Local Anesthetic 2012

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Local anaesthetics (LAs)

Drug which upon local application (topical or injection)

cause REVERSIBLE loss of sensory perception (i.e. pain),

Does not affect consciousness

Blockgeneration and conduction of nerve impulses at all

parts of neurone where they come into contact, withoutcauses any structural damage


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o LAs are amphiphilic molecules

o Weak bases, with pKa around 8-9o LAs consist of :

oINTERMEDIATE CHAIN = ester/ amide bond

oBASIC AMINE GROUP = hydrophilic


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R1

O

ESTER

e.g

Procaine

Aromatic groupEster or

Amide bondAmine portion

R2

NH C R N

R1

R2

O

AMIDE

Cocaine

e.g

Lignocaine

Bupivacaine

Prilocaine


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Drug Onset Duration Potency Plasmahalf life(hr)

Methodgiven

Ester linked

Cocaine

Procaine

Medium Medium Low ~ 1Surfaceanaesthesia

Medium Short Low

Injectable

PharmacokineticsPharmacokineticsPharmacokineticsPharmacokinetics

tendon)

Drug-tissue binding (amide LA binds to 1 acid glycoprotein)

Presence of vasoconstricting substances (eg adrenaline)


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METABOLISM AND EXCRETION

o Ester linked LAs are rapidly hydrolysed byplasma pseudocholinesterase and the remaining

by esterases in the liver short t1/2

PharmacokineticsPharmacokineticsPharmacokineticsPharmacokinetics

o Amide linked LAs are degraded only in the liver

microsomes by dealkylation and hydrolysis.

o The metabolites are excreted by the kidney.


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1. It acts on the intracellular end of voltage-gated sodium channel

2. LA needs to penetrate the nerve sheath and the axon membrane to

reach the inner end of the channel (becomes unionised)

From Netters Illustrated Pharmacology



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3. Once inside the axon, it becomes ionised and binds to the LA bindingsite on the IC end of the sodium channel

4. Decrease the entry of Na+ ions , so that, the neuron is unable to "fire"

impulses to others (action potential)

5. If the nerves doesnt depolarize, or do it partially, no sensation willreach even the brainstem


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Outcome

o Threshold for excitability increases (decreasedexcitability)

o Impulse conduction slows

Rate of rise of the action potential decreases Refractory period lengthens

it takes longer for the channel to leave the inactivated state

o Action potential amplitude decreases


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Effects of pH (Henderson-Hasselbach equation) and pKa of the

drug

o pH= pKa+ log [base]

[acid]

o ,

form is dependent on the tissue pH and the pKa ofthe

drug

o

Decrease in tissue pH shifts equilibrium toward theionized form, delaying the onset time of action


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Effects of pH (Henderson-Hasselbach equation) and pKa of the

drug

o Most LAs are weak bases with pKa of 7.5 - 9.5

o LA with lower pKa (eg lignocaine: 7.6-7.8) are fast

-

better penetration

o LA with higher pKa (eg. bupivacaine : 8.1-8.9), only

15% are unionised, so slow acting


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o Unionized (unprotonated, free base) LA are very

lipophilic and will cross cell membranes readily, but

they

- are NOT very water soluble, so hard to formulate- do NOT exhibit hi h affinit for the Na+ channel bindin site

(but still active)

o Ionized (cationic, acid) local anesthetics are more

hydrophilic and easier to formulate, but they... do NOT readily cross cell membranes

DO exhibit high affinity for the Na+ channel binding site


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o Sensitivity of blockade is determined by

o diameter of the fibre

o type of fibre

o LAs block conduction in the following order:

oSmall myelinated axons (A and C-fibre)

oNon-myelinated axons

oLarge myelinated axons

o Therefore, nociceptor and autonomic fibres are moresusceptible than somatic fibres.


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E.g adrenaline or noradrenaline (1: 100,000 or 1:200,000)

Delay absorption of LA from site of injection into general

circulation which

Prolong the duration of action

Reduce the danger of systemic toxicity

It provides more bloodless field for surgery

Disadvantages:

Reducing oxygen supply and enhancing oxygen consumption in

the affected area delay wound healing, local tissue edema/necrosis

May raise BP and promote arrhythmia in susceptible individuals


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CNS effect

o Most LAs produce a mixture of depressant and stimulant

effects on the CNS.o Depressant effects predominate at low plasma concentrations

o Stimulation at higher concentrations (restlessness, tremor,

convulsions, confusion, agitation). Further increasing the doseproduces profound CNS depression ( ie. respiratory

depression).

