Local Anaesthetics

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  • Membrane stabilizing: Propagation of Impulses by nerves
  • Local Anaesthetics

    1. 1. Local AnaestheticsLocal Anaesthetics Dr. D. K. BrahmaDr. D. K. Brahma Department of PharmacologyDepartment of Pharmacology NEIGRIHMS, SHILLONGNEIGRIHMS, SHILLONG
    2. 2. Common Uses of LocalCommon Uses of Local Anaesthetics:Anaesthetics: Dentistry Excision Dermatology Spinal Anaesthesia
    3. 3. Definition:Definition: • Local anaesthetics are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain in a localized area of the body. – Block generation and conduction of nerve impulses at a localized site of contact without structural damage to neurons. • Clinically - to block pain sensation from—or sympathetic vasoconstrictor impulses to—specific areas of the body – Loss of sensory as well as motor impulses
    4. 4. Some Clinical Examples of theirSome Clinical Examples of their UseUse • Topically: Nasal mucosa and wound margins • Infiltration: Vicinity of peripheral nerve endings and major nerve trunks • Epidural or Subarachnoid spaces: surrounding spinal nerves • Regional anesthesia: Intravenous injection in arm or leg (Bier block)
    5. 5. Local Vs General AnaesthesiaLocal Vs General Anaesthesia General Local Site of action CNS Peripheral nerves Area Whole body Restricted areas Consciousness Lost Unaltered Preferential use Major surgery Minor surgery Use in non-coperative patients Possible Not possible Poor health patient Risky Safer Care for vital functions Essential Not needed
    6. 6. History:History: • In Western Europe between 1750 to 1850 • Chemists and physicians collected sample of coca leaves for experiments • Isolated active principle of coca leaf, synthesized to a drug for patients to feel more relief of pain when taking surgeries • In 1860, German chemist Albert Niemann successfully isolate the active principle of coca leaf; he named it cocaine • Cocaine, an ester of benzoic acid and methylecgonine
    7. 7. What are the drugs?What are the drugs? (Classification)(Classification) • Injectable anaesthetic: – Low potency, short duration – Procaine and Chlorprocaine – Intermediate potency – Lidocaine (Lignocaine) and Prilocaine – High potency and long duration – Tetracaine, Bupivacaine, Ropivacaine, Etidocaine, Mepivacaine and Dibucaine (Cinchocaine) • Surface anaesthetic: – Soluble – Cocaine, Lidocaine, Tetracaine and Benoxinate – Insoluble – Benzocaine, Butylaminobenzoate and Oxethazine • Miscellaneous drugs: – Clove oil, phenol, chlorpromazine and diphenhydramine etc.
    8. 8. Another Classification ?Another Classification ? • Local anesthetics are also classified according to Chemical Structure! • What is it ?
    9. 9. AnswerAnswer – Ester-linked • Short acting • Metabolized in the plasma and tissue fluids • Excreted in urine – Amide-linked • Longer acting • Metabolized by liver enzymes • Excreted in urine REMEMBER: All are weak Bases!
    10. 10. C Chemistry of LA – contd. (LAs areChemistry of LA – contd. (LAs are Weak Bases)Weak Bases) C O O R N R R NH O R N R R Aromatic portion Amine portion Intermediate chain ESTER AMIDE LIPOPHILIC HYDROPHILIC
    11. 11. Chemistry of LAs – contd.Chemistry of LAs – contd. ESTER LINKAGE AMIDE LINKAGE (2 EYES!!) PROCAINE procaine (Novocaine) tetracaine (Pontocaine) benzocaine cocaine LIDOCAINE lidocaine (Xylocaine) mepivacaine (Carbocaine) bupivacaine (Marcaine) etidocaine (Duranest) ropivacaine (Naropin)
    12. 12. Chemistry of LAs (ClinicalChemistry of LAs (Clinical significance)significance) • Cross sensitivity (allergy with ESTER LINKAGE) – Occurs with drugs in the same chemical class – Esters are metabolized to common metabolite PABA – Allergy rarely occurs with amide linkage class • Biotransformation/duration of action – ESTERS are rapidly metabolized in the plasma by a cholinesterase – AMIDES are more slowly destroyed by liver microsomal P450 enzymes.
    13. 13. Mechanism - LAsMechanism - LAs • As you know, entry of Na+ is essential for Action potential • Two things happen: – Rate and rise of AP and maximum depolarization decreases – slowing of conduction. – Finally, local depolarization fails to reach threshold potential – conduction block.
    14. 14. Mechanism of LAs – contd.Mechanism of LAs – contd. • LAs interact with a receptor within the voltage sensitive Na+ channel and raise the threshold of opening the channel • Na+ permeability decreased and ultimately stopped in response to stimulus or impulse • Impulse conduction is interrupted when a critical length of fiber is blocked (2-3 nodes of Ranvier).
