L a agents
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This document provides information on local anesthetic agents including their definition, history, chemistry, mechanism of action, and clinical pharmacology. It defines local anesthetics as drugs that reversibly block nerve impulse generation and conduction. The first effective local anesthetic was procaine, introduced in 1905. Local anesthetics work by inhibiting the passage of sodium ions through voltage-gated sodium channels in nerve membranes. Their onset, duration, and potency depend on factors like protein binding, dose, and site of administration. Local anesthetics are classified based on their relative potency, onset, minimum concentration for conduction blockade, and duration of action.
L a agents
- 1. LOCAL ANAESTHETIC AGENTS GUIDED BY DR. ANAND DALWANI Lecturer Dept. of Anaesthesia
- 2. DEFINITION LA are drugs which block, generation and conduction of nerve impulse at all parts of neurons where they come in contact. Drugs which upon topical application or local injection causes reversible loss of pain, in the restricted region of body without causing permanent damage to the tissue. Applied to mixed nerves causes interruption of sensory and motor impulse resulting in loss of autonomic control and muscular paralysis. HISTORY First LA, isolated from leaves of erythroxylum coca – was cocaine– naturally occuring alkaloid by Neiman. Anaesthetic action was demonstrated by Karl Koller in 1984 in ophthalmic surgery. 1st effective and widely used LA was procaine produced by Einhorn in 1905 from Benzoic acid and diethyl amino ethanol, introduced in clinical practice by Braun.
- 3. Dibucaine - 1st amide, produced by Mischer in 1929 and was used clinically by Mc Elwain in same year. Inspired by this, Lofgren synthesised Lignocaine in 1948 was used clinically by T. Gordh in 1949. Various potent LA are found in subsequent year like – ESTER Tetracaine in 1932 2 – chloroprocaine – 1955 AMIDES Mepivacaine – 1956 Bupivacaine – 1951 Prilocaine – 1959 Etidocaine - 1971
- 4. CHEMISTRY WEAK BASES Basic structure consists of tertiary amine and aromatic ring attached by intermediate chain ester ( - C - O) or amide ( - NHC -) classified as aminoester or aminoamide Dia. 14.1 (Miller) Aromatic gr. Intermediate Bond Tertiary amine (Lipophilic) (Hydrophilic) Lidocaine (aminoamide) Procaine (ester)
- 5. Lipophilicity is concerned with anaesthetic activity. Lengthening the connecting hydrocarbons chain or ↑ no. of carbon atoms on tertiary amine or aromatic ring often result in LA with different lipid solubility, potency, rate of metabolism and duration of action. Difference between Esters and Amides ESTERSESTERS AMIDESAMIDES 1) Combination of aromatic acid1) Combination of aromatic acid and alcoholand alcohol 1) Combination of organic acid1) Combination of organic acid and ammonia or amineand ammonia or amine 2) Detoxified in blood stream by2) Detoxified in blood stream by plasma pseudocholinesteraseplasma pseudocholinesterase 2) Detoxified in liver2) Detoxified in liver 3) Sensitivity reactions are3) Sensitivity reactions are frequent.frequent. 3) Less frequent3) Less frequent 4) Esters are unstable and4) Esters are unstable and cannot be autoclavedcannot be autoclaved 4) Stable and can be4) Stable and can be autoclaved.autoclaved.
- 6. RACEMIC MIXTURES OR PURE ISOMER LA like mepivacaine, bupivacaine ,ropivacaine, levobupivacaine – pipecolic acid derivative of xylidides – amide gr. Are chiral drugs – as they posses an assymetrical carbon atom – have left (S) or right (R) handed configuration. Mepivacaine and bupivacaine – are available in racemic mixtures S – enantiomers of bupivacaine i.e. ropivacaine and levobupivacains produce less neurotoxicity and cardiotoxicity – due to decreased potency at sodium ion channel.
- 7. MECHANISM OF ACTION LA prevents transmission of nerve impulses by inhibiting passage of Na+ ions through ion – selective Na+ channels in nerve membranes. do not alter resting memb- potential or threshold potential. LA slows the rate of depolarization so that threshold potential is not reached and action potential is not propagated.
- 8. (A) SODIUM CHANNEL Exist in activated – open, inactivated – closed and rested closed states during various phases of action potential. In the resting memb, Na+ channels are distributed in equvilibrium between rested closed and inactivated closed. LA binds selectively to inactivated – closed Na+ channels and stabilizes these channels in this configuration and prevent their change to rested – closed and activated – open states in response to nerve impulse.
