The document outlines local anesthetic agents used in surgery. It discusses the definition of local anesthetics, the ideal properties, and brief history. It then covers classification based on biological sites/mechanism of action and chemical structure. The document outlines the anatomy and physiology of neurons involved in nerve conduction and the mechanism of action of local anesthetics in blocking nerve conduction. It discusses pharmacokinetics including uptake, distribution, metabolism and excretion. It also covers factors affecting drug action and applications of local anesthetics in different surgical procedures.

1. LOCAL ANESTHETIC
AGENTS
Dr. Chris Alumona
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2. OUTLINE
 INTRODUCTION
 Definition: the ideal LA
 History
 Statement of Surgical importance
 CLASSIFICATION OF LOCAL ANAESTHETIC AGENTS
 Based on biological sites and mechanism of action
 Based of chemical structure
 ADDITIVES/adjuncts
 Vasoconstrictors
 Alkalis
 Acids
 NEURONS and Mechanism of LA conduction blockade
 Anatomy of neurons
 Physiology of Nerve conduction
 Electrochemistry of Nerve conduction
 Mechanism of action of local anesthetic agents

3. Outline Cont.
 Pharmacokinetics
 Uptake and distribution
 absorption
 metabolism and excretion
 Factors affecting Drug Action
 Lipid solubility
 Protein binding
 PH and pKa
 Peripheral Vascular tone

4. Outline cont.
 Application in Surgery
 Local infiltration
 Nerve blocks
 Hematoma block
 Intravenous regional anesthesia
 Axial blocks
 Principles of Administration
 Relevant history
 Techniques of administration
 Dosing
 Monitoring

5. Outline cont.
 Toxicity
 Local
 Local Anesthetic Systemic Toxicity (LAST)
 Factors affecting toxicity
 Management of Local anesthetic toxicity
 Future trends
 Conclusion
 References

6. INTRODUCTION- Definitions
• Agents that produce a transient and completely
reversible loss of sensation in a circumscribed area
or isolated body part
• Depression of excitability or inhibition of
conduction process in peripheral nerves
• Ability to produce conduction blockade without
loss of consciousness differentiates LA agents from
GA agents
• These agents can be synthetic or naturally
occurring

7. • Local anesthetic agents brought a major
revolution in surgical practice by providing local
and regional anesthesia without attendant loss of
consciousness
• Attendant risks associated with general
anesthesia are thereby eliminated
• Minor and major surgeries can be safely
performed in patients in which GA would have
been risky, impossible or inconvenient
INTRODUCTION- statement of surgical importance

8. • Non irritant, no capacity to cause allergies
• Not cause any permanent structural alteration
• Low systemic toxicity, sterile, capable of withstanding
thermal sterilization
• Effective in inj. and topical use, potent in low
concentrations
• Rapid onset of action
• Long duration of action without extended recovery period
• Stable in solution and readily undergo biotransformation
INTRODUCTION- The Ideal agent

9. • Ancient Incas of Peru: Coca plant
• Albert Niemann: Cocaine (1859)
• Sigmund Freud: “Über Coca” (1884)
• Carl Koller, Leopold Konigstein, John Pembertob (1886)
• Stovaine, procaine: 1903 & 1904
• Peripheral nv blocks: 20th century
• Intravenous regional anesthesia, Spinal anesthesia: August Bier
(1908 and 1899 respectively)
• Epidural Anesthesia: Fidel Pagés (1921)
INTRODUCTION- history

10. INTRODUCTION- timeline of development of LA agents
Esters
(-caines)
Co- pro- tetra- chloropro-
1884 1905 1932 1933 1948 1955 1956 1960 1963 1971 1975 1997 1999
dibu- lido- mepiva- prilo- bupiva- etido- arti- rupiva- levo
bupi-
(-caines)
Amides

11. Classification of Local Anesthetic Agents
Class Site of action Examples
Class A Receptor site on
external surface of
nerve membranes
Bio toxins (tetrodotoxin,
saxitoxin)
Class B Receptor sites on
internal surface of nerve
membranes
Quaternary ammonium
analogs of lidocaine (eg
N-beta-phenylethyl
lidocaine) scorpion
venom
Class C Receptor independent
physico-chemical
mechanism
Benzocaine
Class D Combination of receptor
dependent (90%) and
receptor independent
(10%) mechanisms
Most clinically useful LA
eg lidocaine, articaine
• Based on Biological site and mechanism of action

