Local Anesthetic

• Local anesthetics are drugs used to reversibly depress CNS to prevent or relieve pain in specific regions of the body without loss of consciousness

• Unlike General Anesthetics, they generally don’t block sense of touch, pressure or temperature or relax skeletal muscles

Uses

• Dentistry• Podiatry (treatment of disorders of the foot,

ankle, and leg)• ENT operations• Surgery of skin• Labor pain• Postoperative pain• Skin Trauma

How Nerve conduction occurs?

• Nerve conduction is a both electrical and chemical component

• The electrical component occurs within the axon. It involves membrane bound voltage gated ionic channels (responds to change in voltage across the membrane)

• The chemical component occurs at synapse. It involves membrane bound ligand gated ionic channel (responds to binding of a NT)

Chemical transmission of stimuli occurring at synapse through NT binding to their receptors

Electrical transmission of stimuli occurring through axon bymovement of ion in and out

•When charges are separated by distance, potential difference is created•The inside of cell has more potassium and less Sodium and large anionic Protein (A-) that cannot cross the lipid membrane and is thus localized inside the cell•The outside of the cell has more Sodium and less potassium •This difference is maintained by Na/K pumps that pump in 2K+ ion in cell and pump out 3Na+ ion out. Thus one extra positive charge out•Overall, the inside of the cell has more negative charge and the outside has more positive charge•This gives the cell a resting potential of -70mV

Concept of potential difference and its generation (-70mV) in resting cell

Events during an action potential

An action potential is a temporary “all or nothing” changes in cell membrane potential

Steps in a action potential• (1) A stimulus from a sensory cell or another neuron causes the

target cell to depolarize toward the threshold potential. • (2) If the threshold of excitation (-55mV) is reached, all Na+

channels open and the membrane depolarizes. • (3) At the peak action potential (+30mV) K+ channels open and

K+ begins to leave the cell. The membrane starts to repolarized. At the same time, all Na+ channels close.

• (4) The membrane becomes hyperpolarized (-90mV) as K+ ions continue to leave the cell. The hyperpolarized membrane is in a refractory period and cannot initiate another action potential

• (5) The K+ channels close and the Na+/K+ transporter restores the resting potential (-70mV).

Changes in the resting membrane potentialCell state Active receptors PotentialResting potential Na/K Atphase pump active -70mV

Stimuli causesDepolarization beyond threshold potential (-55mV)

Voltage gated Na+ channel openNa comes inside cell

+30mV

Repolarized state Voltage gated Na+ channel close

Voltage gated K+ channel openK goes outside cell

+30 to -70mV

Hyperpolarized state Voltage gated K+ channel close slowly -90mV

Resting potential Na/K Atphase pump active -70mV

Mechanism of Action

• Local anesthetics work in general by binding to the voltage gated sodium channel receptors inside the cell and thereby inhibiting generation of action potentials in the axon. Thus they reduce the excitability of the neuron.

• The presence of large anionic proteins inside the cell and Na/K ion pumps in the cell membrane , that pump2 K+ intracellular for every 3 Na+ it pumps extracellular, create a -70mV resting potential

Mechanism of Action (cont’d)

• If a stimuli depolarizes the resting potential to reduce the membrane potential to less than -55 mV (ie it goes towards +30mV) then a series of events occur where membrane potential increases to +30mV and back to -70mV.

• The first step of this entire process is opening of voltage gated sodium channel which allows influx of sodium ion to cause increase in membrane potential. LA act here to block the Na influx and thus prevent stimuli propagation through the axon

How LA primarily blocks pain?

• Different neurons carry different stimulus such as pain• cold, warmth, touch and deep pressure.• The neurons differ in the thickness of the axon • Thin axons are most sensitive to drugs• Neurons carrying pain has the thinnest axon• Then comes cold, warmth, touch, deep pressure • Thus effect of LA also follow this order• Also nerve fiber are thinner than muscle fiber, thus they

are blocked preferentially and thus no muscle relaxation occur with LA

Applications of LA

There are different ways to use LA depending on site on application:• Topical• Infiltration• Plexus block• Epidural block• Subarachnoid (spinal) block

• A topical anesthetic is a local anesthetic that is used to numb the surface of a body part. They can be used to numb any area of the skin as well as the front of the eyeball, the inside of the nose, ear or throat, the anus and the genital area. Topical anesthetics are available in creams, ointments, aerosols, sprays, lotions, and jellies. Examples include benzocaine, lidocaine, oxybuprocaine,

• Topical anesthetics are used to relieve pain and itching caused by conditions such as sunburn or other minor burns, insect bites or stings, poison ivy, poison oak, poison sumac, and minor cuts and scratches.

