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Local anesthesia final


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Local anesthesia final

  1. 1. INTRODUCTION Local anesthesia is a widely used and accepted method of pain control during operative dental procedure. The development and acceptance of dental treatment can be credited to local anesthesia which offers freedom from pain. It also helps dentist to achieve the primary goal of their profession i.e. painless treatment & more comfort to the patient. Local anesthetics have also got acceptance during operative procedures under general anesthesia. HISTORICAL BACKGROUND • In 1951, Pravez described the hypodermic syringe. • In 1853, Alexander Wood, a Scottish physician, invented hollow metal needle. Until this date it was difficult to give medication into tissue or i.v. • Cocaine is the first local anesthetic agent and is a naturally occurring alkaloid. • It was isolated by Nieman from the leaves of the coca tree. • Its anesthetic action was demonstrated by Karl Koller. In 1884, he applied the cocaine to the conjuctiva of the human eye and produced local anesthesia • The first effective and widely used synthetic local anesthetic was procaine • It was produced by Einhorn in 1905 from benzoic acid and diethyl amino ethanol. • It anesthetic properties were identified by Biberfield and the agent was introduced into clinical practice by Braun.
  2. 2. • LIDOCAINE was synthesized by LofGren in 1948. The discovery of its anesthetic properties was followed in 1949 by its clinical use by T. Gordh. • Thereafter, series of potent anesthetic soon followed with a wide spectrum of clinical properties. DEFINITION Local anesthesia has been defined as a loss of sensation in a circumscribed area of the body caused by depression of excitation in nerve endings or an inhibition of the conduction process in peripheral nerves. by STANLEY F. MALAMED Local anesthetic agent is any chemical capable of blocking nerve conduction when applied locally to nerve tissue in concentrations that will not permanently damage such tissue. Various methods of inducing local anesthesia are : i) Mechanical trauma ii) Low temperature iii) Anoxia iv) Chemical irritants v) Neurolytic agents such as a alcohol and phenols vi) Chemical agents such as local anesthetics.
  3. 3. IDEAL PROPERTIES OF LOCAL ANESTHESIA The following are the properties deemed most desirable for local anesthetic i) It should be non irritating to the tissues to which it is applied. Most of the local anesthetics are relatively non irritating. Dyclonine, a potent topical anesthetic, is not administered by injection because of its tissue irritating properties. On the other hand, Lidocaine and tetracaine are both effective anesthetics when administered by injection or topical application. ii) It should not cause any permanent alteration of nerve structure. The local anesthetic solution should bring about transitory ionic exchange or alteration in the nerve membrane & should not cause any damage to nerve fibers. iii) The systemic toxicity should be low Toxicity is defined as the adverse reaction of an organism to a given dose of an agent. The end point in determining laboratory toxicity is a fatality. The minimal amount of drug needed to kill 50% of the test animals is the MLD 50. Toxicity may be either general or local. The general toxicity or systemic toxicity refers to the effect of a drug on the entire organism, while the local toxicity refers to the effect on cellular structure and is often termed as ‘cytotoxicity’. iv) It must be effective regardless of whether it is injected into the tissue or applied locally to mucous membranes. i.e. they should be potent enough to produce their action without locally irritating the tissues and increasing the risk of systemic toxicity.
  4. 4. v) The time of onset of anesthesia should be as short as possible. vi) The duration of action must be long enough the permit completion of the procedure yet not so long as to require an extended recovery. vii) It should have a potency sufficient to give complete anesthesia without the use of harmful concentrated solutions. Potency of a local anesthetic drug is defined as the minimal strength and dose of the drug that produces neural blockade and provides the conditions desired that permit surgery. viii) It should be relatively free from producing allergic reactions ix) It should be stable in solution and readily undergo bio-transformation in the body. x) It should either by sterile or be capable of being sterilized by heat without deterioration. PHARMACOLOGY OF LOCAL ANESTHETICS Local anesthetics, when used for the management of pain, differ from most other drugs commonly used in are very important manner. Virtually, all other drugs, regardless of the route through which they are administered, must ultimately enter into the circulatory system in sufficiently high concentrations before they can begin to exert a clinical action. Local anesthetics however, when used for pain control, cease to provide a clinical effect when they are absorbed from the site of administration into the circulation.
