Local anesthetics


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Local anesthetics

  1. 1. Local Anesthetics PharmacologyIyad M.Abou Rabii February , 2010
  2. 2. What are local anesthetics?  Local anesthetic: produce loss of sensation to pain in a specific area of the body without the loss of consciousnessPage  2
  3. 3. History  Genus Erythroxylum discovered in South America, Venezuela, Bolivia, and Peru since pre- Columbian periods  Coca leaves from the genus Erythroxylum contain high concentration of alkaloid up to 0.7-1.8%  In 1571, Pedro Pizarro, a conquistador of Inca, observed nobles and high rank officials of the Inca empire consumed the coca plant.  After the fall of the Inca empire, coca consumption spread widely to the populationPage  3
  4. 4. Development of general and local anesthesia  Took place in Western Europe from 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 cocainePage  4
  5. 5. Development of general and local anesthesia (cont.)  Niemann discovered the effect of numbness of the tongues caused by alkaloid in 1860  Based on Niemann’s discovery, Russian physician Basil Von Anrep did experiments on animals, such as rats, dogs, and cats.  He injected small quantity of 1% solution to his tongue; tongue became insensitive  He concluded cocaine is a good drug for surgical anesthetic  William Steward Halsted and Richard John Hall developed the inferior dental nerve block techniques for dentistryPage  5
  6. 6. Cocaine Addiction  An ophthalmologist Carl Koller realized the importance of the alkaloid’s anesthetic effect on mucous membranes  In 1884, he used the first local anesthetic on a patient with glaucoma  In 1898, Professor Heinrich Braun introduced procaine as the first derivative of cocaine, also known as the first synthetic local anesthetic drug  Trade name is Novocaine®Page  6
  7. 7. Procaine replaced cocaine (Problems) Took too long to set (i.e. to produce the desired anesthetic result) Wore off too quickly, not nearly as potent as cocaine Classified as an ester; esters have high potential to cause allergic reactions Caused high conc. of adrenaline resulted in increasing heart rate, make people feel nervous Most dentists preferred not to used any local anesthetic at all that time; they used nitrous oxide gas.Page  7
  8. 8. Lidocaine  In 1940, the first modern local anesthetic agent was lidocaine, trade name Xylocaine®  It developed as a derivative of xylidine  Lidocaine relieves pain during the dental surgeries  Belongs to the amide class, cause little allergenic reaction; it’s hypoallergenic  Sets on quickly and produces a desired anesthesia effect for several hours  It’s accepted broadly as the local anesthetic in United States todayPage  8
  9. 9. Cell Membrane ReceptorsPage  9
  10. 10. Membrane potential and neurotransmission: Neuron transmits information mainly by two mechanisms: – chemical – and electrical signals. Information within a neuron is mainly transmitted by electrical signals. Electrical signals are propagated by the mechanism called action potential.Page  10
  11. 11. neurotransmission: Resting Potential  Resting neurons maintain an intracellular negative membrane potential.  Na+/K+ ATPase (sodium pump) transports intracellular Na+ to extracellular in exchange of entry of K+ into cells. This creates a concentration gradients of Na+ and K+Page  11
  12. 12. neurotransmission: Resting Potential  The resting neuron cell membrane contains much more open K+ channels than open Na+ and Cl-  channels or channels for other ions. K+ flows to the outside down the concentration gradient, resulting in a negative potential inside the cell.Page  12
  13. 13. neurotransmission: Resting PotentialPage  13
  14. 14. neurotransmission: Action Potential (Depolarisation)  When stimulated (electrically or chemically), a depolarization of the membrane potential in the neuron (axon) membrane opens voltage- gated Na+ channels.  This leads to a burst of flow of Na+ into the cell down the concentration gradient, causing a reverse of the membrane potential (from negative inside to positive inside).Page  14
  15. 15. neurotransmission: Action Potential (Depolarisation)Page  15
  16. 16. neurotransmission: Action Potential (Repolarisation)  Eventually, the influx of Na+ is stopped when Na+ concentration gradient is balanced by the reversed potential gradient.  Na+ channels are closed by the voltage-sensitive regulatory domain  Subsequently, voltage-gated K+ channels open, allowing accelerated outflow of K+. The membrane potential returns to resting statePage  16
  17. 17. neurotransmission: Action Potential (Repolarisation)Page  17
  18. 18. Membrane potential and neurotransmission: Action potential at one site of the neuron causes partial depolarization of neighboring region, activates voltagegated Na+ channels in the neighboring region and thus causes propagation of the action potential (electrical signals) along the axon to synapses.Page  18
  19. 19. MechanismPage  19
  20. 20. MechanismPage  20
  21. 21. MechanismPage  21
  22. 22. How Local Anesthetics Work Altering the basic potential of the nerve membrane Altering the threshold or firing level Decrasing the rate of depolarization Prolonging the rate of repolarizationPage  22