- 10. (B) FREQUENCY DEPENDENT BLOCKADE Na+ channel recover from LA induced conduction blockade between AP and develop additional conduction blockade each time Na+ channels open during an action potential. Therefore, LA gain access to receptor only when Na+ channel present in activated open state. Selective conduction blockade of nerve fibres by LA – related to nerves character, frequency and diameter. Calcium ion channels may also be blocked by . (C) MINIMUM CONCENTRATION (CM) The mini. conc. of LA required to produce conduction blockade of nerve impulses termed the Cm. ↑ tissue pH or high frequency nerve stimulation ↓ Cm. Cm of motor fibres is twice than sensory fibres.
- 11. (D) DIFFERENTIAL CONDUCTION BLOCKADE Nerve differ in their sensitivity to LA Nerve Fibre Classification
- 12. Sequence of blockade of nerve fibres – Order of sensitivity to blockade – 1. Vasomotor and sympathetic efferent 2. Temperature – cold 3. Warm. 4. Slow pain 5. Fast pain 6. Cutaneous discrimination 7. Touch 8. Pressure 9. Motor fibres 10.Muscle, tendon joint sensation 11.Deep pressure.
- 13. Reapperance of sensation occurs from below upwards (reverse direction). Applied to Tongue i) Bitter – First ii) Sweet iii)Sour iv)Salty – last
- 14. CLINICAL PHARMACOLOGY Concern with potency, speed of onset, duration of action and differential sensory and motor blockade. All LA are synthetic compound except cocaine. Contain nitrogen, basic in reaction and bitter in the taste forms salts which are solids with inorganic acids like hydrochloric acid (HCl) and sulphuric acid. Salts are acid in reaction and when treated with alkalies form free base. Free base is insoluble in water and soluble in lipids and lipid solvents. Lowers surface tension. No cross tolerance or cross sensitization between esters and amides.
- 15. I. ONSET OF ACTION OF LA’S Depends upon a) Dissociation constant of LA b) Site of administration c) Dose administered. a) Dissociation constant (pKa) It is the pH at which drug is present in 50% undissociated (unionized) and 50% in dissociated (ionized) form. pKa of commonly used LA is between 7.6 – 8.9. Diffusion across nerve membrane related to unionized form i.e. base form, hence no. of molecules of unionized form determines the speed of onset.
- 16. The physiochemical principles stats that the amount present in the unionized base form is inversely propotional to the pKa of the agent at a given pH of the medium i.e. less pKa more is unionized form. Eg – Mepivacaine, etidocaine, lignocaine and prilocaine have pKa values ranging from 7.6 to 7.9 (pH of body fluids ≈ 7.4) – when these drugs are injected into tissue, 65% will be ionized and 35% nonionized – hence uptake is rapid and onset is fast. In contrast, tetracaine, chlorprocaine, procaine they have pKa values from 8.6 to 8.9 – ionized extensively in tissue at pH 7.4 – upto 95% or more – hence uptake is slow and onset of block delayed.
- 17. b) Onset of action – also depends on site of administration of LA Most rapid onset – following 1. Subcutaneous 2. Subarachnoid administration Slowest onset – after brachial plexus block Rapidity of onset of SAB because of deposition of LA in the vicinity of the nerve roots at spinal cord level and also due to lack of sheaths around the nerves. In brachial plexus block, deposited away from the nerve roots and the longer time for diffusion to the nerves is required.
- 18. c) Dose administered Amt. of durg administered affect the onset duration and quality of anaesthesia. ↑ in the dose within the clinical range enhances the quality of anaesthesia. Dosage can be ↑ed by administrating larger volume or more concentrated solution. Volume influences the spread of anaesthesia. e.g. 30 ml of 1% lignocaine administered into epidural space produces level of anaesthesia 4.3 dermatomes higher than that achieved when 10ml of 3% lidocaine is given.
- 19. DURATION AND DOSAGES Plain SolutionPlain Solution Epinephrine –Epinephrine – Containing SolutionContaining Solution DrugDrug ConcentrationConcentration (%)(%) MaximumMaximum DoseDose (mg)(mg) DurationDuration (min)(min) MaximumMaximum Dose (mg)Dose (mg) DurationDuration (min)(min) Short DurationShort Duration ProcaineProcaine ChloroprocaineChloroprocaine 1.0 – 2.01.0 – 2.0 1.0 – 2.01.0 – 2.0 400400 800800 20-3020-30 15-3015-30 600600 10001000 3030 3030 Moderate DurationModerate Duration LidocaineLidocaine MepivacaineMepivacaine PrilocainePrilocaine 0.5 – 1.00.5 – 1.0 0.5 – 1.00.5 – 1.0 0.5 – 1.00.5 – 1.0 300300 300300 500500 30 – 6030 – 60 45 – 9045 – 90 30 – 9030 – 90 500500 500500 600600 120120 120120 120120 Long DurationLong Duration BupivacaineBupivacaine EtidocaineEtidocaine 0.25 – 0.50.25 – 0.5 0.5 – 1.00.5 – 1.0 175175 300300 120 – 240120 – 240 120 – 180120 – 180 225225 400400 180180 180180
- 20. II. DURATION OF ACTION OF LA –depends on a) Protein binding b) Site of administration a) Protein binding of LA High protein binding associated with prolonged duration of action. On basis of it, LA classified into 3 categories – i. Short duration and low potency ii. Intermediate duration and potency iii. Long duration and high potency.
