LOCAL

ANAESTHETIC
AGENTS
PROF. S. A. EGUMA
DEFINITION OF LOCAL
ANAESTHETIC
A drug which reversibly
prevents transmission
of the nerve impulse in
the region to which it is
applied, without
affecting consciousness.
 HISTORY
 “Erythroxylum coca” well known to the Incas of S. America. In
1860, cocaine was extracted from the leaves of the Erythroxylon
coca bush & introduced to Europe.
 Sigmund Freud, an Austrian psychoanalyst, used cocaine on his
patients and became addicted through self-experimentation.
 In 1884 Karl Koller introduced cocaine to the field of
ophthalmology, and Hall introduced it to dentistry.
 Halsted was the first to report the use of cocaine for nerve blocks,
in the United States in 1885
 In 1904, procaine was synthesised.
 Amethocaine was released in 1930. These agents were esters and
despite a risk of allergic reactions, were widely used.
 Lofgren later developed lidocaine, the most widely used cocaine
derivative, in 1943, during World War II.This was an amide and had
a low risk of allergic reactions.
 This was followed by mepivacaine (1957), prilocaine (1960),
bupivacaine (1963), ropivacaine(1997) and levobupivacaine
(2000).
CLASSIFICATION & CHEMICAL
STRUCTURE
 Classified into ESTERS & AMIDES based on chem. link
between aromatic ring & hydrocarbon chain.
 LA consist of a lipid-soluble aromatic group & a
hydrophylic amine group separated by a hydrocarbon
chain

 CH H2O

-C-O-CH2-CH2- N

Aromatic Amine group

ring
H
CHEMICAL STRUCTURE
LOCAL ANESTHETIC
AGENTS
AMIDES ESTERS

Lidocaine Cocaine

Prilocaine Procaine

Mepivacaine Tetracaine

Etidocaine Amethocaine Chloroprocaine

Bupivacaine Benzocaine

Ropivacaine Levobupivacaine
 ESTERS OF PHENYLCARBAMIC ACID
 Basic esters of alkoxy-substituted phenylcarbamic
acid have shown high LA potency, while maintaining
a relatively safe toxicity profile.
 The most potent phenylcarbamic anaesthetics
exceed the potency of the most common clinically
used local anaesthetics by 100–300 times.
 Their potency uniquely increases with the decreasing
pH of the external medium.
 This is of importance when using LAs in inflamed
tissues, where the action of common LAs is often
problematic. Further study of their action is required.
 Centbucridine
 MECHANISM OF ACTION
 LA act by inhibiting excitation of nerve endings or by
blocking conduction in peripheral nerves.
 They bind to Na channels to inhibit Na permeability &
prevent depolarisation
 By blocking the sodium channels in the nerve
membrane they prevent propagation of the action
potential along the axon.
 Small nerve fibres are more sensitive than large nerve
fibres
 Myelinated fibres are blocked before non-myelinated
fibres of the same diameter.
 Loss of nerve function proceeds as: loss of pain->
temp-> touch-> proprioception -> skeletal muscle
tone.
* This is why people may still feel touch but not pain
when using local anaesthesia but the mechanism for
the block of pain perception without motor block, is still
unclear.
MECHANISM OF ACTION OF LA
DIFFERENCES B/W AMIDES &
ESTERS
AMIDES ESTERS
1. Stable in solution 1. Ester drugs less stable in
solution and cannot be stored
for long.
2. Heat-stable & can be
2. Unstable in heat so cant be
autoclaved.
autoclaved.
3. Metabolism of esters ->
3. Very rarely cause allergic production of PABA associated
reactions. with allergic reactions.
THE IMPORTANCE OF THE pKa OF
Aionised
LOCAL ANAESTHETIC DRUG
 All LA are weak bases i.e. they exist in two forms: unionised &
(BH+).

 The pKa of a weak base defines the pH at which

both forms exist in equal amounts.