  5. 5. Classification of local anesthetics : I. Based on the chemical structure ESTERS : i) Esters of benzoic acid : - Butacaine - Cocaine - Ethyl amino benzoate (benzocaine ) - Hexylaine - Piperocaine - Tetracaine. ii) Esters of Para amino benzoic acid : - Chloroprocaine - Procaine - Propoxycaine AMIDES : - Articaine - Bupivacaine - Dibucaine - Etidocaine - Lidocaine - Mepivacaine - Prilocaine QUINOLINE : - Centbucridine
  6. 6. II. Based on biological site and mode of action : i) Class A  agents acting at receptor site on external surface of nerve membrane e.g. – tetradotoxin, saxitoxin. ii) Class B  agents acting at receptor sites on internal surface of nerve membrane e.g.: quaternary ammonium analogue of lidocaine. - Scorpion venom iii) Class C  agent acting by a receptor independent physio- chemical mechanism e.g.: Benzocaine iv) Class D  agents acting by combination of receptor and receptor independent mechanism. E.g.: - Lidocaine - Mepivacaine - Procaine III. Based on the source : i) Natural – cocaine ii) Synthetic – lidocaine iii) Others – ethyl alcohol IV. Based on mode of application : i) Topical ii) Injectable V. Based on duration of action : i) Ultra short acting (<30 min) - Procaine without vasoconstrictor - 2% chlorprocaine without vasoconstrictor - 2% lidocaine without vasoconstrictor
  7. 7. - 4% prilocaine without vasoconstrictor for infiltration. ii) Short acting (45-75 min) : - 2% lidocaine with 1:100,000 epinephrine - 2% mepivacaine with 1:20,000 levernordefrin - 4% prilocaine when used for nerve block - 2% procaine 0.4% propoxycaine with a vasoconstrictor. iii) Medium acting (90-150 min) : - 4% prilocaine with 1:200,000 epinephrine - 2% lidocaine, 2% mepivacaine with a vasoconstrictor may produce Pulpal anesthesia of this duration iv) Long acting (180 min or longer) : - 0.5% bupivacaine with 1:200,000 epinephrine - 0.5% or 1.5%. etidocaine with 1:200,000 epinephrine. v) Based on onset of action : - Short - Intermediate - Long PHARMACOKINETICS OF LOCAL ANESTHETICS : Uptake : All local anesthetic posses a degree of vasoactivity, most producing dilation of the vascular bed into which they are deposited, although the degree of vasodilation may vary. Esters local anesthetics are potent was dilating drugs. PROCAINE is probably the most potent vasodilator and is after used clinically for vasodilatation when peripheral blood flow has been compromised due to accidental intra arterial injection of thiopental. (thiopental may produce
  8. 8. arteriospasm with an attendant decrease in tissue perfusion, which could lead, if prolonged, to tissue death, gangrene etc. Cocaine is the only local anesthetic that consistently produces vasoconstriction. The initial action of cocaine is vasoconstriction, which is followed by an intense and prolonged vasoconstriction. It is produced by an inhibition of the rupture of catecholamines (example norepinephrine) into tissue binding sites. This results in an excess of free norepinephrine which leads to a prolonged) and intense state of vasoconstriction. A significant clinical effect of vasoconstriction is an increase in the rate of absorption of the local anesthetic into the blood, thus decreasing the duration of pain control while increasing the anesthetic blood lend and the potential for overdose. Oral route : With the exception of cocaine, local anesthetic drugs are absorbed poorly, if at all, from the GIT following oral administration. Additionally, most local anesthetics (especially lidocaine) undergo a significant hepatic first pass effect following oral administration. Following absorption of lidocaine from the GIT into the eneterohepatic circulation, a fraction of drug is carried to the liver, where approximately 72% of the dose is biotranformed into inactive metabolites. This has seriously hampered the use of lidocaine as an oral anti-dysrthythmic drug. In November 1984, Astra pehamae verticals introduced an analogue of Licocaine, TOCHAINIDE hydrochloride, which is effective orally. Topical route : Local anesthetic are absorbed at differing rates after application to mucous membranes: in the tracheal mucosa, uptake is almost as rapid and IV administration, in pharyngeal mucosa, uptake is slower, and in
