LOCAL ANEDTHETICS (Pharmacology lecture) Contrast Between ester and Amides ESTER AMIDES Mechanism of action Chemistry Ester Bond Amide bond  Inhibit nerve conduction by reducing the Representatives PROCANE LODOCANE permeability of the neuronal membrane to sodium Allergy LOW VERY LOW  Prevent sodium influx which is required for Metabolism Plasma Esterase’s Hepatic Enzymes propagation of action potentials. Toxicity Less likely More likely Stability Break down in Very Stable ampules Ideal properties of L.A Onset SLOW FAST Potent local anesthesia Satisfactory Duration Reversible local anesthesia Adequqate tissue penetration Absence of local rxn Low cost AMIDES ONSET DURATION Consideration Absence of systemic rxn Stability in solution( long in Bupivacaine 5-20 m 2-7 hrs Do not use bler solution block,deaths have occurred Absence of allergic rxn Rapid Onset Dibucaine < 15 m 3-4 hrs Monitor for local Sterilization by Autoclave Ease of Metabolism and reaction excretion Chlorocaine 5-20 m 2-7 hrs Less CVS and CNS toxicity

LIDOCAINE <2 m 30-90 m Short acting

Mepivacaine <3-15 m 45-90 m Causion with renal Automatic Losses of Order impairment 1. COLD Prilocaine 1-15 m 45- 90m Advise pxs not to 2. WARMTH bite themselves Rapivacaine 1-20 m 2-6 hrs Good mngt post-op 3. PAIN and obstetrical pain 4. TOUCH 5. PRESSURE ESTER ONSET DURATION COnsideration 6. VIBRATION Benzocaine 1m >60 m Avoid tight 7. PROPRIOCEPTION bandages w/ skin preparation

Butamben Slow 30-60 m Swallowing may be Chemistry of Local Anesthetics difficult if used in  Aromatic Group throat  Intermediate Chain Chloroprocaine 6-5 m 15-75 m Do not use w/ subarachnoid admin  Amino Group Procaine 2-25 m 15-75 m Monitor skin condition if immobile Properties of base And Salt forms of Local Anesthetics Tetracaine 15-30 m 2- 2.5 hrs Keep supine to avoid headache after FREE BASE SALT spinal Viscid liquid/ amorpous solids Crystalline solids Fat soluble (lipophilic) Water soluble (hydrophilic) Instable Stable First Local Anesthetic Alkaline Acid  COCAINE- ester of benzoic acid Incharged, unionized Charged, ionized  PROCAINE- para-aminobenzoic acid Penetrates nerve tissue Active form of site of action From present in tissue (pH From present at dental Infiltration and Block Anesthesia 7.4) cartridge(pH 4.5-6.0)  PIPEROCAINE (Methycaine)  CHLOROPROCAINE(Nesacaine)  HEXYLCAINE (Cyclaine) Characteristics Of L.A *** (seldom used in dentistry)  White and odorless -Piperocaine & Hexylcaine are also used toipically  Viscid liquids or Amorphous Solids -Hexylcaine also use in spinal anesthesia  Fat soluble but relatively insoluble in water  All are BASES and form water soluble salts with Infeltration, Nerve Blocks, & Caudal Anesthesia acids.  ETIDOCAINE (Duranest)

Surface Anesthesia In Opthalmology Components of Local anesthetics  PROPARACAINE (Opthaine) Anesthetic Amide/ Ester Vasoconstrictor Epinephrine /Levonordefrin Suface Anesthesia for the damaged skin and mucosa Antioxidant/ preservatives Sodium Bisulfite/ Sodium  CYCLOMETHYCAINE (Surfacaine) Pyrosulfite  DIPERODON (Diothane)  PRAMOXINE ( Tronothane) Antiseptics Methylparaben

Buffer Sodium bicarbonate Surface Anesthesia

 DIMETHISQUIN (Quotane)

