Download Local anaesthetics

LOCAL
ANAESTHETICS
DR.SUDHIR
MUBARAK AL KABEER HOSPITAL
DEFINITION
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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
HISTORY
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
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Chemical Structure
Physical Properties (structure)
Ester:
R3
R 1—COO—R 2 —N
R 1 — Lipophilic aromatic residue.
R4
Amide:
R3
R 1—NHCO—R 2—N
R 2 — Aliphatic intermediate connector.
R 3, R 4 — Alkyl groups or Amino groups
R4
Example:
C 2H 5
H2 N—
—COO—(CH 2) 2—N
C 2H 5
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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
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COCAINE
PROCAINE
CHLORPORCAINE
TETRACAINE
(AMETHOCAINE)
BENZOCAINE
AMIDES
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LIDOCAINE
PRILOCAINE
MEPIVACAINE
BUPIVACAINE
ROPIVACAINE
ETIDOCAINE
CINCHOCAINE
(DIBUCAINE)
NEURONAL TRANSMISSION
SODIUM & POTASSIUM
CHANNELS
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Voltage sensitive sodium channel
It sorrounds aqueous pore
Three subunits- α β1 β2
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 base considerations
related to mode of action
Rules
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
Rules
Hydrophilic = Ionized molecules (charged)
Lipophilic = Non-ionized molecules (non
charged)
Lipophilic molecules penetrate membranes
Hydrophilic molecules dissolve in water
Depending if a molecule is ionized
or not determines if it can pass
through a cell membrane
MEMBRANE
Non-Ionized Molecule
CELL
Ionized Molecule
Basic Drug
Basic drugs – become more NON ionized in basic pH
I
pH 2
N
I
pH 6
N
I
pH 8
What’s the pKa for this drug?
N
I
pH 9
base
pH = pKa + log acid
= Ionized molecules
= Non ionized molecules
MODE OF ACTION
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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 + HCO3 - = B + H2CO3 + CLSo 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 expansion- causing swelling of
lipoprotein matrix of Na+ channel .
Tetrodotoxin & saxitoxin- directly block Na+ channel
from the exterior of the membrane,close to the external
pore
PHYSIOCHEMICAL PROPERTIES
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LIPID SOLUBILITY
TISSUE PROTEIN BINDING
pKa
STEREO SPECIFICITY
VOSODILATATION
MINIMUM CONCENTRATION
FREQUENCY DEPENDANT BLOCKADE
DIFFERENTIAL BLOCKADE
LIPID SOLUBILITY
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)
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Tissue protein binding
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It primarily affects the Duration of LA
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Etidocaine(96%) > Bupivacine(95%)>
Ropivacaine(94%)>mepivacine>tetracine>
lidocaine(65%)> prilocaine> procaine (6%)
pKa Value- disscociation constant
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
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Onset time & Duration
Agent
Onset
(mins)
Duration
Effect of
Adreanaline
Bupivacaine
20-30
8-9 hrs
X1
Chlorprocaine
Fast in 3%
30-60 mins
Etidocaine
15-20
6-8 hrs
X 1.5
Lidocaine
20
60 mins
X4
Mepivacaine
20
2 hrs
X2
Prilocaine
20
2 hrs
X2
Ropivacaine
20
8-9 hrs
X1
STEREO SPECIFICITY
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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
Frequency or use dependent
blocakde
Local anesthetics block trains of action potentials
>> single action potentials
 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
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Differential nerve blocakde
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)
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Factors Causing Differential Nerve Block
Critical length
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– 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
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Progressive blockade as you move down the axon
results in failure to conduct after a sufficient length is
exposed to drug
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Pain fibers and sympathetic fibers fire in high frequency
bursts, whereas motor fibers fire at lower frequencies.
