This document provides an overview of local anesthetics, including their physicochemical properties, mechanisms of action, classifications, toxicity risks, and clinical applications. It discusses how local anesthetics reversibly block sodium channels, preventing nerve impulse generation. The summary properties like lipid solubility, ionization, and protein binding determine onset and duration. Local anesthetics are classified as amide and ester types, with differences in stability and allergic potential. Toxicity can impact the central nervous system or cardiovascular system. Additives like epinephrine or bicarbonate alter anesthetic properties. Common amide and ester local anesthetics like lidocaine, bupivacaine, and cocaine are compared in terms of metabolism and indications.

2. Outline
 Introduction
 Physicochemical properties
 Mechanism of action
 Classification
 Local anesthetic toxicity
 Additives
 Clinical application

3. LOCAL ANAESTHETICS
 Local anesthetics: are drugs which cause reversible
loss of sensory perception, especially of pain, in a
restricted area of the body where they are applied.
 They block generation and conduction of nerve
impulse at any part of the neurons with which they
come in contact, without causing any structural
damage

4. Local anesthetic properties
Activity of these drugs maybe affected by
 Percent of ionization at Physiological Ph
 Lipid solubility
 Affinity for protein binding
 Vasodilatation effect

5. PROPERTY CONT..
 Lipid solubility
 This is the most significant property of local anesthetics
molecules in determining the drug potency
 Lipophilic molecules penetrate the nerve cell membrane
and become intracellular, resulting into more blockades’
E.g Bupivacaine is more lipid soluble and thus more potent
than lidocaine

6. PROPERTY CONT..
 Ionization
 These drugs exists in ionized and non ionized forms
which is determined by Ph of the medium
 The non ionized form is the portion that is capable of
diffusing across nerve membranes and blocking sodium
channel
 The non ionized also has a fast onset of action due to rapid
diffusion.
 When equilibrium pH of a specific local anesthetic
approaches the physiological pH of the tissue (i.e 7.35-7.45)
the more rapid onset of action

7. PROPERTY CONT..
 A decrease in pH shifts the equilibrium towards the
ionized form and thus delays onset of action
 This explains why local anesthetics have delayed onset
of action and less effective in inflammation as
inflammation creates more acidic environments
 By addition of Na bicarbonate to local anesthetic may
reverse this however over alkalization can cause local
anesthetic to precipitate

8. Protein binding Vasodilatation
 Those with high binding
capacity tend to have
increased duration of action
such as bupivacaine and
etidocaine unlike those
which are less protein bound
such as procaine
 α 1-acid glycoprotein and
albumin are the main sites
for local anesthetic binding
 Except cocaine most have
biphasic effect on vascular
smooth muscles
 At low dosage the cause
vasoconstrictions
 At high dosage they cause
vasodilatation via direct
relaxation of arterioles
smooth muscles fibers
 The more vasodilator effect
it has the more it gets
washed away and thus the
short duration of action

9. MOA
 They reversibly binds to voltage gated sodium channel
once they reach the neurons; blocking Na+ movement
through the channel and thus blocking the action
potential and neural conduction
 Finally, local depolarization fails to reach the
threshold potential and conduction, block ensues

10. General mechanism of action
 Na+ channel receptors can
be found in 3 forms
 RESTING,ACTIVATED,
INACTIVATED
 LA receptor is located
within the channel in its
intracellular half.
 Cationic form(BH)+ of the
LA which primarily binds
to the receptor.
 Note after entering cell
they dissociates .
 The order of LA affinity
activated, inactivated and
finally resting .

11. Classification

12. Classification cont;
 Amide and ester local anesthetics differ in their chemical
stability, metabolism, and allergic potential.
 Amides are extremely stable, whereas esters are relatively
unstable, particularly in neutral or alkaline solution.
 Amide compounds undergo enzymatic degradation in the
liver, whereas the ester compounds are hydrolyzed in
plasma by the pseudo-cholinesterase enzymes
 Note: Cocaine, an ester, is an exception, as it is metabolized
predominantly by the liver.
 The metabolites of esters include para-
aminobenzoicacid(PABA), which can occasionally induce
allergic-type reactions. Allergies to amides are extremely
rare.

13. Classification cont..
 Amides
Produce more intense and longer
lasting anesthesia
• Bind to α1 acid glycoprotein in plasma
• Not hydrolyzed by plasma esterase
• Rarely cause hypersensitivity
reactions;
no cross sensitivity with ester LAs
 Lidocaine,
 bupivacaine,
 dibucaine,
 prilocaine,
 ropivacaine.
 Esters
 Short duration of action short
duration
 less intense analgesia
 Higher risk of hypersensitivity
 The ester-linked LAs are rarely used
for infiltration or nerve block, but
are still used topically on mucous
membranes.
 Cocaine,
 procaine,
 chloroprocaine,
 Tetra Caine, benzocaine.