 DIBUCAINE (Nupercaine) Role of Vasoconstrictor   Prolong local block Chemical Classification of Amides  Delay systemic absorption  XYLIDINE Derivatives  Limit toxicity Lidocaine (Xylocaine)

Mepivacaine (Carbocaine)

Pyrrocaine

Etidocaine ( Duranest)

Bupivacaine (Marcaine)

 TULUIDINE Derivatives Drug Interaction Prilocaine (Citanest)  CNS depressant potentiate the cardiac & respiratory Other: Dibucaine (Nuperacaine) depression of local anesthetics Other L.A  Both te esters type of L.A and succinylcholine are Chlorobutanol metabolized by pseudocholinestarase. Prolonged Dyclonine apnes could result from simultaneous administration of these drug Chemical Classification of Esters  Induction of microsomal enzymes by the barbiturates  P.A.B.A could result in an increased metabolism of the Butethamine (Menocaine) amide-type L.A. This could reduce the plasma levels Procaine (Novocaine) of these agents. Chloroprocaine (Nesacaine) Proparacaine (Ophthaine) Dose preparation Propoxycaine (Ravocaine)  Carpules are available that contain 0.15 % tetracaine & 2% of procaine, w/ 1:20,000 levonordefrin,  BENZOIC ACID 1:30,000 levorterenol, or 1:2,500 phenylephrine. Cyclomethycaine (sulfacaine) Metabutoxycaine (Primacaine) Consentration of Vasoconstrictor 1:1000 (ratio)  1 gm= 1000 mg Metabolism  1000 mg of solute (drug) in 1000 ml of solution ESTER  1000 mg in 1000 ml = 1mg/ml (Procaine & Chloroprocaine)  1:1000 conc. = 1:1000 conc. -hydrolyzed by both plasma pseudocholinesterases & liver  To produce a 1:1000 conc. esterases  1:1000 sol’n is added to 9 ml solvent H2O  1:1000= 0.1 mg/ml AMIDE (Prilocaine) Concentration of Epinephrine in mg/ml -metabolized primarily in the liver then in the plasma & also Concentration Mg/ml in the kidney. 1:1000 1.0

Pharmacologic Effects of L.A 1;2,500 0.4  Peripheral Nerve Conduction 1:10,000 0.1  CNS Effects  Myocardial Effects 1:20,000 0.05  Smooth Muscle Effects 1:30,000 0.033  Analgesic Effect  Anticonvulsant effect 1:50,000 0.02 1:80,000 0.0125 Adverse Effects of L.A 1:100,000 0.01 Central Nervous System  Descending stimulation 1:200,000 0.005  During Excitation phase CONVULSIONS may occur

 If RESPIRATORY DEPRESSION Calcium of Milligram/ Cartridge  Is prominent, mechanical ventilation is indicated % sol’n mg/ml Vol. of cart Mg/ cartridge

0.25 2.5 1.8 4.5 Cardiovascular System  In the Hearth, local anesthetics suppress excitability 0.40 4.0 1.8 7.2 & conducting system 0.50 5.0 1.8 9.0  In the blood vessels, anesthetics relax vascular 1.0 10.0 1.8 18.0 smooth muscle 1.5 15.0 1.8 27.0 2.0 20.0 1.8 36.0 Allergic Reaction 3.0 30.0 1.8 54.0  L.A can trigger an array of hypersensitivity reaction 4.0 40.0 1.8 72.0 ranging from allergic dermatitis to anaphylaxis Vasoconstrictors Labor and Delivery  L.A can depress uterine contractility & maternal Drug Conc. In MSD MSD MSD MSD expulsion effort Dentistry (normal (norm (cardi (cardac adult) al ac patient  Both action can prolong labor mg adult) patien 0 ml  It can also cross the placenta, causing bradycardia & ml t) mg depression in the neonate. Epinephrine 1:100,00 0.2 20 0.04 4 0 Toxicity of L.A (1mg/10 0ml)  Descending stimulation of the CNS followed by Levonordephr 1:20,000 0.5 20 0.2 8 DEPRESSION of certain areas of the brain. ine (1mg/20 ml0 Classic Progression Leverteranol 1:30,000 0.34 10.2 0.14 4.2  Restlessness, Apprehension & tremors  mg ECXITEMENT & convulsion (1mg/30  Increased Blood pressure ml)  Increased Respiratory Rate Phenylephrin 1:20,000 4 10 1.6 4 e (2mg/5  Respiratory & Cardiovascular Depression with loss of ml) reflexes & consciousness

