Local Anesthetics (pharmacology lecture)

LOCAL ANEDTHETICS (Pharmacology lecture) Mechanism of action  Inhibit nerve conduction by reducing the permeability of the neuronal membrane to sodium  Prevent sodium influx which is required for propagation of action potentials. Ideal properties of L.A Potent local anesthesia Reversible local anesthesia Absence of local rxn Absence of systemic rxn Absence of allergic rxn Sterilization by Autoclave

Satisfactory Duration Adequqate tissue penetration Low cost Stability in solution( long in solution Rapid Onset Ease of Metabolism and excretion

Contrast Between ester and Amides ESTER Chemistry Ester Bond Representatives PROCANE Allergy LOW Metabolism Plasma Esterase’s Toxicity Less likely Stability Break down in ampules Onset SLOW

AMIDES Amide bond LODOCANE VERY LOW Hepatic Enzymes More likely Very Stable FAST

AMIDES Bupivacaine Dibucaine Chlorocaine LIDOCAINE Mepivacaine Prilocaine Rapivacaine ESTER Benzocaine Butamben Chloroprocaine Procaine Tetracaine

ONSET 5-20 m < 15 m 5-20 m <2 m <3-15 m 1-15 m 1-20 m ONSET 1m Slow 6-5 m 2-25 m 15-30 m

DURATION 2-7 hrs 3-4 hrs 2-7 hrs 30-90 m 45-90 m 45- 90m 2-6 hrs DURATION >60 m 30-60 m 15-75 m 15-75 m 2- 2.5 hrs

Consideration
Do not use bler block,deaths have occurred Monitor for local reaction Less CVS and CNS toxicity Short acting Causion with renal impairment Advise pxs not to bite themselves Good mngt post-op and obstetrical pain

Automatic Losses of Order 1. COLD 2. WARMTH 3. PAIN 4. TOUCH 5. PRESSURE 6. VIBRATION 7. PROPRIOCEPTION Chemistry of Local Anesthetics  Aromatic Group  Intermediate Chain  Amino Group Properties of base And Salt forms of Local Anesthetics FREE BASE SALT Viscid liquid/ amorpous solids Crystalline solids Fat soluble (lipophilic) Water soluble (hydrophilic) Instable Stable Alkaline Acid Incharged, unionized Charged, ionized Penetrates nerve tissue Active form of site of action From present in tissue (pH From present at dental 7.4) cartridge(pH 4.5-6.0) Characteristics Of L.A  White and odorless  Viscid liquids or Amorphous Solids  Fat soluble but relatively insoluble in water  All are BASES and form water soluble salts with acids. Components of Local anesthetics Anesthetic Amide/ Ester Vasoconstrictor Epinephrine /Levonordefrin Antioxidant/ preservatives Sodium Bisulfite/ Sodium Pyrosulfite Antiseptics Methylparaben Buffer Sodium bicarbonate Role of    Vasoconstrictor Prolong local block Delay systemic absorption Limit toxicity

COnsideration
Avoid tight bandages w/ skin preparation Swallowing may be difficult if used in throat Do not use w/ subarachnoid admin Monitor skin condition if immobile Keep supine to avoid headache after spinal

First Local Anesthetic  COCAINE- ester of benzoic acid  PROCAINE- para-aminobenzoic acid Infiltration and Block Anesthesia  PIPEROCAINE (Methycaine)  CHLOROPROCAINE(Nesacaine)  HEXYLCAINE (Cyclaine) *** (seldom used in dentistry) -Piperocaine & Hexylcaine are also used toipically -Hexylcaine also use in spinal anesthesia Infeltration, Nerve Blocks, & Caudal Anesthesia  ETIDOCAINE (Duranest) Surface Anesthesia In Opthalmology  PROPARACAINE (Opthaine) Suface    Anesthesia for the damaged skin and mucosa CYCLOMETHYCAINE (Surfacaine) DIPERODON (Diothane) PRAMOXINE ( Tronothane)

Surface Anesthesia  DIMETHISQUIN (Quotane)  DIBUCAINE (Nupercaine)  Chemical Classification of Amides  XYLIDINE Derivatives Lidocaine (Xylocaine) Mepivacaine (Carbocaine) Pyrrocaine Etidocaine ( Duranest) Bupivacaine (Marcaine)

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TULUIDINE Derivatives Prilocaine (Citanest) Other: Dibucaine (Nuperacaine) Other L.A Chlorobutanol Dyclonine

Chemical Classification of Esters  P.A.B.A Butethamine (Menocaine) Procaine (Novocaine) Chloroprocaine (Nesacaine) Proparacaine (Ophthaine) Propoxycaine (Ravocaine)  BENZOIC ACID Cyclomethycaine (sulfacaine) Metabutoxycaine (Primacaine)