- 21. b) Site of administration Duration of action decreased at highly vascular site because of rapid absorption from site. Addition of vasoconstrictor (Like adrenaline) increases duration of action. e.g. Bupivacaine – Epidural – 4 hour Brachial plexus block – 10 hours
- 22. PHARMACODYNAMIC CLASSIFICATION OF LA’S AGENTAGENT RELATIVERELATIVE POTENCYPOTENCY ONSETONSET PkaPka DURATION CMDURATION CM I. LOW POTENCY SHORT DURATIONI. LOW POTENCY SHORT DURATION ProcaineProcaine 11 SlowSlow 8.98.9 60 – 9060 – 90 ChlorprocaineChlorprocaine 11 FastFast 8.78.7 30 – 4530 – 45 II. INTERMEDIATE POTENCY AND DURATIONII. INTERMEDIATE POTENCY AND DURATION LignocaineLignocaine 22 FastFast 7.97.9 90 – 20090 – 200 MepivacaineMepivacaine 22 FastFast 7.67.6 120 – 240120 – 240 PrilocainePrilocaine 22 FastFast 7.97.9 120 – 240120 – 240 III. HIGH DURATION AND LONG DURATIONIII. HIGH DURATION AND LONG DURATION TetracaineTetracaine 88 SlowSlow 8.58.5 180 – 600180 – 600 BupivacaineBupivacaine 88 IntermediateIntermediate ↓↓ 8.18.1 180 – 600180 – 600 EtidocaineEtidocaine 66 FastFast 7.77.7 180 – 600180 – 600 DibucaineDibucaine 1212 SlowSlow 220 – 600220 – 600 RopivacaineRopivacaine 1010 FastFast 8.18.1 300 – 400300 – 400
- 23. PHARMAKOKINETICS OF LA Described under Absorption Distribution Metabolism Excretion ABSORPTION OF LA Depends upon a) Site of injection b) Total dosage and concentration c) Specific pharmacological characteristic of agent. d) Effect of vasoconstrictor.
- 24. a)Site of injection Greater the vascularity, greater is the absorption in absence of vasoconstrictor.
- 25. b) Total dosage and concentration Total dosage α rate of absorption and peak plasma levels. Conc. of drug may influence the rate of absorption. c) Specific LA agent Except cocaine and ropivacaine, all LA have intrinsic vasodialator activity and degree of this action influences the absorption rate. Act directly on vascular smooth muscles and occurs in innervated as well as denervated blood vessels and is Ca++ dependant. Order of absorption of various LA Lignocaine > Mepivacaine > Bupivacaine > etidocaine > prilocaine > procaine. Lignocaine reduces vascular resistance and dilates capacitance vessels.
- 26. d) Role of vasoconstrictor Vasoconstriction decreases rate of absorption of LA’s. Epinephrine is used most commonly in conc. Of 1 : 2,00,000 or 5 µg/ml Absorption of lignocaine, mepivacaine and procaine is reduced by approx 30% reguardless of site of injection. Absorption of prilocaine, bupivacaine and etidocaine after peripheral nerve blocks are reduced but epinephrine has little influence on the absorption of these drugs from the epidural space. This might be because of strong affinity for the neural receptors.
- 27. DISTRIBUTION After vascular absorption from various injection sites, distributed to all body organs and throughout the total body water. Great percentage of administered dose is distributed to large skeletal mass, although the conc. is low, the amount is significant. Uptake and tissue conc. i.e. amt/gm of tissue is greater in lungs, kidneys. Various phases of distribution in body after vascular absorption. i. Pi phase – Peak plasma levels are reached rapidly with lower lipid solubility, vice versa. ii. Alpha phase – initial rapid disappearance from plasma due to distribution to rich vascular tissues having high perfusion rates (brain, heart and kidney) iii. Beta phase – slower secondary phase related to distribution to slowly perfused tissue including skeletal muscles and fat. iv. Gamma phase – In this phase, metabolism and excretion of the agent occurs.
