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Local Anaesthetics

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  • 1. LOCAL ANAESTHETICS Presenter : Dr Unnikrishnan P Coordinator : Dr C Madhusoodhanan Pillai Moderators : Dr Ushakumari Dr Kiran DEPARTMENT OF ANESTHESIOLOGY
  • 2. … .framework
  • 3. What they do?
  • 4. Chronology of local anesthetics Cocaine Benzocaine Procaine Tetracaine Lidocaine Cl2 procaine Mepivacine Bupivacaine Ropivacaine Niemann Salkowski Einhorn Eisler Lofgren Marks, Rubin Ekenstam Ekenstam Sandberg 1860 1895 1904 1928 1943 1949 1956 1957 1989 Ester Ester Ester Ester Amide Ester Amide Amide Amide
  • 5. 1884…..
  • 6. ANATOMY & PHYSIOLOGY OF NERVE CONDUCTION
  • 7. … .. Me neuron
  • 8.
  • 9. UNITY IN DIVERSITY ! TYPE DIA [um] VEL [m/sec] LOCATION FUNCTION SUSC TO LA
    • A
    6-22 30-120 EFFERENT TO MS MOTOR TO Sk M ++
    • A
    6-22 30-120 AFFERENT FROM SKIN &JOINTS TACTILE , PROPRIO ++
    • A
    3-6 15-35 EFFERENT TO MUSCLE SPINDLES MUSCLE TONE ++++
    • A
    1-4 5-25 AFFERENT SENSORY NERVES
    • P,C,T,T
    +++ B <3 3-15 PRE GANGLIONIC SYMP AUTO ++ Sc C 0.3-1.3 0.7-1.3 POST GANGLIONIC SYMP AUTO ++
    • D C
    0.4-1.2 0.1-2.0 AFFERENT SENSORY NERVES AUTO, DULL Pn,Wmt, Tch +
  • 10. AXOLEMMA
  • 11. SCHWANN CELLS & MYELIN
  • 12. MYELIN …MYELIN….MYELIN
    • Schwann cells groups and covers axon
    • Plasma membrane – Myelin
    • UM – single shirt for many!
    • M – individual shirts!
  • 13. MYELINATED NERVE FIBERS ARE UNIQUE
    • Nodes of Ranvier
    • Why this gap important?
    • How the current passes in M & UM
    • Advantage : M
  • 14. The coverings…
  • 15. PHYSIOLOGY OF NERVE CONDUCTION
  • 16. A resting state….. is necessary .
  • 17. The gradients….
  • 18. 3 Na + High [Na + ] Low [Na + ] 2 K + Low [K + ] High [K + ]
  • 19. CLOSED or RESTING STATE OF Na CHANNEL
  • 20. Na + channels close and K + channels open, K + floods out of neurone Resting potential © 2008 Paul Billiet ODWS -70 -55 0 +35 Threshold mV Time Resting potential Action potential
  • 21. Fig. 2-17, p. 45
  • 22. Depolarization is due to the influx of Na + Na +
  • 23. The flow of Na + ion into the axon makes the membrane adjacent more permeable to sodium ions. Consequently a wave of Na + influx moves along the length of the axon. Na +
  • 24. OPEN STATE OF Na CHANNEL
  • 25. Na + channels close and K + channels open, K + floods out of neurone Resting potential © 2008 Paul Billiet ODWS -70 -55 0 +35 Threshold mV Time Resting potential Action potential
  • 26. INACTIVATED STATE OF Na CHANNEL
  • 27. The combined movement of sodium ions into the axon followed by the flow of potassium ions out of the axon makes up what is called the nerve impulse Na + K +
  • 28. Active pumping of Na + out and K + in during the refractory period Hyperpolarisation of the membrane © 2008 Paul Billiet ODWS -70 -55 0 +35 Threshold Time mV Resting potential Resting potential Action potential
  • 29. Fig. 2-19, p. 46
  • 30. Ty
  • 31. Structural characteristics of Na v channels
    • 1 larger  subunit (260 kD) (has ion conducting path)
    • 1 or 2 smaller  subunits ( 30 kD)
    • All subunits heavily glycosylated
    From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
  • 32. Structural characteristics of Na v channels
    • 1 larger  subunit (260 kD) (has ion conducting path)
    • 1 or 2 smaller  subunits ( 30 kD)
    • All subunits heavily glycosylated
    From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
  • 33. Structural characteristics of Na v channels
    • 1 larger  subunit (260 kD) (has ion conducting path)
    • 1 or 2 smaller  subunits ( 30 kD)
    • All subunits heavily glycosylated
    From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
  • 34. Structural characteristics of Na v channels
    • 4 domains
    • have 6
    • membrane-
    • spanning
    • α -helical
    • segments
    • (S1-S6)
    • S5-S6 P-loop part of ion-conducting pore
    Plummer, Meisler. Genomics 1999;57:323-31 Cytoplasm
  • 35. ..that’s all about the nerve..
