MUBARAK AL KABEER HOSPITAL

 They are defined as drugs that can produce reversible inhibition of excitation
& conduction in perpipheral nerve fibres & nerve endings & thus produce a loss of sensation in a circumscribed area of the body

 Captain James cook – puffer fishtetrodotoxin – 18 th century
 1884 – Cocaine – Freud & Koller – used first for corneal anaesthesia
 1905 – Procaine – Einhorn – first synthetic local anaesthetic
 1943- Lidocaine – Lofgren

Ester :
Amide
:
Example:
R 3
R 4
R 3
R 4

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Changes to any part of the molecule lead to alterations in activity & toxicity
Increases in the length of the intermediate alcohol group, up to a critical length , result in greater anaesthetic potency
Beyond this critical length, increased toxicity results
Compounds with an ethyl ester, such as procaine, exhibit the least toxicity
The length of the two terminal groups on the tertiary amino-N group are similarly important
The addition of a butyl group to mepivacaine results in bupivacaine, which differs by, a. increased lipid solubility & protein binding b. greater potency c. a longer duration of action

ESTERS
 COCAINE
 PROCAINE
 CHLORPORCAINE
 TETRACAINE
(AMETHOCAINE)
 BENZOCAINE
AMIDES
 LIDOCAINE
 PRILOCAINE
 MEPIVACAINE
 BUPIVACAINE
 ROPIVACAINE
 ETIDOCAINE
 CINCHOCAINE
(DIBUCAINE)

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Voltage sensitive sodium channel
It sorrounds aqueous pore
Three subunitsα β
1
β
2
α unit –largest- MW 260 kDa
It’s a single long peptide containing four hydrophobic regions – I,II,III,IV
They are connected to each other by intracellular bridges
Each region concists of six membrane spanning segments( S1- S6)
S4 segment is the voltage sensor
The intracellular bridge between III & IV is the
Inactivation gate
This gate is responsible for occluding Na+ channel & hence inactivation.
Potassium channel is similar but with 4 subunits- 14 types of k+ channels are present

Acid drugs – become more NON ionized in acidic pH
Basic drugs – become more NON ionized in basic pH (alkaline pH)
Acid Drug Basic Drug
Acid pH
Environment
NON-ionized IONIZED
Basic pH
Environment
IONIZED NON-ionized

Hydrophilic = Ionized molecules (charged)
Lipophilic = Non-ionized molecules (non charged)
Lipophilic molecules penetrate membranes
Hydrophilic molecules dissolve in water

Ionized Molecule
Non-Ionized Molecule

Basic drugs – become more NON ionized in basic pH
I
N
I N I N I pH 2 pH 6 pH 8 pH 9
What’s the pKa for this drug?
= Ionized molecules a

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Most LA are tertiary amine Bases(B) which are administered as water soluble hydrochlorides(B.Hcl).
After injection ,the base is liberated by Alkaline pH of the ECF
B.HCL + HCO
3
= B + H
2
CO
3
+ CL -
So the LA is present in both ionised (BH + ) & non –ionised forms(B) in tissues
The proportion of each depends on Pka of drug and the ph medium into which it is adimistered

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The non ionised base( B) only can diffuse through the nerve sheath,perinural tissues & neurilemma to reach neuroplasm
In the neuroplasm it gets again ionised by H + ions
B + H + = BH +
This BH + the sodium channel
from INSIDE
They are believed to interact with phenyalanine & tyrosine residues in the S6 segment of region IV
Thus they block Na+ channels and prevent depolarisation ( Phase 0)
Benzocaine Membrane expansioncausing swelling of lipoprotein matrix of Na+ channel .
Tetrodotoxin & saxitoxindirectly block Na+ channel from the exterior of the membrane,close to the external pore

 LIPID SOLUBILITY
 TISSUE PROTEIN BINDING
 pKa
 STEREO SPECIFICITY
 VOSODILATATION
 MINIMUM CONCENTRATION
 FREQUENCY DEPENDANT BLOCKADE
 DIFFERENTIAL BLOCKADE