    15. 15. + + - - + + -- - - + + + + - - Na+ + ++ + - - - - Resting (Closed**) Open (brief) inactivated Very slow repolarization in presence of LA LA receptor LA have highest affinity for the inactivated form Refractory period Mechanism of LA – contd.Mechanism of LA – contd.
    16. 16. Mechanism of LA – contd.Mechanism of LA – contd. - Higher concentration of Ca++ reduces inactivation of Na+ channel - Blockade is not due to hyperpolarization (RMP is unaltered as K+ channels are not blocked) - Blockade is related to pKa of particular drug: - 7.6 to 7.8: e.g. lidocaine - fast acting drugs (more undissociated form) - 8.1 to 8.9 – slow acting – slow acting (more dissociated form)
    17. 17. Voltage gated Sodium ChannelVoltage gated Sodium Channel Composed of (I) 2 large alpha and (II) 2 small beta-1 and beta-2 subunits
    18. 18. Voltage gated Sodium ChannelVoltage gated Sodium Channel
    19. 19. B + H + BH+ (active form) B + H + BH+ B + H + BH+ axoplasm B Specific action Non-specific action pH = 7.4 pH = 6.9 pH = 7.4 Most LA are in this form at pH 7.4 Nerve sheath
    20. 20. Summary of Mechanism - LAsSummary of Mechanism - LAs • All local anesthetics are membrane stabilizing drugs – slows down speed of AP - ultimately stop AP generation • Reversibly decrease the rate of depolarization and repolarization of excitable membranes • Act by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell - voltage-gated sodium channels • When the influx of sodium is interrupted - action potential cannot rise and signal conduction is inhibited • Local anesthetic s bind (located at inner surface) more readily to sodium channels in activated state – and slows its reversion to the resting state – refractory period is increased - “state dependent blockade” - no action on resting nerve. • Blockade develops rapidly on stimulation of nerves repeatedly (Greater the stimulation higher is the blockade) • Many other drugs also have membrane stabilizing properties, all are not used as LA, e.g. propranolol
    21. 21. Influencing factor of LA actionInfluencing factor of LA action Lipid solubility • All local anesthetics have weak bases. Increasing the lipid solubility leads to faster nerve penetration, block sodium channels, and speed up the onset of action. Influence of pH • Lower pKa (7.6 – 7.8) – faster acting (lidocaine, mepivacaine) • Higher pKa (8.1 – 8.9) – slower acting (procaine, tetracaine, bupivacaine) Vasoconstrictors • Cocaine itself is vasoconstrictor • Adrenaline – Potential adverse effects of vasoconstrictors • DON’T use in areas of toes, fingers, ear lobes, penis (ischemia) and necrosis Inflammation tends to produce lower pH in tissues therefore • LA are more ionized - don’t penetrate very well • Blood flow • Decreased ability of LA to produce effects
    22. 22. Actions of LA - LocalActions of LA - Local • All LAs have effects on nerves acting via Na+ channel – sensory endings, nerve trunks, NM junctions, ganglion and receptors • Injected near Mixed nerve – anaesthesia of skin and paralysis of voluntary muscles • Sensory and Motor fibres are equally sensitive – depends on diameter and types of fibres (gr. C & gr A etc.) – Smaller fibers are more sensitive than larger ones – Frequency dependence – Myelinated nerves are blocked earlier than non-myelinated ones • Autonomic fibres are more susceptible than somatic ones
    23. 23. Functions lost with LAFunctions lost with LA Answer – Pain perception – Temperature – Touch sensation – Proprioception – Skeletal muscle tone • The order of blockade: – Initially gr.`C` fibres are blocked – pain and sympathetic vasoconstrictors – Then gr.`A` fibres • Pain – temperature – touch - pressure and vibration –motor fibres (Muscle) • Tongue: bitter – sweet – sour - salt
    24. 24. Undesired effects of LA – contd.Undesired effects of LA – contd. • CNS Stimulation: • (More sensitive than cardiac) – Dose-related spectrum of effects and All effects are due to depression of neurons • First an apparent CNS stimulation (convulsions most serious) • Followed by CNS depression (death due to respiratory depression) • Premonitory signs include: ringing in ears, metallic taste, numbness around lips – Cocaine - euphoria (unique in its ability to stimulate CNS) – Lidocaine - sedation even at non- toxic doses
    25. 25. Cardiovascular SystemCardiovascular System • ARRHYTHMIAS: direct effect (More resistant than CNS) • Decrease cardiac excitability and contractility • Decreased conduction rate • Increased refractory rate (bupivicaine) • ALL can cause arrhythmias if conc. is high enough Note: cocaine is exception......it stimulates heart • HYPOTENSION: Arteriolar dilation is a result of: – Direct effect (procaine and lidocaine have most effect) – Block of postganglionic sympathetic fiber function – CNS depression – Avoid by adding vasoconstrictor to the preparation – Cocaine is exception: produces vasoconstriction, blocks catecholamine reuptake
    26. 26. • Methemoglobinemia – Some LA metabolites have significant oxidizing properties – This may cause a significant conversion of hemoglobin to methemoglobin and compromise ability to carry oxygen – May be a problem if cardiopulmonary reserve is limited – Treat with oxygen and methylene blue (converts methemoglobin to hemoglobin) • prilocaine benzocaine lidocaine have been implicated Undesired effects of LA – contd.Undesired effects of LA – contd.
