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
From Netters Illustrated Pharmacology
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From Netters Illustrated Pharmacology
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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Any query ????