Local Anesthetics
• Local anesthetics are drugs used to reversibly
depress CNS to prevent or relieve pain in specific
regions of the body without loss of consciousness
• They achieve this by preventing the transient
increase in sodium permeability of the excitable
membrane.
• Unlike General Anesthetics, they generally don’t
block sense of touch, pressure or temperature or
relax skeletal muscles
• Local anesthetics are used to abolish the
sensation of pain in restricted area of the body
and for minor surgical operations when loss of
consciousness is not desirable.
Uses
• Dentistry
• Podiatry (treatment of disorders of the foot,
ankle, and leg)
• ENT operations
• Surgery of skin
• Labor pain
• Postoperative pain
• Skin Trauma
How Nerve conduction occurs?
• Nerve conduction is a both electrical and
chemical component
• The electrical component occurs within the
axon. It involves membrane bound voltage
gated ionic channels (responds to change in
voltage across the membrane)
• The chemical component occurs at synapse.
It involves membrane bound ligand gated
ionic channel (responds to binding of a
neurotransmitters).
Chemical transmission of stimuli Electrical transmission of stimuli
occurring at synapse through occurring through axon by
neurotransmitter binding to their movement of ion in and out
receptors
Mechanism of Action of local
anesthetics
• Local anesthetics work in general by binding to the
voltage gated sodium channel receptors inside the
cell and thereby inhibiting generation of action
potentials in the axon. Thus they reduce the
excitability of the neuron.
• The presence of large anionic proteins inside the cell
and Na/K ion pumps in the cell membrane , that
pump 2 K+ intracellular for every 3 Na+ it pumps
extracellular, create a -70mV resting potential.
Mechanism of Action (cont’d)
• The first step of this entire process is
opening of voltage gated sodium channel
which allows influx of sodium ion to cause
increase in membrane potential. LA act
here to block the Na influx and thus
prevent stimuli propagation through the
axon.
How LA primarily blocks pain?
ü Different neurons carry different stimulus such as
pain, cold, warmth, touch and deep pressure.
ü The neurons differ in the thickness of the axon
ü Thin axons are most sensitive to drugs
ü Neurons carrying pain has the thinnest axon
ü Then comes cold, warmth, touch, deep pressure
ü Thus effect of LA also follow this order
ü Also nerve fiber are thinner than muscle fiber,
thus they are blocked preferentially and thus no
muscle relaxation occur with LA.
CHEMICAL CLASSIFICATION OF
LOCAL ANESTHETICS
1. Esters of benzoic acid
• Cocaine
• Eucaine
• Meprylcaine
• Hexylcaine
2. Esters of para amino benzoic acid
– Benzocaine
– Procaine
– Chlorprocaine
– tetracaine
3. Amides
– Lignocaine
– Cinchocaine
– Bupivacaine
– Mepivacaine
CHEMICAL CLASSIFICATION
ACCORDING TO CLINICAL USE
1. Surface anesthesia
2. Infiltration anesthesia
3. Nerve block anesthesia
4. Spinal anesthesia
5. Epidural anesthesia
SARs of Local Anesthetics
1) The Aromatic Ring:
• The aromatic ring adds lipophillicity to the anesthetic
and helps the molecule penetrate through biological
membranes.
• It is also thought to have direct contact with the local
anesthetic binding site on the sodium channel.
• Local anesthetic block Na + channel and prevent
inward movement and depolarization. So if electron
withdrawing group such as NO 2 group is attached
then it decreases the potency of local anesthetic.
2) The Linker:
• The linker is usually an ester or an amide group along with a
hydrophobic chain of various lengths.
• In general, when the number of carbon atoms in the linker is
increased, the lipid solubility, protein binding, duration of
action and toxicity increases.
3) The Nitrogen:
• Most local anesthetics contain a tertiary
nitrogen with a pKa between 7.5 and 9.5.
• Therefore, at physiological pH, both the
cationic and neutral form of the molecule
exists.
• To keep the anesthetic soluble in commercial
solutions, most preparations are acidified.
• In an attempt to decrease pain on injection
and to increase the onset of action, some
prac ti ti o ners advo cate a d d i n g s o d i u m
bicarbonate to the commercial preparation
The Ester of benzoic acid
1-Cocaine:
• Cocaine was the first agent used for topical anesthesia.
• In 1884, a German surgeon demonstrated the successful use of cocaine to
anesthetize the cornea during eye surgery.
• Today, cocaine is used for topical anesthesia of mucous membranes using a
4% to 10% solution. If the solution remains on the membrane for 5 minutes,
anesthesia and vasoconstriction of the area will occur.
• It is natural source as lead compound for synthesis of new drugs
2) Eucaine:
• it is ester of benzoic acid.
• Eucaine is free from addiction but still cause
CNS toxicity.
• It is withdrawn from the market due to its toxic
reactions.
• Its toxicity is due to its
rings.
Esters of para amino benzoic acid
3-Procaine:
• Procaine is also included in some formulations of penicillin G to
decrease the pain of intramuscular injection.
• Procaine is not used topically because of its inability to pass through
lipid membranes and finds use as an infiltration agent for cutaneous or
mucous membranes, for short procedures. (Local infiltration
anesthesia is the technique of producing loss-of-sensation restricted to
a superficial, localized area in the body. A low concentration of
anesthetic agent is infiltrated into the tissues in the area that requires
anesthesia)
• Procaine is also used for peripheral nerve block and as an epidural
agent to diagnose pain syndromes.
• Procaine is very quickly metabolized in the
plasma by cholinesterases and in the liver via
ester hydrolysis by a pseudocholinesterase.
• The para-aminobenzoic acid (PABA) metabolite,
common to the ester class of drugs, is believed to
be responsible for the allergic reactions some
patients have experienced with local anesthetics.
4-Benzocaine:
• The onset of action is within 30 seconds and the
duration of drug action is 10 to 15 minutes.
Benzocaine is used for endoscopy, bronchoscopy,
and topical anesthesia.
• Toxicity to benzocaine can occur when the topical
dose exceeds 200 to 300 mg resulting in
methemoglobinemia.
Methemoglobinemia:
• Cyanosis (a bluish-purple hue to the skin) as a result of the
fo r m a t i o n o f m e t h e m o g l o b i n e m i a m ay o c c u r a f t e r t h e
administration of the local anesthetics lidocaine, prilocaine, and
benzocaine.
• When normal hemoglobin is oxidized by a drug or drug metabolite,
it forms methemoglobin. Methemoglobin contains the oxidized
form of iron, ferric iron (Fe3+) rather than the reduced ferrous iron
(Fe2+) that hemoglobin contains.
• The oxidized iron cannot bind to oxygen and methemoglobinemia
results when the methemoglobin concentration in the blood
reaches 10 to20 g/L.
Include children younger
than 2 years, anemic
patients, those with a
genetic deficiency of
glucose-6-phosphate
dehydrogenase or
nicotinamide adenine
dinucleotide
methemoglobin reductase
or those exposed to
excessive doses of the
causative local anesthetic.
Amides
5-Lidocaine/Lignocaine:
• Lidocaine was the first amino amide synthesized in 1948 and has
become the most widely used local anesthetic. It contains amide
linkage.
• it has fast onset of action and it is long acting due to amide
linkage, so this feature make it useful for clinical use.
• The liver is responsible for most of the metabolism of lidocaine
and any decrease in liver function will decrease metabolism.
• Toxicity increases in patients with liver disease and those with
acidosis, which decreases plasma protein binding of lidocaine.
ØUses
– Surface or topical anesthetic
– Spinal anesthetic
– Infiltration anesthetic