    27. 27. Undesired effects of LA – contd.Undesired effects of LA – contd. • Hypersensitivity: – Common with ester-linked LA – Rashes, angio-edema, dermatitis and rare anaphylaxis – Sometimes typical asthmatic attack • Neurotoxicity: – LA can cause concentration-dependent nerve damage to central and peripheral NS – Mechanism(s) not clear – Permanent neurological injury is rare – May account for transient neurological symptoms after spinal anesthesia • Cauda equina syndrome
    28. 28. Pharmacokinetic of LAPharmacokinetic of LA • Absorption: - Surface anesthetics from mucus membrane and abraded areas - Depends on Blood flow to the area, total dose and specific drug characteristics - Procaine has poor penetration in mucus membrane - Procaine is negligibly bound to plasma protein but amides are bound to alpha 1 acid glycoprotein • Distribution: - Widely distributed in the body: (lipophilic) - Enters brain, heart, liver and kidney - Followed by muscle and other viscera
    29. 29. Pharmacokinetic of LA – contd.Pharmacokinetic of LA – contd. • METABOLISM – Ester type LA • Hydrolysis by cholinesterase in plasma to PABA derivatives – pseudo cholinesterase or butrylcholinesterase • Generally, short acting and low systemic toxicity • Prolonged effects seen with genetically determined deficiency or altered esterase (cholinesterase inhibitors) - Amide type LA • Bound to alpha1 acid glycoprotein • Hydrolyzed by liver microsomal enzymes (P450) • Longer acting & more systemic toxicity than esters • High first pass metabolism on oral ingestion
    30. 30. Individual LA -Individual LA - CocaineCocaine • Natural alkaloid from Erythroxylon coca • Medical use limited to surface or topical anesthesia (corneal or nasopharyngeal) – Constriction of corneal vessels and sloughing and drying • A toxic action on heart may induce rapid and lethal cardiac failure – reuptake inhibition of Adr. And NA • CNS: Stimulation of vasomotor, vomiting and temperature centre etc. – Initially euphoria followed by dysphoria (DA reuptake) • Avoid adrenaline because cocaine already has vasoconstrictor properties. (EXCEPTION!!!) • A marked pyrexia is associated with cocaine overdose • Not used presently
    31. 31. Esters – contd.Esters – contd. Procaine (Novocaine) – Topically ineffective - disadvantage – Used for infiltration because of low potency and short duration but most commonly used for spinal anesthesia – Short local duration ......produces significant vasodilation. Adrenaline used to prolong effect – Systemic toxicity negligible because rapidly destroyed in plasma – Procaine penicillin
    32. 32. Individual LA - AmidesIndividual LA - Amides LIDOCAINE (Xylocaine) Most widely used and popular LA – Effective by all routes – topical, infiltration, spinal etc. – Faster onset (3 Vs 15 min), more intense, longer lasting (30 – 60 min.), than procaine – Addition of Adr in 1:200,000 prolongs the action for 2 Hrs – More potent than procaine but about equal toxicity – Quicker CNS effects than others (drowsiness, mental clouding, altered taste and tinnitus) – Overdose (muscle twitching, cardiac arrhythmia, fall in BP, coma and respiratory arrest) – Antiarrhythmic – Available as Injections, topical solution, jelly and ointment etc.
    33. 33. Individual LA (Amides) – contd.Individual LA (Amides) – contd. Bupivacaine (Marcaine) – No topical effect – Slower onset and one of longer duration agents (8 Hrs.) – Used for infiltration, spinal, nerve block and epidural – Unique property analgesia without significant motor blockade (popular drug for analgesia during labor) – High lipid solubility, high distribution in tissues and less in blood (benefit to fetus) – More cardio toxic than other LA (prolong QT interval) – not given IV – Available as 0.25%, 0.5% inj.