- 28. METABOLISM Esters Hydrolysis in plasma occur by alkaline breakdown -accelerated by plasma pseudocholinesterase. Benzoic acid and PABA are principle break Down product and diethyl aminoethanol is secondary product. Amides Enzymatic degradation in liver Oxidative dealkylation converts tertiary amine into secondary amine. Secondary amine is clevated by Hydrolysis by amidases and oxidases.
- 29. EXCRETION Via kidney Renal clearance is inversely proportional to protein binding and pH of urine i.e. acidified urine more excretion. PHYSIOLOGICAL EFFECTS OF LAS 1. EFFECT ON CIRCULATION Stimulatory effect by central action ↑CO, ↑ HR, BP, ↓PR. Contraction of smooth muscles - ↑ venous rectum ↑ C.O. Intra arterial injection - ↑ smooth muscle tone Delayed conduction in heart ↑ pulmonary vascualr resistance ↓ splanchnic vascular resistance
- 30. 2) EFFECT ON RESPIRATION Blood- gas tension are not influenced N ↑ response to hypercapnia resultant in respiratory stimulation. But LAS depress common hypoxia. 3) ANTITHROMBIC EFFECT Inhibits platelet aggregation - Ca+ influx blocked - Intracelluler stores are mobilized ↑ antithrombin III 4) ON SMOOTH MUSCLES Low concentration – direct stimulatory effect in blood vessels, GIT musculature. High concentration – vasodilatation, relaxation of smooth muscles of GIT.
- 31. CLINICAL IMPLICATION Intraperitoneally or I.V. LA may induce faster return of propulsive motility in the colon in the post op period. 1. ANTIINFLAMMATORY EFFECT Potent anti-inflammatory action. Inhibition of peritonitis when instilled in peritoneum. MECHANISM- a) Inhibition of PG synthesis. b) Inhibition of migration of granulocytes into the inflammatory area. c) Inhibition of granulocytes release of lysosomal enzymes and the production of tissue toxic oxygen free radical.
- 32. Analgesic effects – IV lignocaine is effective a) Chronic painful diabetic neuropathy b) Adiposa dolorosa (Dercum’s disease) c) Chr. Pain of differentation type. e.g. post operative pain, burn pain. d) Sub cut. Inj of lignocaine for malignant pain. 4) PREGNANCY • Spread and depth of anaesthesia (epidural and spinal) are reported to be greater hence dose required less Factors a) Dilated epidural vein ↓ed epidural and subarchnoid space. b) Alteration of harmones in pregnancy ↑ progesterone level in CSF cause more rapid onset and ↑sensitivity to LA induced conduction blockade.
- 33. VARIOUS LA AGENTS (INDIVIDUALS LAS) I) COCAINE 1st LA used for ocular anaesthesia in 1984 Obtained from leaves erythroxylum coca. Benzoic acid esters of base ecognine. Used for topical application Rapid absorption from nasopharyngeal membrane Vasoconstrictor causes shrinkage of mucous membrane and ↓bleeding after topical application. Instilled into nostrils, enlargement of nasal passage occur used for nasotracheal intubation.
- 34. DOSE: 1 – 2 mg/kg,. Max – 200mg CAUSES: ↑ myocardial O2 demands ↓ coronary artery diameter ↓ coronary sinus bld flow action is α - agonistic TOXICITY : CNS – Stimulant – seizures CVS - ↑HR, BP – Arrythmias, IHD Hyperpyrexia Anxiety Tactile hallucination-cocaine bugs coma, and death
- 35. II. PROCAINE PABA ester of diethylamino ethanol. Synthesized by Einhorn in 1905 Duration of action 30-60 min Uses 1. 0.5 and 1% solution – Infiltration 2. 1.5 and 2% sol – Nerve blocks Drug interactions: Procaine and curare are additive at autonomic ganglia – ganglion blockade ↓ BP ↑ HR Procaine- sulphonamide antagonism PABA the degradation product is sulphonamide antagonist
- 36. III. CHLORPROCAINE: Analogue of procaine, Introduced by Folder in 1952 2-4 times more potent than procaine approaches the ideal for N. block anaes. Because: 1. Rapid onset of action 2. Slow incidence of failure 3. Lack of systemic reaction. 4. Adequate duration of action with 5. Low potential for toxicity Uses: 3% high recommended dose 800 – 1000mg with adrenaline Clinical uses: Peripheral N. blocks, obst. Epidural.
