This document provides an overview of local anesthetics including their ideal properties, commercial preparations, structure-activity relationships, mechanisms of action, pharmacokinetics, side effects, and individual local anesthetics. It discusses topics such as how local anesthetics work by producing reversible conduction blockade along nerves, their absorption, distribution, metabolism and excretion from the body, and potential adverse effects including neurological, cardiovascular and respiratory side effects.

1. LOCAL ANAESTHETICS BY :DR SUHAIMI TAJUDIN MODERATOR : PROF MADYA DR SHAMSUL HUSM ANESTESIOLOGI DEPARTMENT

2. OUTLINE Introduction Ideal properties Comercial preparation Structure activity relationship Mechanism of action Pharmacokinetic Side effects Individual LA

5. 3. Commercial Preparations Poorly soluble in water – marketed most often as water-soluble hydrochloride salt These HCl salts are acidic(pH 6) – contributing to the stability of LA An acidic pH also important if epinephrine is present in LA solution, becoz this cathecolamine is unstable at alkaline pH sodium metabisulphite (strongly acidic), may be added to LA-ephephrine solutions to prevent oxidative decomposition of epinephrine

6. COMERCIAL PREPARATION Alkalinization of LA solution By adding sodium bicarbonate Will shortens the onset (more nonionized form) Enhance dept of sensory and motor blockade (increase potency) Increase spread of epidural blockade

7. 4.Structure Activity Relationship LIPOPHILIC PORTION HYDROPHILIC PORTION HYDROCARBON CHAIN

9. Usually unsaturated aromatic ring e.gpara-aminobenzoic acid

10. lipid soluble

11. Potency

12. Hydrophilic portion

13. Is usually tertiary amine

14. Water soluble

15. Connecting hydrocarbon chains .ester( -CO.O-) .amide(-NH.CO) the nature of this bond is the basis of classification of LA, relate to site of metabolism and potential to produce allergic reaction

17. ( -CO.O-)

18. Procaine, tetracaine, amethocaine, cocaine

19. Relatively unstable in solution

20. Allergic reactions are common

21. Rapidly metabolised by plasma and liver cholinesterase

22. One metabolite, para-aminobenzoic acid, thought to be responsible for allergic rxn

23. Metabolism may be prolonged when pl cholinesterase is low

24. E.g liver disease, pregnancy and atypical enzymes

25. Amides

26. (-NH.CO)

27. lignocaine, etidocaine, prilocaine, mepivacaine, bupivacaine,ropivacaine, levobupivacaine

28. Relatively stable in solution

29. Allergic reaction is rare, may be ass with preservative vehicle

30. Slowly metabolised by amidases in liver

33. About 70mV with the inside membrane being negative compare to outside

34. The Na-K-ATPase is electrogenic , pumps 3Na out of cell in exchange for 2K pumped intracellularly. This pump sets up concentration different of Na & K across the cell membrane

35. small net intracellular loss of +ve charge

36. The membrane is permeable to Na and K, so these ion tend to leak across membrane down their concentration gradient

37. membrane is 100x more permeable to K, > K lost from cell than Na enters the cellNet result is larger amt of +ve charge left the cell than has entered it so inside of membrane left with net negative charge result in RMP are being negative compare to outside

39. Last only 1-2ms

40. Electrical or chemical trigger initially cause slow rise in membrane potential until threshold potential (50mV) is reached

41. Voltage sensitive Na channels then open, increasing Na pemeability dramatically and membrane potential briefly reaches +30mV, at which Na channels close

42. The membrane potential return to its resting value with an increased efflux of K

44. Mechanism of action LA selectively binds to Na channel in inactivated-closed state. It stabilizes it in this configuration and prevent their change to rested-closed and activated-open states in response to nerve impulse Na channel impermeable to Na Slows the rate of depolarisation, threshold potential not reached & action potential not propagated