 As the pH of the tissues differs from the pKa of the specific drug,
more of the drug exists either in its ionised or unionised form.
PHARMACODYNAMICS
In clinical use, LA described in terms of

 Potency

 Duration of action

 Speed of onset of action

 Differential sensory blockade


FACTORS AFFECTING ACTION
Physiologic activity of LAs is a function of their lipid solubility,
diffusibility, affinity for protein binding, percent ionization at
physiologic pH, and vasodilating properties.

 Dose - affects duration & potency

 Site of administration-spinal fastest, plexus slowest
 e.g. adrenaline> vasoconstriction &
Additives-
duration
 clonidine, NaHCO3 , opioids, glucose
Other additives –

hyaluronidase.
 increased temperature shortens
Temperature –
onset of action i.e. makes it work faster.
 FACTORS AFFECTING
Block duration influenced by several factors:
ACTION
 OF LA
The drug concentration (the higher the conc., the
longer the block).

The drug volume (the
larger the volume the faster
the onset and the more dense the block).

Use of additives (Adrenaline
& sodium
bicarbonate speed the onset and prolong
the block).

Type of block (Leg
blocks last longer than arm
blocks. This is a function of nerve size and
vascularity.
 LIPID SOLUBILITY
 Lipid solubility determines potency.
 Potency is directly related to lipid solubility, because 90% of
the nerve cell membrane is composed of lipid.
 Increased lipid solubility leads to faster nerve penetration and
blockade of sodium channels.

 The more lipid soluble drug penetrates the cell membrane

more & so is more potent.
pKa & Diffusability = SPEED OF ONSET
OF ACTION
 The pKa of a local anaesthetic determines the amount which
exists in an ionised form at any given pH.
At physiological pH (7.4) all LAs are more ionised than
unionised (as all the pKa values are greater than 7.4). As the
drug must enter the cell in order to have its effect it must
pass through the lipid cell membrane.
 Unionised drugs do this more readily than ionised drug. So
the drug which is more unionised at physiological pH will
reach its target site more quickly than the drug which is less
so.
 E.g. Lignocaine has a pKa of 7.9 and is approximately 25%
unionised at pH 7.4. Bupivacaine has a pKa of 8.1 hence less
of the drug is unionised at pH 7.4 (about 15%).
 This explains why lignocaine has a faster onset of action
than bupivacaine.
 Diffusibility of the LA through tissue other than nerve tissue
also influences the speed of action onset.
pKa

 Lignocaine 7.9
 Bupivacaine 8.1
Why do LAs not work well in infected
tissues?
 Infected tissue tends to be more acidic than
normal.
 Asthe pH is reduced, the fraction of
unionised local anaesthetic is reduced and
consequently the effect is delayed and
reduced.

 Infected
tissue may also have an increased
blood supply & hence more anaesthetic may
be removed from the area before it can affect
the neurone.
 DURATION OF ACTION
 The duration of action of the drug is related to the length of the
intermediate chain joining the aromatic and amine groups.
 Protein binding - an important determinant of duration of action.
The more protein bound, the longer the duration of action.
 E.g. lignocaine is approx. 65% protein bound whereas
bupivacaine is 95% protein bound therefore one can predict that
bupivacaine will have a longer duration of action than lignocaine
– which is in fact the case.
 Procaine (an ester) is only 6% protein bound and has a very
short duration of action.
 Differences in protein binding also result in differing duration of
unwanted side effects. This is one of the reasons that
bupivacaine is considered more toxic than lignocaine.
PHARMACOKINETICS OF LAs
Absorption and distribution
 LAs are administered to the areas around the nerves to be
blocked – which include skin, subcutaneous tissues, intrathecal
& epidural spaces.
 Some of the drug is absorbed into the systemic circulation: how
much will depend on the vascularity of the area to which the
drug has been applied and the effects of the drug on vessel
diameter.
 Some LAs have vasodilatory effects at low concentrations,
increasing their systemic absorption.
 Only Cocaine has a vasoconstrictive effect.
 The distribution of the drug is influenced by the degree of tissue
and plasma protein binding of the drug.
 The more protein bound the agent, the longer the duration of
action as free drug is more slowly made available for
metabolism.