- 37. IN 1980 Neurotoxicity observed fallowing epidural anaesthesia Cauda equina syndrome. Anterior spinal artery syndrome. due to toxicity of 0.2% Na bisulplate used as antioxidant IV. TETRACAINE Synthetic derivative of PABA Ist prepared by Eisleb in 1928 and used by klers in 1930 8 times more potent and toxic than procaine Total permissible dose Infiltration – 40-60mg – 0.05 – 0.15% Nerve blockade 40-60mg Topical Anaestnesia 20-40mg, 1% and 2%
- 38. V. DIBUCAINE Ist amide LA Prepared by Miescher and introduced in 1929 by MC Elwain Synthetic quinoline derivatives, parent alkaloid related to quinine The base is readily ppted by alkalies so should be stored in alkaline free gases container Most potent, most toxic and longest acting 16 times more toxic and 22 times more potent than procaine Mainly used as surface anaesthesia on less delicate mucous membrane like anal canal concentration 0.1% and 1% Occasionaly for spinal anaesthesia 0.5% hyperbaric
- 39. VI. LIGNOCAINE Introduced in 1948 by Lofgren An amide formed from reaction of dietheyl amino acetic acid and xylene Molecular wt. of base is 234 and that of HCL salt is 270 Physiochemical properties 1. Freely soluble in water, very stable 2. Sterilized by boiling or autoclaving 3. Non irritating to tissue even at conc of 85% 4. 1.5 times more potent and 3 times more toxic than procaine Causes maximum vasodilatation so rapid absorption without vasoconstrictor. Broad spectrum LA.
- 40. Onset of action : 2-3 min duration of action 90 – 200 min Concn used Max recommended dose 0.5 – 2% infiltration-nerve blocks 200mg 500mg with adrenaline 5% in 7.5% Glucose intra thecally 100mg 4% for topical 200mg Viscouse 2% 300mg Recommended dose 200 – 400 Total dose should not exceed 4-5 mg | kg Uses: 1. Surface anaesthesia 2. Infiltration 3. Nerve blocks 4. Epidural, spinal 5. Intra venous regional anaesthesia
- 41. 1. Cardiac action : Class IB antiarrythmic agent used for ventricular tachycardta and digitalis toxicity Dose I.V. 50-100mg bolus. (1-2 mg/kg) followed by 1-3 mg/min for infusion Therapeutic plasma concn – 2-3µg/ml Peak level attended = Initial dose administered x 0.3 2. Skeletal muscles: Extrusion of Ca++ from sarcoplasmic reticulum VII. MEPIVACAINE - Ist prepared by Dhuner and used clinically by Ekenstar in 1956. - Pharmacological properties similar to lignocaine - More toxic to neonate thus not used in obstetrical anaesthesia-as they have lower bld pH (7.25) and mepivacaine 7.6-forms more active drug in neonate Concentration used – 0.5-2% Maximum dose – 5mg/kg
- 42. VIII. BUPIVACAINE Introduced by Ekenstam in 1957 Molecular wt. Of salt 325 and that base form 288 Base is sparingly soluble but HCL salt is readily soluble in water. Highly stable and can withstand repeated autoclaving 4 times more potent than lignocaine and 8 times than of procaine Duration 2-3 times longer than lignocaine Onset of action 7-8 min intermediate Duration of action 180-600min Produce excellent and prolonged duration of sensory anaesthesia than motor blockade
- 43. Used for : Infiltration, Nerve blocks caudal blocks epidural blocks SAB DOSAGE I. Infiltration 0.25% 70-90ml with epinsptione II. Never block 0.5% 35ml plain (For large. N) 45ml with epinephra (For small N) 45ml with epinepnrine I. Caudal 0.25% 30ml obstetric anaes and perianal anaes 0.5% 30ml lower limb surg I. Epidural 0.25% 20ml – obstetric and perineal surgery 0.75% 20ml – abd surgery I. SAB 0.5% heavy 3-4ml lower limb, abdominal surgery
- 44. Not used for I.V. anaesthesia because of cardiotoxicity Sev. Ventricular arrythmias and myocardial depression Lignocaine and bupivacaine both block cardiac Na++ channels rapidly during systole Bupivacaine dissociates more slowly than lignocaine during diastole It also block Ca++ channel Central action on medulla Cardiac toxicity is difficult to treat and severity is enhanced by acidosis, hypercarbia and hypoxemia