  9. 9. esophageal and bladder mucosa, uptake is even slower than occurs through the pharynx. Whenever there is no layer of intact skin present; local anesthetics exert their action following the topical application. Sunburn remedies usually contain lidocaine, benzocaine etc in ointment formulation. Applied to intact skin do not provide an anesthetic action, EMLA has been developed to provide surface anesthesia for intact skin. Injection : The rate of uptake of local anesthesia after injection (s.c., I m., i.v.) is related to both the vascularity of the injection site and the vasoactivity of the drug. i.v. Administration of local anesthetics provides the most rapid elevation of blood levels and is used in the primary treatment of ventricular dysrhythmias such as premature ventricular contractions. Metabolism : A significant different between the two major classes of local anesthetics, the esters and the amides, is the means by which they undergo metabolic breakdown. Metabolism of local anesthetics is important, because the overall toxicity of a drug depends on a balances between its rate of absorption into the blood stream at the site of injection and its rate of removal from the blood through the processes of tissue uptake and metabolism. Esters : Ester local anesthetics are hydrolyzed in the plasma by enzyme pseudocholine-esterase. The rate of hydrolysis has an impact on the potential toxicity of a local anesthetic. Chloroprocaine, the most rapidly
  10. 10. hydrolyzed (4.7 µmol/ml/hr), is the least toxic, where a tetracaine, hydrolyzed 16 times more slowly than chloroprocaine (0.3 µmol/ml/hr) has the greatest potential toxicity. Procaine undergo hydrolysis to para-amino benzoic acid (PABA) and diethyl amino alcohol. Allergic reactions that occur in response to ester drugs are usually not related to the parent compound i.e. procaine, but rather to PABA. Approximately 1 out of every 2800 persons has an atypical form of pseudocholine esterase, which causes an inability to hydrolyze ester local anesthetics and other chemically related drug (e.g. succinylcholine). Its presence leads to a prolongation of higher blood levels of the local anesthetic and an increased potential for toxicity. Succinylcholine is a short-acting muscle relaxant employed frequently during the induction phase of general anesthetics. It produces respiratory arrest (apnea) for a period of approximately 2-3 min. Then plasma pseudocholinesterase hydrolyzes succinylcholine, blood level falls, and spontaneous respiration resumes. Persons with atypical pseudocholine esterase are unable to hydrolyze succinylcholine at a normal rate; therefore the duration of apnea is prolonged. Amides: The metabolism of the amide local anesthetic is more complete them that of esters. The primary site of biotransformation of amide drugs is the liver. Prilocaine undergoes primary metabolism in the liver, with some also possibly occurring in the lungs. Prilocaine undergoes most rapid biotransformation than the other amides. Patients with lower than usual hepatic blood flow (hypotension, congestive heart failure) or poor liver function (cirrhosis) are unable to
  11. 11. biotransform amide local anesthetics at a normal rate. This leads to increased anesthetic blood levels and potentially increased toxicity. Prilocaine, the parent compound, cannot produce methemoglobinemia, but orthotoluidine, a primary metabolite of prilocaine, does induce the formation of methemoglobin, which is responsible for methemoglobinemia. Lidocaine does not produce sedation, however, its two metabolites – monoethyl glycinexylidide and glycinexylidide – are currently thought to be responsible for this clinical action. Excretion : The kidney are the primary excretory organ for both the local anesthetic and its metabolites. A percentage of a given dose of local anesthetic drug will be excreted in the urine unchanged. Esters appear in only very small concentrations as the parent compound in the urine. This is because they are hydrolyzed almost completely in the plasma. Amides are usually present in the urine as the parent compound in a greater percentage than are esters, primarily because of their more complex process of biotransformation. Patients with significant renal impairment may be unusable to eliminates the parent local anesthetic compound or its metabolites from the blood, resulting in slightly elevated blood levels and an increased potential for toxicity.