45. Frequency- dependent blockade Defines a situation where the more frequent the channel are activated, the greater the degree of block produced After AP, Na channel develop a low affinity state where some drugs dissociate/ unbind and Na channel recover If another AP arrived before all LA dissociates it regain access into the Na channel at open activated state -> additional increment of block ↑ Frequency of AP - ↑ degree of blockade

46. Membrane volume expansion theory Lipophilic LA incorporated into lipid bilayer causing a volume expansion & distortion to the conformation of axonal membrane and hence the Na channel resulting in its inactivation Mode of action of Benzocaine, and other LA when given in high dosage

47. 6.PHARMACOKINETIC Physicochemical properties Absorption Distribution Metabolism Excretion

48. PHYSICOHEMICAL PROPERTIES The chemical structure and physicochemical characteristics of LA affect their clinical properties Modification of the chemical structure (lengthening of the hydrocarbon chain within critical length or increasing the number of carbon atoms in the aromatic ring or tertiary amine ) may alter lipid solubility, potency, rate of metabolism & duration of action In particular, these are modified by Lipid solubility Protein binding Dissociation constant (pKa value)

49. a) Lipid solubility Lipid solubility of different anaesthetics governs their ability to penetrate perineuronal tissues and neural membrane, and reaches their site of action in neuroplasm More lipid soluble – penetrates membrane more easily, less molecule requires for nerve conduction blockade i.e. more potent E.g. Bupivacaine, levobupivacaine and ropivacaine are app 3-4x as potent as lidocaine or prilocaine, dt differences in their lipid-solubility

50. Physicochemical properties

52. Plasma protein binding acts as depotE.g Procaine is not extensively bound to tissue protein, has short duration of action Bupivacaine, levobupivacaine & ropivacaine are extensively bound to plasma and tissue protein --- prolonged effect

53. Physicochemical properties

54. c) Dissociation constant (pKa value) pKa is equal to pH at which the concentration of ionized base and non-ionized base are equal Is the most important factor affecting rapidity of onset of axn pKa value governs the proportions of LA that is present in non-ionized form at physiological pH values and therefore available to diffuse across tissue barrier to its site of axn LA with a pKa near physiological pH will have a greater degree of unionized molecules -> More LA diffused across membrane -> rapid onset of action

55. Physicochemical properties

56. ABSORPTION Absorption of LA from its site of injection into systemic circulation is influenced by; Site of injection Dosage Addition of vasoconstrictor Physicochemical properties of LA Vasoactive properties of the LA Pathophysiological process – acidity of tissue reduces absorption ( e.g. abscess, metabolic acidosis)

58. Blood concentration in decreasing order

61. c. Addition of vasoconstrictor By addition of adrenaline 5g/ml (1:200000) Higher Dosage offers no additional benefits but increases symphatomimetic activites limit systemic absorption and maintain the drug concentration in nerve fibre and prolong the time the drug in contact with nerve fibre Ropivacaine & Cocaine has intrinsic vasoconstrictor activities Lignocaine, mepivacaine, bupivacaine, etidocaine exhibit vasodilator effects

62. Vasoactive properties of LA Influence potency and duration of action All LA has vasodilator effect except ropivacaine and coccaine More vasoactive like lidocaine more greater systemic absorption result in shorter duration of action Pathophysiological process Acidosis environment Will increase ionized fraction of the drug Result in poor quality of LA Physiocochemical properties Lipid solubility Protein binding Dissociation constant

66. Lung extraction The lung capable of extracting local anesthetic such as lidocaine and bupivacaine from circulation Limit the concentration of drug that reaches systemic circulation to be distributed to coronary & cerebral circulation Placental transfer Highly plasma protein binding LA limits diffusion across placenta Esters undergo rapid hydrolysis hence not available for transfer across placenta Acidosis in fetus, which may occur during prolonged labour, can result in accumulation of LA molecules in the fetus (ion trapping)

68. Rate of hydrolysis varies, and resulting metabolites are pharmacologically inactive

69. Paraaminobenzoic acid metabolite may be responsible for allergic reaction

70. CSF – lacks estrase enzyme; so the termination of action of intrathecal injection of LA depends on absorption into bld. Stream

