LOCAL ANAESTHETIC AGENTS in Anaesthesia.pptx

local anaesthetic agents used in anaesthesia with emphasis on their pharmacology

1. LOCAL ANAESTHETIC AGENTS PRESENTED BY DR FAITH K. BULUS 11/29/2023 1

2. OUTLINE INTRODUCTION STRUCTURE AND CLASSIFICATION OF LOCAL ANAESTHETIC(LA) AGENT. INTRINSIC PROPERTIES DETERMINING ACTION OF L.A AGENTS MECHANISM OF ACTION OF L.A AGENT. PHARMACOKINETICS OF L.A AGENT. EFFECTS OF L.A PHARMACODYNAMICS OF L.A L.A ADDITIVES USES OF L.A L.A SYTEMIC TOXICITY AND MANAGEMENT CONCLUSION REFERENCES 11/29/2023 2

3. INTRODUCTION A local anaesthetic agent is a drug that reversibly prevents transmission of the nerve impulse in the region to which it is applied without affecting consciousness. Local anaesthetic agents are used to provide anaesthesia as well as analgesia intra- operatively or post operatively. 11/29/2023 3

4. STRUCTURE AND CLASSIFICATION OF L.A 11/29/2023 4

5. The structure of a local anaesthetic structure consists of 3 parts; Lipophilic(Hydrophobic) Group-an aromatic group that is usually an unsaturated benzene group. Intermediate bond- a hydrocarbon connecting chain that is either an ester (-CO) or amide (NHC-) Hydrophilic group- usually a tertiary amine and proton acceptor. 11/29/2023 5

6. AMIDES( Lidocaine,bupivacaine,Prilocaine etc ) ESTERS( Tetracaine,procaine cocaine ) Stable in solution-can be stored for long Unstable, short acting and require preservatives. Heat stable so can be autoclaved Not heat stable Metabolised by N- dealkylation and hydrolysis by liver amidases . Metabolised by plasma & tissue esterases (except cocaine Not prone to allergic reactions Propensity for allergic reactions ( PABA, methylparaben ) Short half-life Longer half-life 11/29/2023 6

7. INTRINSIC PROPERTIES DETERMINING ACTION OF L.A LIPID SOLUBILITY(correlates with potency) Pka (correlates with onset of action) Protein binding(correlates with duration of action) 11/29/2023 7

8. MECHANISM OF ACTION OF L.A LA action is dependent on blockade of the voltage gated Na+ channel. Unionised lipid-soluble drug passes through the phospholipid membrane into the axoplasm , becomes ionised & gains a proton. In this ionised form it binds to the internal surface of a Na+ channel, preventing influx of Na+ ions thereby preventing an action potential. Alternative mechanism- “membrane expansion” - unionised drug dissolves into the phospholipid membrane causing swelling of the Na+ channel/lipoprotein matrix, resulting in its inactivation. 11/29/2023 8

9. 11/29/2023 9

10. PHARMACOKINETICS OF L.A ABSORPTION- The rate of absorption of local anaesthetic agents Depends on: Site of injection - The more vascular the tissue the greater the uptake and subsequent blood concentrations. Dose and volume - Higher blood concentrations are associated with large volumes of dilute local anesthetic when compared to the same dose in a smaller volume Addition of a vasoconstrictor(epinephrine) Pharmacologic profile- more lipid soluble local anaesthetics are highly tissue bound and also more slowly absorbed. 11/29/2023 10

11. DISTRIBUTION A phase – rapid disappearance phase related to uptake to high perfusion areas such as the brain, lung, kidney, and heart. Β phase- slow disappearance phase which is the function of the individual local anesthetic and distribution to muscle tissue and the gut. Local anesthetics are distributed to all body tissues. Higher concentrations are found in the highly perfused tissue. Largest reservoir of local anaesthetics is skeletal muscles. 11/29/2023 11

12. Biotransformation and Excretion of Esters Esters undergo extensive hydrolysis in the plasma by pseudocholinesterase enzymes (plasma cholinesterase or butyrylcholinesterase ). Hydrolysis is rapid and results in water soluble metabolites that are excreted in the urine. Cocaine is the exception. It is partially metabolized in the liver (N-methylation) in addition to ester hydrolysis. Ester local anesthetics placed in the CSF are not metabolized until absorbed by the vascular system. No esterase enzymes in the CSF. 11/29/2023 12

13. Biotransformation and Excretion of Amide Local Anaesthetics Primary metabolism is by the microsomal P-450 enzymes in the liver (N- dealkylation and hydroxylation) and to a lesser extent by other tissues. Rate of metabolism among amides varies according to the individual local anesthetic. Amides metabolised in the liver by amidases . Reduced hepatic blood flow or hepatic dysfunction can decrease amide metabolism. 11/29/2023 13

14. Prilocaine metabolites include o-toluidine derivatives which can accumulate after large doses (>10 mg/kg) and result in methemoglobinemia . Excretion of amides occurs in the kidneys. Less than 5% of the unchanged medication is excreted by the kidneys . Factors affecting metabolism of amides include; Age: elderly and newborns. Newborns have an immature hepatic enzyme system whereas the elderly have decreased hepatic blood flow. Disease: any disease process that impairs blood flow to the liver or the livers ability to produce enzymes. 11/29/2023 14

15. EFFECTS OF L.A LAs cause vasodilatation -> increased tissue absorption. (except cocaine). Addition of a vasoconstrictor increases block duration and the LA toxicity risk decreases. LAs block conduction in the following order: small myelinated > non- myelinated > large myelinated . Therefore, nociceptive and sympathetic transmission blocked first. Loss of nerve function proceeds as: loss of pain-> temperature-> touch-> proprioception -> skeletal muscle tone. 11/29/2023 15

