More Related Content
Similar to local anesthetics pharmacology
![10. Local anaesthetics [Autosaved].pptx](https://cdn.slidesharecdn.com/ss_thumbnails/10-230227080146-90018189-thumbnail.jpg?width=640&height=640&fit=bounds)
local anesthetics pharmacology
- 1. JJM MEDICAL COLLEGE DAVANGERE DEPARTMENT OF ANAESTHESIOLOGYSEMINAR ONPHARMACOLOGY OF LOCAL ANAESTHETICS CHAIRPERSON PRESENTED BY DR.RAVI.R DR.RAVIVARMA.D PROFFESSOR PG IN ANAESTHESIA DEPT OF ANAESTHESIA
- 3. INTRODUCTIONLocal and regionalanaesthesia techniques depend on group of drugs “ local anaesthetics “ that produces transient loss of sensory,motor and autonomic functions Detailed knowledge about the pharmacology is essential for the better use of these drugs in clinical practice
- 4.
- 5. A brief lookat how it all startedCocaine --- natural product
- 6.
- 7. Chewed coca drippedon trepanning sites
- 8. Mixed with cornstarch, chewed with guano, CaCO3, or ash; first example of “free basing”
- 9. Monardes brings cocaleaves back to Europe (1580); fail to achieve instant popularity of tobacco
- 10. It all startedwith cocaineCocaine HCl isolated by Albert Niemann (1860)
- 11. Merck produces 100g cocaine (1862)
- 12. Koller and Gartnerreport local anesthesia (1884)
- 13. Merck produces 1450kg (1884); 72,000 kg (1886)
- 14. Coca-Cola (1886) andmany other products contain cocaine
- 15.
- 16.
- 17. Basic conceptsWhat istertiary amine ?
- 18. What is quaternaryamine ?Crossing the wall
- 19. Common framework oflocal anaesthetics1. The aromatic ring gives thelipophillic character. 2. The tertiary amine is relatively hydrophilic. 3. The intermediate bond mayEstericor Aminoamide.
- 20. The switch regulatortheoryAROMATIC RINGTHE AMINE COMPONENT
- 22. Lipophillic hydrophilic balanceThisbalance depends on the size of the alkyl substituents on or near the tertiary amine and on the aromatic ring.
- 23. Compounds with morelipophillic nature is obtained by increasing the alkyl substituents.
- 24. When the compoundis more lipophillicit means that it is more potent and long acting.The Pka influence
- 25. More chemistryLocal anestheticbases are poorly to sparingly soluble in water but are quite soluble in relatively hydrophobic organic solvents.
- 26. Therefore, as amatter of chemistry (and to optimize shelf life), most of these drugs are formulated as hydrochloride salts. Who is the fastest?an irony
- 27. The protein bindingLocalanaesthetics which are alkaline binds avidly to alpha 1 acid glycoprotein
- 28. Acidic drugsbind to albumin
- 29. The protein binding indirectly denotes the avidity with which the receptor protein is bound by the local anaesthetics.
- 30. More the localanaesthetic is protein bound, longer is its duration of action. Eg : bupivacaine.classification
- 31.
- 32. Fast recap ofnerve physiology
- 33.
- 34. Ionic currents inaction potential genesis1.what is resting membrane potential? 2. which ion maintains the RMP ? 3. what is the RMP of the nerve ? 4. what is all or none law ?
- 35.
- 36.
- 37. The positive loopof action potential
- 38. Pattern of currentpropagation what is the difference ?NON MYELINATED FIBRESB. MYELINATED FIBRES
- 39. Mechanism of actionoflocal anaesthetics
- 40. Electrophysiological effects1. whatdo these terms mean ?2. what is frequency dependent block ? 3. what is the reason for it ?Tonic inhibitionPhasic inhibition
- 41. Understanding the sodiumgatesresting activated inactivated the upper gate is voltage dependent the lower gate is time dependent
- 42. Binding of localanaesthetics is increased by membrane depolarization for two reasons: 1 . More binding site becomes accessible during activation – The guarded receptor model 2. drug dissociation from the inactivated channels is slower than from the resting channel – The modulated receptor model
- 43. Structural conformations ofsodium channel
- 44. Sodium channelcomes in ten types10 distinct Na channel genes in mammals
- 45. 10 human geneson 4 chromosomes (5 on Chr 2 and 3 on Chr 3)
- 46. Nav1.2 channels inaxons of unmyelinated neurons
- 47. Nav1.6 channels innodes of Ranvier
- 48. Nav1.8, Nav1.9 insmall DRG nociceptorsVersatility of the sodium currents Long distance propagation of action potentials in nerve and muscle
- 49. Shape and filtersynaptic inputs
- 50. Back propagation ofdendritic action potentials (associate synapticplasticity)
- 51. Initiate, maintain cellularoscillations (sinus node) and burst generation
- 52.