    34. 34. ConclusionConclusion Anesthetic pKa Onset Duration (with Adrenaline) in minutes Max Dose (with adrenaline) Procaine 9.1 Slow 45 - 90 8mg/kg – 10mg/kg Lidocaine 7.9 Rapid 120 - 240 4.5mg/kg – 7mg/kg Bupivacaine 8.1 Slow 4 hours – 8 hours 2.5mg/kg – 3mg/kg
    35. 35. Individual LA (Amides) – contd.Individual LA (Amides) – contd. EMLA = eutectic mixture of local anesthetics – Eutectic = two solid substances mixed together in equal quantities by weight form a eutectic mixture – the melting point of the mixture is lower than the melting points of the individual components • EMLA = lidocaine and prilocaine becomes an oily mixture
    36. 36. Individual LA (Amides) – contd.Individual LA (Amides) – contd. lidocaine/prilocaine combination is indicated for dermal anaesthesia – Specifically it is applied to prevent pain associated with intravenous catheter insertion, blood sampling, superficial surgical procedures; and topical anaesthesia of leg ulcers for cleansing or debridement – it can also be used to numb the skin before tattooing. – EMLA cream is also used in the treatment of premature ejaculation
    37. 37. Individual LA (Amides) – contd.Individual LA (Amides) – contd. TAC: (LET) • tetracaine 0.5%, adrenaline1 in 2000 and cocaine 10% • topical anesthetic mixture found to be effective for nonmucosal skin lacerations to the face and scalp • applied directly to the wound using a cotton- tipped applicator with firm pressure that is maintained for 20 to 40 minutes • maximum dose for children-0.05ml/Kg • toxicity due to cocaine
    38. 38. EMLA applicationEMLA application
    39. 39. CLINICAL APPLICATIONS (TECHNIQUES)CLINICAL APPLICATIONS (TECHNIQUES) OF LOCAL ANAESTHESIAOF LOCAL ANAESTHESIA 1. Surface anaesthesia: – Mucous membranes and abraded skin – Nose, mouth, bronchial tree, cornea and urinary tracts • Lidocaine, tetracaine 1. Infiltration anaesthesia: – Direct injection into tissues to reach nerve branches and terminals – Used in minor surgery = incisions, hydrocele, herniorrhaphy etc. 1. Field block: – Injection of LA subcutaneously – Aim is to anaesthetize the region distal to the site of injection – Examples – forearm, anterior abdominal wall, scalp and lower extremity 1. Nerve Block: - LA is injected around the nerve trunks or plexuses - Area of anaesthesia is large in comparison to the amount of drug used - Lasts longer than the field or infiltration methods - Flooding technique for plexus block - Examples: Trigeminal nerve blocks (face) , Ophthalmic nerve block (eyelids and scalp), Supraorbital nerve block (forehead)
    40. 40. Clinical applications of LA – contd.Clinical applications of LA – contd. Spinal anaesthesia: • Site of injection – Subarachnoid space between L 2-3 or L 3-4 • Site of action – nerve root in the cauda equina • Level of anaesthesia – vol. & speed of injection; baricity of drug soln. with CSF and posture of patient • Order of anaesthesia – sympathetic > motor • Uses – lower limbs, pelvis, lower abdomen, prostatectomy fracture setting and obstetric procedures • Problems - Spinal headache, hypotension, bradycardia and respiratory depression, cauda equina syndrome and nausea-vomiting • Drugs - Lidocaine, tetracaine
    41. 41. Clinical applications of LA – contd.Clinical applications of LA – contd. • Epidural and Caudal Anaesthesia: – Site of injection – sacral hiatus (caudal) or lumber, thoracic or cervical region – Catheters are used for continuous infusion – Unwanted effects similar to that of spinal except less likely because longitudinal spread is reduced - • Drugs - Lidocaine, bupivacaine, ropivacaine • Regional anaesthesia (Intravenous) - Injection of LA in a vein of a torniquet occluded limb - Mostly limited to upper limb - Orthopaedic procedures
    42. 42. Local AnestheticsLocal Anesthetics DESIRABLE CHARACTERISTICSDESIRABLE CHARACTERISTICS Rapid onset of action Brief, reversible block of nerve conduction Low degree of systemic toxicity Soluble in water and stable in solution Effective on all parts of the nervous system, all types of nerve fibers and muscle fibers
    43. 43. Newer Techniques of LANewer Techniques of LA Iontophoresis: Lidocaine-soaked sponges
    44. 44. Newer Techniques of LANewer Techniques of LA Liposomes: Liposomal Bupivacaine Formulation
    45. 45. B + H + BH+ (active form) B + H + BH+ B + H + BH+ axoplasm B Specific action Non-specific action pH = 7.4 pH = 6.9 pH = 7.4 Most LA are in this form at pH 7.4 Nerve sheathThank You Thank You

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