73. EXCRETION Poor water solubility of LA limit renal excretion of unchanged drugs to < 5% of injected dose (except cocaine 10-12%) Water soluble para-aminobenzoic acid readily excreted

75. Central

76. Peripheral neurotoxicity

77. TNS

78. Caudaequina syndrome

79. Anterior spinal artery syndrome

80. Cardiovascular system

81. Blood

82. methemoglobinemia

83. Respiratory

84. Ventilatory response to hypoxia

85. Git

88. As the plasma concentration increased, LA readily cross the BBB and produce cns changes

89. Restlessness, vertigo, tinnitus and difficulty in focusing

90. Slurred speech and skeletal muscle twiching- face and extremities

91. Seizures and CNS depression

92. Plasma concentration of LA depend on specific drug involve

93. Lidocaine, mepivacaine, prilocaine (5-10ug/ml)

94. Bupivacaine (4.5-5.5ug/ml)

96. Convulsions should be treated by maintaning adequate ventilation and oxygenation, and controlled by anticonvulsant drugs

97. Diazepam 10-20mg iv

98. Thiopental 150-250mg iv

99. Accidental injection of large vol of LA into CSF during epidural or paravertebral block can produce total SA

101. Resolving within 1 week

102. Ass with use of vasoconstrictor

104. Sensory anaesthesia

105. Bowel and bladder sphincter dysfunction

106. paraplegia

107. Following repeated doses of 5% lidocaine & 0.5% tetracaine used in continuous spinal anesthesia

109. CVS Overdose of LA may cause profound hypotension, bradycardia, bradyarhythmias and even cardiac arrest, and usually follows sign of CNS toxicity E.g. – high systemic conc of bupivacaine are particularly ass with significant toxicity Produce prolonged blockade of Na channel also affects myocardial Ca and K channels, and is preferentially bound by cardiac muscle Myocardial contractility and conduction in junctional tissue is depressed, with widening of QRS complex and distortion of St segment

110. Predispose to re-entrant phenomena and ventricular arrthyhmias, which are potentiated by hypoxia, acidosis and hyperK Arrthyhmias and bradycardia may respond to iv atropine (1.2-1.8mg) and colloid/crystalloid infusions may be required to expand pl vol Current evidence suggest that use of LA enantiomers with (S)-configuration reduce risk of cardiac depression and cardiotoxicity, and ropivacaine (an S-isomer) and levoupivacaine (S-bupivacaine) may have significant advantages compare to racemic bupivacaine

111. Hematology --Methemoglobinemia Rare but potentially life treatening complication (decreased O2-carrying capacity) Cause by oxidation of Hb to methemoglobin more rapidly than methemoglobin is reduced by Hb Prilocaine ( > 600mg @ >10mg/kg) Amide LA that is metabolized to othotoluidine Othotoluidine is oxidizing compound, capable of converting Hb to methemoglobin ---- methemoglobinaemia Cause pt to appear cyanotic Also caused by Benzocaine ( topical application > 200-300mg) Is readily reversed by administration of iv methylene blue, 1-2mg/kg over 5 min (total dose 7-8mg/kg)

112. Respiratory Lidocaine at high plasma concentration depress ventilatory response to arterial hypoxaemia So patient with CO2 retention which resting ventilation depend on hypoxic drive may be at risk of ventilatory failure when lidocaine is administered for treatment of cardiac dysrythmia

113. Hepatotoxicity Continous or intermittent epidural administration of bupivacaine to treat postherpetic nuralgia has been associated with increase plasma concentration of liver transaminase enzyme that normalized when bupivacaine infusion was discontinued It could be due to a direct toxic injury or an allergic reaction Dysphoria Vivid fear of imminent death and a delusional belief of having died

