LOCAL ANAESTHETICS
Presenter : Dr Unnikrishnan P
Coordinator : Dr C Madhusoodhanan PillaiModerators : Dr Ushakumari Dr KiranDEPARTMENT OF ANESTHESIOLOGY
….framework
What they do?
Chronology of local anesthetics
CocaineBenzocaineProcaineTetracaineLidocaineCl2 procaineMepivacineBupivacaineRopivacaine
NiemannSalkowskiEinhornEislerLofgrenMarks, RubinEkenstamEkenstamSandberg
186018951904192819431949195619571989
EsterEsterEsterEsterAmideEsterAmideAmideAmide
1884…..
ANATOMY & PHYSIOLOGY OF NERVE CONDUCTION
…..Me neuron
…
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
+
AXOLEMMA
SCHWANN CELLS & MYELIN
MYELIN …MYELIN….MYELINSchwann cells groups and covers
axonPlasma membrane – Myelin UM – single shirt for many! M – individual shirts!
MYELINATED NERVE FIBERS ARE UNIQUE
Nodes of Ranvier
Why this gap important?
How the current passes in M & UM
Advantage : M
The coverings…
PHYSIOLOGY OF NERVE CONDUCTION
A resting state….. is necessary.
The gradients….
A short section of the axon
cell membrane
cytoplasm
extracellular fluid
3 Na+
High [Na+]
Low [Na+]
2 K+
Low [K+]
High [K+]
CLOSED or RESTING STATE OF Na CHANNEL
-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
Fig. 2-17, p. 45
+ + + - - - - - - -
- - - + + + + + + +
+ + + - - - - - -
- - - + + + + + +
neurotransmitter
Depolarization is due to the influx of Na+
Na+
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+
OPEN STATE OF Na CHANNEL
-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
INACTIVATED STATE OF Na CHANNEL
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+
-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
Fig. 2-19, p. 46
Ty
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
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
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
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
..that’s all about the nerve..
MECHANISM OF ACTION
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
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
Neutral base Vs Cationic moiety
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
In short….
HYDROPHOBICITY DELIVERS THE DRUG INSIDE [is the pass ticket] AND CHARGE KEEPS IT THERE[is the stay ticket]
How the nerve react?
Δ Height of AP decrease..
Δ Firing threshold elevated...
Δ Velocity decrease…
Δ Refractory period lengthened..
KAUN BANEGA……..KAUN BANEGA……..
Which compound blocks Na channel from outside?
meperidine TCA tetrodotoxin ketamine
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)
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
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
USE DEPENDENT / PHASIC BLOCK
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.
DIFFERENTIAL SENSITIVITY
Small myelinated A gamma, A delta
Large myelinated A alpha, A beta
Small non myelinated- least-slowest
Difference in critical length
Manifests as… LSAB
Manifests as ….epidural
Na channel also comes in 10 different forms
Aberrant impulses susceptible even to systemic Lignocaine
PHARMACOLOGY
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
Basic structure
Why these two parts?
Lipophilic aromatic ring aids in penetration
Hydrophilic part accepts protons and occupies Na channel
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
AMIDES HAVE…
AMIDES ESTERS
LIDOCAINEPRILOCAINEMEPIVACAINEETIDOCAINEBUPIVACAINEROPIVACAINELEVOBUPIVACAINE
COCAINEPROCAINECHLOROPROCAINETETRACAINEBENZOCAINE
………………TWO “i” s
,
MODIFICATIONS
Lengthening carbon chains..carbon chains..Lipid solubility increasePotency increaseDuration of axn increase
structures
PROCAINE VS TETRACAINE
MODIFICATIONS
HalogenationHalogenation
Decrease duration of axn
Decrease toxicity
E.g. procaine to chloroprocaine
PIPECOLOXYLIDIDES
E.G. MEPIVACAINE BUPIVACAINE ROPIVACAINE
Butyl to mepivacaine : BupivacainePropyl to mepivacaine : Ropivacaine
MODIFICATION
Increasing the length of intermediate alcohol
Increase the potency up to c3-c7
PIPECOLOXYLIDIDES are CHIRALs
mepivacaine and bupivacaine are racemic mixtures
Ropivacaine as pure S enantiomer
POTENCY
FACTORS AFFECTING…
• HYDROPHOBICITY• CHARGE• VASOACTIVE PROPERTIES• TISSUE SEQUESTRATION• RMP• Ph• Freq & durn of dep pulses• TEMPERATURE• K+ BLOCKADE: pro / lido• MYELIN DEPO: etido
ONSET
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
Duration of action
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
DOSE
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
Site of injection
reasons
Carbonattion
Soda bicarbonate ?pain?
Mixture of LA
Pregnancy / dose decreased
PHARMACOKINETICSPHARMACOKINETICS
www.bioteach.ubc.ca
ABSORPTION
SITE
ORDER
PHYSIOLOGIC DISPOSITION
So….
I.V. or intra arterial more dangerous?
Biotransformation & excretion
renal
PATIENT STATUS
STATUS
Balanced emotions….
Take home message….
The best way to take revenge is ….
…..to select a topic and conduct a symposium.
….
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