• In dentistry, topical anesthetics are used to numb oral tissue before injecting a dental local anesthetic to prevent pain due to the entry of the needle into the soft tissues of the oral cavity

Infiltration• It is the application of LA in intradermal or subcutaneous

layers• Only the nerve fibers near the injected site is affected• The adequate dosage required depends on

– the extent of the area to be anesthetized – on the expected duration of the surgical procedure.

• Patients frequently experience pain immediately after infiltration injection of local anesthetic solutions. This response is due in part to the acidic nature of these solutions.

• neutralization of LA solutions by addition of sodium bicarbonate reduces pain

• Used for postoperative pain control at incision site and suturing

Plexus block

• plexus or ganglion are a group of nerves that transmits pain caused to a specific organ or body region. Use of LA in these region causes analgesia in the organs or region associated with it

• Brachial plexus blocks are employed for surgery of shoulder, arm, forearm, wrist and hand.

• A celiac plexus block is performed for surgery of the abdomen

The spinal cord run through a tunnel formed by bones of vertebrae called spinal canal

The spinal cord is surrounded by a sac (sac means bag, pouch) containing a liquid called cerebrospinal fluid. This is the site of spinal block ie right into this sac

Epidural block is given in region just outside of this sac within the spinal canal

Epidural block

• Application of LA in the epidural space, ie just outside of the sac of cerebrospinal fluid, and thus blocking the transmission of pain signals from peripheral sensory neuron

Uses• More effective and safe than N2O during labor pain• Management of back pain for hospitalized patient • As a supplement to general anesthesia so that use of opiod

analgesics can be avoided• gynaecological surgery, orthopaedic (muscle n bone)

surgery, vascular (artery n veins) surgery

Spinal block• Application of LA in the region containing cerebrospinal

fluid ,which holds the spinal cord, thus blocking the transmission of pain signals from peripheral sensory neuron

• Uses: Total Hip Replacement, Total Knee Replacement, Caesarean sections, Lower limb Vascular surgery

• limited to procedures involving regions below the upper abdomen.

• Use in higher levels may affect the ability to breathe by paralyzing the intercostal respiratory muscles and the disturb heart rate by paralyzing cardiac nerve fibres

Epidural vs SpinalEpidural Spinal

Dose is high (10-20 ml) Dose is low (1.5-2 ml)

Onset is slow (25-30 min) Onset is fast (5 min)

does not cause as significant neuromuscular block

Does cause as significant neuromuscular block

Multiple dosing possible Single dose only

Can be given at various point along the Backbone

Can only be given at specific point along the Backbone to avoid damaging the spinal cord

Block vs Infiltration

• A block is placement of the local anesthetic adjacent to a major nerve or a major branch of the nerve that stops sensation from that point to the terminal end of the nerve. Everything "down stream" from where the block was placed will be numb.

Infiltration is placement of local anesthetic near (or in) the area you want anesthetized. Mostly it affects the terminal branches of the nerves. Typically, an infiltration will only affect that area and not beyond. (thus it is the most localized LA!)

Local anesthetics used in eye onlyOphthalmic anesthetics are topical agents that act locally to block pain signals at the nerve endings in the eyes. They are available as eye drops, ointment and gels.Uses• Perform a applanation tonometry.(Tonometry

determines the intraocular pressure)• Perform a Schirmer's test. ( Schirmer's test determines

whether the eye produces enough tears to keep it moist)• Remove small foreign objects from the uppermost layer

of the cornea or conjunctivaDrugs used are Tetracaine 0.5% and Proparacaine 0.5%

Eutectic mixture of LA• A topical anesthetic made from equal parts of lidocaine and

prilocaine which separately are solid but together take a liquid form with melting point of 18oC

• This property where a mixture of substances having a melting point lower than that of any of its components is called Eutectic mixture

• Manufactured as a 5% oil in water emulsion containing 2.5% each of lidocaine/prilocaine

• It is applied as a cream on unbroken skin, then covered with an occlusive dressing, to kill pain prior to – venipuncture, intramuscular injections, intravenous

cannulation,

Advantages over other topical LAa) the local anesthetic bases are present in their permeable

uncharged forms; b) water is used as the vehicle which is a poor solvent for these

drugs. This causes drug to rapidly saturated water (at low concentrations) and then move on to act on the skin

c) Simply use of an oily vehicle would effect distribution coefficients of the active substances between the skin and the formulation

d) the droplets consist of dissolvable drug and act as reservoirs to obtain steady-state release; and

e) the fluid state of the excess drug provides a higher dissolution rate than from a solid state.