 There is a close relation between lipid solubility and potency
 Bupivicaine is approx 4 times more potent than lidocaine because of lipid solubility
 Etidocaine(5000) > Bupivacine(4000)>
Ropivacaine>tetracine> lidocaine(150)> prilocaine=mepivacine> procaine (1)

 It primarily affects the Duration of LA
 Etidocaine(96%) > Bupivacine(95%)>
Ropivacaine(94%)>mepivacine>tetracine> lidocaine(65%)> prilocaine> procaine (6%)

 This is the most important factor determining the rapidity and onset of action
 Low pKa – more non-ionised- rapid onset
 Procaine (8.9)> Tetracaine(8.5) >
Bupivacine(8.1) = Ropivacaine> lidocaine = prilocaine = etidocaine(7.7)>
Mepivacaine(7.6)
 High pKa value – better differential blockade

Agent
(
Onset mins )
Duration Effect of
Adreanaline
X 1 Bupivacaine 20-30 8-9 hrs
Chlorprocaine Fast in 3% 30-60 mins
Etidocaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine
15-20
20
20
20
20
6-8 hrs
60 mins
2 hrs
2 hrs
8-9 hrs
X 1.5
X 4
X 2
X 2
X 1

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 Most ester LA are (procaine,chlorprocaine,) are achiral compounds
Most amides are chiral drugs ( exception- lidocaine )
Most used clinically are Recemic mixtures
But recently s-enantiomers are produced(S-bupivacinechirocaine)
They have enhanced vasoconstricion
So longer acting
But can cause less duration & intensity of block
Also has less cardiotoxicity

 Local anesthetics block trains of action potentials
>> single action potentials
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The more frequent the A.P, the more often Na+ channels are open.
Also, affinity of the binding site increases.
 Magnitude and rate of block increase
 Depolarized membranes are more sensitive to local anesthetic action
 The more depolarized the membrane, the more
Na+ channels are open

 LA cause differential nerve block
 pain > temperature > touch > deep pressure > motor
 Small diameter, unmyelinated C fibers
(pain and autonomic) and Aδ fibers (pain) blocked before large diameter, myelinated
Aα, Aβ or Aγ nerves (motor, limb position)

Factors Causing Differential Nerve Block
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Critical length
– About 3 nodes of Ranvier need to be blocked to completely prevent a.p. conduction down a nerve
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The larger the fiber, the greater the distance between nodes and the larger the area that needs to be exposed to LA
Inhibition of >70% of Na+ channels will reduce the a.p. size
 Progressive blockade as you move down the axon results in failure to conduct after a sufficient length is exposed to drug

 Pain fibers and sympathetic fibers fire in high frequency bursts, whereas motor fibers fire at lower frequencies.
 LA with high use dependence (bupivacaine) therefore provide a better preferential block of pain and autonomic over motor function
 Axons at the periphery of a nerve (outside) are blocked more readily than those in the core because they are exposed to higher concentrations
 Proximal tissues are blocked more readily because their nerves lie in the perimeter of the nerve bundle
 In large mixed nerves, motor fibers lie on the outside

Cm
 It is the minimum concentration of LA necessary to produce conduction blockade of nerve impulses
 It is analogous to MAC
 Larger nerve fibres – more Cm
 An increased tissue pH or high frequency nerve stimulation will decrease Cm

 Cocaine – vasoconstrictor
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( moffett’s solution)
 cocaine 10% 1 ml + adrenaline 1ml
1:1000 + NaH(CO
3
)
2
2ml 8.4%.
 Vosodilatation
 Pro >pri> l > M > B > R
 S-isomers less vasodilataion

It depends on
 Dose
 Vasoconstrictor presence
 Site of injection
 Intercostal block > caudal > paracervical> epidural> brachial plexus > intrathecal

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Esters are not significantly protein bound(5-10% or less)
Amides are highly protein bound by α
1 glycoprotein
-acid
 There order is
 B>R>M>L>Pri
 In Pregnancy there is increased sensitivity to LA
 High protein bound drugs have low UV:M ratio
 For bupivacaine 0.2( so less transfer)
 For prilocaine 0.5 ( sp more transfer)