- 45. IX. ETIDOCAINE Introduced in 1972 Onset of action like lignocaine Duration of action longer like bupivacaine Produces preferential motor blockade Cardiac toxicity similar to bupivacaine Useful for surgeries requiring intense skeletal muscle relaxation Concn used : 1-1.5% High dose – 4mg.kg Max dose – 300mg
- 46. X. PRILOCAINE Intermediate action and potency Pharmacologic similar to lignocaine but causes less vasodilation so can be used without vasoconstriction More volume of distribution in body so causes less CNS toxicity so can be used I.V.R.A. S/E.: Methemoglobinaemia as consequence of metabolism of aromatic ring to o-toludine. Haem of Hb is in Fe+++ (oxidised form) -dose dependent seen after 8 mg/kg T/t : I.V methylene blue 1-2 mg/kg Limited use in obst. Practice because of risk of methemoglobinemia in newborn. Fetal Hb has low resistance to oxidant stresses Neonatal enzyme are immature to convert Fe+++ Fe++ state Used concn – 0.5-2% Max. reco. Dose. = 400mg
- 47. XI. EMLA PATCH Eutectic mixture of La Mixture having its melting point less than melting point of individual components. Contains lignocaine 2.5% + pricocaine 2.5% mixed at 250 C to form oil in water emulsion (25mg and 25mg 1gm) Used for surface anaesthesia Indication Skin biopsy / grafting Venepucture in childrens Arterial puncture Removal of excessive granulation E.g. genital warts Surgical debridement of leg ulcer Circumcision
- 48. Application time on intact skin should be 1-3 hrs and on mucous membrane 5-10min Should not be used in children < 3 months (Fetal Hb) and in childrens 3-12 months who undergo medical treatment with drugs inducing methemoglobin formation (e.g sulpha drugs) Application time: 1. Minor procedure (Needle insertion) 2gm Minimum 60min to max 5hrs 2. Superficial skin grafting 1.5-3gm Minimum 2hrs to max 5hrs
- 49. XII. ROPIVACAINE Recently developed LA A pipecolic acid derivaties of xylide with propyl group on piperidine nitrogen atom of molecule Long acting but less cardiotoxic, short duration Highly protein bound and lower solubility Lipid solubility is intermediate between lignocaine and bupivacaine. Metabolisim of ropivacaine is 3 hydrory ropivacaine Concn – 0.5% 0.75%, and 1% Onset of motor blockade require 25min for all concentration
- 50. DOSE USED: 1. Extradural analgesia in labour 10ml of 0.5% followed by top up 0.25% 10ml 2. Extradural anaesthesia in LSCS 0.5% 30ml bolus 3. Peripheral N. block – 0.5% - 33ml -onset of sensory block < 4min and it last for 14hr 4. Ropivacaine is not recommended for SAB as safety is yet to be confirmed: TAC: For topical anaesthesia Paediatric surgery (TAC – 0.5%) Recommended dose 3-4ml for adult 0.05ml/kg for children Ineffective through intact skin Absorbed from mucosal surface leading to toxic reacition Applied to laceration that require suturing
- 51. DIBUCAINE NUMBER (DN) 1. Used for distinguish between normal and atypical plasma pseudocholinesterases 2. Potent inhibitor of normal plasma cholinesterase but reacts poorly with atypical ones 3. In testing procedures 1. Benzylcholine is used as substrate 2. Specifically hydrolysed by normal and atypical ch E but not true RBC CHE 4. DN is % inhibition of hydrolysis of benzyl choline by dibucaine added to plasma mixtures or % of CHE inhibited by dibucaine Normal plasma che – 70-80% of benzylcholine is intact Homozygous atypical < 20% of benzylcholine is intact Heterozygous atypical plasma CHE 40-70% of benzyl choline is intact
- 52. POTENTIATION OF LA ACTION I. ALTERATION OF PHYSIOCHEMICAL PROPERTIES OF LA A. pH adjustment to alkalanity Increasing pH of LA with functional range increases amount of free base in soln with early onset. soln can be made alkaline by a. Carbonation of solution with CO2 gas Gassing LA soln with 10-20% CO2 results in ↑ ed block by ten folds Dissolution of CO2 in soln influence the LA in following way.
