Local anesthetic agents

a synopsis of local anesthetic agents in medicine

1. LOCAL ANESTHETIC AGENTS Dr. Chris Alumona NOH I L 2 1 9

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 L i do caine 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

22. 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

23. 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

24. 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.

25. 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 +)

26. 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

27. 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

28. LA agents and pH/ pKa LA agents are weak bases hence unstable in solution (pH 6.5) Prepared as salts acids eg HCL to improve stability (hence Lidocaine HCL etc ) LA containing epinephrine are further acidified (pH 3.5 ) to prevent oxidation on the vasoconstrictor Elevating pH (alkalization) of a LA solution speeds its onset of action, increases clinical effectiveness and make its injection more comfortable 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 p H) 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. Lipid solubility Protein binding Local tissue PH Additives Peripheral Vascular tone Factors affecting LA agents efficacy

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

34. 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

35. Toxicity

36. 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

37. Surgical Applications of Local Anesthetic Agents

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

39. 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

40. 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

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

42. 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

43. 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

44. 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

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

46. 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

47. 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

48. 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.

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

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

51. 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.

52. Thanks you for listening

53. 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 . 9 th April, 2019 Jasvindar chawla : Epidural nerve block, article 149646: ttps://emedicine.medscape.com . 10 th April, 2019 Subarachnoid Hemorrhage: Overview and Procedure; article 2000841 ; 149646: ttps://emedicine.medscape.com . 10 th April, 2019 Yagiela JA: What’s new with Phentolamine mesylate ; a reversal agent for local anaesthesia ?: SAAD Dig. 2011 Jan; 27:3-7 References