  • 36. MECHANISM OF ACTION
  • 37. General Info:
    • Weak bases
    • pKa 7.5-9.5
    • HCl salts
    • Ph @ 4-7
    • Neutral bases & cationic species
    • Physiological buffers
    • More HP moiety>easy crossing
    • Acidic env inside
    • Ion trapping
  • 38. true OR false
    • Cm is the min conc of LA that will block nerve conduction
    • High pKa fastens onset
    • Cl2 pro has a high pKa but faster onset
    • Readymade ligno with adr has a slower onset than “handmade”
    • Tachyphylaxis not occurs in case of LA
  • 39. Neutral base Vs Cationic moiety
  • 40. Duality!
  • 41. In short….
    • HYDROPHOBICITY DELIVERS THE DRUG INSIDE [is the pass ticket] AND CHARGE KEEPS IT THERE [is the stay ticket]
  • 42. How the nerve react?
    • Height of AP decrease..
    • Firing threshold elevated...
    • Velocity decrease…
    • Refractory period lengthened..
  • 43.  
  • 44. KAUN BANEGA……..
    • Which compound blocks Na channel from outside?
    • meperidine
    • TCA
    • tetrodotoxin
    • ketamine
  • 45. Many classes of compounds bind and inhibit Na channels
    • Local anesthetics
    • General anesthetics
    • Ca channel blockers
    •  2 agonists
    • Tricyclic antidipressants
    • Substance P antagonists
    • Many nerve toxins
      • Batrachotoxin
      • Grayanotoxin
      • Tetrodotoxin (TTX)
  • 46. LAs bind and inhibit many differing receptors and channels
    • Do not assume LA toxic side effects arise from Na channel inhibition!
    Anesthesiology 1990; 72:711-34
  • 47. LAs bind and inhibit many differing receptors and channels
    • Na, K, Ca channels
    • G-protein modulation of channels
    • Many enzymes
      • Adenylyl cyclase
      • Guanylyl cyclase
      • Lipases
    • Many receptors
      • Nicotinic acetylcholine
      • NMDA
      • β 2 -adrenergic
    Anesthesiology 1990; 72:711-34
  • 48. USE DEPENDENT / PHASIC BLOCK
  • 49. Thanks God!
    • During onset & recovery the blockade is partial…
    • Who keeps the patient calm?
    • But clinically time taken to cross the whole nerve more important.
  • 50.  
  • 51. DIFFERENTIAL SENSITIVITY
    • Small myelinated A gamma, A delta
    • Large myelinated A alpha, A beta
    • Small non myelinated- least-slowest
    • Difference in critical length
  • 52. Manifests as… LSAB
  • 53. Manifests as …. epidural
  • 54. Na channel also comes in 10 different forms
    • Aberrant impulses susceptible even to systemic Lignocaine
  • 55. PHARMACOLOGY
  • 56. Local anesthetics: amides vs. esters
    • Common structure
      • Aromatic ring
      • Tertiary amine
      • Alkyl chain
    • Linking bond
      • Amide bond ( see lidocaine )
      • Ester bond ( see procaine )
    Lidocaine Procaine
  • 57.  
  • 58. Basic structure
  • 59. Why these two parts?
