumoral paresthesia, mild relaxation/sedation, generalized analgesia Moderate Euphoria, lightheadedness, dysphoria, slurred speech, drowsiness, sensory changes (blurred, double vision), twitching Moderate to High Disorientation, tremor, unconsciousness, seizures High Coma, respiratory arrest

33. EO 003.19 Vascular & Cardiac Effects of LA’s Cocaine causes an intense vasoconstriction which can lead to destruction of tissue by reducing blood supply Cocaine causes an intense vasoconstriction which can lead to destruction of tissue by reducing blood supply Other local anesthetics show an initial vasoconstriction, then vasodilation Other local anesthetics show an initial vasoconstriction, then vasodilation Higher concentrations decrease cardiac conduction velocity, automaticity, contractility, cardiac output and blood pressure = cardiovascular collapse. Normally, there will be signs of CNS toxicity first; these cardiac effects occur at high plasma concentrations. Higher concentrations decrease cardiac conduction velocity, automaticity, contractility, cardiac output and blood pressure = cardiovascular collapse. Normally, there will be signs of CNS toxicity first; these cardiac effects occur at high plasma concentrations.

34. EO 003.19 Special Populations Pregnancy: no good studies, but retrospective analyses show no risk to fetus. LA’s do cross the placenta. Pregnancy: no good studies, but retrospective analyses show no risk to fetus. LA’s do cross the placenta. Breast feeding: some distribution into breast milk, but appears safe. Breast feeding: some distribution into breast milk, but appears safe. Infants: under 9 months, have low plasma protein concentrations, which may enhance effects of bupivicaine. Lidocaine preferred. Infants: under 9 months, have low plasma protein concentrations, which may enhance effects of bupivicaine. Lidocaine preferred.

35. EO 003.19 Individual Agents…

36. EO 003.19 Bupivacaine (Marcaine®) Onset of action: intermediate (slower than lidocaine) Onset of action: intermediate (slower than lidocaine) Duration of action: long (3 to 10 hours) Duration of action: long (3 to 10 hours) Products: available as 0.25% and 0.5% solutions, with and without epinephrine, in various volumes and containers. Multidose vials contain parabens; products with epinephrine also contain Na metabisulfite (antioxidant) Products: available as 0.25% and 0.5% solutions, with and without epinephrine, in various volumes and containers. Multidose vials contain parabens; products with epinephrine also contain Na metabisulfite (antioxidant)

37. EO 003.19 Bupivicaine Dosing (Adult) Based on healthy, 70 kg young male Based on healthy, 70 kg young male Peripheral nerve block: 12.5 to 175 mg (5 to 70 mL of 0.25% soln) Peripheral nerve block: 12.5 to 175 mg (5 to 70 mL of 0.25% soln) Local infiltration: up to 175 mg (70 mL) of 0.25% solution without epi. Local infiltration: up to 175 mg (70 mL) of 0.25% solution without epi. If using epi, max dose = 225 mg. If using epi, max dose = 225 mg. Total daily doses may go up to 400 mg. Total daily doses may go up to 400 mg.

38. EO 003.19 Lidocaine Parenteral Solution (Xylocaine®) Rapid onset; duration 1 to 3 hours. Rapid onset; duration 1 to 3 hours. Products: Products: 1% and 2 % parenteral solutions, with and without epi. Note that the multidose vials contain parabens, but are to be discarded 3 days after initial puncture. Use single dose vials and discard remaining solution if possible. Sodium metabisulfite present in the “with” solutions. 1% and 2 % parenteral solutions, with and without epi. Note that the multidose vials contain parabens, but are to be discarded 3 days after initial puncture. Use single dose vials and discard remaining solution if possible. Sodium metabisulfite present in the “with” solutions.

39. EO 003.19 Lidocaine Parenteral Solution Adult dose: Adult dose: Digits (no epi !): 1 to 5 mL of 1% solution (onset fast, within 2- 5 minutes) Digits (no epi !): 1 to 5 mL of 1% solution (onset fast, within 2- 5 minutes) local infiltration: less than 40 mL of 1% solution (onset within 1-2 minutes) local infiltration: less than 40 mL of 1% solution (onset within 1-2 minutes) Percutaneous: less than 30 mL of 1% solution Percutaneous: less than 30 mL of 1% solution

40. EO 003.19 Lidocaine Endotracheal Gives surface anesthesia for procedures involving nasal/ respiratory tracts Gives surface anesthesia for procedures involving nasal/ respiratory tracts Delivers 10 mg/ spray Delivers 10 mg/ spray New canisters must be primed (5 to 10 pumps). Don’t need to re-prime after changing nozzle, just void air. New canisters must be primed (5 to 10 pumps). Don’t need to re-prime after changing nozzle, just void air. For procedures in oropharynx, 2 to 6 sprays. For procedures in oropharynx, 2 to 6 sprays. For intubation, 5 sprays to 40. For intubation, 5 sprays to 40.