- 53. i. When ampoule is opened some CO2 diffuses out ,this effervances raises pH and its base form ii. On. Inj around N. CO2 diffuse through neural membrane – enter interior of N –decrases pH –enhance neural blocked b. Using carbonate salts of LAS Commonly used salts are hydrochloride salt Instead carbonate salts are used Effect it similar to that with CO2 addition B. Altering LA pka by warming of LAS Warming soln to 1000 F significantly increases speed of onset and extent of spread The mech similar to alkalinisation and carbonation
- 54. II. IMPROVING INTENSITY AND DURATION OF BLOCKED DONE BY a. Opioid addition – Synergistic effect b. Monoamine neurotransmitter addition c. Vasoconstrictor i. Epinephrine (1:200,000 or 5ug/ml) – MC used - Contrraindition – in plastic surgery esp in local infiltration of skin flaps - Blocks of digits, foot, penis - In obstetric regional anaesthesia - In clinical conditions like severe HT, dysarrythmias, toxemia ii. Fely pressine (synth – analogue of vasopressin) – action more on venous microcirculation so absorption is delayed ιιι. α2 adrenergic agents like clonidine
- 55. d. Potassium addition Alteration of Na++, k+ ion balance around nerve ↑ level of K out side nerve causes ↓in resting potential resulting in conduction blockade miscellaneous Dyes Propylene glycol Vegetable oils hyaluronidase
- 56. Types of regional anaes produced by LAS 1. TOPICAL APPLICATON Surface application of LA to skin or mucous membrane Method – Spray – Spreading of an ointment – Instillation with syringe into urethra Nebulised lidocaine is used to produce surface anaesthesia of upper and lower respiratory tract before fiberoptic laryngoscopy / broncnoscopy e.g. EMLA, TAC
- 57. 2. INFILTRATION ANAESTHESIA Inj LA into tissue to be cut Nerve ending likely to be disturbed by surg manipulation- are infiltrated with LA Duration varies, epinephrine prolong duration Dose depends upon extent of area to be anaesthetised and expected duration of surgery. Pt. experience pain immediately after subcut inj of LA sol that is due to acidic nature of drugs It can be prevented by addition of Na bicarbonate and improvement of action 3. FIELD BLOCK Inj. LA into tissue around periphery of area in which surgeon is going to operate
- 58. 4. CONDUCTION ANAESTHESIA Deposition of LA soln along course of nerve or nerve supplying a region of body. e.g. Nerve block of trunk Epidural block – N – N root in epidural space. SAB – Nerve root in Subarachnoid space 5. INTRAVENOUS REGIONAL ANAESTHESIA I.V. admin of La into torniquet occluded limb (i.e. Bier block) LA diffuses from peripheral vascular bed to non vascular tissue e.g. Axon, nerve ending I.V. anaesthesia used for surgical procedure of upper limb and shorter proced by foot. Lidocaine is most frequently used without preservative 3mg/kg lidocaine with out epinephrine used for upper extremity procedure. 50-100ml of 0.25% ltdocaine used for lower limb surgery.
- 59. C. TOXICITY OF LAS 1. Physical status : Hyper purexia - ↑ absorption Debility – affect metabolism Shock Starvation Old age Vit. C deficiency 2. Types and site of procedure are: Highly vascular area - ↑ absorption
- 60. 3. Detoxification potentials Slow metabolism – greater chancer of toxicity ↓ plasma pseudoche - ↓ metabolism of espe– in Liver disease Sever anemia Malnutrition Renal dysfunction failure to eliminate breakdown product or unchanged drugs. 4. Nutrition Hypoproteinemia – More free drug Vit C deficiency - ↓ ability to handle LA
- 61. A. CENTRAL NERVOUS SYSTEM 1. STIMULATION: a. Cerebral cortex Convulsions (incidence 1:1300 to 4:1000) b. Medullary vagal centres ↑respiratory and cardiovascular activity with or without activity of vomiting centre 2. DEPRESSION: a. Cerebral cortex: Psychomoter inpairment ↓ co-ordinating skills ↓ Reaction capacity Unconsciounsness b. Medulla i. Vasomotor – Syncope ii. Respiratory – depression to arrest
- 62. B. CARDIO VASCULAR SYSTEM 1. Cardiac Bradycardia – Procaine Tachycartia – cocaine 2. Vascular Vasodilatation - ↓ C.O., hypotension C. ALLERGIC RESPONSES 1. Cutaneous Rashes urticaria 2. Respiratory Bronchospasm, laryngospasm D. Miscellaneous Reactions 1. Psychogenic 2. Other Drugs – vasopressor and additives
- 63. CNS TOXICITY Site of action subcortical level Hippocampous Limbic system sp. Amygdala Relative CNS toxicity of LAS in decreasing order Bupivacaine > Tetracaine > Etidocaine > Prilocaine > Lignocaine > Mepivacaine > procaine chlorprocaine
- 64. S/S OF CNS TOXICITY Symptomatology is progressive Mild : Light headedness – Most common perioral numbness Tinnitus Drowsiness Disorientation Moderate : Restlessness Headache Blurring of vision Nausea and vomiting Severe : Muscle twitching Tremours of face and extrimities Unconsciousness Generalised convulsions Respiratory arrest
- 65. PROPHYLAXIS OF CNS TOXICITY 1. Least amount and lowest conc. of LA necessary should be given 2. Precautions to minimise absorption and high blood levels should be taken Ex. Vasoconstrictors No intravasuclar injection 3. Threshold of reaction of CNS is raised Ex. By sedation with diazepam 4. Test should be done to recognise IV placement of needles Ex. In epidural and plexus blocks Injection of small dose of epinephrine 15µg in 3.0ml of anaesthetic solution is recommended Tachycardia occurs on IV injection
- 66. 5. Injection should be done slowly Rate < 10ml / min esp for epidural procedures is preferable 6. In IVRA, injections should be done slowly and the tourniquet should not be released until at least 20 min have elapsed from the time of completing injection.