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Plasma concentration declines in a Biexponential manner
Rapid distribution phase( 1- 3 mins) brain,myocardium,lungs,liver
Followed by slower decline phase( muscle & fat)
Terminal half life of most ester anaesthetics is short- 10 mins due to rapid hydrolysis by plasma
& tissue cholinesterases
The amides half life range from 100 mins -200 mins
Volume of distribution> total body water
Plasma clearance is comparable with liver blood flow
Low cardiac output and hepatic cirrhosis will decrease there clearance

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Most esters broken down by esterase enzymes
Procaine- PABA – diethyamino ethanol – diethyglycine
 Exceptionally, COCAINE is resistant to hydrolysis by ChE.
 It is metabolised in liver
 Metabolites- Norcocaine, Ecgonine, benzoylated analouges
 They may be responsible for stumulant effects on CNS

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Extensively metabolised in LIVER by
AMIDASES
Prilocaine- rapidly metabolised in liver and some extent in kidney & lung
Its principle metabolite are N-Propylamine & o-
Toludine – Methaemoglibinmia(> 600 mg)
S-prilocaine produces less o-Toludine
Bupivacaine- low hepatic clearance- slowly metabolised in liver
Pipecolic acid & pipeco xylidine – metabolites
lidocaine

Convulsive properties
Lidociane dealkylated
Monoethy Glycine-xylidine + acetaldehyde hydrolysed
N-Ethyl Glycine + 2,6 Xylidine
4-OH- 2,6 Xylidine
(urine)
• Glycine-Xylidine, a minor metabolite is a CNS depressant – has long half life

Pulmonary Extraction
 Pulmonary extraction from the venous circulation limits the amount of local anesthetic (lidocaine , bupivacaine ), & prilocaine (Citanest)) that will reach the systemic circulation
 Bupivacaine : dose-dependent, first pass extraction (saturable, uptake)
 Propranolol inhibits bupivacaine extraction
 Propranolol reduces lidocaine & bupivacaine plasma clearance

 Has central & Peripheral effects
 Both effects are caused by inhibition of uptake1 in central & peripheral nerve endings
 Tachycardia , arrhthmias, vosoconstriction, pupillary dilatation & other sympathomimetic effects
 Corneal anaesthesia
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Nasal anaesthesia ( Moffets solution)
C.I with TCA’s , pressor drugs
 Dependence & abuse

 Procainamide – not broken down by ChE.
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So its used for its antiarrhythmic property Class
Ia – increases APD
Vosodilator – Rx of vascular spasm caused by inadverdent intra-arterial injection
 Cardioplegia- CPB
( does not ionise, acts by ME)
 Topical ,ear drops,ointments

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Most commonly used LA
Dose limits : the maximum recommended doses in the adult are, a. plain ~ 3 mg/kg b. with adrenaline ~ 7 mg/kg
2-4% - gels,ointments,creams
10 % - sprays
1-2 % epidural
Hyperbaric solutions( dextrose) 5% - Intrathecal
Hypobaric solutions( water)

 0.25% to 0.75%
 0.5% heavy ( hyperbaric) most commonly used drug in UK intrathecally.
 the maximum recommended doses in the adult are,
 a. plain ~ 2 mg/kg
 b. with adrenaline ~ 2 mg/kg
 NB: this equates to ~ 25 ml of 0.5% in a 70 kg adult

Chlorprocaine
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Used mostly in USA
Used in OBS practice- 3% solution
Differs from procaine by additon of chlorine atom , so its
4 times more quickly hydrolysed & has more rapid onset
Preservative – neurotoxic
Ropivacaine similar to bupivacaine, less cardiotoxic
Etidocaine
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Amide derived from lidocaine
It produces a more profound effect on motor than sensory nerves

 1.Caused by overdosage
 2.As a part of Therapeutic procedure
 3.Caused by Added vasoconstrictor
 4.Specific Effects

CNS TOXICITY
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Biphasic effects
Small dose (2-4 mg/kg) will have anticonvulsant effects-Rx status epilepticus
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Large dose will cause numbeness of tongue & mouth,light headedness,visual disturbances,slurring of speech,muscular twitching & tremors,restlessness & irrational conversation
Grand mal convulsions can occur( 10 mics/ml-lidocaine , 2 mics/ml – bupivacaine)
Hypoxia & acidosis potentiates convulsions
Prociane is relatively free from convulsant activity
Initial effects- depression of inhibitory cortical pathways
Profound effects- cortical & medullary depression