- 53. Mutations lead tomuscle, cardiac, neural diseasesOther targets of local anaesthetics Inhibition of adenylcyclase This property of bupivacaine explains the difficulty in resuscitating patients withepinephrine during bupivacaine induced cardiac arrest .
- 54. Other targets Inhibitionof cardiac calcium channels: The inhibition of calcium channels in the cardiomyocytes has been proposed as an additional reason for the negativeionotropiceffect of local anaesthetics.
- 55.
- 56.
- 57. β2-adrenergic EnzymesGuanylylcyclase
- 58. LipasesImportant for spinal,epidural effects of local anaesthetics ?
- 59. Odd man outBenzocaine….Doesnot exist in a charged form how does it work?
- 60. Most likely byexpanding the lipid membrane of the axon and therefore inhibiting the transport mechanisms of Na and K ions.“susceptibility”Different fiber types in the nerve are affected differently during local anesthesia. At least part of this difference arises from pharmacokinetic factors
- 61. “Different fiber typesare also differentially sensitive to local anesthetic blockade. In vivo experiments in which continuous superperfusion of peripheral nerve analogous to clinical peripheral nerve block, show unequivocally that small myelinated axons (Aγmotor and Aδ sensory fibers) are the most susceptible to impulse annihilation. Next in order of block are the large myelinated (Aα and Aβ) fibers, and the least susceptible are the small, nonmyelinated C fibers”
- 62. “ The generalizednotion that local anesthetics block the smallest fibers first or most is clearly wrong.”
- 63. summary1. Solutionsof local anesthetic are deposited near the nerve. Removal of free drug molecules away from this locus is a function of tissue binding, removal by the circulation, and local hydrolysis of aminoester anesthetics. 2. Local anesthetic molecules then permeate the nerve's axon membranes and reside there and in the axoplasm. The speed and extent of these processes depend on a particular drug's pKaand on the lipophilicity of its base and cation species.
- 64. 3. Binding oflocal anesthetic to sites on voltage-gated Na+ channels prevents opening of the channels by inhibiting the conformational changes that underlie channel activation. Local anesthetics bind in the channel's pore and also occlude the path of Na+ ions. 4. The clinically observed rates of onset and recovery from blockade are governed by the relatively slow diffusion of local anesthetic molecules into and out of the whole nerve, not by their much faster binding and dissociation from ion channels.
- 65.
- 66. difference The ester and amide local anesthetics differ in their chemical stability, locus of biotransformation, and allergic potential.
- 67.
- 68. Onset of actionOnsetof action primarily depends on the Pka of the given local anaesthetics as described earlier .
- 69. Chloroprocaine has arapid onset of action in humans despite the fact that its Pka is approximately 9 and its proportion of chargedmolecules is high (97 % ) why is that so ?
- 70. It is becausechloroprocaine is used in large concentration ( 3 % ) due to its low toxicity.
- 71. So clinicallyconcentration of the drug also plays a pivotal role in determining the latency.
- 72. Duration of actionProteinbinding of the local anaesthetic mainly determines the duration of action
- 73. The pheripheral vasculareffects of local anaesthetic also influences the duration of action
- 74. Usually they havea biphasic effect on vasculature
- 75. Key lies inthe degree of vasodilatation
- 76. Eg : Lidocaineis a more potent vasodilator than Bupivacaine.Anesthetic potencyHydrophobicity appears to be a primary determinant of intrinsic anaesthetic potency.
- 77. Clinically however thisis not as precise as in an isolated nerve.
- 78. Eg : Etidocaineis more potent than Bupivacainein isolated nerve but the same does not holds good in vivo, where Bupivacaine is slightly more potent.
- 79. Due to interplayingof several factors in vivoDifferential blockadeWhat is differential blockade ?