Drug Interaction  CNS depressant potentiate the cardiac & respiratory depression of local anesthetics  Both te esters type of L.A and succinylcholine are metabolized by pseudocholinestarase. Prolonged apnes could result from simultaneous administration of these drug  Induction of microsomal enzymes by the barbiturates could result in an increased metabolism of the amide-type L.A. This could reduce the plasma levels of these agents. Dose preparation  Carpules are available that contain 0.15 % tetracaine & 2% of procaine, w/ 1:20,000 levonordefrin, 1:30,000 levorterenol, or 1:2,500 phenylephrine. Consentration of Vasoconstrictor 1:1000 (ratio)  1 gm= 1000 mg  1000 mg of solute (drug) in 1000 ml of solution  1000 mg in 1000 ml = 1mg/ml  1:1000 conc. = 1:1000 conc.  To produce a 1:1000 conc.  1:1000 sol’n is added to 9 ml solvent H2O  1:1000= 0.1 mg/ml Concentration of Epinephrine in mg/ml Concentration Mg/ml 1:1000 1;2,500 1:10,000 1:20,000 1:30,000 1:50,000 1:80,000 1:100,000 1:200,000 1.0 0.4 0.1 0.05 0.033 0.02 0.0125 0.01 0.005

Metabolism ESTER (Procaine & Chloroprocaine) -hydrolyzed by both plasma pseudocholinesterases & liver esterases AMIDE (Prilocaine) -metabolized primarily in the liver then in the plasma & also in the kidney. Pharmacologic Effects of L.A  Peripheral Nerve Conduction  CNS Effects  Myocardial Effects  Smooth Muscle Effects  Analgesic Effect  Anticonvulsant effect Adverse Effects of L.A Central Nervous System  Descending stimulation  During Excitation phase CONVULSIONS may occur  If RESPIRATORY DEPRESSION  Is prominent, mechanical ventilation is indicated Cardiovascular System  In the Hearth, local anesthetics suppress excitability & conducting system  In the blood vessels, anesthetics relax vascular smooth muscle Allergic Reaction  L.A can trigger an array of hypersensitivity reaction ranging from allergic dermatitis to anaphylaxis Labor and Delivery  L.A can depress uterine contractility & maternal expulsion effort  Both action can prolong labor  It can also cross the placenta, causing bradycardia & depression in the neonate. Toxicity of L.A  Descending stimulation of the CNS followed by DEPRESSION of certain areas of the brain. Classic Progression  Restlessness, Apprehension & tremors  ECXITEMENT & convulsion  Increased Blood pressure  Increased Respiratory Rate  Respiratory & Cardiovascular Depression with loss of reflexes & consciousness

Calcium of Milligram/ Cartridge % sol’n mg/ml Vol. of cart 0.25 2.5 1.8 0.40 4.0 1.8 0.50 5.0 1.8 1.0 10.0 1.8 1.5 15.0 1.8 2.0 20.0 1.8 3.0 30.0 1.8 4.0 40.0 1.8 Vasoconstrictors
Drug Conc. In Dentistry MSD (normal adult) mg MSD (norm al adult) ml

Mg/ cartridge 4.5 7.2 9.0 18.0 27.0 36.0 54.0 72.0

MSD (cardi ac patien t) mg

MSD (cardac patient 0 ml

Epinephrine

Levonordephr ine Leverteranol

Phenylephrin e

1:100,00 0 (1mg/10 0ml) 1:20,000 (1mg/20 ml0 1:30,000 mg (1mg/30 ml) 1:20,000 (2mg/5 ml)

0.2

20

0.04

4

0.5

20

0.2

8 4.2

0.34

10.2

0.14

4

10

1.6

4

Maximum Recommended Dose
Drug Procaine Lidocaine Mepivacaine Prilocaine Tetracaine Propoxycaine Max.dose 400 mg 300 mg 300 mg 400 mg 30 mg 30 mg Max.dose 20 m 15 ml 15 ml 10 ml 20 ml 7.5 ml % conc. 2 2 2 4 0.15 0.4 carridge 11.1 8.3 8.3 5.6 11.1 4.2

LIDOCAINE (Xylocaine, Octocaine)  Amide derivatives of xylidine  Replacesd procaine as the standard to which other L.A are compred  Rapid Onset  2% conc. Provides profound anesthesia  Little or no vasodilation, less vasoconstrictor required Toxicity Reaction  CNS depression initially rather than CNS stimulation characteristics of other L.A’s Routes       Uses of      of Administration of Lidocaine TOPICAL INFILTRATION BLOCK SPINAL EPIDURAL CAUDAL Lidocaine IV to treat cardiac arrhythmias during surgery Depress laryngeal & pharyngeal reflexes Reduced the pruritus of jaundice & the pain produced by malignancy or burns Control seizures of status epilepticus Topical anesthesia 5% of ointment 10% spray 25 viscous solution