16. PHARMACODYNAMICS OF L.A NEUROLOGICAL SYSTEM LA have a bi-phasic effect. Inhibitory interneurons are blocked first followed by initial excitatory phenomena, resulting in circumoral tingling, visual disturbance, tremors and dizziness.This is followed by convulsions. Finally , all central neurones are depressed, leading to apnoea and coma. AUTONOMIC SYSTEM- When used in spinals and epidurals, LAs block sympathetic outflow. This results in hypotension & bradycardia 11/29/2023 16

17. RESPIRATORY SYSTEM L.A relaxes bronchial smooth muscle. IV administration of lidocaine can block bronchoconstriction during laryngoscopy, endotracheal intubation, extubation & bronchoscopy. Lidocaine depresses the ventilatory response to PaO2. Apnea can result from phrenic and intercoastal nerve paralysis or depression of the medullary respiratory center following direct exposure to L.A 11/29/2023 17

18. CARDIOVASCULAR SYSTEM L.A depresses myocardial contractility and conduction velocity. IMMUNOLOGICAL SYSTEM Esters are more likely to produce an allergic reaction especially those with the metabolite PABA. Amides with preservatives containing methylparaben similar to PABA have also been noticed to cause allergic reactions. HAEMATOLOGICAL SYTEM L.A especially lidocaine depresses normal blood coagulation(reduced thrombosis and decreased platelet aggregation) 11/29/2023 18

19. L.A ADDITIVES Adrenaline – vasoconstriction, prolonged block, reduced toxicity Clonidine – increased duration & quality Felypressin - vasoconstriction Sodium bicarbonate- increases speed onset, Improves quality of block, Prolongs duration of block Glucose – (80mg/ml) increased baricity 11/29/2023 19

20. USES OF L.A TOPICAL- as gels, sprays, creams, lozenges. INFILTRATION - action almost immediate . PERIPHERAL NERVE BLOCKS (individual nerve blocks, plexus blocks) INTRAVENOUS REGIONAL ANAESTHESIA (Bier) CENTRAL NEURAXIAL BLOCKS – spinal, epidural, CSE 11/29/2023 20

21. LIDOCAINE Used in clinical practice for almost 60 years. It has a rapid onset of action but the block is of a relatively short duration. Recommended maximum safe dose : LIDOCAINE WITHOUT Adrenaline = 3 mg / kg LIDOCAINE WITH Adrenaline = 7 mg / kg  11/29/2023 21

22. CLINICAL USE Skin Infiltration - 0.2–1.0 % lidocaine . Use with adrenaline 1:200,000 or 1:400,000  Biers Block (IVRA) - 40ml of 0.5% lidocaine (without adrenaline).  Peripheral nerve blocks - 1–2% lidocaine (with or without adrenaline).  Dental blocks – lidocaine 2% (with adrenaline 1:80,000).  Topical anesthesia – 2% gel (urethra) or 4% spray Subarachnoid block – 2% lidocaine plain (no adrenaline). Lignocaine may be used as an antiarrhythmic. Lidocaine can be carbonated by adding sodium bicarbonate. This shortens the onset and prolongs both the intensity and duration of block. 11/29/2023 22

23. BUPIVACAINE Has been used in clinical practice for more than 40 years. Commercially available in 0.25% and 0.5% solutions (with and without epinephrine).  Spinal “heavy” bupivacaine (0.5% bupivacaine + 8%(80mg) glucose) is also available.  4X more potent than lidocaine . Therefore 0.25% bupivacaine is equipotent with 1 % lidocaine .  Particularly cardiotoxic and & should never be used in iv blocks.  Binds tightly to tissues, so has long duration of action ( 2-4hrs ). Adding adrenaline will decrease its toxicity by delaying the drug absorption but will have minimal effect on the duration of the block. Recommended maximum safe dose of bupivacaine: BUPIVACAINE WITHOUT adrenaline ------- 2.0 mg / kg BUPIVACAINE WITH adrenaline ------- 2.5 mg / kg 11/29/2023 23

24. 11/29/2023 24

25. LOCAL ANAESTHETIC TOXICITY Local anaesthetic systemic toxicity is a life threatening adverse event that may occur after administration of L.A drugs through a variety of routes This occurs when blood concentration of L.A drug is too high either following direct intravascular injection of L.A agents,injection into highly vascularized tissues or use of L.A above recommended safe doses. 11/29/2023 25

26. Signs and symptoms CNS The symptoms of CNS toxicity include; light headedness, restlessness, tinnitus, slurred speech, circumoral paraesthesia , metallic taste in mouth , drowsiness , muscle twitching. In severe toxicity convulsions, unconsciousness, and coma. CVS Tachycardia with sub convulsive doses, but bradycardia and hypotension with convulsive doses RS Respiratory depression 11/29/2023 26

27. Management of severe L.A toxicity 11/29/2023 27

28. 11/29/2023 28

29. CONCLUSION Local anaesthetic agents are safe and effective, they also offer quick recovery when used in anaesthesia,with the right understanding of their actions and interactions, maximum patient safety and satisfaction can be achieved with their use. 11/29/2023 29

30. REFERENCES Larry F,Andrea J: Manual of clinical anaesthesiology 1 st edition,2011, pg 125-136 John F,David M,John W: Morgan and Mikhail’s Clinical anaesthesiology 5 th edition Alan R.A,Ian K.M,Jonathan P.T: Smith&Aitkenhead’s textbook of anaesthesia 6 th edition,2014 Ajay Y: Short textbook of anaesthesia , 6 th edition 11/29/2023 30

31. THANK YOU FOR LISTENING 11/29/2023 31