Pharmacology of local anesthetics


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  • Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Modified and reproduced, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J PharmacolExpTher 1975;195:225.)
  • Pharmacology of local anesthetics

    2. 2. WHAT ARE LOCAL ANESTHETICS? Local anesthetic: produce loss of sensation to pain in aspecific area of the body without the loss ofconsciousness
    3. 3. MANY CLASSES OF COMPOUNDS BIND AND INHIBIT NACHANNELS Local anesthetics General anesthetics Ca channel blockers 2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Batrachotoxin Grayanotoxin Tetrodotoxin (TTX)
    4. 4. HISTORY Alkaloid has natural nitrogen bases foundin the coca leaves, also known as cocaine discovered in South America, Venezuela,Bolivia, and Peru since pre-Columbianperiods Earliest cultivation and use of the coca leafwent back to about 700 BC in Bolivia andAndes regions
    5. 5.  Cocaine HCl isolated byAlbert Niemann (1860) Merck produces 100 gcocaine (1862) Koller and Gartner reportlocal anesthesia (1884) Merck produces 1450 kg(1884); 72,000 kg (1886) Coca-Cola (1886) and manyother products containcocaineCocaine HCl powder
    6. 6. Cocaine Niemann 1860Benzocaine Salkowski 1895Procaine Einhorn 1904Dibucaine Meischer 1925Tetracaine Eisler 1928Lidocaine Lofgren 1943Chloroprocaine Marks, Rubin 1949Mepivacaine Ekenstam 1956Bupivacaine Ekenstam 1957Ropivacaine Sandberg 1989CHRONOLOGY OF LOCAL ANESTHETICSAfter: Cartwright & Fyhr. Reg Anesth 1988;13:1-12
    7. 7.  Niemann discovered the effect of numbness of thetongues caused by alkaloid in 1860 Based on Niemann’s discovery, Russian physician BasilVon Anrep did experiments on animals, such asrats, dogs, and cats. He injected small quantity of 1% solution to his tongue;tongue became insensitive He concluded cocaine is a good drug for surgicalanesthetic William Steward Halsted and Richard John Halldeveloped the inferior dental nerve block techniques fordentistry
    8. 8. COCAINE Cocaine is the only anesthetics producingvasoconstriction acts by inhibiting the uptake ofcatecholamines, leading to prolongedvasoconstriction
    9. 9. CHEMISTRY Local anesthetics are weak bases the pKa of most local anesthetics is in the range of8.0–9.0 Cationic form is the most active form The uncharged form is important for rapidpenetration of biologic membranes
    10. 10. CHARACTERISTICS OF LAS Physical and chemical Increasing lipid solubility Increased protein binding Pharmacological & toxicological Increasing potency Prolonged onset time Prolonged duration of action Increasing tendency to produce severecardiovascular toxicity In general, all tend to sort together
    11. 11.  Local anesthetics most commonly exertdilation of vascular bed, vasodilation .• Some local anesthetics producevasoconstriction.• Procaine is the most potent vasodilatorclinically given for treating arteriospasmcaused by arterial injection of thiopental
    12. 12. PHARMACOLOGY OF LOCAL ANESTHETICS: THECLINICIAN’S PERSPECTIVE LA potency LA speed of onset LA duration of action Tendency to produce cardiac toxicity Tendency to produce differential block
    13. 13. ADDITIVES AND MODIFIERSVasoconstrictors: ↑duration,↑block success, ↓[LA]LAs bind and inhibit NachannelsPotency, lipid solubility, proteinbinding, onset time, duration,CV toxicity tend to sort together
    14. 14. PHARMACODYNAMICS With increasing concentrations of a local anesthetic The threshold for excitation increases Impulse conduction slows The rate of rise of the action potential declines The action potential amplitude decreases The ability to generate an action potential is completelyabolished These effects result from binding of the localanesthetic to more and more sodium channels
    15. 15. CLASSIFICATION OF LOCAL ANESTHETICS Esters” Esters of benzoic acid1. Butacaine2. Cocaine3. Benzocaine4. Hexylcaine5. Piperocaine6. Tetracaine7. Esters of paraaminobenzoic acid Chloroprocaine Procaine propoxycaine
    16. 16.  Amides1. Articaine2. Bupivacaine3. Dibucaine4. Etidocaine5. Lidocaine6. Mepivacaine7. Prilocaine8. Ropivacaine9. Quilonine10. centbucridine
    17. 17. LOCAL ANESTHETICS:AMIDES VS. ESTERS Common structure Aromatic ring Tertiary amine Alkyl chain Linking bond Amide bond (see lidocaine) Ester bond (see procaine)LidocaineProcaine
    18. 18. METABOLISM Esters: esters are hydrolysed in the plasma by theenzyme pseudo cholinesterase Procaine undergoes hyrolysis to paraamino benzoicacid the major metabolic product. Which can causeallergy Xxxxxx----- persons with atypical form ofpsedocholinesterase which causes inability tohydrolyse ester local anesthetics and other drugssuccinylcholine Persons who are given general anesthesia should bechecked for this to prevent respiratory arest.