12. – Lipophilic portion:
aromatic (benzoic acid,
aniline or thiophene)
– Hydrophilic portion:
amino derivative of ethyl
alcohol or acetic acid
– Intermediate chain:
Ester (COOR) or Amide
(NHCO) linkage
Classification of Local Anesthetic Agents
• Classification based on molecular structure (Class C&D)

13. • Esthers
– Cocaine
– Procaine
– Benzocaine
– Tetracaine
– Propoxycaine
• Amides
– Lidocaine
– Etidocaine
– Mepivacaine
– Bupivacaine
– Prilocaine
– Articaine

14. • Vasoconstrictors: epinephrine,levonordefrine,
norepinephrine
– Decreases blood flow to site of administration
– Lowers absorption of agent into circulation; decreases
risk of systemic toxicity
– Maintains local concentration of agent at site
prolonging duration of action
– decreases heamorrahge
• Sodium bicarbonate
– Increases pH thereby increasing absorption and onset
of action
• Fentanyl
Additives

15. • Structural unit of the nervous system: sensory,
motor or relay neurons
NEURONS- anatomy

16. NEURONS- anatomy cont.

17. NEURONS- anatomy cont.

18. Organization of peripheral nerves
Structure Description
Nerve fibre Single nerve cell
Endoneurium Covers each fibre
Fasciculi Bundles of 500-1000 nerve
fibres
Perineurium Covers fasciculi
Perilemma Innermost layer of perineurium
Epineurium Alveolar connective tissue
suporting fasciculi and carrying
nutrient vessels
Epineural sheath Outer layer of epineurium
NEURONS- anatomy cont.

19. • Nerves relay messages from one point of the
body to another
• Impulses: electrical action potentials
• Nerve membranes are polarized at rest
• Stimulus causes membrane depolarization
resulting in brief increase in permeability of
membranes to Na+ and K+
NEURONS- physiology

20. Intracellular and extracellular ion concentrations (mEq/L)
Ion ICF ECF Ratio
K+ 110-170 3-5 27:1
Na+ 5-10 140 1:14
Cl- 5-10 110 1:11
NEURONS- Electrophysiology of nerve conduction
• The resting membrane potential of nerves is a
negative potential (-70mV)
• Produced by differing concentration of ions on
either side of the membrane
• Interior of the nerve is more negative than the
exterior

21. • Resting state: nerve membrane is
– Slightly permeable to Na+ (inward diffusion)
– Freely permeable to K+& Cl- (no diffusion)
• Depolarization phase:
– Inc. permeability to Na+ ass: passive Na+ infux
– Progressive decrease in negative membrane potential till
firing threshold
– Dramatic inc in memb. permeability to Na+ (passive)
– Reversal of membrane potential
• Repolarization phase:
– Inactivation of increased Na permeability
– Inc permeability to K+: passive K+ efflux
– Active transport of Na+ out via ATPase
NEURONS- Electrophysiology of nerve conduction

23. • When a nerve is stimulated
– An initial phase of slow depolarization: electrical potential
within the nerve becomes less negative
– An extremely rapid phase of depolarization when the
falling electrical potential reaches a critical level: the
threshold potential/firing threshold (15mV)
– The electrical potential across the nerve membrane is
reversed (interior becomes more positive than exterior.
+40mV)
– Action potential is generated and propagated along the
nerve
– Repolarization: restoration of resting potential (-70mV)
NEURONS- Electrophysiology of nerve conduction cont

24. • Mode of action:
– Decreases rate of depolarization
– Failure to achieve threshold potential
• Site of action
– Nerve membrane
– Within membrane channels
(@ Nodes of Ranvier in myelinated nerves fibres)
• Theories (how)
– Membrane expansion
– Specific receptor
– *(Acetylcholine theory, calcium displacement, and surface
charge/repulsion theory) not supported by evidence
Mechanism of Action of LA

25. • Membrane expansion
Theory
– Explains conduction
blockade of neutral LA
eg Benzocaine
– High lipid solubility
enables LA to diffuse
into hydrophobic
portion of the
phospholipid bi-layer
– Causes conformation
changes that narrows
Na+ channels
Mechanism of Action cont.