Local anesthetics and vasoconstrictors

• LA are removed from site of application due to absorption into blood

• Vasoconstrictors increase the duration of local anesthesia by constricting the blood vessels, so that less blood flow and consequently less absorption into blood occurs. Thus it allows LA to work for an extended duration, as well as reducing hemorrhage. Examples include:

• Prilocaine hydrochloride and epinephrine• Lidocaine, bupivacaine, and epinephrine (recommended

final concentrations of 0.5%, 0.25% and 1:200, respectively)

The classification of local anesthetics

Ester• Cocaine• Procaine• Tetracaine

Amides• Lidocaine• Bupivicaine

Ether• Pramoxine

Ketones• Dyclonine

Structure Activity Relationship

•Most drugs are salts of weak acids or weak bases• But how to know by just

looking at structure if a drug is acidic or basic?

Use of pKa?• Pka can’t tell the difference of acid/base• It only tells how strong an acid or base is but

doesn’t tell if it’s an acid or baseParacetamol Pka is 9.5 but it is an acidIt is weaker acid than acetic acid those Pka is 4.5

Diazepam Pka is 3.4 but it is a baseIt is weaker base than NH3 those pKa is 10

The key is to look for the specific functional groups

• Acidic drugs contain one of these groups

• ALL Basic drugs contain Nitrogen as amine groups, (all except quaternary amine) or double bonded to C (C=N)

NH2 H3C

HN

CH3H3C H3C

N

CH3

CH3

primary amine Secondary amine tertiary amineH3C

N

CH3

CH3

quanternary amine

CH3

All basic to the same degree Not basic

OHH2N

O

RH3C

O

R

AmideAldehyde /ketonePhenol

R COOH

carboxylica acid

R

SAR of LA

• All local anesthetics have an amine on one end to an aromatic ring on the other

• The amine end is hydrophilic, and the aromatic end is lipophilic.

• The two groups are connected by mostly an ester or an amide group and less commonly by ether or ketones

• Thus two main classes of local anesthetics exist: Amides and Esters

• Esters have an ester link between the amine chain and the aromatic end.

• Amides have an amide link between the amine chain and the aromatic end

• They have pka in range of 7.5 to 9.5

• Esters and amino amides differ in metabolism, stability and adverse effects

• Esters are metabolized in the plasma but Amides are metabolized in the liver.

• Esters are unstable in solution, but amides are very stable in solution.

• Esters are much more likely than amides to cause allergic reactions

Lipophilic group• Lipophilicity is important to penetrate the lipid layer and

reach the binding site on the inside of the cell• Presence of electron withdrawing group in ortho or para

(not meta) position decreases Lipophilicity but still increases activity for only ester group

O

C

O

H2C

CH2

N

C2H5

C2H5

H2N

O

C

O

H2C

CH2

N

C2H5

C2H5

Procaine is more potent if it has a e- donating amine group in the aromatic ring

Procaine

Note: Other e donating groups in decreasing order are –OH > -NH2 > -Oalkyl (OCH3) > -alkyl (CH3) (valid everywhere)

Less potent than procaine

• This increase in activity (valid for ester only) is due to possibility of Zwitterionic form which enhances activity due to formation of quanternary amine which is important for binding

O

C

O

H2C

CH2

N

C2H5

C2H5

H2NProcaine

O-

C

O

H2C

CH2

N

C2H5

C2H5

H2N+ Zwitterioninc

form

What n when is ortho, para ,meta?

No substituionNo ortho, para ,meta

CH3

Single substituionAgain, no ortho, meta, para

CH3

CH3

CH3 CH3

CH3

CH3

H3C

H3C

Only in bi-substituted there is ortho, meta and para

Ortho

Meta

CH3

CH3

Para

• Presence of e- withdrawing halogens in ortho position only can decrease duration of action by making the ester more Likely for a nucleophilic attack

O

C

O

H2C

CH2

N

C2H5

C2H5

H2N

Procaine

O

C

O

H2C

CH2

N

C2H5

C2H5

H2N

Chlorine in ortho group makes the carbonyl carbon more positive and more likely to be attacked by nucleophiles that causes breakdown of compound.Nucleophiles contain a lone pair of electron. They attack atoms with positive charges. More positive the atom, the better the attack

Cl

longer actingshorter acting

chloroprocaine

• For amide only, presence of di-ortho substituted group prevent breakdown of amide and thus increase it’s stability in both liquid formulation and the body enzymes

