Local Anaesthetics

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

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

ANATOMY & PHYSIOLOGY OF NERVE CONDUCTION

UNITY IN DIVERSITY ! TYPE DIA [um] VEL [m/sec] LOCATION FUNCTION SUSC TO LA ,[object Object],6-22 30-120 EFFERENT TO MS MOTOR TO Sk M ++ ,[object Object],6-22 30-120 AFFERENT FROM SKIN &JOINTS TACTILE , PROPRIO ++ ,[object Object],3-6 15-35 EFFERENT TO MUSCLE SPINDLES MUSCLE TONE ++++ ,[object Object],1-4 5-25 AFFERENT SENSORY NERVES ,[object Object],+++ B <3 3-15 PRE GANGLIONIC SYMP AUTO ++ Sc C 0.3-1.3 0.7-1.3 POST GANGLIONIC SYMP AUTO ++ ,[object Object],0.4-1.2 0.1-2.0 AFFERENT SENSORY NERVES AUTO, DULL Pn,Wmt, Tch +

MYELIN …MYELIN….MYELIN ,[object Object],[object Object],[object Object],[object Object]

MYELINATED NERVE FIBERS ARE UNIQUE ,[object Object],[object Object],[object Object],[object Object]

PHYSIOLOGY OF NERVE CONDUCTION

A resting state….. is necessary .

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

CLOSED or RESTING STATE OF Na CHANNEL

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 +

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

Structural characteristics of Na v channels ,[object Object],[object Object],[object Object],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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Plummer, Meisler. Genomics 1999;57:323-31 Cytoplasm

..that’s all about the nerve..

General Info: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

true OR false ,[object Object],[object Object],[object Object],[object Object],[object Object]

Neutral base Vs Cationic moiety

How the nerve react? ,[object Object],[object Object],[object Object],[object Object]

KAUN BANEGA…….. ,[object Object],[object Object],[object Object],[object Object],[object Object]

Many classes of compounds bind and inhibit Na channels ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

LAs bind and inhibit many differing receptors and channels ,[object Object],Anesthesiology 1990; 72:711-34

LAs bind and inhibit many differing receptors and channels ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Anesthesiology 1990; 72:711-34

Thanks God! ,[object Object],[object Object],[object Object]

DIFFERENTIAL SENSITIVITY ,[object Object],[object Object],[object Object],[object Object]

Na channel also comes in 10 different forms ,[object Object]

Local anesthetics: amides vs. esters ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Lidocaine Procaine

Why these two parts? ,[object Object],[object Object]

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 ,[object Object],[object Object],[object Object],[object Object]

PIPECOLOXYLIDIDES ,[object Object],[object Object],[object Object],[object Object],[object Object]

MODIFICATION ,[object Object],[object Object]

PIPECOLOXYLIDIDES are CHIRAL s ,[object Object],[object Object]

FACTORS AFFECTING… ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Duration of action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

D I F F E R E N T I A L BLOCKADE ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Vaso constrictors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

PHARMACOKINETICS www.bioteach.ubc.ca

Take home message…. ,[object Object],[object Object]

Local Anaesthetics

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Local Anaesthetics