Metabolism and excretion
Esters and amides bind to alhpa 1 glycoprotein then to albumin
.
 Esters (except cocaine) are broken down rapidly by plasma
esterases to inactive compounds and excreted by the kidneys.
 Cocaine is hydrolysed in the liver.
 Amides are metabolised hepatically by amidases. This is a
slower process, hence their half-life is longer and they can
accumulate if given in repeated doses or by infusion.
 Prilocaine is also metabolised extrahepatically.
 Amides cross placenta & may result in ion trapping
 CLINICAL USES OF LAs
Preparations
 LAs are available as solutions for injection, sprays, creams and
gels. They are prepared as the hydrochloride salt to enable them
to be dissolved in water (resulting in an acidic solution).
 Topically (conjunctiva, skin, mucous membranes and ear drum).
 Infiltration-Larger nerves (e.g. sciatic) are thicker and well
myelinated. The LA takes longer to penetrate these nerves and
hence the onset time is longer.
 Anti-arrythmics –LAs act on heart muscle cells & cause
pacemaker suppression resulting in bradycardia and cardiac
arrest.
 There is also a negative inotrophic effect. Bupivacaine can cause
ventricular fibrillation which is difficult to treat.
 Dosages of Local Anaesthetics
Maximum Dose Duration
Drug Onset
(with Epinephrine) (with Epinephrine)

Lidocaine Rapid 4.5 mg/kg (7 mg/kg) 120 min (240 min)

Mepivacaine Rapid 5 mg/kg (7 mg/kg) 180 min (360 min)

Bupivacaine
Slow 2.5 mg/kg (3 mg/kg) 4 hours (8 h)
Ropivacaine
Medium 2-3 mg/kg 3 hours (6 h)
Levobupivacai
Medium 2.0 mg/kg or 400mg in 24 hrs 4-6 hours (8-12 h)
ne

Procaine Slow 8 mg/kg (10 mg/kg) 45 min (90 min)

Chloroprocaine Rapid 10 mg/kg (15 mg/kg) 30 min (90 min)

Etidocaine Rapid 2.5 mg/kg (4 mg/kg) 4 hours (8 h)

Prilocaine Medium 5 mg/kg (7.5 mg/kg) 90 min (360 min)

Tetracaine Slow 1.5 mg/kg (2.5 mg/kg) 3 hours (10 h)

 SIDE EFFECTS
 Toxicity-unexpected LA toxicity can occur
where the pharmacokinetics of the drug are
altered by comorbidity such as cardiac or
hepatic failure (reducing metabolism of the
drug), alterations in plasma protein binding,
or interactions with other drugs.
CNS effects:
-tinnitus, circumoral tingling & numbness,
slurred speech, tremors, seizures.
Cardiac effects: - Bradycardia, hypotension,
arrhythmias, cardiac arrest.
 CC/CNS RATIO
 The ratio of dosage or blood levels required to
produce irreversible cardiovascular collapse to
that level required to produce convulsions.

 The lower the ratio, the more potentially hazardous

the drug is.

 This is the reason why we don't use bupivacaine

for iv regional blocks.