    19. 19. AMIDE LOCAL ANESTHETICS Primary biotransformation in the liver Toxicity can be seen in patients with hypotension,congestive heart failure, and liver cirrhosis large doses of prilocaine can causemethemoglobinemia Lidocaine metabolite monoethylglycinexylidide andglycine xylidide can cause sedation
    20. 20. SYSTEMIC ACTIONS OF LOCAL ANESTHETICS CNS: Local anesthetics readily crosses the blood brainbarrier At low therapeutic, non toxic levels no cns effects Anti convulsive levels______0.5 – 4 ug/ml presizure signs and symptoms---- 4.5- 7 ug/ml Tonic clonic seizure---------------- greater than7.5ug/ml
    21. 21. LIDOCAINE In 1940, the first modern localanesthetic agent was lidocaine,trade name Xylocaine® It developed as a derivative ofxylidine Lidocaine relieves pain during thedental surgeries Belongs to the amide class, causelittle allergenic reaction; it’shypoallergenic Sets on quickly and produces adesired anesthesia effect forseveral hours
    22. 22. LIDOCAINE HYDROCLORIDE Amide 2 diethylamino 2’, 6’ acetoxylidide Lofgren Metabolism in liver by microsomal fixed functionoxidases Ph- 6.5 Half life- 90 minutes We use 2% lignacaine Maximum recommended dose 7mg/kg body weightwith epinephrine not to exceed 500mg Mrd without epinephrine 4.4mg/kg not to exceed300mg
    23. 23. TIME TO ACHIEVE PEAK BLOOD LEVELS Intravenous----- 1 min Topical========5 min Intramuscular------5-10 min Subcutaneous------ 30-90 min Skin---- solarcaine is used EMLA- FOR SKIN a eutectic mixture of oil inwater emulsion of lidocaine and prilocaine 5%cream 25mg lido and 25mg prilocaine
    24. 24. INJECTION OF LA AND DISTRIBUTION Absorption into the blood , LA undergoes distribution kidney------- cardiac output 22 Gi T--------------------------------21 Skeletal muscle-----------15 Brain-----------14 Skin--------6 Liver--------6 Bone-------5 Heart muscle-------3 Others--------8 Highest is the kidney so elimination is an important part Elimination half life is time needed for 50% reduction inblood levels
    25. 25. PRECONVULSIVE SIGNS AND SYMPTOMS OF CNSTOXICITY Slurred speech Shivering Muscular twitching Tremor of muscles of face and extremities Generalized light headedness Dizziness Visual disturbance Auditory disturbance Drowsiness disorientation
    26. 26. CARDIOVASCULAR SYSTEM Local anesthetics produce myocardial depression,decrease electrical excitability of the myocardiumdecrease the conduction rate, force of contraction. Blood levels normally noted of injection of 1 or 2dental cartridgres -- 0.5- 2ug/ml Therapeutic levels of lidocaine for antidysrhytmicactivity--- 1.8- 6ug/ml Overdose beyond 6ug/ml
    27. 27. MINIMAL TO MODERATE OVERDOSE LEVEL Signs; Talkativeness Apprehension Excitability Slurred speech Generalized slutter Euphoria Dysarthria Nystagamus Sweating Vomiting Elevated blood pressure Elevated heart rate Elevated respiratory rate
    28. 28. MODERATE TO HIGH OVERDOSE LEVELS Tonic clonic seizure Generalized cns depression Depressed blood pressure, heart rate, respiratoryratew
    29. 29. OTHER DRUGS Bupivicaine (Marcaine® 1 Butyl 2,6 pipecoloxylidide HCL--Produce very long acting anestheticeffect to delay the post operative painfrom the surgery for as long aspossible--0.5% solution with vasoconstrictor--Onset time is longer than other drugsb/c most of the radicals (about 80%)bind to sodium channel proteinseffectively--most toxic local anesthetic drug
    30. 30.  Prilocaine (Citanest)--Identical pKa and same conc. withlidocaine--Almost same duration as lidocaine--Less toxic in higher doses than lidocaineb/c small vasodilatory activity Articaine (Septocaine)--newest local anesthetic drug approved byFDA in 2000--Same pKa and toxicity as lidocaine, but itshalf life is less than about ¼ of lidocaine--Used with vasoconstrictor.--Enters blood barrier smoothly--The drug is widely used in most nationstoday
    31. 31. CONCLUSIONAnesthetic pKa Onset Duration (withEpinephrine) inminutesMax Dose (withEpinephrine)Procaine 9.1 Slow 45 - 90 8mg/kg – 10mg/kgLidocaine 7.9 Rapid 120 - 240 4.5mg/kg – 7mg/kgBupivacaine 8.1 Slow6-10min4 hours – 8hours2.5mg/kg – 3mg/kgPrilocaine 7.9 Medium90 - 360 5mg/kg – 7.5mg/kgArticaine 7.8 Rapid 140 - 270 4.0mg/kg – 7mg/kg
    32. 32. TOPICAL ANAESTHETIC Lidocaine 2-5% Mepivicaine 12-15% Procaine 10-20% Effective upto 2-3 mm Benzocaine in 140mg per ml Dyclonine HCL 0.5% solution Tetracaine HCL 0.7mg metered spray
    33. 33. EMLA Lidocaine 2.5% Prilocaine 2.5% Eutectic mixture
    34. 34. THANKYOU