- 67. T/T OF CNS TOXICITY 1. 100% O2 administration in very early stages ↑ PaO2 raises threshold for seizure If toxicity is progressive and convulsions start 2. Provide an adequate airway by endo tracheal incubation 3. Institute artificial controlled ventilation with 100% O2. 4. If convulsions do not stop with in 15 seconds anticonvulsants should be administered a. IV diazepam – 0.25 mg/kg b. IV short acting barbiturate like thiopentone 3-5 mg/kg 5. In CNS depression is seen, all the above misuses are taken except for anticonvulsant use
- 68. CVS TOXICITY Generally cardiovascular system is resistant to effects of LA as compared to CNS Ex. Dose of lignocain causing CVS toxicity is three times greater than that causing CNS toxicity Negative chronotropism - ↑ PR interval, ↑ QRS duration AV blocks Negative inotropism - ↓ cardiac output ↓ B.P. Ultimately may lead to circulatory failure
- 69. T/T 1. Establishment of airway 2. Oxygen therapy 3. IV infusion 4. Vasopressors 5. Antiarrythmic agents like bretyllium 6. Cardiac resuscitation (Massage, defibrillation) CC/CNS ration for bupivacaine and etidocaine found to be lower than lidocaine CC/CNS dose ratio – for lido caine – 7.1 ± 1.1 for bupivacaine – 3.7 ± 0.5 CC/CNS blood ratio - for lido caine – 3.6 ± 0.3 for bupivacaine – 1.6 to 1.7
- 70. ALLERGIC REACTIONS Usually rare Drugs are non-protein, non-antigenic and do not induce an antibody response Drug metabolite may act as hapten and may combine with protein or polysaccharide to produce antigen May be immediate or delayed
- 71. 1. IMMEDIATE: i. Mucocutaneous Urticaria Skin rashes Conjunctivitis Rhinttis Angioneurotic edema Edema of larynx, pharynx ii. Respiratory Bronchospasm Edema of bronchial mucosa ANAPHYLACTOID REACTIONS Due to massive release of histamine 2. DELAYED REACTIONS Urticaria and rashes several hours after injection Subcutaneous edema over injection site spreading to adjacent area Edema of face and neck Swelling of pharynx, tongue and floor of month
- 72. SKIN TESTING (INTRADERMAL TESTING) 0.02 to 0.04ml of drug injected intradermally Response noted in 15-20 minutes Around an injection site Pseudopodia may occurs Quantitiative grading is as fallows ≤ 4mm – Negative 5mm - + 5 – 8 mm - ++ 8 – 12 mm - +++ ≥ 12 mm - ++++ Of pseudopodes appear, the rating is higher for any area of erythema
- 73. REACTIONS TO PRESERVATIVES IN LA SOLUTIONS Additives and preservatives used in LA solution 1. Antioxidants: Bisulphites Sulpher dioxides Na or K sulphite Na or K metabisulphite Urticaria, angioedema, bronchospasm 2. Buffers: Sodium pyrosulphite Acidification prevents oxidation of added epinephrine ↓ pH affects the pKa LA and hence penetration and activity so higher dose may be required leading to toxicity
- 74. 3. Bacteriostatics : Parabens Methylparabens May act as haptens leading to allergic TACHYPHYLAXIS AND LA Repeated inj of the same dose of LA leads to ↓ efficacy Influenced by dosing interval Short dosing intervals that do not permit pain to occur may not associated tachyphylaxis
- 75. ADVANTAGES AND DISADVANTAGES OF LAS ADVANTAGES 1. Practical, Cheap, Safer 2. Can be used when pt is not NBM 3. Pt breathes spontaneously and normally 4. Pharyngeal and lanyngeal reflexes are preserved 5. Needs little equipments 6. Pt can co-operate DISADVANTAGES 1. Less reliable than GA 2. Dose is limited, so the area to be anaesthetized is limited. 3. Difficulty may be encountered if pt fatty 4. Can not be given through infected tissues 5. Not suitable for children and uncooperative patient