  12. 12. INDIVIDUAL LOCAL ANESTHETIC AGENTS Although many drug are classified as local anesthetics and find use within the health professions, only a handful are currently used in dentistry. 1. Lidocaine: Concentration - 2% Potency - 2X Procaine Toxicity - 2X Procaine Metabolized - Liver Excreted - Kidney % Vasoconstrictor Duration 2 without pulp - 5-10 mins tissue - 1-2 hrs 2 1:50,000 epi pulp - 60 mins tissue - 3-5 hrs 2 1:100,000 epi pulp - 60 mins tissue - 3-5 hrs Time to onset 2-3 mins Half life 90 mins Maximum recommended dose (Malamed) 4.4 mg/kg (2 mg/lb) (manufac.) w/o epi 4.4 mg/kg (2 mg/lb)
  13. 13. with epi 6.6 mg/kg (3 mg/lb) Maximum safe dose - 2% with 1:100,000epi Malamed - 300 mg or 8 carpules manufac. - 500 mg or 13.5 carpules 2. Mepivacaine Concentration - 2% or 3% Potency - 2X Procaine Toxicity - 1.5-2X Procaine Metabolized - Liver Excreted - Kidney % Vasoconstrictor Duration * 3 without pulp - 20-40 mins tissue - 2-3 hrs 2 1:20,000 pulp - 60-90 mins Levonordefrin tissue - 3-5 hrs 2 1:100,000 epi pulp - 45-60 mins 1:200,000 epi tissue - 2-5 hrs * weak vasodilator Time to onset 1.5-2 mins Half life 1.9 hrs Maximum recommended dose (Malamed) 4.4 mg/kg (2 mg/lb)
  14. 14. (manufac.) 6.6 mg/kg (3 mg/lb) Maximum safe dose - 3% w/o vasoconstrictor Malamed - 300 mg or 5.5 carpules manufac. - 400 mg or 8 carpules Maximum safe dose - 2% with constrictor Malamed - 300 mg or 8 carpules manufac. - 400 mg or 11 carpules 3. Prilocaine Concentration - 4% Potency - 2X Procaine Toxicity - 1X Procaine Metabolized - Liver and Lungs orthotoluidine produced Excreted - Kidney % Vasoconstrictor Duration 4 without pulp - 10 mins infiltra. 60 mins block tissue - 1.5-4 hrs 4 1:200,000 epi pulp - 60-90 mins tissue - 3-8 hrs
  15. 15. Time to onset 2-4 mins Half life 1.6 hrs Maximum recommended dose all forms 6 mg/kg (2.7 mg/lb) Max safe dose all forms 400 mg or 5.5 carpules 4. Bupivacaine Concentration - 0.5% Potency - 8X Procaine (4X Lidocaine) Toxicity - 8X Procaine (4X Lidocaine) Metabolized - Liver Excreted - Kidney % Vasoconstrictor Duration 0.5 1:200,000 epi pulp - 90-180 mins tissue - 4-9 hrs, up to 12 hrs reported Time to onset 6-10 mins Half life 2.7 hrs Maximum recommended dose 1.3 mg/kg (0.6 mg/lb) Maximum safe dose 90 mg or 10 carpules
  16. 16. 5. Etidocaine Concentration - 1.5% Potency - 8X Procaine (4X Lidocaine) Toxicity - 4-8X Procaine (2-4X Lidocaine) Metabolized - Liver Excreted - Kidney % Vasoconstrictor Duration 1.5 1:200,000 epi pulp - 90-180 mins tissue - 4-9 hrs Time to onset 1.5-3 mins Half life 2.6 hrs Maximum recommended dose 8 mg/kg (3.6 mg/lb) Maximum safe dose 400 mg or 15 carpules 6. Procaine Concentration - 2-4% Potency - 1 Toxicity - 1 Metabolized - hydrolyzed in plasma by pseudocholinesterase to PABA Excreted - Kidney No longer available in dental carpules Time to onset 6-10 mins Half life 0.1 hr Duration pulp - 30-60 mins
  17. 17. (with v/c) tissue - 2-3 hrs Maximum recommended dose 6.6 mg/kg (3 mg/lb) Maximum safe dose 400 mg Strong vasodilation - very short duration of pulpal anesthesia High incidence of allergic reactions Drug of choice for Tx of inadvertant intra-arterial injection (relieves pain and spasm) RATING OF DRUGS In the search for more potent and less toxic agents, simultaneously there has developed a number of methods for testing these drugs to evaluate their usefulness and safety in clinical practice. Two drugs are used as a standard for comparison. - Procaine - Cocaine • Hirshfelder and Bieter originally received many techniques for comparing activity and toxicity. Most method used laboratory animals for initial testing and screening. These include the skin of a frog, cornea of a rabbit, and muscle-nerve preparations. • The intra-dermal wheal technique in humans provides information both on potency and on cytotoxicity . • A sensitive technique to determine both functional change and organic cellular change was the tissue culture technique developed by Corssen and Allen. Excised strips of human tracheal and bronchial mucosa were cultivated in a balanced physiologic solution. The explants showed
