Local anesthetics

Dr. Saad Baddai

 Objectives
• To know the concept of local anesthesia
• To know the groups of local anesthetics
• To know the mechanism of local anaesthsia
• To know the main agents of local
anaesthetics and their individual
characteristics.
 Pain
• Pain occurs due to different causes from within or outside
the body.
• Pain sensation awareness is called (nociception).
• Nociception is transmitted from receptors at the
peripheral tissue to the central nervous system.
• Pain awareness or sensation or nociception can be
blocked by the drugs.
• There are several mechanisms of pain reduction by drugs.
• Local anaesthetics act by a specific mechanism.
• Local anesthetics (LA) produce an effective,
transient and reversible loss of sensation in a
circumscribed region of the body without
loss of consciousness.
• Normally, the process is completely
reversible.
• They are usually administered by injection to
the dermis or soft tissue around the nerves or
by topical application (cream, ointment, gel,
spray)– transdermal, transmucosal.
 Chemistry
• Most of local anesthetics are weak bases (pKa 8-9).
• At physiological pH they are cations.
• Most of them consist of a lipophilic group connected
by an intermediate chain into hydrophilic (ionizable)
group.
• The intermediate chain that connect both groups
contains either ester or amide
• According to the linking group local anaesthetics are
classified into esters and amides.
• Esters links are easier in hydrolysis than amide links
thus, they have shorter duration of action
 Classification of LA
1. Esters :
- Cocaine
- Procaine
- Tetracaine
- Benzocaine
2. Amides:
- Lidocaine
- Mepivacaine
- Bupivavacaine
- Articane
- Ropivacaine
• Local anaesthetics medical preparations are salts to increase
solubility and stability.
• The cationic form is the most active at the receptor site because
it can not exit from closed channels.
• The uncharged form is important for rapid penetration of
biologic membranes. This is very important for LA in order to
reach from outside the neurons to inside and produce their
action.
• Therefore, LA are less effective if they are injected into acidic
media (e.g. infected tissue) because less uncharged (lipophilic)
molecules will be available in acidic media. i.e. in low pH
tissue efficacy of LA will be less.
 Pharmacokinetics:
• The absorption and distribution of LA plays an
important role in the offset more than the onset of
the LA drug.
• Esters are not well studied because of their rapid
destruction in the plasma.
• CNS and cardiac toxicity are related to the
pharmacokinetic properties of the LA drug.
 1. Absorption:
• Local anesthetics, except cocaine, are poorly absorbed from
the GI tract.
• Injected LA absorption by the tissue depends on:
- Dosage of the drug
- Site of injection: different rate of absorption in different parts
of the body e.g. intercostal > epidural > brachial plexus>
sciatic nerve.
- Local tissue blood supply and flow : More rapid absorption in
tissue with high blood supply e.g. tracheal mucosa. And less in
lower blood supply e.g. tendon
- Use of vasoconstrictors (e.g. adrenaline).: adding adrenaline
(epinephrine) to LA reduces its tissue absorption because of
adrenaline vasoconstrictor effects.
- Physicochemical properties of the drug itself.
 2. distribution:
• Amide type of LA are widely distributed after i.v.
injection.
• Initial rapid distribution phase occur by uptake
into highly perfused organs e.g. brain, liver, heart
and kidney.
• Later, moderate absorption phase occurs with
uptake into well-perfused organs e.g. muscles
and GIT.
• Regarding ester type distribution is not well
understood because of their short half-lives.
 3. Metabolism and excretion
• Amide type: converted in the liver into more water-soluble
compounds. While ester type converted in the plasma.
• both metabolites are excreted in urine, LA in the uncharged form is
less excreted in urine . Acidification of urine promote ionization of
hydrophilic group leading to more water-soluble form and thus
excretion.
• Ester type: metabolized very rapidly in the blood via
pseudocholinesterase.
• Therefore, procaine and chloroprocaine have very short half life.
• The amide linkage is hydrolyzed by hepatic microsomal system
cytochrome CYP-450.
• there is a considerable variation in liver metabolism rate of amides.
Prilocaine (fastest)>lidocaine> mepivacaine>bupivacaine (slowest).
• Thus hepatic disease reduce amide metabolism and toxicity.
• The potency of local anesthetics is
positively correlated with their lipid
solubility, which may vary 16-fold, and
negatively correlated with their molecular
size.
• All local anesthetics, except cocaine, are
vasodilators at therapeutic doses.
 Pharmacodynamics:
• Mechanism of action:
• LA act by blocking neuronal voltage- gated sodium channels and the
conduction of action potentials along sensory nerves.
• Blockade is voltage dependent and time dependent.
• The excitable neuronal membrane resting potential is -90 to -60 mV.
• During excitation sodium channels open and sodium fast inward and
current quick depolarization leads to sodium equilibrium potential
+40 mV.
• Then, sodium channels inactivation occurs and potassium channels
open facilitating K outward flow. Repolarization of membrane to -95
mV
• Repolarization returns sodium channels to resting state with
refractory period (no action potential generation).
• During excitation the cationic charged form of local anesthetics
interacts preferentially with the inactivated state of the Na+
channels on the inner aspect of the sodium channel to block
sodium current and increase the threshold for excitation.
• LA binding to more and more sodium channels reduces the
amplitude of action potential then depolarization and current
propagation will be abolished.
• Blocking action potential generation in a critical part of the
neuron will block the current propagation through the neuron
leading to sensory loss.
• Resting sodium channels have lower affinity to LA than
activated and inactivated state. So the effect of LA is more
prominent in rapidly firing neurons.
 • These anesthetics are selected for use on the basis of:
1. the duration of drug action
• Short: 20 min
• Intermediate: 1—1.5 hrs
• Long: 2—4 hrs
2. effectiveness at the administration site
3. potential for toxicity
All local anesthetics, except cocaine, are vasodilators at
therapeutic doses.