    • Lipophilic aromatic ring aids in penetration
    • Hydrophilic part accepts protons and occupies Na channel
  • 60. Comparing them… AMIDES ESTERS Heat..? No problem…. Low pKa. More penetration Less allergy Enzymatic / liver Linear: less, cyclic:lesser Use dep block less Oh God.. No never Less.. ‘ PABA’llergy! p. Cholinesterase -> PABA Potent ester &ether! More
  • 61. AMIDES HAVE… AMIDES ESTERS LIDOCAINE PRILOCAINE MEPIVACAINE ETIDOCAINE BUPIVACAINE ROPIVACAINE LEVOBUPIVACAINE COCAINE PROCAINE CHLOROPROCAINE TETRACAINE BENZOCAINE
  • 62. ……………… TWO “i” s
  • 63. ,
  • 64. MODIFICATIONS
    • Lengthening carbon chains..
    • Lipid solubility increase
    • Potency increase
    • Duration of axn increase
  • 65. structures
  • 66. PROCAINE VS TETRACAINE
  • 67. MODIFICATIONS
    • Halogenation
    • Decrease duration of axn
    • Decrease toxicity
    • E.g. procaine to chloroprocaine
  • 68. PIPECOLOXYLIDIDES
    • E.G. MEPIVACAINE
    • BUPIVACAINE
    • ROPIVACAINE
    • Butyl to mepivacaine : Bupivacaine
    • Propyl to mepivacaine : Ropivacaine
  • 69. MODIFICATION
    • Increasing the length of intermediate alcohol
    • Increase the potency up to c3-c7
  • 70. PIPECOLOXYLIDIDES are CHIRAL s
    • mepivacaine and bupivacaine are racemic mixtures
    • Ropivacaine as pure S enantiomer
  • 71. POTENCY
  • 72. FACTORS AFFECTING…
    • HYDROPHOBICITY
    • CHARGE
    • VASOACTIVE PROPERTIES
    • TISSUE SEQUESTRATION
    • RMP
    • Ph
    • Freq & durn of dep pulses
    • TEMPERATURE
    • K+ BLOCKADE: pro / lido
    • MYELIN DEPO: etido
  • 73. ONSET
  • 74. Duration of action
    • PROTEIN BINDING
    • increase /= better binding with Na c
    • alpha 1 acid GP
    • hypoxia/ hyperCO2/ acidemia inc
    • neo and child
    • VASOACTIVITY
    • biphasic
    • LIDO-MEPI-PRILO …duration = but..
    • ROPI-BUPI…duration = but Ropi
  • 75. Duration of action
  • 76. D I F F E R E N T I A L BLOCKADE
    • Lipid solubility & pKa: bupi & ropi
    • Critical length
    • Density of Na- diameter- so A delta i.e. pain and temp first disappear
    • Length of drug exposed nerve
    • Na over K
    • Differences in susceptibility of Na
    • Repetitive stimuli
  • 77. DOSE
  • 78. Vaso constrictors
    • Epinephrine 5ug/ml or 1:200000
    • Decrease absorption
    • Act as a marker
    • Alpha receptors in spinal cord activate endo mechanisms
    • Lidocaine best friend/ 50%
    • Bupi motor- sensory +
    • Nor epi /phenyl ephrine… hmm No
  • 79. Site of injection
  • 80. reasons
  • 81. Carbonattion
  • 82. Soda bicarbonate ? pain ?
  • 83. Mixture of LA
  • 84. Pregnancy / dose decreased
  • 85. PHARMACOKINETICS www.bioteach.ubc.ca
  • 86. ABSORPTION
  • 87. SITE
  • 88. ORDER
  • 89. PHYSIOLOGIC DISPOSITION
  • 90. So….
    • I.V. or intra arterial more dangerous?
  • 91. Biotransformation & excretion
  • 92. renal
  • 93. PATIENT STATUS
  • 94. STATUS
  • 95. Balanced emotions….
  • 96. Take home message….
    • The best way to take revenge is ….
    • … ..to select a topic and conduct a symposium.
  • 97. … .