114. Death Toxicity 26 24 22 20 18 16 14 12 10 8 6 4 2 0 Ventricular Arrest Cardiac Arrhythmia Respiratory arrest Coma Myocardial depression Loss of conciousness Convulsion Muscle twitching CNS excitation Visual disturbances Lightheadness, tinnitus, circumoral & tongue numbness Positive inotropy, anticonvulsant, antiarrythmic Plasma lidocaine concentration µg/ml

116. Ropivacaine

117. Lignocaine

118. Cocaine

120. Presentation – clear colourless, aques solution (bupivacaine hydrochloride )

121. Plain (0.25%, 0.5%, 0.75%)

122. With 1:200 000 (5µg/ml ) adrenaline

123. Heavy 0.5% with 80mg/ml dextrose ( SG 1.026) used for SA

124. Recommended max dose 2mg/kg, 0.75% produces more prolonged motor block

125. Clinical- acts within 10-20min and almost immediate with intrathecal administration,

126. Duration of action 4-8hrs.

127. 4X as potent as lidocaine, propensity for cardiotoxicity

130. Excretion – 5% excreted as PPX, 16% excreted unchanged in urine, Cl 0.47L/m t½ 0.31-0.61Hr (after IV admin)

132. Presentation – Clear colourless solution containing 0.2/ 0.75/ 1.0% ropivacaine hydrochloride

133. Recommended dose –3.5mg/kg, 250mg (150mg for C-section under epidural), not currently intended for intrathecal admin and in children < 12 years

134. Clinical – sensory blockade similar in time course to that produced by bupivacaine; motor blockade is slower in onset & shorter in duration than after an equivalent dose of bupivacaine; less cardiotoxic than bupivacaine; Intrinsic vasoconstrictor, mild CNS Sx

137. Excretion – 86% (mostly conjugated) excreted in the urine, 1% unchanged

140. Presentation – Clear aq solution lidocaine hydrochloride

141. Plain 0.5%( local infiltration, IVRA ), 1%, 2%(nerve blocks, extradural anaesthesia)

142. with adrenaline 1:200 000

143. Gel 2% with or without chlorhexidine

144. 4% aq solution for topical application to pharynx, larynx, trachea

145. 10% spray for oral cavity & upper resp tract

146. Recommended max dose 3mg/kg (7mg/kg with adrenaline), toxic plasma level >10ug/ml

147. Acute ventricular dysrhythmia ( class 1)– 1mg/kg over 2 min followed by infusion 4mg/kg/min (30min), 2mg/kg/min ( 2 hr) & subsequently 1mg/kg/min.

148. Reduce stress response – 1-2mg/kg IV 5min before intubation

149. Clinical –

152. Excretion - <10% excreted unchangedCl – 6.8-11.6ml/kg/min t½ - 90-110min

154. Presentation – clear colourless aq prilocaine hydrochloride

155. Plain 1%, 4%

156. Solution with 0.03 u/ml felypressin(3%) for dental infiltration

157. EMLA

158. Recommended max dose – 5mg/kg; with felypressin 8mg/kg

159. Clinical –

160. rapid onset, intermediate duration between lidocaine & bupivacaine; potency similar to lidocaine; less toxic

161. may be used for IVRA(0.5%); 1-2% for nerve block

162. problem with metHb (>600mg IV)

166. Restricted use to surface analgesia because of its toxicity

167. Commonly used as 10% spray or paste to reduce bleeding caused by nasal intubation

168. Causes vasoconstriction by preventing uptake of noradrenaline by presynaptic nerve endings, also inhibit monoamine oxidase

169. Recommended dose – admin topically 3mg/kg

170. Clinical – inhibit uptake of adrenaline and noradr by central and peripheral symphatetic nerve endings, and enhances effect of sympt nerve stimulation

171. CNS – increased neuronal activity in symphatetic pathways in hypothalamus and medulla

172. It may produce mental stimulation, euphoria, hallucinations, vasoC, pupillary dilatation, hypertension, tachycardia and arrhythmias