26. • Specific receptor theory
– Biochemical and
electrophysiological
describe specific
receptor site on the
external and internal
axoplasmic surface of
sodium channels
– Action mediated by
direct binding of LA
to specific receptors
on the sodium
channel
– Binding to these sites
decrease or
eliminate membrane
permeability to Na
Mechanism of Action cont.
(These sites are normally occupied by Ca+)

27. Putting it all together
Displacement of Ca+ from Sodium channel receptor site
Binding of LA agents to this receptor site
Blockade of the Sodium channel
Decrease Sodium conductance
Depression in the rate of electrical depolarization
Failure to develop propagated action potential
Conduction Blockade

28. • Factors affecting uptake and distribution of LA
– Related to LA agent
• Lipid solubility
• Protein binding
• pH & pKa
• Concentration
• additives
– Tissue related
• pH
• Diametre of nerve fibres
• Myelinated vs unmeylinated
• Peripheral vascular tone
– Technique related
Pharmacokinetics: uptake and distribution cont

29. • LA are available as acid salts dissolved in
sterile water for injection or saline
• In this solution the LA agent dissociates into
an uncharged molecule/base (RN) and a
positively charged molecule/cation (RNH+)
RNH+ RN + H+
RNH+ RN + H+ (high pH)
RNH+ RN + H+ (low pH)
pKa is the degree of affinity of LA to H+ or the pH at
which both RN and RNH+ exist in equal proportion
Pharmacokinetics: pH and pKa

30. • LA agents are natural vasodilators except
cocaine
• Vasodilatation enhances systemic absorption
and hence decreased efficacy of agents
• Epinephrine is added to cause
vasoconstriction thereby increasing efficacy
and safety
Pharmacokinetics: Absorption

31. • Esters
– Hydrolyzed in plasma by pseudo-cholinesterase
– Metabolites such as PABA are responsible for
allergic reactions
– Excreted via the kidneys
• Amides:
– The liver is the primary site for biotransformation
– Excretion is via the kidneys, lungs
Pharmacokinetics: Metabolism and excretion

32. Dosing and Safety
• Concentration of solution
• Presence of Vasoconstrictor
• Body weight
• Co-morbidities

35. Calculating Maximum Recommended Dosage
• Total dose that can be used
– Maximum dose of lidocaine is 4.5mg/kg
– Sample patient weight of 10kg
– Total dose : 4.5mg/kg x 10kg = 45mg
• Maximum volume of lidocaine that can used
– Depend on the concentration of solution
– E.g. for 1% lidocaine, 1000mg/100ml ie 10mg/ml
– Max vol of 1% lidocaine that can be used for
above pt = 45mg/10mg/ml = 4.5ml

36. Toxicity

37. • Local
• Local Anesthetic Systemic Toxicity (LAST)
• Factors affecting toxicity
• Rates of absorption vs metabolism
• Generation of metabolites
• Co-morbidities
• Technique
• Mgt of Local anesthetic toxicity
• Supportive
• Close monitoring
• Reversal

38. Surgical Applications of Local
Anesthetic Agents

39. • Topical
• Local infiltration
• Nerve blocks
• Hematoma block
• Intravenous regional anesthesia
• Axial blocks

40. • Topical eg EMLA (lidocaine+prilocaine)
– Applied over unbroken skin
– Indications: prior to insertion of needles, Skin
grafts, skin laser surgery, wart excision
– Contraindication: allergy, broken skin
• Local infiltration
– For excisional biopsies
– Surgical wound edge infiltrations
– Laceration repairs
– Sub mucosal infiltrations

41. Nerve
blocks
Nerves Site of Inj Area of anaesthesia
Brachial Plexus Interscalene location Shoulder, upper arm, elbow
and forearm
Supraclavicular location Upper arm, elbow, wrist and
hand
Infraclavicular location Upper arm, elbow, wrist and
forearm
Axillary location Forearm, wrist, hand, and
elbow including the
musculocutaneous nv
Median, ulnar and radial
nerves
Elbow Hand and forearm
Femoral nerve Femoral crease Anterior thigh, femur, knee,
skin over medial aspect of the
leg bellow the knee
Sciatic nerve Subgluteal location Post. thigh, ant, lat, and post.
Lower leg, ankle and foot
Popliteal location Ant, lat, and post lower leg
ankle and foot
Saphenous, superficial &
deep peroneal, post. tibial
and sural nerves
Ankle Entire foot
Digital blocks Base of digits digits
Cervical plexus block Carotid endarterectomy