CH3

CH3

NH C

O

CH2 N

C2H5

C2H5

NH C

O

CH2 N

C2H5

C2H5

CH3 groups make it difficult to hydrolyze. thus it is Stable in water and blood. Sufficient duration of action

No protection against hydrolysis by disubstituted group. Thus unstable in water and blood. Not enough duration of action

Note: instead of CH3, other groups such as OCH3 can also be used

Linker group

• Linker group has short alkynene (-CH2-) chain containing few carbon atoms and various functional group such as Amides, Esters, Ether or Ketones

• Increasing the length of alkylene chain increases the pKa which reduces potency because more drug get ionized outside the membrane and thus can’t penetrate into the binding siteNote: -CH2- group is called methylene, -C2H4- is called ethylene

-CH3 is called methyl, -C2H5 is called ethyl CH4 is methane, C2H6 is ethane

Hydrophillic group• Useful LA have a secondary or tertiary amine group • This is important because it is believed that when

they enter the cell, they will accept a proton and form positively charged quanternary form which is needed for binding to voltage gated ion channels

O

C

O

H2C

CH2

N

C2H5

C2H5

H2N

O

C

O

H2C

CH2

N

C2H5

C2H5

H2N

H

charged Quanternary formis beleived to bind to receptor

Procaine believed to bind to it’s receptor when the amine group is positively charge quanternary form

• However, Benzociane has no anime portion but is still an effective topical LA

• Thus the use of Amine part could only be for proper water solubility and not directly related to proper binding

O

C

O

CH2CH3

NH2

Benzocaine has no amine but is still effctive LA

PROCAINE

• Procaine is a local anesthetic drug of the ester group• effective parental but are relatively weak when applied

topically • slow onset (4-5 min), short duration, pKa=8.8• Procaine has the advantage of constricting blood vessels*

which reduces bleeding, unlike other local anesthetics like lidocaine

• is metabolized by the plasma enzymes to form para-amino benzoic acid (PABA) which is causes allergic effect

• MOA – blocks pain by depressing CNS by antagonizing votage gated Na+ channel thus inhibiting generation of action potential

•This sud increase duration of action like with lidocaine and epinephrine but it can’t because esters are such functional groups that get naturally quickly hydrolyzed/metabolized than other functional groups such as amide, alcohol

Which is more lipophillic?Which can exist as enantiomers?

Lidocaine

• Most commonly used potent amide type local anesthetic for both parenteral and topical use

• has a rapid onset of action (Intravenous - 45 to 90 seconds). and more lipid solubility than procaine, pka = 7.8

• Di-ortho methyl groups make the amide group resistant to hydrolysis thus it has moderate duration of action (1-2 hrs)

• Produces eutectic mixture with prilocaine• Class IB Antiarrhythmic function • MOA – blocks pain by depressing CNS by antagonizing

votage gated Na+ channel thus inhibiting generation of action potential

Bupivacaine

• A potent amide type local anesthetic used mostly parenterally • It has rapid onset of action and higher lipid solubility and lower

hepatic degradation and thus longer duration of action (6-8 hrs) than the structurally similar lidocaine, pKa = 8.1

• It exists in racemic form. The R isomer has greater affinity for Voltage gated Na+ channels and is linked with cardiotoxicity

• The S isomer, called levobupivacaine, is clinically used as it has lower cardiotoxicity and CNS toxicity

• MOA – blocks pain by depressing CNS by antagonizing votage gated Na+ channel thus inhibiting generation of action potential

Procaine synthesisH2N C

O

OH HO CH2CH2N(C2H5)2

H2SO4

-HOH

H2N C

O

OCH2CH2N(C2H5)2

HCl

Procaine

para- amino benzoic acid 2-Diethylamino-ethanol

H2N C

O

OCH2CH2N(C2H5)2.HCl

condensation

Procaine hydrochloride

Lignocaine synthesisCH3

NH2

CH3

CH3

CH3

NHCOCH2ClCl.COCH2Cl

Chloroacetylchloride

2,6-Dimethyl-phenylamine

Diethyl amine

CH3

CH3

NHCOCH2N(C2H5)2

-HCl

NH(C2H5)2

Lignocaine

HCl

CH3

CH3

NHCOCH2N(C2H5)2.HCl

Lignocaine Hydrochloride

ReviewGeneral Anesthetic Local Anesthetic

Blocks pain in entire body Blocks pain in specific region on body

Blocks sensation of temperature, touch and pressure

Selective to blocking pain only.