Maximum Recommended Dose LIDOCAINE (Xylocaine, Octocaine) Drug Max.dose Max.dose % conc. carridge  Amide derivatives of xylidine Procaine 400 mg 20 m 2 11.1  Replacesd procaine as the standard to which other L.A are compred Lidocaine 300 mg 15 ml 2 8.3  Rapid Onset Mepivacaine 300 mg 15 ml 2 8.3  2% conc. Provides profound anesthesia Prilocaine 400 mg 10 ml 4 5.6  Little or no vasodilation, less vasoconstrictor required

Tetracaine 30 mg 20 ml 0.15 11.1 Toxicity Reaction Propoxycaine 30 mg 7.5 ml 0.4 4.2  CNS depression initially rather than CNS stimulation characteristics of other L.A’s

Working Conference of the America dental association

& American Heart Association Routes of Administration of Lidocaine  Recommended Concentrations  TOPICAL Epinephrine  INFILTRATION 1:50,000- 1:250,000  BLOCK Levarterenol  SPINAL 1:30,000  EPIDURAL Levonordefrin  CAUDAL 1:20,000

Phenylephrine Uses of Lidocaine 1:2,500  IV to treat cardiac arrhythmias during surgery

 Depress laryngeal & pharyngeal reflexes

 Reduced the pruritus of jaundice & the pain produced Antihistamines as Local Anesthetics by malignancy or burns  TRIPELENNAMINE (Pyribenzamine)  Control seizures of status epilepticus  1% DIPHENHYDRAMINE HYDROCHLORIDE  Topical anesthesia

5% of ointment Clinical Consideration of Antihistamines as Local 10% spray Anesthetics 25 viscous solution  Average volume used as injection 3 ml & a maximal

dose of 5 ml Duration of Action  Onset is slower as compared to Lidocaine  Lidocaine with 1:100,000 epinephrine  Duration of action is half that of lidocaine w/ 1-1 1/2 – hour duration of pulpal anesthesia epinephrine of 1:100,000 3-4 hours- soft tissue anesthesia

 Epinephrine concentration of 1:50,000 is used for PROCAINE (Novocaine) hemostasis.  PABA ester

 Replaces cocaine as the most frequently used L.A MEPIVACAINE until the late 1950’s  Amide derivaatives of xylidine  Fast onset toxicity & potency of about half that of  Rate of onset, duration, potency & toxicity are lidocaine similar to Lidocaine  Causes marked local vasocodilation thus has a  No cross allergenicity between mepivaciane & ester relative shirt duration of action unless used w/ a type of L.A & amides. vasoconstrictor.

 Rapid hydrolysis in plasma to PABA & diethylamino- Usual Dosage form in Dentistry ethanol makes procaine one of the safest , if not the  2% SOLUTION safest, local anesthetics ever known. With 1:20,000 levonordephrine  Should not be used w/ sulfonamides  Made available in a 3% solution w/ out

vasoconstrictor due to less vasodilation. Use of Procaine

 Drug of choice in the management of arterial spasm PRILOCAINE produced by intra-arterial injection  Toluidine derivatives  Principal use in dentistry of procaine HCL is as a 2 %  Less potent & less toxin than Lidocaine but has a solution combined w/ a more potent L.A such as slightly longer duration of action tetracaine or propoxycaine.  4% conc. w/ 1:200,000 epinephrine or 4% sol’n  Used intravenously in the treatment of cardiac without epinephrine arrythymias & seizures of status epilipticus  A dose of 400 mg produces a methemoglobinemia  Used as antifibrillatory agent & is combined w/ level of 1%. penicillin to form procaine penicillin G.