  18. 18. continued ciliary activity and rotary motion, and increased or decreased rotary motion is evidence of drug influence. A comparative study showed that procaine and lidocaine affected the tissue at concentration of 0.1% and failed to produce permanent injury even at concentrations upto 20%. Tetracaine and dibucaine should a considerably higher toxicity. Cocaine occupied an intermediate position. SAFETY OF LOCAL ANESTHESIA The safety of a local anesthetic drug is dependent on the relation to potency to toxicity. Safety α potency If potency is high, toxicity is low and the margin of safety will be large. • The ratio of potency to toxicity is called the anesthetic index SURGICAL CONSIDERATIONS Pre-block evaluation: All patients who are candidates for regional anesthesia should be completely evaluated. A complete history and physical examination should be done. It is very important to know the types of medication the patient may be taking for various medical conditions. It is equally important to determine if the patient is on any type of anticoagulant. 1 Toxicity α
  19. 19. Facilities: A nerve block should be considered to be a surgical procedure. The environment used while performing the technique must be given serious consideration. The obtain maximum success, the operating room should have following features: - Prefer ventilation - Adequate lighting - Temperature control - Provisions for asepsis Equipment necessary for treatment of complications and drug reactions must be provided. This includes an oxygen supply and means for administration by positive pressure. Asepsis : Aseptic precautions are similar to those that attend any surgical procedure. The field should be prepared should be given special consideration, since the patient is not anesthetized, any irritating chemicals should be Betadine have been successful. For outpatients, plain 70% ethyl or isopropyl alcohol is most suitable sinus it is an effective antiseptic, leaves no skin coloration, and doss not stain clothes. Sterile drapes are placed judiciously with respect to the site of the block. Skin preparation : The classic technique of preparing the skin consists of a soap-water scrub and/or 70% ethylorisopropyl alcohol for 5 minutes. Skin contains an average of 200-600 bacteria per square inch of surface area, and this technique will reduce the bacterial count to less than 100 bacteria/square inch, when followed by the application of 70% ethylorisopropyl alcohol, the
  20. 20. number of bacteria will be reduced further to 20-40 bacteria /inch. However, the efficacy of antiseptics over the use of soap-water, alcohol sequences is not well established. Iodine preparations are recommended and have been singularly effective. The disinfectant property is directly related to the amount of free iodine. Tincture of iodine (1%) provides over 300ppm of free iodine; povidone- iodine (betadine) contains about 20-25ppm. For maximum protection and the use of a single application of an antiseptic, chlorhexidine 0.5% in 70% ethylorisopropyl alcohol or 1% tincture of iodine is most effective, and from the antimicrobial point is presented as the gold standard. ANATOMIC CONSIDERATIONS To understand the mode of action of local anesthetic drugs, the fundamental of nerves should be understood; thus a review of the relevant characteristics and properties of nerve anatomy and physiology is described here. Structure of nerve fibers: The neuron The neuron or nerve cell is the structural unit of the nervous system. There are two basic types of neuron : • The sensory (afferent) neuron • The motor (efferent) neuron Sensory neurons that are capable of transmitting the sensation of pain consists of three major portions. The dendritic zone, which is compared of an arborization of the nerve endings, is the most distal segments of the sensory neuron. These free nerve endings respond to stimulation produced
  21. 21. in the tissues in which they lie, provoking an impulse that is transmitted centrally along the axon. The axon is thin cable-like structure that may be quite long. At its mesial (or central) end there is an arborization similar to that seen in dendritic zone. However, in this cover the arborizations from synapses with various nuclei in the CNS, to distribute incoming (sensory) impulses to their appropriate sites within the CNS for interpretation. The cell body, or soma, is the third fait of the neuron. In the sensory neuron, the