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LA with high use dependence (bupivacaine) therefore
provide a better preferential block of pain and autonomic
over motor function
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Axons at the periphery of a nerve (outside) are blocked
more readily than those in the core because they are
exposed to higher concentrations
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Proximal tissues are blocked more readily because their
nerves lie in the perimeter of the nerve bundle
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In large mixed nerves, motor fibers lie on the outside
Minimum concentration( 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
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vasodilatation
Cocaine – vasoconstrictor
 ( moffett’s solution)
 cocaine 10% 1 ml + adrenaline 1ml
1:1000 + NaH(CO3)2 2ml 8.4%.
 Vosodilatation
 Pro >pri> l > M > B > R
 S-isomers less vasodilataion
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SYSTEMIC ABSORPTION
It depends on
 Dose
 Vasoconstrictor presence
 Site of injection
 Intercostal block > caudal > paracervical>
epidural> brachial plexus > intrathecal
PLASMA PROTEIN BINDING &
PLACENTAL TRANSFER
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Esters are not significantly protein bound(5-10%
or less)
Amides are highly protein bound by α1-acid
glycoprotein
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)
PHARMACKOKINETICS
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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
METABOLISM & ELIMINATION
Ester metabolism
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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
Amide metabolism
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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 & oToludine – 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)
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Propranolol inhibits bupivacaine extraction
 Propranolol reduces lidocaine &
bupivacaine plasma clearance
DRUGS
COCAINE
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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
Nasal anaesthesia ( Moffets solution)
C.I with TCA’s , pressor drugs
Dependence & abuse
Procaine
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Procainamide – not broken down by ChE.
So its used for its antiarrhythmic property Class
Ia – increases APD
Vosodilator – Rx of vascular spasm caused by
inadverdent intra-arterial injection
Cardioplegia- CPB
Benzocaine
( does not ionise, acts by ME)
 Topical ,ear drops,ointments
Lidocaine
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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)
Bupivacaine
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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
TOXICITY
Toxicity
1.Caused by overdosage
 2.As a part of Therapeutic procedure
 3.Caused by Added vasoconstrictor
 4.Specific Effects
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overdosage
CNS TOXICITY
 Biphasic effects
 Small dose (2-4 mg/kg) will have anticonvulsant effects-Rx
status epilepticus
 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
 Bupivacine is more carditoxic
 It acts on K+ & Ca2+ channels in addtion to Na+
channels.
 Myocardial conduction is depressed
 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
As a part of theraupatic procedure
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Intercostal block > caudal > paracervical>
epidural> brachial plexus > intrathecal
Caused by vasoconstrictor
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Sympathomimetic amines will cause cardiac
arrhythmias and hypertension
Should not be added to digital nerve block,penile
block .
Specific effects
Allergic responses- currently rare
 Skin rash
 Anaphylactic reactions
 Esters – PABA – more often cause this
 PABA antagonises sulphonamides
 Methaemoglobinaemia – o-toludine
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ADDITIVES & MIXTURES
pH adjustment – NaOH & HCl
 Tonicity- NaCl
 Baricity- Glucose & H2O
 Preservatives – methyhydroxy benzoate
( fungicide)
 Reducing agents – Sodium Metabisulphate
- to prevent oxidation of adrenaline
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ADDITIVES & MIXTURES
vasoconstrictors
Slows the rate of absorption
 Prolongs duration
 Reduces toxicity
 Enhnances the intensity of block
 Contraindicated:
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 End
arteries- ring blocks, penile blocks
 IVRA
Adrenaline :
 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
 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
CO2 (cabonated solutions)
It is supposed to speed the onset of
action
 CO2 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.
 CO2 is rapidly buffered by intracellular
proteins and these solutions are
unstable & can precipitate
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Dextrans :
 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 :
 It aids in spreading LA by breaking down tissue
bariers
 Used mostly in Opthal practice.
Mixtures-compounding
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Lidocaine + Bupivacaine
To cause faster onset with long duration
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
Eutectic mixture
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
 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
Other topicals
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.
CLINICAL USES
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Regional anaesthesia
 Topical or surface anaesthesia
 Local infiltration
 Peripheral nerve blocks
 Bier block
 Epidural
 Spinal
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Anlagesia (propofol)
To reduce intubation response
To decrease ICT
Ventricular dysrhytmias
Suppression of grand mal seizures