local anaesthetics
TRANSCRIPT
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LOCAL ANAESTHETICS
Presenter : Dr Unnikrishnan P
Coordinator : Dr C Madhusoodhanan PillaiModerators : Dr Ushakumari Dr KiranDEPARTMENT OF ANESTHESIOLOGY
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….framework
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What they do?
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Chronology of local anesthetics
CocaineBenzocaineProcaineTetracaineLidocaineCl2 procaineMepivacineBupivacaineRopivacaine
NiemannSalkowskiEinhornEislerLofgrenMarks, RubinEkenstamEkenstamSandberg
186018951904192819431949195619571989
EsterEsterEsterEsterAmideEsterAmideAmideAmide
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1884…..
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ANATOMY & PHYSIOLOGY OF NERVE CONDUCTION
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…..Me neuron
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…
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UNITY IN DIVERSITY!TYPE DIA
[um]VEL [m/sec]
LOCATION FUNCTION
SUSC TO LA
α A 6-22 30-120 EFFERENT TO MS MOTOR TO Sk M
++
β A 6-22 30-120 AFFERENT FROM SKIN &JOINTS
TACTILE , PROPRIO
++
۷ A 3-6 15-35 EFFERENT TO MUSCLE SPINDLES
MUSCLE TONE
++++
δ 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 ++
۷D C 0.4-1.2 0.1-2.0 AFFERENT SENSORY NERVES
AUTO, DULL Pn,Wmt, Tch
+
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AXOLEMMA
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SCHWANN CELLS & MYELIN
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MYELIN …MYELIN….MYELINSchwann cells groups and covers
axonPlasma membrane – Myelin UM – single shirt for many! M – individual shirts!
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MYELINATED NERVE FIBERS ARE UNIQUE
Nodes of Ranvier
Why this gap important?
How the current passes in M & UM
Advantage : M
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The coverings…
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PHYSIOLOGY OF NERVE CONDUCTION
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A resting state….. is necessary.
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The gradients….
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A short section of the axon
cell membrane
cytoplasm
extracellular fluid
3 Na+
High [Na+]
Low [Na+]
2 K+
Low [K+]
High [K+]
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CLOSED or RESTING STATE OF Na CHANNEL
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-70
-55
0
+35
Threshold
mV
Time
Resting potential Action potential
Na+ channels close and K+ channels open, K+ floods out of neurone
Resting potential© 2008 Paul Billiet ODWS
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Fig. 2-17, p. 45
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+ + + - - - - - - -
- - - + + + + + + +
+ + + - - - - - -
- - - + + + + + +
neurotransmitter
Depolarization is due to the influx of Na+
Na+
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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+
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OPEN STATE OF Na CHANNEL
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-70
-55
0
+35
Threshold
mV
Time
Resting potential Action potential
Na+ channels close and K+ channels open, K+ floods out of neurone
Resting potential© 2008 Paul Billiet ODWS
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INACTIVATED STATE OF Na CHANNEL
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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+
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-70
-55
0
+35
Threshold
Time
mV
Resting potential Resting potential
Action potential
Active pumping of Na+ out and K+ in during the refractory period
Hyperpolarisation of the membrane
© 2008 Paul Billiet ODWS
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Fig. 2-19, p. 46
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Ty
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Structural characteristicsof Nav 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-S48Ann Rev Biochem 1995;6:493-531Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
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Structural characteristicsof Nav 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-S48Ann Rev Biochem 1995;6:493-531Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
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Structural characteristicsof Nav 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-S48Ann Rev Biochem 1995;6:493-531Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
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Structural characteristicsof Nav 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
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..that’s all about the nerve..
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MECHANISM OF ACTION
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General Info:
Δ Weak basesΔ pKa 7.5-9.5Δ HCl saltsΔ Ph @ 4-7Δ Neutral bases & cationic speciesΔ Physiological buffersΔ More HP moiety>easy crossingΔ Acidic env insideΔ Ion trapping
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true OR falsetrue OR false
Cm is the min conc of LA that will block nerve conductionHigh pKa fastens onsetCl2 pro has a high pKa but faster onsetReadymade ligno with adr has a slower onset than “handmade”Tachyphylaxis not occurs in case of LA
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Neutral base Vs Cationic moiety
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Duality!
14
2
3
H+
R-N + H+ R-NCH3
CH3
CH3
CH3
H+
R-N + H+ R-NCH3
CH3
CH3
CH3
Outer
Inner
1. Uncharged form enters cell
2. Charged form binds to inhibitory site
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In short….