42. Hematoma block
• Allows painless manipulation of fractures
• A sterile procedure
• Blindly or image guided
• Confirm needle within hematoma by
aspirating blood

43. Intravenous Regional Anesthesia/Bier block
• Used in exsanguinated extremity after
tourniquet
• High dose of LA agent without adrenaline is
injected as distal as possible
• Bupivacaine and etidocaine are
contraindicated
• Contraindicated in sickle cell disease
• Benzodiazepines and fentanyl are added to
improve block

44. Epidural Anesthesia/Analgeisa
• Indications
– Orthopedics: surgeries the lower limbs,
Epidural steroid injection, amputations
– Obstetrics: cesarean delivery
– Urology: prostate and bladder surgeries
– General surgery: abdominal surgeries,
hernia repair
– Epidural analgesia post op. PCEA
– Combined Spinal Epidural: peadiatric
surgeries, thoracic surgeries eg
thoracotomy, cardiac bypass
– Combined with GA: reduces post operative
pneumonia in COPD pts

45. Subarachnoid Anesthesia
• Indications: surgeries in the lower
extremity, perineum, lower abd
wall, CS, epidural steroid inj
• Bupivacaine commonly employed
• Lidocaine, ropivacaine and teracaine
are alternatives

46. Caudal block
• Indication
– Surgical procedures
below the umbilicus
– As an adjuvant to GA
– Sole anaesthesia in
fully awake ex-
premature infants

47. Contraindications to neuraxial anesthesia
• Absolute
– Patient’s refusal
– Local anesthetic allergy
– Insurmountable technical difficulties
– Active infection at site of proposed cannulation
– Cardiopulmonary instability
• Relative
– Bleeding diathesis (INR>1.2 or Plt count <80x109/l)
– Thrombophilia
– Continuing anticoagulation
– Uncorrected hypovolemic
– Severe stenotic cardiac disease
– Raised intracranial pressure
– Previous surgery at proposed site of infection

48. Complications of neuraxial blocks
• Common immediate complications
– Failure or incomplete blockade
– Hypotension
– Nausea and vomiting from hypotension
– Shivering
– Itching (with opioids)
– Temporary blockade
• Uncommon immediate complication
– Bradycardia from blockade of the sympathetic supply to the
heart (T1-T4)
– Impairment of the accessory muscles of respiration
– Horner’s syndrome
– Phrenic nerve paralysis if cervical roots 3-5 are involved
– Cranial nerve palsies

49. • late complications
– Dural puncture headache
– Urinary retention
– Neurological damage from direct trauma
– Neurological damage from epidural hematoma and spinal
cord hematoma
– Epidural abscess formation
– Meningitis
– Arachnoiditis
Complications cont.

50. – Relevant history
– Examination
– Investigation
– Patients selection
– Agent selection
– Technique selection
– Techniques of administration
Principles of Administration

51. Future Trend
• Newer agents with higher potency at lower
doses
• Buffered anesthetic solutions
• Needle free injections
• Aneasthetic off switch using phentolamine
mesylate

52. Conclusion
Local anesthetics agents are safe and
effective. With the right understanding
of the actions and interactions of this
class of drugs, maximum patient safety
and satisfaction can be achieved for
both surgeon and patient.

53. • Thanks you for listening

54. • Covinho BG: Pharmacology of Local Anesthetic agents, Br J anaesth 58:701-716, 1986
• de jong RH, Wagman IH: physiological mechanism of peripheral nerve blocks by Local
Anesthetic agents
• Covino BG, Vassallo HG: Local anesthetics: mechanism of action and clinical use, New
York, 1976, Grune & Stratton
• Stanley F. malamed: Handbook of Local Anesthetesia,
• Maximum recommended doses and duraton of local anesthetics: Iowa head and neck
protocols, University of Iowa health Care; https://medicine.uiowa.edu. 9th April, 2019
• Jasvindar chawla: Epidural nerve block, article 149646:ttps://emedicine.medscape.com.
10th April, 2019
• Subarachnoid Hemorrhage: Overview and Procedure; article 2000841;
149646:ttps://emedicine.medscape.com. 10th April, 2019
• Yagiela JA: What’s new with Phentolamine mesylate; a reversal agent for local
anaesthesia?: SAAD Dig. 2011 Jan; 27:3-7
References