  23. 23. LOCAL ANESTHETICS CALSIFICATION – Esters Cocaine, Procaine Chlore procaine ,Tetracaine . – Amids : Lidocaine Mepivacaine, Prilocaine Articaine Popivacaine, Etidocaine. – Ketons :Dyclon. – Quinoline: Centbucridine .Page  23
  24. 24. Differences of Esters and Amides  Two classes of local anesthetics are amino amides and amino esters. Amides: Esters: --Amide link b/t intermediate --Ester link b/t intermediate chain and chain and aromatic ring aromatic ring --Metabolized in liver and very --Metabolized in plasma --Cause allergic reactionsPage  24
  25. 25. Differences of Esters and Amides  All local anesthetics are weak bases. Chemical structure of local anesthetics have an amine group on one end connect to an aromatic ring on the other and an amine group on the right side. The amine end is hydrophilic (soluble in water), and the aromatic end is lipophilic (soluble in lipids)Page  25
  26. 26. Structures of Amides and Esters The amine end is hydrophilic (soluble in water), anesthetic molecule dissolve in water in which it is delivered from the dentist’s syringe into the patient’s tissue. It’s also responsible for the solution to remain on either side of the nerve membrane. The aromatic end is lipophilic (soluble in lipids). Because nerve cell is made of lipid bilayer it is possible for anesthetic molecule to penetrate through the nerve membrane.Page  26
  27. 27. Structures of Amides and EstersPage  27
  28. 28. Structures of Amides and EstersPage  28
  29. 29. Pharmacokinetics Following injection into the area of nerve fibers to be blocked, local anesthetics are absorbed into blood. – Ester-linked local anesthetics are quickly hydrolyzed by butyrylcholinesterase in blood. – Amide-linked local anesthetics can be widely distributed via circulation. Amide- linked local anesthetics are hydrolyzed by liver microsomal enzymes. Thus, half lifes of these drugs are significantly longer and toxicity is more likely to occur in patients with impaired liver function.Page  29
  30. 30. Pharmacokinetics Absorption of local anesthetics is affected by following factors: – dosage, – site of injection, – drug-tissue-binding and – Presence of vaso-constricting drugsPage  30
  31. 31. Factors Affect the Reaction of Local AnestheticsLipid 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. The more tightly local anesthetics bind to the protein, the longer the duration of onset action. Local anesthetics have two forms, ionized and nonionized. The nonionized form can cross the nerve membranes and block the sodium channels. So, the more nonionized presented, the faster the onset action.Page  31
  32. 32. Factors Affect the Reaction of Local Anesthetics pH influence  Usually at range 7.6 – 8.9  Decrease in pH shifts equilibrium toward the ionized form, delaying the onset action.  Lower pH, solution more acidic, gives slower onset of actionPage  32
  33. 33. Factors Affect the Reaction of Local Anesthetics (cont.) Vasodilation  Vasoconstrictor is a substance used to keep the anesthetic solution in place at a longer period and prolongs the action of the drug  vasoconstrictor delays the absorption which slows down the absorption into the bloodstream  Lower vasodilator activity of a local anesthetic leads to a slower absorption and longer duration of action  Vasoconstrictor used the naturally hormone called epinephrine (adrenaline). Epinephrine decreases vasodilator. Side effects of epinephrine  Epinephrine circulates the heart, causes the heart beat stronger and faster, and makes people feel nervous.Page  33
  34. 34. Toxicity  Toxicity is the peak circulation levels of local anesthetics  Levels of local anesthetic concentration administered to patients are varied according to age, weight, and health.  Maximum dose for an individual is usually between 70mg to 500mg  The amount of dose also varied based on the type of solution used and the presence of vasoconstrictor Example: ---For adult whose weight is 150lbs and up, maximum dose Articaine and lidocaine is about 500mg ---For children, the dosage reduced to about 1/3 to ½ depending on their weight. The doses are not considered lethal. Some common toxic effects: --light headedness ---shivering or twitching --seizures --hypotension (low blood pressure)Page  34 --numbness
  35. 35. Drugs used in dental anesthesia The most common local anesthetic used is called lidocaine. Others might include mepivacaine, bupivacaine and prilocaine. All of the drugs will most likely end with a caine. Procaine, which is commonly known as novacaine is no longer used as the other drugs mentioned here are more effective as numbing agent.Page  35
  36. 36. Drugs used in dental anesthesia Bupivicaine (Marcaine®--Produce very long acting anesthetic effect to delay the post operative pain from the surgery for as long as possible--0.5% solution with vasoconstrictor--toxicity showed by the pKa is very basic--Onset time is longer than other drugs b/c most of the radicals (about 80%) bind to sodium channel proteins effectively--most toxic local anesthetic drugPage  36