HYDROPHOBICITY DELIVERS THE DRUG INSIDE [is the pass ticket] AND CHARGE KEEPS IT THERE[is the stay ticket]
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How the nerve react?
Δ Height of AP decrease..
Δ Firing threshold elevated...
Δ Velocity decrease…
Δ Refractory period lengthened..
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KAUN BANEGA……..KAUN BANEGA……..
Which compound blocks Na channel from outside?
meperidine TCA tetrodotoxin ketamine
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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)
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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
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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
– β2-adrenergic
Anesthesiology 1990; 72:711-34
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USE DEPENDENT / PHASIC BLOCK
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Thanks God!
Δ During onset & recovery the blockade is partial…
Δ Who keeps the patient calm?
Δ But clinically time taken to cross the whole nerve more important.
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DIFFERENTIAL SENSITIVITY
Small myelinated A gamma, A delta
Large myelinated A alpha, A beta
Small non myelinated- least-slowest
Difference in critical length
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Manifests as… LSAB
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Manifests as ….epidural
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Na channel also comes in 10 different forms
Aberrant impulses susceptible even to systemic Lignocaine
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PHARMACOLOGY
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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
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Basic structure
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Why these two parts?
Lipophilic aromatic ring aids in penetration
Hydrophilic part accepts protons and occupies Na channel
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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 ðer!
More
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AMIDES HAVE…
AMIDES ESTERS
LIDOCAINEPRILOCAINEMEPIVACAINEETIDOCAINEBUPIVACAINEROPIVACAINELEVOBUPIVACAINE
COCAINEPROCAINECHLOROPROCAINETETRACAINEBENZOCAINE
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………………TWO “i” s
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,
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MODIFICATIONS
Lengthening carbon chains..carbon chains..Lipid solubility increasePotency increaseDuration of axn increase
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structures
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PROCAINE VS TETRACAINE
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MODIFICATIONS
HalogenationHalogenation
Decrease duration of axn
Decrease toxicity
E.g. procaine to chloroprocaine
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PIPECOLOXYLIDIDES
E.G. MEPIVACAINE BUPIVACAINE ROPIVACAINE
Butyl to mepivacaine : BupivacainePropyl to mepivacaine : Ropivacaine
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MODIFICATION
Increasing the length of intermediate alcohol
Increase the potency up to c3-c7
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PIPECOLOXYLIDIDES are CHIRALs
mepivacaine and bupivacaine are racemic mixtures
Ropivacaine as pure S enantiomer
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POTENCY
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FACTORS AFFECTING…
• HYDROPHOBICITY• CHARGE• VASOACTIVE PROPERTIES• TISSUE SEQUESTRATION• RMP• Ph• Freq & durn of dep pulses• TEMPERATURE• K+ BLOCKADE: pro / lido• MYELIN DEPO: etido
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ONSET
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Duration of action
PROTEIN BINDING increase /= better binding with Na c alpha 1 acid GP hypoxia/ hyperCO2/ acidemia inc neo and childVASOACTIVITY biphasic LIDO-MEPI-PRILO …duration = but.. ROPI-BUPI…duration = but Ropi
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Duration of action
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DIFFERENTIAL BLOCKADE
Lipid solubility & pKa: bupi & ropiCritical lengthDensity of Na- diameter- so A delta i.e. pain and temp first disappearLength of drug exposed nerveNa over KDifferences in susceptibility of NaRepetitive stimuli
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DOSE
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Vaso constrictors
Epinephrine 5ug/ml or 1:200000Decrease absorptionAct as a markerAlpha receptors in spinal cord
activate endo mechanismsLidocaine best friend/ 50%Bupi motor- sensory +Nor epi /phenyl ephrine… hmm No
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Site of injection
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reasons
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Carbonattion
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Soda bicarbonate ?pain?
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Mixture of LA
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Pregnancy / dose decreased
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PHARMACOKINETICSPHARMACOKINETICS
www.bioteach.ubc.ca
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ABSORPTION
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SITE
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ORDER
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PHYSIOLOGIC DISPOSITION
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So….
I.V. or intra arterial more dangerous?
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Biotransformation & excretion
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renal
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PATIENT STATUS
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STATUS
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Balanced emotions….
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Take home message….
The best way to take revenge is ….
…..to select a topic and conduct a symposium.
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….