41. EO 003.19 Lidocaine 2% Jelly For surface anesthesia/ lubrication of urethra (ie during catheterization); proctoscopy, rectoscopy, endoscopy. For surface anesthesia/ lubrication of urethra (ie during catheterization); proctoscopy, rectoscopy, endoscopy. Not effective on intact skin Not effective on intact skin Endotracheal intubation: about 2 mL applied to end of trach tube Endotracheal intubation: about 2 mL applied to end of trach tube Female urethra: 5 to 10 mL Female urethra: 5 to 10 mL Male urethra: about 20 mL for entire surface; 5 to 10 mL for anterior portion Male urethra: about 20 mL for entire surface; 5 to 10 mL for anterior portion

42. EO 003.19 Lidocaine 2% Viscous For topical anesthesia of mouth and pharynx, surface anesthesia with introduction of instruments into digestive/ resp tracts, pain due to esophagitis For topical anesthesia of mouth and pharynx, surface anesthesia with introduction of instruments into digestive/ resp tracts, pain due to esophagitis “pink lady” = mixed with Diovol “pink lady” = mixed with Diovol For mouth and throat: 5 to 10 mL; swish and spit or swallow slowly For mouth and throat: 5 to 10 mL; swish and spit or swallow slowly For esophagitis: 5 to 15 mL, swallowed in a single gulp For esophagitis: 5 to 15 mL, swallowed in a single gulp Max 60 mL in 24 hours Max 60 mL in 24 hours Onset within 5 minutes; lasts 20 to 30 minutes Onset within 5 minutes; lasts 20 to 30 minutes

43. EO 003.19 Lidocaine Topical 5% Comes in 50 mL plastic bottles; spearmint flavoured. Comes in 50 mL plastic bottles; spearmint flavoured. For pain due to inflamed tissue in mouth, or for surface oral anesthesia for dental procedures For pain due to inflamed tissue in mouth, or for surface oral anesthesia for dental procedures 1 to 4 mL applied with a cotton swab 1 to 4 mL applied with a cotton swab

44. EO 003.19 Lidocaine/ Prilocaine Topical EMLA: Eutectic Mixture of Local Anesthetics Intact skin: anesthesia for needle insertion or for superficial surgical procedures. Used, especially in children, to reduce pain of vaccination. OK with MMR, DPTP, Hib, Hep B. Leg Ulcers: cleansing and debridement Genital Mucosa: surface anesthesia for short surgical procedures or infiltration anesthesia

45. EO 003.19 Lidocaine/ Prilocaine Topical DO NOT USE FOR: application to mucus membrane except for adult genital mucosa. application to mucus membrane except for adult genital mucosa. Application inside the ear due to possibility of ototoxicity Application inside the ear due to possibility of ototoxicity Area around the eyes; it irritates the cornea Area around the eyes; it irritates the cornea Infants less than 3 months old Infants less than 3 months old infants predisposed to methemoglobinemia; this includes those receiving sulfonamides. infants predisposed to methemoglobinemia; this includes those receiving sulfonamides.

46. EO 003.19 EMLA Application Intact skin: cream applied thickly to area; occlusive dressing applied; or may use patch form. Area is cleaned prior to procedure. After 1 hour, get about 3 mm depth of anesthesia. Intact skin: cream applied thickly to area; occlusive dressing applied; or may use patch form. Area is cleaned prior to procedure. After 1 hour, get about 3 mm depth of anesthesia. Genitalia: cream applied without occlusion; anesthesia occurs in 5- 10 minutes Genitalia: cream applied without occlusion; anesthesia occurs in 5- 10 minutes Leg ulcers: apply up to 10 g; remove after 30 to 60 minutes and clean/ debride. Leg ulcers: apply up to 10 g; remove after 30 to 60 minutes and clean/ debride.

47. EO 003.19 SUMMARY Choice of Ideal LA for Indication:  Quick onset  Appropriate duration  Lowest toxicity  Highest specificity  Minimize allergic potential