Containdication for Prilocaine Routes of Administration of Procaine  Infants  INFILTRATION  Patients w/ methemoglobinemia  BLOCK  Anemia  SPINAL  Hypoxia  EPIDURAL  Heart failure  CAUDAL  Pregnancy  (not effective topicaly)  Patients receiving para-aminophenols

( acetaminophen or phenacetin)

Management of Methemoglobinemia

 IV injection of 1 % methylene blue ( 1-2 mg/kg)

PROPOXYCAINE COCAINE  Ester PABA  Naturally occurring ester benzoic acid  Slightly less potent & less toxic than tetracaine but  1st local anesthetics has a long duration of action  Only local anesthetics that causes definite vasoconstriction PYRROCAINE  Subjects of consideration drug abuse  Amides derivatives of xylidine  Classified as a SCHEDULE II DRUG under the  Onset,potency, duration of action are similar to those Controlled substance Act of Lidocaine & mepivacaine  It is used topically in medicinal practice but has no  Available in carpules in 2% solutions with 1:150,000 application in dentistry & 1:250,000 epinephrine  Because of its toxicity & possible addiction potential, it is no longer used parenterally. TETRACAINE  Ester of PABA CNS Effects of Cocaine  Slow onset & longduration  EXCITEMENT  10x the potency & toxicity of procaine  TREMORS  Topically, it is rapidly absorbed  TACHYCARDIA  Maximal dose of 20mg is recommended for topical  TACHYPNEA administration (1 ml of a 2% sol’n) BENZOCAINE (Ethyl p- aminobenzoate) Forms of Tetracaine  Ester of PABA  SPRAY  Lack basic nitrogen so cannot be converted to a  SOLUTIONM water soluble form for injection  OINTMENT ( for topical application)  Poorly soluble, poorly absorbed - 2% CONCENTRATION  Prolong duration of action  Interfere with action of sulfonamides BUPIVACAINE  Repeated use resulted to local allergic reaction  Amide  Available in many proprietary products promoted for  4x more potent than other amides a wide variety of conditions from erupting teeth yo  Major Advantage: long duration od action hemorrhoids.  Vasodilating property is more than the other amides but less than procaine DYCLONINE (Dyclone) Uses of Bupivacaine  Ketone  Prolong dental procedure in which pulpal anesthesia  Cross sensitization with other local anesthetics of greater than 1 ½ hours is needed or in which does not occur post-operative pain is extended  Onset of action is slow ( up to 10 min)  Low toxicity due to poor solubility in water Characteristics of Bupivacaine as compared to 2%  Not injected to tissue Lidocaine  Available in 0.5% solution.  Onset of 0.5 %bupivacaine w/ epinephrine is slightly longer  Duration of action is 2x that of Lidocaine THE END   

ETIDOCAINE  Amide  Rapid onset & duration of action as compared to bupivacaine

Routes of Adminidtration of Etidocaine  INFILTRATION  BLOCK  EPIDURAL

Uses & forms of Etidocaine  Used for infiltration & block anesthesia  Dental carpules contain no. 4% propoxycaine & 25 procaine w/ 1:20,000 levonordefrin or 1:30,000 levarterenol.

 The concentration of vasoconstrictor normally used in dental local anesthetic solutions is not contraindicated in patient with cardiovascular disease when administered carefully & with preminaryaspiration.

TOPICAL ANESTHETICS  LIDOCAINE  TETRACAINE  COCAINE  BENZOCAINE  DYCLONINE