- 80. Bupivacaine is morepopular than etidocaine(which is also long acting) because of the differential blockade property.
- 81. The older conceptof fiber diameter based susceptibility to local anaesthetics is no longer valid for explaining the differential blockade. Why ?
- 82. Newer concepts: 1. The length of drug exposed nerve in the intrathecal space. 2. Selective ability to inhibit Na channels over K channels.
- 83. Factors influencing anaestheticactivity in humans
- 84. dosageAs the dosageis increased the probability and duration of satisfactory anaesthesia increase and the time of onset is shortened.
- 85. The dosage canbe increased by increasing the volume or concentration of the drug.
- 86. The volume perse influences the spread of anaesthesia.
- 87. Eg : 30ml of 1 % lidocaine administered into the epidural space produced level of anaesthesia that is 4.3 dermatomes higher than that achieved when 10 ml of 3 % lidocaine was used.Addition of vasoconstrictorsWhat is rationale of use of epinephrine ?
- 88. What is theconcentration used commonly ?
- 89. What are thephysiological effects ?
- 90. Which combination isadvantageous ?
- 91. Problems with betablockers ?
- 92. What is themisconception regarding TCA s ?PHYSIOLOGICAL EFFECT
- 93. The effect ofbeta blockers
- 94. Site of injectionMostrapid onset and shortest duration of action – intrathecal administration
- 95. Longest latencies anddurations -- brachial plexus blocks
- 96. Why is thatso ?Carbonation of local anaestheticsWhat is the rationale of increasing the Ph of local anaesthetic solution using sodium bicarbonate ?
- 97. Controversies exists concerningthe clinical utility of carbonated local anaesthetics !
- 98. Alkalinization of bupivacaine,levobupivacaine is difficult than that of lidocaine.
- 99. What amount ofsodium bicarbonate is to be used for different anaesthetics ?Mixtures of local anaestheticsIdea is to combine a anaesthetic which has a rapid onset but shorter duration with another anaesthetics which has a longer duration but long latency period.
- 100. Has mixed resultsin different studies
- 101. The use ofcatheter techniques for regional blocks has alleviated the need for anaesthetic mixtures. CAUTION: do not use the maximum doses of two local anaesthetics in combination in the mistaken belief that their toxicities are independent.
- 102. pregnancyThe spread anddepth of epidural and spinal anesthesia are greater in pregnant than in nonpregnant women
- 103. Anatomical factors andhormonal factors
- 104. Hormonal alterations areprobably the more important of these two factors because greater spread of epidural anesthesia occurs during the first trimester of pregnancy, before any gross change in vascular dimensions within the epidural or subarachnoid spaces.
- 105. The dosageof local anesthetics should probably should be reduced in patients in all stages of pregnancy.Clinical use
- 106. Infiltration anaesthesiaOnset ofaction is almost immediate for all agents after intradermal or subcutaneous administration; however, the duration of anesthesia varies.
- 107. When largesurface areas have to be anesthetized, large volumes of dilute anesthetic solutions should be used.
- 108. As an example,consider a 4-kg infant receiving infiltration anesthesia with the maximum safe dose of lidocaine, 5 mg/kg. Dosing to 5 mg/kg × 4 kg permits 20 mg, which is 1 mL of a 2% solution or 4 mL of a 0.5% solution.
- 109. Lidocaine is effectivefor infiltration in concentrations as dilute as 0.3% to 0.5%, so the more dilute solution can be used more safely to anesthetize a larger area.
- 110. ivraLidocaine has beenthe drug used most frequently for intravenous regional anesthesia
- 111. One might supposea safety advantage with the aminoester-linked compounds because of their hydrolysis in blood; however, thrombophlebitis has been reported in several patients with chloroprocaine.
- 112. Cardiovascular collapsehas occurred after the use of bupivacaine for intravenous regional anesthesia, and this use of bupivacaine is discouraged.
- 113. In general,approximately 3 mg/kg (40 mL of a 0.5% solution) of preservative-free lidocaine without epinephrine is used for upper extremity procedures. For surgical procedures on the lower limbs, 50 to 100 mLof a 0.25% lidocaine solution has been used.Minor nerve blocks
- 114.
- 115.
- 116.
- 118. emlaA variety oftopical local anesthetic formulations have been developed to penetrate intact skin.
