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 &ether!

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.

….