 CC/CNS Ratio is 4 for bupivacaine, 7 for lignocaine

 SIDE EFFECTS
Respiratory effects:
 Respiratory depression
 Apnea
 Allergic reactions,
 Reaction to vasoconstrictor drugs
 Prilocaineis metabolised to O-toluidine which
can cause methemoglobinemia in susceptible
individuals.
 Cocaine is a potent vasoconstrictor and may
cause problems in patients already on
vasoconstricting drugs such as monoamine
oxidase inhibitors.
 MX OF LA TOXICITY
 Maintain patent airway
 Give 100% oxygen
 Assist or control ventilation
 Give diazepam 5-10mg or midazolam or
thiopentone 150mg to control convulsions
 Give iv fluids
 Give atropine if necessary
 Treat arrhythmias
 Intralipids
 DRUG LIDOCAINE PRILOCAINE BUPIVACAINELEVOBUPIVACAINE ROPIVACAINE
Description Amide Amide Amide Amide Amide
Relative
2 2 8 8 6
Potency
Onset 5-10 mins 5-10 mins 10-15 mins 10-15 mins 10-15 mins
Duration
without 1-2 hours 1-2 hours 3-12 hours 3-12 hours 3-12 hours
epinephrine
Duration
2-4 hours 2-4 hours 4-12 hours 4-12 hours 4-12 hours
with epinephrine
Max Dose
without 3 mg / kg 6 mg / kg 2 mg / kg 2.5 mg / kg * 3 mg / kg *
epinephrine
Max Dose
7 mg / kg 9 mg / kg 2.5 mg / kg 3 mg / kg * 4 mg / kg *
with epinephrine
* INDICATES PROBABLE SAFE MAXIMUM DOSE (INSUFFICIENT DATA).
LIDOCAINE
Used in clinical practice for almost 60 years. It has a rapid onset of action but
(LIGNOCAINE
the block is of a relatively ,XYLOCAINE)
short duration.
CLINICAL USE
 Skin Infiltration - 0.2–1.0 % lidocaine. Use with epinephrine 1:200,000 or
1:400,000
 Biers Block (IVRA) - 40ml of 0.5% lidocaine (without epinephrine).
 Peripheral nerve blocks - 1–2% lidocaine (with or without epinephrine).
 Dental blocks – lidocaine 2% (with epinephrine 1:80,000).
 Topical anesthesia – 2% gel (urethra) or 4% spray (oro-pharyngo-laryngo-
tracheal).
 Subarachnoid block – 2% lidocaine plain (no epinephrine).
 Lignocaine may be used clinically for its cardiac effects as an
antiarrhythmic.
 The recommended maximum safe dose of lidocaine:
LIDOCAINE WITHOUT EPINEPHRINE ------ 3 mg / kg
LIDOCAINE WITH EPINEPHRINE ------ 7 mg / kg
 Patients vary both in body habitus and metabolism and rates of absorption
vary in tissues depending on the blood flow.
 Lidocaine can be carbonated by adding sodium bicarbonate. This shortens
the onset and prolongs both the intensity and duration of block.
 BUPIVACAINE (MARCAIN)
 It is stable in solution and is commercially available in 0.25% &
0.5% solutions (with & without epinephrine).
 Spinal (heavy) bupivacaine (0.5% bupivacaine + 6% glucose).
 It is 4 times more potent than lidocaine. Therefore 0.25%
bupivacaine is equipotent with 1 % lidocaine.
 Bupivacaine is particularly cardiotoxic and should never be used
in Biers blocks.
 Bupivacaine binds tightly to tissues & thus has a long duration of
action (up to 24 hours in some cases). Adding epinephrine will
decrease its toxicity by delaying the drug absorption but will
have minimal effect on the duration of the block.
 The recommended maximum safe dose of bupivacaine:

Bupivacaine Without Epinephrine ------- 2.0 mg / Kg

Bupivacaine With Epinephrine ------- 2.5 mg / Kg
 LEVOBUPIVACAINE
 This is a relatively new agent and is the same as
bupivacaine. Bupivacaine is a racemic mixture of the
R and S enantiomers. Levobupivacaine contains the S
enantiomer only.
 Compared to bupivacaine it is said to have greater
vasoconstrictive action and less motor block.
 It is less cardiotoxic. It has replaced bupivacaine for
safety reasons but it is more expensive.
 It is not currently licensed for subarachnoid injection
so it is used only for epidural analgesia.

Recommended maximum safe dose of

levobupivacaine:
LEVOBUPIVACAINE ----- 2.5 – 3.0 mg / kg
 PRILOCAINE (CITANEST)
 This drug is closely related to lidocaine and is very similar in its
clinical action.
-Its advantage is that it is more rapidly metabolized and hence
less toxic.
-It can cause methaemoglobinemia when used in high dosage (>
600 mg). Methaemoglobinemia causes a blue skin discoloration
and results in false pulse oximeter readings. The treatment is
methylene blue 1 mg / kg iv over 5 minutes.

 Prilocaine is safer if large doses of local anesthetic are being

used.
Prilocaine 0.5% is the drug of choice in Biers block.