- 119. It isa eutectic mixture of 2.5% lidocaine base and 2.5%prilocaine base
- 120. It iswidely used for venipuncture, intravenous cannulation, skin grafting, and a range of other uses, including circumcision.
- 121. This preparation mustbe applied under an occlusive bandage for 45 to 60 minutes to obtain effective cutaneous anesthesiapharmacokinetics
- 122. absorptionThe systemic absorptionof local anesthetics is determined by the site of injection, dosage and volume, addition of a vasoconstrictor agent, and the pharmacologic profile of the agent itself.biotransformationThe pattern of metabolism of local anesthetic agents varies according to their chemical classification.
- 123. The ester, orprocaine-like, drugs undergo hydrolysis in plasma by the pseudocholinesterase enzymes; clearance of chloroprocaineis especially rapid.
- 124. The aminoamide drugsundergo enzymatic degradation primarily in the liver. Lidocaine is metabolized somewhat more rapidly than mepivacaine, which in turn is more rapidly metabolized than bupivacaine.
- 125. Excretion of themetabolites of amide-type local anesthetics occurs via the kidney. Patient status
- 126.
- 127. forewordLocal anaesthetics areusually safe in appropriate dosage and in correct anatomical location.
- 128. However local andsystemic toxicities can arise usually as a result of accidental intravascular or intrathecal injection or administration of excessive dose.Systemic toxicityMainly CNS and CVS are involved.
- 129. In general CNSis more susceptible to actions of systemic local anaesthetics compared to that of CVS
- 130. Hence the bloodlevels of LA used to cause CNS toxicity is usually lower than that resulting circulatory collapse.Central nervous system toxicityInitial symptoms are light headedness and dizziness followed frequently by visual and auditory disturbances such as tinnitus.
- 131. Objective signs areusually excitatory in nature like shivering, twitching particularly in face and distal parts of the extremities.
- 132. These can leadto development of generalized tonic clonicseizures.
- 133. If dose injectedintravascularly is really high then patient goes into a state of generalized depression which ultimately goes for respiratory arrest.Why excitation ,when la usually blocks sodium channelsTwo reasons has been quoted : 1. The inhibitory pathways are blocked earlier so that the facilitatory neurons functions in unopposed manner. 2. It can also be caused by the net stimulation of release of glutamate in the central nervous system.
- 134. La dose andblood concentrations producing convulsion in sheepRutten. AnesthAnalg 1989;69:291-9
- 135. The influence ofacidosis Respiratory and metabolic acidosis increases the risk of CNS toxicity of LA by : 1. Enhancing the cerebral blood flow 2. Causing intracellular acidosis 3. Ion trapping 4. Decreased protein binding What is the clinical implication ?
- 136. Cardiovascular systemic toxicityDirectcardiac effects : 1. The primary effect is the decrease in the rate of depolarization in the fast conducting tissues of purkingefibres and ventricular muscle. 2. Bupivacaine depresses the rapid phase of depolarization to a greater extent than lidocaine 3. ECG shows an increase in PR interval and the duration of QRS complex 4. All LA exert a dose dependent negative ionotropicaction on cardiac muscle.
- 137. Why cant bupivacainebe used as anti arrhythmic
- 138.
- 139. Direct peripheral vasculareffectLocal anaesthetics exert biphasic action on the vascular smooth muscle
- 140. Low concentrations oflidocaine and bupivacaine causes vasoconstriction while higher doses cause vasodilatation
- 141. Cocaine is theonly LA which causes vasoconstriction in all doses and it is neurogenicComparitive cardiovascular toxicityThe cardiotoxicity of bupivacaine appears to differ from that of lidocaine in the following manner: 1. The CC / CNS ratio of bupivacaine is much lower than that of lidocaine2. Ventricular arrhythmias are more common with bupivacaine than lidocaine 3. The 0.75 % bupivacaine is no longer recommended for obstetric patients in united states 4. Cardiac resuscitation is more difficult after bupivacaine induced cardiac arrest when compared to lidocaine
- 142. La blood concentrationproducing cardiac arrest in dogsμg/mlGroban et al AnesthAnalg 2000;91:1103-11
- 143. VENTRICULAR ARRHYTHMIAS AFTERSUPRA CONVULSANT DOSES OF LAFeldman et al AnesthAnalg 1989;69:794-801
- 144. Preventive and treatmentaspectsNo medications are uniformly effective in facilitating resuscitation from bupivacaine induced cardiac arrest or arrhythmias
- 145.