173. Pharmacokinetic

174. Absorption – well absorb from mucosa; bioavailability-intranasal 0.5%

175. Distribution – 98% protein bound, Vd 0.9-3.3L/kg

176. Metabolism – degraded by plasma esterase predominantly to benzoylecgonine, ecgonine

177. Excretion – metabolites excreted in urine , 10-12% unchanged Cl 26-44ml/kg/min t½ 25-60min

179. CNS stimulation: convulsions at high doses, followed by central depression and apnoea

180. Symphatetic stimulation: arrhythmias, tachycardia and hypertension may occur

181. Addiction may occur with chronic use

182. Cardiomyopathy and sudden death have been associated with chronic abuse

184. Mixture of 2.5% lidocaine + 2.5% prilocaine as oil- water emulsion

185. Melting point of each LA is lowered by presence of the other

186. May produce blanching (addition of nitroglycerine ointment may promote venodilation) and increase in metHb (esp < 3mths- immature reductase pathway)

187. Useful for children

188. Effective analgesia 60-90 min after topical application and covering with occlusive dressing

189. Uses described include analgesia for venopuncture, venous and arterial cannulation, lumbar puncture, epidural injection, superficial skin surgery and relief of tourniquet pain during IVRA

191. mcq 1. Lidocaine can cause: a) sedationb) convulsionsc) slowed A-V conductiond) prolongation of the cardiac action potentiale) shortening of the refractory phase f) Is more potent than ropivacaine

192. mcq 1. Lidocaine can cause: a) sedation Tb) convulsions Tc) slowed A-V conduction Td) prolongation of the cardiac action potential Fe) shortening of the refractory phase T f) Is more potent than ropivacaine F

193. 2. Regarding local anaesthetic agents (LA):a) the potency of LAs is proportional to their lipid solubilityb) the duration of action is dependent on protein bindingc) agents with low pKa have a faster onset of actiond) all local anaesthetics are vasodilatorse) the depth of local anaesthetic block is increased by increasing the dose

194. 2. Regarding local anaesthetic agents (LA):a) the potency of LAs is proportional to their lipid solubility Tb) the duration of action is dependent on protein binding Tc) agents with low pKa have a faster onset of action Td) all local anaesthetics are vasodilators Fe) the depth of local anaesthetic block is increased by increasing the dose T

195. 3. Concerning local anaesthetics: a) they are absorbed more rapidly after intercostal block than after caudal administration b) in the foetus they are able to cross the placenta as readily as from the mother c) they are weak acids d) those which are esters are rapidly metabolised by liver enzymes e) pKa is the pH at which more than half of a local anaesthetic exists in non-ionised form

196. 3. Concerning local anaesthetics: a) they are absorbed more rapidly after intercostal block than after caudal administration Tb) in the foetus they are able to cross the placenta as readily as from the mother Fc) they are weak acids Fd) those which are esters are rapidly metabolised by liver enzymes Fe) pKa is the pH at which more than half of a local anaesthetic exists in non-ionised form F

197. 4.Cocaine: A. Blocks reuptake of dopamine and noradrenaline B. Central effects are due to noradrenaline C. Crosses lipid soluble membranes because its pKa is 2.8 D. Is not metabolised by plasma pseudocholinesterase E. Rapidly absorbed by nasal mucosa

198. Cocaine: A. Blocks reuptake of dopamine and noradrenaline T B. Central effects are due to noradrenaline F C. Crosses lipid soluble membranes because its pKa is 2.8 F D. Is not metabolised by plasma pseudocholinesterase F E. Rapidly absorbed by nasal mucosa ?

199. 5.Ropivacaine A. Is a pure R isomer B. Is an isomer of bupivacaine C. Provides more motor block than bupivacaine D. Has more toxicity than bupivacaine E. Has similar physico-chemical properties to bupivacaine

200. 5.Ropivacaine A. Is a pure R isomer F B. Is an isomer of bupivacaine F C. Provides more motor block than bupivacaine F D. Has more toxicity than bupivacaine F E. Has similar physico-chemical properties to bupivacaine T

201. THANK YOU Q&A