  37. 37. Drugs used in dental anesthesia Prilocaine (Citanest®)--Identical pKa and same conc. with lidocaine--Almost same duration as lidocaine--Less toxic in higher doses than lidocaine b/c small vasodilatory activity Articaine (Septocaine®)--newest local anesthetic drug approved by FDA in 2000--Same pKa and toxicity as lidocaine, but its half life is less than about ¼ of lidocaine--Used with vasoconstrictor.--Enters blood barrier smoothly--The drug is widely used in most nations todayPage  37
  38. 38. Anesthetic pKa Onset Duration Max Dose (with (with Epinephrine) Epinephrine) in minutes 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 2.5mg/kg – hours 3mg/kg Prilocaine 7.9 Medium 90 - 360 5mg/kg – 7.5mg/kg Articaine 7.8 Rapid 140 - 270 4.0mg/kg – 7mg/kgPage  38
  39. 39. The Other Drugs in a Local Anesthesia Carpule The dentist will make a solution for the local anesthesia to be administered prior to the surgery. Some of the other drugs in the solution may contain an antioxidant to prevent a breakdown of the vasoconstrictor, sodium hydroxide to adjust the acidity of the anesthetic so it works more effectively, sodium chloride, to help the solution enter the bloodstream more effectively and sometimes epinephrine which also works to narrow blood vessels to help the anesthetic last longer.Page  39
  40. 40. Vasoconstrictors Vasoconstrictors, such as epinephrine and norepinephrine, are commonly contained in local anesthetics to decrease systemic toxicity and prolong the duration of action by retarding anesthetic absorption.Page  40
  41. 41. Clinical ConsiderationThese catecholamines have varying degrees of α and β adrenergiceffects, resulting in cardiac and hemodynamic changesIn cardiac patients, the administration of low concentration of epinephrinemight be necessary according to the degree of severity of the disease.These doesn`t mean the use of epinephrine free local anesthetics but tomake sure that it is not directly administrated in the blood.Page  41
  42. 42. How is it administered? There are two local anesthesia injections a dentist will use. There is something called an infiltration injection which numbs a small area and there is a block injection which numbs a larger region. All of the injections are done in the interior of the mouth.Page  42
  43. 43. Side Effects: One possible side effect is hematoma, which is a blood filled swelling that can form when the needle accidentally punctures a blood vessel. You may also feel numbness outside the targeted area and this may cause drooping in your eyelid or lips. The effects of drooping will disappear when the anesthesia wears off. Allergic reactions are also rare; however it is important to tell your doctor about any medication you are taking.Page  43
  44. 44. Side Effects: Some of the side effects include a numb mouth, which is of course the point of the anesthetic in the first place but other effects include dizziness and the feeling that you have a fat or swollen lip. Other than that, side effects are very rare, which is part of the reason the local anesthetic is so popular in dental procedures.Page  44
  45. 45. References  Calatayud Jesús and González Ángel. History of the Development and Evolution of Local Anesthesia Since the Coca Leaf. © 2003 American Society of Anesthesiologists Volume 98(6) June 2003 pp 1503-1508.  Peter C. Meltzer, Shanghao Liu, Heather S. Blanchette, Paul Blundell, Bertha K. Madras. Design and Synthesis of an Irreversible Dopamine-Sparing Cocaine Antagonist. @ Bioorganic & Medicinal Chemistry Volume 10, Issue 11 , November 2002, Pages 3583-3591  Shigeki Isomura, Timothy Z. Hoffman, Peter Wirsching, and Kim D. Janda. Synthesis, Properties, and Reactivity of Cocaine Benzoylthio Ester Possessing the Cocaine Absolute Configuration. J. AM. CHEM. SOC. 2002, Issue 124, p.3661-3668  Mazoit, Jean-Xavier; Dalens, Bernard J. Pharmacokinetics of local anesthetics in infants and children. Clinical Pharmacokinetics (2004), 43(1), 17-32.  Alejandro A. Nava-Ocampo and Angelica M. Bello-Ramirez. Lipophilicity Affects the Pharmacokinetics and Toxicity of Local Anaesthetic Agents Administered by Caudal Block. Clinical and Experimental Pharmacology and Physiology (2004) 31, 116-118.  Don R Revis, Jr. Local Anesthetics. October 14,2004: (Medline) http://www.emedicine.com/ent/topic20.htmPage  45
  46. 46. Copyright notice Feel free to use this PowerPoint presentation for your personal, educational and business. Do • Make a copy for backups on your harddrive or local network. • Use the presentation for your presentations and projects. • Print hand outs or other promotional items. Don‘t • Make it available on a website, portal or social network website for download. (Incl. groups, file sharing networks, Slideshare etc.) • Edit or modify the downloaded presentation and claim / pass off as your own work. All copyright and intellectual property rights, without limitation, are retained by Dr. Iyad Abou Rabii. By downloading and using this presentatione, you agree to this statement. Please feel free to contact me, if you do have any questions about usage. Dr Iyad Abou Rabii Iyad.abou.rabii@qudent.edu.saPage  46