14. LOCAL ANESTHETIC TOXICITY

15. CNS TOXICITY
Order of toxicity
 Central toxicity results from
high levels of local
anaesthetic agent within the
brain.
 This may be due to direct
spread from subarachnoid
injection or by excessive
systemic absorption.
 Transfer across the blood–
brain barrier is influenced by
lipid solubility and degree of
ionisation.
 Numbness and paraesthesiae
of tongue, mouth and lips
 Metallic taste
 Light headacheness
 Tinnitus
 Slurred speech
 Muscle twitching
 Shivering
 Tremors

16.  Tonic clonic convulsions
 Coma
Apnea
 Apnea and convulsions result in hypoxia, hypercapnia
and metabolic acidosis.
 The acidosis increases the proportion of ionized local
anesthetic agent.
 Toxicity results from the presence of ionised drug
within the cell blocking the ion channel.
 Acidosis effectively reduces the proportion of
diffusible drug within the cells, and slows clearance

17. CARDIOVASCULAR TOXICITY
 Cardiovascular system
 Most local anesthetic agents (except cocaine) relax
vascular smooth muscle, causing vasodilatation.
 Direct cardiovascular toxicity is caused by the
membrane-stabilizing activity of the drugs on
myocardial muscle, which is a feature of blockade of
voltage-gated fast sodium channels.

18. Cardiac toxicity may result in any of the following
effects:
 Prolongation of PR interval
 Supra ventricular tachycardia
 Decreased automaticity
 Widening of QRS complex
Ventricular ectopic beats
 Prolongation of ST interval
 T-wave changes

20.  Respiratory system
 The respiratory effects of local anesthetic agents are due
combination of peripheral neuronal blockade and
systemic toxicity.
 Apnea with systemic toxicity affecting the respiratory centre
 Broncho dilatation secondary to relaxation of bronchial
smooth muscle
 Other effects
 Local anesthetic drugs have a weak neuromuscular
blocking action.
 Amides block plasma cholinesterase
 They may cause anaphylactic reaction due to
preservatives

21. METABOLISM
 Ester local anesthetics are rapidly metabolized by
plasma cholinesterase, and systemic toxicity is rarely
a problem.
 Amide local anesthetics are metabolized by the liver,
 Hepatic failure must be very severe for their metabolism
to be affected.

22. THE ISSUES OF ADDITIVES
 Glucose
 Standard solutions of local anesthetic agents are slightly
hypobaric at body temperature and ph.
 Tend to move upwards in the cerebrospinal fluid away
from the gravitational pull.
 Glucose is added to these local anesthetics to make
hyperbaric
 E.g hyperbaric lignocaine and bupivacaine
 Epinephrine
 Epinephrine is added to local anesthetic solutions to
reduce vascularity of the area by direct vasoconstriction.
 This in turn reduces the systemic uptake of the drug

23.  pH manipulation
 Alkali nation of solutions by addition of bicarbonate
increases tissue ph. This results in a higher proportion of
non-ionized drug, which diffuses into the neurons more
rapidly.

24. Amide-linked agents
 Bupivacaine
 Bupivacaine is a long-acting local anesthetic agent with
a slow onset of action.
 Blockade of a large peripheral nerve such as the sciatic
nerve may take 60 minutes, depending on the approach
 Intrathecal injection in contrast produces an acceptable
block within a few minutes
 prone to causing myocardial depression.
 Reversal may be slow due to high Pk and high affinity to
cardiac proteins

25.  To avoid systemic effect, this drug should be avoided
in
 Avoid bupivacaine in IVRA
 Avoid 0.75% bupivacaine in obstetric practices
 Limit dose to 2mg/kg .
 Metabolism
 N-dealkylation to pipecolylxylidine (N-
desbutylbupivacaine).Hydroxybupivacaine is also
produced.
 The metabolites are excreted in the urine.

26.  Lidocaine (lignocaine)
 Lidocaine is primarily classified as a local anesthetic
agent but is also a Class IB antiarrhythmic
 Has rapid onset of action and intermediate effect up to
45 min.
 May be combined with bupivacaine to balance the onset
of action and duration of action between these two
drugs
 Metabolism
N-dealykalation followed by hydrolysis to form
ethylgylcine and xylidide which are excreted by the
kidneys.

27.  Prilocaine
 This is more related to lidocaine in terms of
pharmacological effects
 They have the same Pka- 7.9
 Can lead to Methaemoglobinaemia which can lead to
cyanosis.

28. Ester-linked agents
Cocaine
 Cocaine is a naturally occurring ester derived from
benzoic acid.
 Can be extracted from the leaves of Erythroxylumcoca.
 Available in solution and paste formulation in conc
of 1% and 10%
 It is mainly used for topical anesthesia and to reduce
bleeding during nasal surgery
Indication-The only indication for cocaine is in ocular
anesthesia

29.  Effects in the CNS
 Cocaine initially blocks the inhibitory pathways
resulting.
 euphoria
 hyperthermia
 altered vision and hearing, nausea
 eventually convulsions.
 Higher levels of cocaine also block the excitatory
pathways, resulting in central nervous depression
leading to sedation and unconsciousness, with
respiratory depression.

30.  Amethocaine
 Amethocaine (tetra Caine) is an ester local anesthetic
agent used for topical anesthesia.
 It is available as a gel (4%) for local anesthesia of the
skin before intravascular cannulation.

31. INDICATIONS OF LOCAL
ANAESTHETICS
 1. Surface anesthesia
 It is produced by topical application of a surface
anesthetic to mucous membranes and abraded skin.
 2. Infiltration anesthesia
 Dilute solution of LA is infiltrated under the skin in
the area of operation
 blocks sensory nerve endings
 . Onset of action is almost immediate and duration is
shorter than that after nerve block,

32.  3. Conduction block
 The LA is injected around nerve trunks so that the area
distal to injection is anaesthetized and paralyzed.
 This can be
 Nerve block- -a specific nerve is blocked
 Field block--all nerves coming to a particular field are
blocked.
 4. Spinal anesthesia
 5. Epidural anesthesia
 6. Intravenous regional anesthesia