 The recommended maximum safe dose of prilocaine:

PRILOCAINE WITHOUT EPINEPHRINE ----- 6 mg / kg

PRILOCAINE WITH EPINEPHRINE ----- 9 mg / kg
 ROPIVACAINE (NAROPIN)
 Concerns about bupivacaine toxicity led to the
development of ropivacaine.
 It is less cardiotoxic than bupivacaine.
 The addition of epinephrine or sodium bicarbonate
does not appear to alter the speed of onset or
duration of the block.
 The intensity and duration of the motor block is
less than with bupivacaine.
It is slightly less potent than bupivacaine (in
peripheral nerve blockade 0.5% bupivacaine is
equipotent with 0.6% ropivacaine).
 It is not currently licensed for subarachnoid
usage.
 Recommended maximum safe dose = 3 - 4 mg / kg

ARTICAINE
Relatively new LA used in dentistry as 4% solution.
 It is an amide & instead of benzene ring, it contains a
thiophene ring that increases its lipid solubility.
 Unlike other local anaesthetics, articaine contains an
additional ester group that is rapidly metabolised by plasma
esterase to articainic acid.
 Short half-life, about 20 minutes, compared to other LAs.
 Advantages are low lipid solubility, high plasma protein
binding rate, fast metabolism, fast elimination half time,
and low blood levels.
 Can cause methaemoglobinaemia, neuropathies
 LA of first choice in tissues with suppurative inflammation,
for adults, children (> 4 years), elderly, pregnant &
breastfeeding women, and patients with hepatic disorders
and renal impairment.
 Must not be used in persons who are allergic to sulphite,
due to the content of sodium metabisulphite as the
vasoconstrictor’s antioxidant in it
ADDITIVES TO LOCAL
ANESTHETICS
 Most LA preparations contain a preservative agent such as 0.1%
sodium metabisulphite, with or without a fungicide & 1mg/ml of
methyl parahydroxybenzoate.
 LAs may also be combined with other LAs (e.g. EMLA cream –
eutectic mixture of local anesthetics)
 Adrenaline 1 in 200,000, bicarbonate (e.g. 0.15ml of 8.4% solution
added to 10ml 0.5% bupivacaine).
 Adrenaline acts as a vasoconstrictor to minimise the vasodilator
effect and decrease the rate at which drug is removed from the site
of action by absorption into the systemic circulation. It also reduces
blood loss from the site by the same mechanism.
 Bicarbonate added to LA increases the pH of the environment when
administered so more drug is present in its unionised form and
speed of onset of anesthesia is increased.
 Glucose (usually 80mg.ml-1) is added to bupivacaine in order to
increase the baricity of the solution to greater than that of CSF.
When administered as a spinal anesthetic this results in more
controlled spread of solution within the intrathecal space.
 ADDITIVES
 Additives act to prolong the duration & intensity of the block as well as
reducing the risk of LA toxicity.
ADRENALINE
 Adrenaline is added to LA to cause vasoconstriction. This reduces the LA
absorption and results in prolongation of block duration and reducing
toxicity.
 Adrenaline does not significantly prolong the duration of bupivacaine or
ropivacaine but it does slow the absorption of these agents and reduces
peak plasma levels. This reduces the toxicity risk of these two LAs.
 Adrenaline is commercially available in two ampoule sizes:
A 1 ml ampoule containing 1 mg (ie 1:1000).
A 10 ml ampoule containing 1 mg (ie 1:10,000).
 MAXIMUM SAFE DOSE OF ADRENALINE = 4 MICROGRAMS PER KG.
Therefore an 80 kg man = 320 micrograms = 64 ml of a 1:200,000
solution.
This maximum dose should be reduced in cases of serious ischemic heart disease, thyrotoxicosis and hypertension. In such
cases, avoid epinephrine all together.