Muscle relaxation occurs Muscle relaxation not caused

Drug intended to penetrate brain Drug not intended to penetrate brain but act on local nerves branches

Receptor is ligand gated chlorine channel and Binding site is outside of cell membrane

Receptor is voltage gated Sodium channel and Binding site is inside of cell membrane

Chemical transmission of stimuli occurring at synapse through NT binding to their receptors

Electrical transmission of stimuli occurring through axon bymovement of ion in and out

Q) Why LA only blocks pain?Ans: Sensitivity to LA depends on thickness of axon. Thinner neuron are easily effected.

Neuron function Thickness (uM) Sensitivity to LA

motor 12-20 +

Touch , pressure 5-12 ++

Temperature 2-5 +++

Pain 0.4-1.2 ++++

MOA: blocks Voltage gated Sodium channel --> Prevent generation of action potential -->blocks neuronal transmission of stimuli (especially pain)

• What is a stimuli?A thing or event that evokes a specific functional reaction in an organ or tissue

Applications of LAsame drug can be used

• Topical - skin, eye or any body cavity (vagina, nose, ear, interior surfaces)

• Infiltration – maximum localized LA, acts on finer nerve branches

• Plexus block – blocks a major nerve branch and its associated region– Brachial plexus blocks are employed for surgery of

shoulder, arm, forearm, wrist and hand. – A celiac plexus block is performed for surgery of the

abdomen

Block vs Infiltration

shoulder

arm

forearm

hand

thumb

fingers

Spinal cordLeft armRight arm

•Block used in major nerve branch•Infiltration in minor/local nerve branch

Site of Epidural and Spinal block

Epidural vs SpinalEpidural Spinal

Dose is high (10-20 ml) Dose is low (1.5-2 ml)

Onset is slow (25-30 min) Onset is fast (5 min)

does not cause as significant neuromuscular block

Does cause as significant neuromuscular block

Multiple dosing possible Single dose only

Can be given at various point along the Backbone

Can only be given at specific point along the Backbone to avoid damaging the spinal cord

•Epidural block is widely used in labor pain•Spinal block used in Caesarean sections

SAR of LA

•Hydrophillic part imp for penetration inside the cell to reach binding site

•Hydrophillic amine group binds to receptor in chargedQuanternary form

Ester Amide

relatively unstable than amides Relatively More stable than esters,

Metabolism by plasma enzymes Metabolism by liver

Allergic effect due to metabolic production of PABA (para amino benzoic acid)

No allergic effect of metabolic product

Presence of diortho methyl groups (or methoxy) Increases stability of amides

Presence of amine in aromatic ring increases Potency due to charge on nitrogen due to Possibility of Zwitterionic form

O

C

O

H2C

CH2

N

C2H5

C2H5

H2N

O

C

O

H2C

CH2

N

C2H5

C2H5

Procaine is more potent if it has a e- donating amine group in the aromatic ring

Procaine

Note: Other e donating groups in decreasing order are –OH > -NH2 > -Oalkyl (OCH3) > -alkyl (CH3) (valid everywhere)

Less potent than procaine

• All LA have Pka between 7.5 – 9.5• Anything beyond this range and there will be

more ionization at pH 7 of the blood.• More ionization blocks the penetration of drug

through the lipid membrane and they can’t reach their biding site which in inside of cell

CH3

CH3

NH C

O

CH2 N(C2H5)2

CH3

CH3

NH C

O

CH2 CH2

CH3

CH3

NH C

O

CH2 CH2 CH2 N(C2H5)2

N(C2H5)2

pKa = 7.8

pKa = 9.0

pKa = 9.5

All LA are basic drugs because they contain amine group

As pKa increases, the drugs become more basic and thus more ionized in the blood

In ionized form, they can't cross the lipid membrane and reach their binding site

increasing pKa = increased ionized form= decreased potency

Effect of increasing linker length in lidocaine

Increasing CH2 group = increased pKa (increased basicity) = increased ionized form = decreased potency

CH3

CH3

NH C

O

CH2N

CH3

CH3

NH C

O

CH2N

C2H5

C2H5

C2H5

C2H5H

Factors effecting Duration of action as by the SAR

Phenobarbital Thiopental Sodium

Branched R group

Short ethyl chainTotal carbon = 2 (not counting aromatic)

Long chain of R groupTotal C = 7

Additional improvements to Thiopental Sodium tofurther decrease duration of action•N methylation (potency also inc)•Unsaturated R group

Thank you

• This is a “photo”of a protein (tertiaryStructure )• It has 347 aminoacids

Same protein but shown in helix( red ) and sheets (blue)And loops

Same protein but now there is a drug binding to it

This is the binding site of that drug

Only showing amino acids of the binding siteRemember: proteins are made of amino acids

This is what the drug is doing in the binding site--> making chemical

bonds with it