  22. 22. cell body is located at a distance from the axon, or the main pathway of impulse transmission in this nerve. The cell body of the sensory nerve is therefore not included in the process of impulse transmission, its primary function being to provide the vital metabolic support for the entire neuron. Nerve cells that conduct impulses from the CNS peripherally are termed motor neurons and are structurally different from the sensory nervous, in that their cell body is interposed between the axon and the dendrites. In motor neurons the cell body not only is an integral component of the impulse transmission system but also provides metabolic support for the cell. Microscopy Resolution of the membrane structure and its histochemistry reveal a bimolecular lipid layer around on each side by a protein sheet. The lipid molecules are arranged with the hydrophobic arms extending toward each other and the hydrophobic poles oriented toward either the extracellular fluid or the axoplasm. Between the lipid molecules are water filled channels. Permeability of the membrane is mediated by these ion channels, such channels are formed in the lipid membrane layers by various short-chain peptides in a helical manner of approximately four turns in length the outer lipoprotein molecules are tightly packed and impede the movements of sodium ions, amino acids and proteins, but potassium and chloride ion pass relatively freely. Hence the membrane is designated as semi permeable.
  23. 23. Schwann cells and myelin: All nerve fibers are incompletely surrounded by nucleated cells called Schwann cells. As the more complex nervous systems have evolved and the need arouse to rapidly convey sensory and motor impulses, insulation of nerve fibers become necessary. This is structurally accomplished for certain nerve fibers by the sheath cells manufacturing myelin, a fatty substance with insulating properties. This myelin is deposited around the membrane of the
  24. 24. nerve fiber in cylindrical of the nerve fiber in cylindrical layers or concentric lamellae. Such insulation reduces current loses and enhances the efficiency of impulse transmission. Myelinated nerve fibers : Most mammalian nerve fibers, except the smallest, are myelinated. At regular intervals, the myelin coaling is thin or absent these points or gaps occur approximately every 0.5 –3 mm and are known as the nodes of Ranvier. At these points, the nerve fiber itself comes into contact with extracellular fluid. Impulses are there fore promulgated jump-wise (Saltatory) fashion. It is to be recognized that myelin limit access of local anesthetics to the nerve fiber membrane to produce conduction block in myelinated fibers thus requires a higher concentration of local anesthetic. Furthermore, a sufficient amount of the anesthetic must be available and applied for a minimum distance along the length of any nerve fiber (usually at a minimum span of two –three adjacent nodes) or a minimum distance of 8-10 mm of the nerve must be exposed. Anatomy of a mixed nerve :
  25. 25. Most peripheral nerves are mixed, consisting of various afferent and efferent fibers tightly packed together. Individual fibers or axis cylinders are each cased by a thin membrane, or endoneurium; a variable number of 100-1000 of such are bound together in bundles or fasciculi by the perineurium. The perineurium of a fasciculus is compared of 5-15 layer of fibroelastic tissue, depending on the diameter of a bundle. It is noted that the perineurium is thicker at distal sites (i.e. at the wrist) than at the axillae. Furthermore, the
  26. 26. inner most layer of the perineurium, the perilemma, is lined with a smooth mesothelial membrane. This appears to be the main diffusional barrier. Embryologically, the perilemma is a continuation of the pia - arachnoid membrane covering the brain and spinal cord. It is the peripheral equivalent of the control blood brain barrier. A collection of 5-20 or more of these bundles are surrounded by the epineurium and lie in a matrix of the epineural space consisting of loose areolar tissue, nutrient blood vessels, lymphatics and fat. In such construction, one can identify those fasciculi that are centrally located called the core bundles & those which are close to the surface or nerve sheath called the mantle bundle of axons. PHYSIOLOGIC CONSIDERATIONS Many fundamental discoveries have led to more complete understanding of the action of local anesthetic agents. Such findings have been anatomic, physiologic and biochemical. The function of a nerve is to carry messages from one part of the body to another. These messages, in the form of electrical action potentials are called impulses. The nerve impulse is a transient wave of electrical excitation that travels from point to point down to length of a nerve fiber. Action potentials are transient membrane depolarizations that result from a brief increase in the permeability of the membrane to sodium, and usually also from a delayed increase in the permeability to potassium, impulses are initiated by chemical, thermal, mechanical, or electrical stimuli. Note : Once an impulse is initiated by a stimulus in any particular nerve fiber, the amplitude and shape of that impulse remain constant, regardless of changes in the quality of the stimulus or its strength.