Working Conference of the America dental association & American Heart Association  Recommended Concentrations Epinephrine 1:50,000- 1:250,000 Levarterenol 1:30,000 Levonordefrin 1:20,000 Phenylephrine 1:2,500 Antihistamines as Local Anesthetics  TRIPELENNAMINE (Pyribenzamine)  1% DIPHENHYDRAMINE HYDROCHLORIDE Clinical Consideration of Antihistamines as Local Anesthetics  Average volume used as injection 3 ml & a maximal dose of 5 ml  Onset is slower as compared to Lidocaine  Duration of action is half that of lidocaine w/ epinephrine of 1:100,000 PROCAINE (Novocaine)  PABA ester  Replaces cocaine as the most frequently used L.A until the late 1950’s  Fast onset toxicity & potency of about half that of lidocaine  Causes marked local vasocodilation thus has a relative shirt duration of action unless used w/ a vasoconstrictor.  Rapid hydrolysis in plasma to PABA & diethylaminoethanol makes procaine one of the safest , if not the safest, local anesthetics ever known.  Should not be used w/ sulfonamides Use of Procaine  Drug of choice in the management of arterial spasm produced by intra-arterial injection  Principal use in dentistry of procaine HCL is as a 2 % solution combined w/ a more potent L.A such as tetracaine or propoxycaine.  Used intravenously in the treatment of cardiac arrythymias & seizures of status epilipticus  Used as antifibrillatory agent & is combined w/ penicillin to form procaine penicillin G. Routes       of Administration of Procaine INFILTRATION BLOCK SPINAL EPIDURAL CAUDAL (not effective topicaly)

Duration of Action  Lidocaine with 1:100,000 epinephrine 1-1 1/2 – hour duration of pulpal anesthesia 3-4 hours- soft tissue anesthesia  Epinephrine concentration of 1:50,000 is used for hemostasis. MEPIVACAINE  Amide derivaatives of xylidine  Rate of onset, duration, potency & toxicity are similar to Lidocaine  No cross allergenicity between mepivaciane & ester type of L.A & amides. Usual Dosage form in Dentistry  2% SOLUTION With 1:20,000 levonordephrine  Made available in a 3% solution vasoconstrictor due to less vasodilation.

w/

out

PRILOCAINE  Toluidine derivatives  Less potent & less toxin than Lidocaine but has a slightly longer duration of action  4% conc. w/ 1:200,000 epinephrine or 4% sol’n without epinephrine  A dose of 400 mg produces a methemoglobinemia level of 1%. Containdication for Prilocaine  Infants  Patients w/ methemoglobinemia  Anemia  Hypoxia  Heart failure  Pregnancy  Patients receiving para-aminophenols ( acetaminophen or phenacetin) Management of Methemoglobinemia  IV injection of 1 % methylene blue ( 1-2 mg/kg)

PROPOXYCAINE  Ester PABA  Slightly less potent & less toxic than tetracaine but has a long duration of action PYRROCAINE  Amides derivatives of xylidine  Onset,potency, duration of action are similar to those of Lidocaine & mepivacaine  Available in carpules in 2% solutions with 1:150,000 & 1:250,000 epinephrine TETRACAINE  Ester of PABA  Slow onset & longduration  10x the potency & toxicity of procaine  Topically, it is rapidly absorbed  Maximal dose of 20mg is recommended for topical administration (1 ml of a 2% sol’n) Forms of Tetracaine  SPRAY  SOLUTIONM  OINTMENT ( for topical application) 2% CONCENTRATION BUPIVACAINE  Amide  4x more potent than other amides  Major Advantage: long duration od action  Vasodilating property is more than the other amides but less than procaine Uses of Bupivacaine  Prolong dental procedure in which pulpal anesthesia of greater than 1 ½ hours is needed or in which post-operative pain is extended Characteristics of Bupivacaine as compared to 2% Lidocaine  Onset of 0.5 %bupivacaine w/ epinephrine is slightly longer  Duration of action is 2x that of Lidocaine ETIDOCAINE  Amide  Rapid onset & duration of action as compared to bupivacaine Routes    of Adminidtration of Etidocaine INFILTRATION BLOCK EPIDURAL

COCAINE  Naturally occurring ester benzoic acid  1st local anesthetics  Only local anesthetics that causes definite vasoconstriction  Subjects of consideration drug abuse  Classified as a SCHEDULE II DRUG under the Controlled substance Act  It is used topically in medicinal practice but has no application in dentistry  Because of its toxicity & possible addiction potential, it is no longer used parenterally. CNS Effects of Cocaine  EXCITEMENT  TREMORS  TACHYCARDIA  TACHYPNEA BENZOCAINE (Ethyl p- aminobenzoate)  Ester of PABA  Lack basic nitrogen so cannot be converted to a water soluble form for injection  Poorly soluble, poorly absorbed  Prolong duration of action  Interfere with action of sulfonamides  Repeated use resulted to local allergic reaction  Available in many proprietary products promoted for a wide variety of conditions from erupting teeth yo hemorrhoids. DYCLONINE (Dyclone)  Ketone  Cross sensitization with other local anesthetics does not occur  Onset of action is slow ( up to 10 min)  Low toxicity due to poor solubility in water  Not injected to tissue  Available in 0.5% solution. THE END   

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.

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