For this reason a vasoconstrictor (e.g., adrenaline)

should be given with a local anesthetic because :
1. reduces local blood flow .
2. This reduces systemic absorption of the local
anesthetic from the site of application, and prolongs
action of local anaesthetic .
• Adrenaline :
• should not be coadministered for nerve block
in areas such as fingers and toes that are
supplied with end-arteries because it may
cause ischemia or necrosis
• Local anaesthetic with adrenaline should be
used carefully in:
• patients in labor
• patients with thyrotoxicosis or cardiovascular
disease because it increase arrhythmia.
Specific drugs and their therapeutic uses

Amides

Lidocaine (lignocaine) (Xylocaine)®

Lidocaine is the prototype amide
it has an intermediate duration of action.
Lidocaine given with distiled water of some injections e.g.
ceftriaxone vial (antibiotic)
Lidocaine is generally preferred for:
infiltration blocks (with or without adrenaline)
epidural anesthesia.
Oromucosal gel and spray (with cetrimide –antiseptic-).
 ) Mepivacaine
• intermediate duration of action that is longer
than that of lidocaine.
• Actions:
• similar to those of lidocaine
• it causes less drowsiness and sedation.
c) Bupivacaine, Ropivacaine,
These drugs have a long duration of action.
Bupivacaine:
has greater cardiotoxicity than other amides
may cause hypotension.
Slow onset of action (30 min.)
Used for epidural anaesthesia
Ropivacaine may have less cardiotoxicity than
bupivacaine.
1. Esters

A. Procaine
- Procaine is short-acting agent .
- Procaine is not effective topically.

b) Usually given with some painful intramuscular

injections (e.g. procaine penicillin)
 B. Cocaine
• Cocaine is a short-acting
• used for the topical anesthesia of mucous membranes like
nose, mouth and throat for surgical procedures.
• Cocaine is a schedule II controlled substance that is
subject to abuse.
• With newer LA drugs , cocaine use in this purpose was
reduced.
 c. Tetracaine

• Used for topical application

• Anesthesia before cannulation or venipuncture.
• Rapidly absorbed from mucous membrane
• Should not be applied into inflamed and highly
vascular areas because of potential toxicity and
lidocaine is a safer choice.
• Hypersensitivity reactions and cross reactions
 Medical uses of local anaesthtics

1. Acute pain
Acute pain may occur due to trauma, surgery, infection, disruption
of blood circulation, or many other conditions in which tissue
injury occurs.
2. Chronic pain:
3. Surgery :
-Dentistry
-Eye surgery
-Shoulder and arm surgery
-Bone surgery
-Skin surgery
-Gynecology and obstetrics
4. Diagnostic tests
 Adverse effects and toxicity of local anesthetics

• Adverse effects occur in both therapeutic dose and overdose.

• They affect many systems
- ( CNS, cardiovascular system, and others).
 CNS and neurotoxicity
• All LA can produce CNS and neurotoxicity
• dizziness, restlessness, tinnitus, tremor, and visual
disturbances.
• Lidocaine and procaine may cause sedation and sleep.
• At high dose, local anesthetics produce nystagmus,
shivering, tonic-clonic seizures, respiratory depression,
coma, and death.

• Neurotoxicity : lidocaine and chloroprocaine are more

neurotoxic if given in spinal anaesthesia.
 Adverse cardiovascular system effects:
• CV toxicity occurs due to direct effect (blocking cardiac sodium
channels and affecting pacemaker activity and cardiac
excitability and conduction, and indirect through autonomic
nervous system.
• Local anaesthetics except cocaine depress cardiac contractility
and causes arteriolar dilatation.
• Bupivacaine has a potent cardiotoxic effect because longer
sodium channel blocking effect in the cardiac tissue than nerves.
• Cardiotoxic effects include:
• Bradycardia develops as a result of the block of cardiac sodium
channels and the depression of pacemaker activity.
• Hypotension develops from arteriolar dilation and decreased
cardiac contractility. Cocaine causes hypertension.
• Arrhythmia
• Cardiac arrest
 Allergic reactions
• include rare rash, edema, and anaphylaxis.

• These reactions are usually associated with ester-type drugs

that are metabolized to derivatives of para-aminobenzoic
acid.
• Allergic reactions are very rare in amide agents