- 146. Continuous attention tothe ECG
- 147. Intralipid20 % transfusionIntralipid20 %Animals not resuscitated using ACLS recovered when given lipid emulsion
- 148. Lipid may drawbupivacaineinto plasma from binding site(s) in the heart
- 149. No human studiesbut plenty of case reports are available
- 150. Dose : rapidbolus of 1.5 ml/kg and if necessary 0.25 ml/kg/min for the next 10 minIntralipid 20%Weinberg. Anesthesiology 1998;88:1071-5
- 151. Indirect cardiovascular effectsHighlevels of spinal and epidural blockade can produce severe hypotension
- 152. Usually occurs inhigh dermatomal levels of blockade, liberal use of sedatives, delays in recognition of the problem, delays in administration of direct acting combined alpha and beta agonists such as epinephrine
- 153. The dose isincremental ranging from 0.1 to 1 micro gram / kgmethemoglobinemiaA unique side effect of large doses of prilocaine
- 154. More than 600mg is required for the development of clinically significant levels of methemoglobinemia in adults
- 155. Hepatic metabolism ofprilocaine generates O-toluidine , which oxidizes hemoglobin to methemoglobin
- 156. EMLA should beregarded as very safe in the great majority of newbornsallergiesEven though patients receiving LA may experience a range of local and systemic reactions, studies confirm that very few of this reactions are confirmed to be allergic reactions
- 157. Aminoesters may produceallergic reaction more commonly than amides but even with esters, vast majority of reactions are not allergic
- 158. Esters are PABAderivatives
- 159. Methylparaben used asa preservative in amides closely resemble the chemical structure of PABALocal tissue toxicityMore commonly seen with lignocaine and chloroprocaine.
- 160. A meta-analysis concludedthat the pooled relative risk for transient neurologic symptoms after spinal anesthesia with lidocaine was 6.7-fold higher than with bupivacaine and 5.5-fold higher than with prilocaine
- 161. Studies suggest thatthe combination of low pH, sodium bisulfite, and inadvertent intrathecal dosing is responsible in part for the neurotoxic reactions observed after the use of large amounts of chloroprocaine solutionChiral local anaesthetic Commercial bupivacaine is a racemicmixture of (R)- and (S)-stereoisomers.
- 162.
- 163. Ropivacaine (Naropin)and levo-(S)-bupivacaine(Chirocaine)were formulated to exploit this stereoselectivity.
- 164. Ropivacaine is asingle (S)-stereoisomer that differs from levobupivacaine in the substitution of a propyl for the butyl group on the piperidine ring .
- 165. Conversely, it appearsthat the (S)-enantiomers of bupivacaine are metabolized by the liver more slowly than the corresponding (R)-enantiomers.
- 166. The very slowreversal of Na+ channel blockade after a cardiac action potential, which is a hallmark of bupivacaine, is considerably faster with ropivacaine.
- 167. Overall, itappears that ropivacaine is slightly less potent than (1 : 1.3 to 1 : 1.5) bupivacaine for regional anesthesia.
- 168. The overall impressionis that ropivacaineis less cardiotoxic than bupivacaine. futureSeveral methods for producing long-duration nerve blockade are under investigation.
- 169. Liposomal encapsulation canprolong nerve blockade, depending on the dose and the physical properties of the liposome (surface charge, size, lamellar structure).
- 170. Local anesthetics canbe incorporated into biodegradable polymer microspheres for sustained release. These preparations produce peripheral nerve blockade in animal models and human volunteers ranging from 2 to 8 days, depending on the dose, site, and species.
- 171. Prolonged-duration local anesthesiaalso appears to be feasible with the use of site 1 sodium channel toxins.REFERENCES : 1.MILLERS ANAESTHESIA 7th edition2.STOELTING’S PHARMACOLOGY 4th edition3.BASIC PHARMACOLOGY – KATZUNG 10th edition.4.CLINICAL ANAESTHESIOLOGY – MORGAN 4th edition5.ESSENTIALS OF LOCAL ANAESTHETIC PHARMACOLOGYAnesthProg. 2006 Fall; 53(3): 98–109.6.CLINICAL ANAESTHESIA – BARASH 6th edition7.NYSORA – WEBSITE
- 172.