CVS TOXICITY
It follows CNS toxicity
 Hypotension, bradycardia, bradyarrhythmias, & cardiac arrest
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Bupivacine is more carditoxic
It acts on K + & Ca 2+ channels in addtion to Na + channels.
Myocardial conduction is depressed
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Widening of QRS complex & distortion of ST- segemnts
High doses can cause ventricular arrhythmia
Tachycardia can enhance frequency dependent block of cardiac sodium channels & cause more cardiotoxicity
S-bupivacaine & S-Ropivacaine have less carditoxicity

 Intercostal block > caudal > paracervical> epidural> brachial plexus > intrathecal
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Sympathomimetic amines will cause cardiac arrhythmias and hypertension
Should not be added to digital nerve block,penile block .

 Allergic responses- currently rare
 Skin rash
 Anaphylactic reactions
 Esters – PABA – more often cause this
 PABA antagonises sulphonamides
 Methaemoglobinaemia – o-toludine

 pH adjustment – NaOH & HCl
 Tonicity- NaCl
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Baricity- Glucose & H
2
O
Preservatives – methyhydroxy benzoate
( fungicide)
 Reducing agents – Sodium Metabisulphate
- to prevent oxidation of adrenaline

 Slows the rate of absorption
 Prolongs duration
 Reduces toxicity
 Enhnances the intensity of block
 Contraindicated:
 End arteries- ring blocks, penile blocks
 IVRA

Adrenaline :
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Most commonly used & potent
Conc: 1 in 80,000(12.5µg/ml) to
1 in 300,000(3.3µg/ml)
Max dose should not exceed 0.5 mg.
Noradrenaline :
 1 in 80,000 were used but now rarely used due to its pressor effects
Felypressin :
 Non catecholamine vasoconstrictor- vasopressin analouge, causes only peripheral vosoconstriction,no action on heart
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Safer for IHD patients but can cause pallor constrict coronary circulation.
Dental use – 0.03 i.u./ml
Phenyehrine
 Not used now , less effective than adrenaline

2
 It is supposed to speed the onset of action
 CO
2 rapidly diffuses across neurilemma & decreases intracellular pH ,so enhances the conversion of tertairy base(B) to the active form(BH + )
 But in clinical practice ,doubtful.
 CO
2 is rapidly buffered by intracellular proteins and these solutions are unstable & can precipitate

Dextrans :
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Prolong the duration because of its high molecular weight & are effective with combination with adreanline
“Macromolecules” are formed between dextrans and LA & they are held in tissues for long periods.
Hyaluronidase :
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It aids in spreading LA by breaking down tissue bariers
Used mostly in Opthal practice.

 Lidocaine + Bupivacaine
 To cause faster onset with long duration
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Will decrease there individual doses and thus reduce toxicity
However ‘ toxicity is additve’ if it occurs.
 If ester is combined with amide, toxicity may increase because amide slows hydrolysis of ester by inhibiting plasma cholinesterase

The combined melting point of the eutectic mixture is less than the either of the drugs
EMLA- 5% cream
 Mixture of unionised(base) 2.5% prilocaine &
2.5% lidocaine
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It takes 1-2 hours to act- pediatrics
Infants –contraindicated- methaemoglobinemia
TAC solution
 The combination of tetracaine , adrenaline , and cocaine (TAC) has commonly been used for repair of lacerations in the face and scalp of children

PRAMOXINE :
 Minor burns ,pruritis, sigmidoscopy, laryngoscopy
 DYCLONINE
 HEXYLCAINE
 PIPERCOLINE
 All can be used before direct laryngoscopy and they are not amides or esters ,so useful for patients allergic to them.

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 Regional anaesthesia
 Topical or surface anaesthesia
 Local infiltration
 Peripheral nerve blocks
 Bier block
 Epidural
 Spinal
Anlagesia (propofol)
To reduce intubation response
To decrease ICT
Ventricular dysrhytmias
Suppression of grand mal seizures