*Always inject large volumes slowly and listen carefully to the pulse oximeter. A sudden onset tachycardia is an emergency
stop sign!.
 ADDITIVES
FELYPRESSIN (OCTAPRESSIN):
 Felypressin- a synthetic derivative of vasopressin from the posterior
pituitary. It causes vasoconstriction but has minimal antidiuretic effect. It
has no effect on cardiac rate or rhythm and is therefore popular in dental
surgery where, used in conjunction with 3% prilocaine, it increases the
intensity and duration of dental nerve blocks.
 Felypressin is useful when epinephrine is contraindicated (e.g. serious
ischemic heart disease, thyrotoxicosis and hypertension).
 The commonly used vasoconstrictive concentration is 0.02 – 0.03 U / ml.
CLONIDINE (CATAPRES):
Clonidine is an alpha-2 adrenoreceptor agonist used to treat hypertension.
 Clonidine acts on the brain to cause sedation and has analgesic effects on
the central and peripheral nervous systems. It prolongs and intensifies
blocks when added to local anesthetics.
 Adding clonidine 75 – 100 micrograms can extend the duration of
peripheral blocks by 50 – 100%.
For Biers blocks (IVRA), clonidine 150 micrograms can be added to the LA
solution. It reduces tourniquet pain and causes no adverse effects when the
tourniquet is released.
 Clonidine is regularly used when prolonged post operative analgesia is
required.
 ADDITIVES
SODIUM BICARBONATE:
 Sodium bicarbonate is added to LAs to raise the pH
of the solution.
 This has the effect of increasing the unionized LA
which enables the LA to penetrate the nerve
membranes more readily. Thus the speed of onset is
increased.
 It also prolongs the duration and intensity of the
block.
 Bicarbonate reduces the pain of injection (injection
pain is associated with a low pH and cold solution).
 The recommended dose is 1 ml of 8.4% sodium
bicarbonate per 10 ml of LA.
 TIPS ON USE OF LAs
 For surgical cases where rapid onset peripheral blockade is
required, use lignocaine 1 - 2% or prilocaine 1 - 2%.
 If prolonged postoperative analgesia is required, use
bupivacaine 0.25% - 0.5%. (or ropivacaine 0.4 – 0.7%).
 If large doses of LA are used (e.g. plexus blocks and extensive
skin infiltration) it is safer to use ropivacaine or
levobupivacaine.
 Always aspirate before injection
 Do not inject if patient complains of severe pain.
 There should be no resistance to injection.
 NEVER exceed the maximum recommended dose.
 NEVER inject epinephrine- containing solutions of LA
into end organs (fingers, toes, penis, nose, ears).
A LITTLE EXERCISE TO WAKE YOU
UP!

TO WAKE YOU UP
LA DOSE CALCULATION
 Localanaesthetics often come
prepared in a % mixture. Converting a
% to mg is very easy.
 Allthat is required is to move the
decimal point one place to the
right.
 E.g.
1ml of 1% lignocaine contains
10mg of lignocaine
 5mlof 2% lignocaine contains
100mg lignocaine
ADRENALINE DOSE
 Adrenaline concentration is measured
differently.
A 1:1000 adrenaline vial contains 1 mg
per ml of adrenaline
A 1: 10,000 adrenaline solution contains
100micrograms / ml (0.1mg)
A 1:100,000 solution contains
10micrograms (0.01mg)
A 1:200,000 Adrenaline solution contains
5 micrograms per ml i.e. 0.05mg/ml
 Example
A local anaesthetic contains 1:200,000
adrenaline. A 1:200,000 ratio means that
there is 1 g of adrenaline diluted in 200,000
ml or 1000 mg in 200,000ml of solution
 1g = 1000mg = 1mg
200,000ml 200ml
1 mg = 1000mcg
200ml
= 10 mcg/ 2ml
= 5 mcg per 1 ml
 QUESTION 1

How do you prepare a 1:200,000

solution of Adrenaline in 1%
lignocaine?
 ANSWER

 Take0.1 ml of Adrenaline from a

1:1000 ampoule and add it to 19.9 ml
of 1% plain lignocaine.
OR
 Draw up the whole 1ml of Adrenaline
from a 1:1000 ampoule in a 10ml
syringe and add water to make it up to
10ml. Now take 1ml of this solution and
add it to 19.9 ml of 1% plain lignocaine.
 THANK YOU FOR YOUR
ATTENTION

HAVE A BUSY
WEEK!!!