Local Anaesthetics

LOCAL ANAESTHETICS Presenter : Dr Unnikrishnan P Coordinator : Dr C Madhusoodhanan Pillai Moderators : Dr Ushakumari Dr Kiran DEPARTMENT OF ANESTHESIOLOGY

… .framework

What they do?

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

1884…..

ANATOMY & PHYSIOLOGY OF NERVE CONDUCTION

… .. Me neuron

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 +

AXOLEMMA

SCHWANN CELLS & MYELIN

MYELIN …MYELIN….MYELIN
Schwann cells groups and covers axon
Plasma 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….

3 Na + High [Na + ] Low [Na + ] 2 K + Low [K + ] High [K + ]

CLOSED or RESTING STATE OF Na CHANNEL

Fig. 2-17, p. 45

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

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 +

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

Fig. 2-19, p. 46

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

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

..that’s all about the nerve..

MECHANISM OF ACTION

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

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

Neutral base Vs Cationic moiety

Duality!

In short….
HYDROPHOBICITY DELIVERS THE DRUG INSIDE [is the pass ticket] AND CHARGE KEEPS IT THERE [is the stay ticket]

How the nerve react?
Height of AP decrease..
Firing threshold elevated...
Velocity decrease…
Refractory period lengthened..

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
β 2 -adrenergic
Anesthesiology 1990; 72:711-34

USE DEPENDENT / PHASIC BLOCK

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.

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 &ether! More

AMIDES HAVE… AMIDES ESTERS LIDOCAINE PRILOCAINE MEPIVACAINE ETIDOCAINE BUPIVACAINE ROPIVACAINE LEVOBUPIVACAINE COCAINE PROCAINE CHLOROPROCAINE TETRACAINE BENZOCAINE

……………… TWO “i” s

MODIFICATIONS
Lengthening carbon chains..
Lipid solubility increase
Potency increase
Duration of axn increase

structures

PROCAINE VS TETRACAINE

MODIFICATIONS
Halogenation
Decrease duration of axn
Decrease toxicity
E.g. procaine to chloroprocaine

PIPECOLOXYLIDIDES
E.G. MEPIVACAINE
BUPIVACAINE
ROPIVACAINE
Butyl to mepivacaine : Bupivacaine
Propyl to mepivacaine : Ropivacaine

MODIFICATION
Increasing the length of intermediate alcohol
Increase the potency up to c3-c7

PIPECOLOXYLIDIDES are CHIRAL s
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

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

Duration of action

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

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

Site of injection

reasons

Carbonattion

Soda bicarbonate ? pain ?

Mixture of LA

Pregnancy / dose decreased

PHARMACOKINETICS www.bioteach.ubc.ca

ABSORPTION

PHYSIOLOGIC DISPOSITION

So….
I.V. or intra arterial more dangerous?

Biotransformation & excretion

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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Local Anaesthetics

by Unnikrishnan P on Oct 09, 2009

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Local Anaesthetics — Presentation Transcript