o Cocaine is an exception; produces euphoria even at low doses


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CVS effect

o The primary site of action is the myocardium,

o Decreases electrical excitability, conduction rate, and force of

contraction

o Most LAs cause arteriolar dilation BP

Other A/Eo Local tissue injury delayed wound healing

o Allergic reaction rashes, dermatitis, asthma. More

frequently with local anesthetics of the ester type

o Specific a/e mucosal irritation (cocaine) and

methaehemoglobinaemia (prilocaine)


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o Is a natural alkaloid

o Good surface anaesthesia and rapidly absorbed from mucous

membrane

o Never injected protoplasmic poison and can cause necrosis

o

surgery, although it is now predominantly used for nasal and

lacrimal ductsurgery

o Major disadvantages: i) vasoconstrictor activity

ii) potential cardiovascular toxicity


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o Is the first synthetic LA introduced in 1905.

o No longer used

o It is not a good surface anaesthesia because it is poorly

o Its metabolite Paraaminobenzoic acid (PABA) can

antagonise the action of sulfonamide, which is used to

treat infection

o Can cause allergy, CNS and CVS adverse effects


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Most widely used LA

Good for (i) surface application (to relieve itching, burning

and pain from skin inflammations) (ii) injection(dentalanesthetic and minor surgery)

Is also a o ular anti-arrh thmic dru

It is used for surface application, infiltration, nerve block,

epidural, spinal and iv regional block

Overdose causes muscle twitching, convulsions, cardiac

arrhythmias, fall in BP, coma and respiratory arrest


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o Similar to lignocaine but does not cause vasodilatation at

the site of infiltration

o Lower CNS toxicity due to larger volume of distribution

o Can cause methaemo lobinemia with hi h dose so not

used for obstetric analgesia

o Used mainly for infiltration, nerve block (dentistry) and iv

regional block.


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o Widely used due to its long duration of action

o Is indicated for local anaesthesia including infiltration,

nerve block, obstetrics epidural, and intrathecal

anaesthesia

o Has greater cardiotoxicity slows conduction

o Not used for iv regional aneasthesia

o Ropivacaine (bupivacaine congener) equally long acting

but less cardiotoxic


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1. Surface anaesthesia

2. Infiltration anaesthesia3. Field block

Conduction block

5. Intravenous (i.v.) regional anaesthesia

6. Spinal anaesthesia

7. Epidural anaesthesia


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1. Surface anaesthesia

o Application of local anaesthetic spray, solution or

cream to the skin or a mucous membrane.

o The effect is short lasting and is limited to the

area of contact.

o E.g. lignocaine


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2. Infiltration anaesthesia

o Diluted solution of LA is infiltrated under the skin

in the area of operation block sensory nerveterminals.

o Onset of action is almost immediate and duration is

shorter than that of nerve blocko Used for minor operation (incisions and

excisions,etc).

o Larger amount of LA required compared to the areaanaesthetized


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3. Field block

o Subcutaneous injection of a LA in an area

bordering on the field to be anaesthetized

block all nerves coming to a particular area.o Used for appendicectomy, scalp stitching,

operations on the forearm and legs.


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4. Nerve block

o LA is injected close to (NOT INTO)

nerve trunkto anaesthetize whole

area of distribution of nerve.

o Type of nerve block intercostal,

ulnar, sciatic, femoral, brachial plexus,

.

o Used for tooth extraction, operations

of the eye, limbs, abdominal wall etc.

o Last longer than field block or

infiltration.


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6. Spinal anaesthesia

o LA is injected into the cerebrospinal

fluid, usually at the lumbar spine

(subarachnoid space - in the lower

back).o The resulting anaesthesia usually

extends from the legs to the abdomen

or c es .

o Is used for operations on lower

limbs, pelvis, lower abdomen,

prostatectomy, caesarean section etc.

o Adv. Effects : Hypotension, Headache,Nausea and vomiting, Post operative

pain, Respiratory paralysis(rare)


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7. Epidural anaesthesia

o LA is injected into the epidural space

where it acts primarily on the spinal

nerve roots.

o anesthetized area varies from limitedareas of the abdomen or chest to

large regions of the body (Depends

volume injected).

o Useful for painless childbirth and for

post-operative pain relief.

o Less post-anaesthetic complicationscompared to spinal anaesthesia.

o E.g lignocaine and bupivacaine


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Rang and Dales Pharmacology. Rang, Dale,Ritter & Flower. 6th Edition.

Basic & Clinical Pharmacology. Ed: Katzung.11th Edition.

Basis of Therapeutics. 11th Edition.

Lippincotts illustrated Reviews:Pharmacology. Ed:Harvey & Champe. 4th

Edition.


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Local Anesthetic 2012

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