  27. 27. The impulse remains constant without loosing strength as it passes along the nerve because the energy used for its propagation is derived from energy that is released by the nerve fiber along its length and not solely from the initial stimulus. De Jong described impulse conduction as being like the active progress of a spark along a fuse of gunpowder. Once lit, the fuse burns steadily along its lengths, one burning segment providing the energy required to ignite its neighbour such is the situation with impulse propagation along a nerve. ELECTROPHYSIOLOGY OF NERVE CONDUCTION : The following is a description of electrical events that occur within a nerve during the conducting of an impulse: Step 1 : A nerve processes a resting potential. This is a negative electrical potential of 10mV, that exists across the nerve membrane, produced by differing concentrations of ion on either side of the membrane. The interior of the nerve is negative in relation to the exterior. Step 2 : A stimulus excites the nerve, leading to following sequence of events. a) An initial phase of slow depolarization the electrical potential within the nerve becomes slightly less negative. b) When the falling electrical potential reaches a critical level, an externally rapid phase of depolarization results, this is termed as threshold potential or firing threshold. The firing threshold is actually the magnitude of the decrease in negative transmembrane potential that is required to initiate an action potential (impulse).
  28. 28. c) This phase of rapid depolarization results in a reversal of the electrical potential across the nerve membrane. The interior of the nerve is now electrically positive in relation to the exterior. An electrical potential of +40mV exists on the interior of the nerve cell. Step 3 : Following these steps of depolarization, repolarization occurs. The electrical potential gradually becomes more negative inside the nerve cell relative to the outside until the original resting potential of 10mV is again achieved. The entire process requires 1msec; depolarization takes 0.3msec and depolarization takes 0.7msec. ELECTROCHEMISTRY OF NERVE CONDUCTION : The preceding sequence of events depends on two important factors. i) The concentration of electrolytes in the axoplasm (interior of the nerve cell) and extracellular fluids. ii) The permeability of the nerve membrane to sodium and potassium ions. INTRACELLULAR AND EXTRACELLULAR IONIC CONCENTRATIONS Ion Intracellular (MEQ/L) Extracellular (MEQ/L) Ratio Potassium (K+ ) 110-170 3-5 27:1 Sodium (Na+ ) 5-10 140 1:14 Chloride (Cl- ) 5-10 110 1:11 These significant differences in ion concentration exists because the nerve membrane exhibit selective permeability.
  29. 29. RESTING STATE : In the resting state the nerve membrane is : • Slightly permeable to sodium ions • Freely permeably to potassium ion • Freely permeably to chloride ions. Potassium remains within the axoplasm, despite its ability to diffuse freely through the nerve membrane and its concentration gradient (passive diffusion usually occurs from a region of greater concentration to one of lesser concentration), because the negative charge of the nerve membrane restrains the positively changed ions by electrostatic attraction. Chloride remains outside the nerve membrane instead of moving along its concentration gradient into the nerve all because the apposing, nearly equal, electrostatic influence forces out ward migration. The net result is no diffusion of chloride through the membrane. Sodium can migrates is usually because both the concentration (grater outside) and the electrostatic gradient (positive ion attracted by negative intracellular potential) favor such migration only the fait that the resting nerve membrane is relatively impermeably to sodium prevents a massive influx of this ion.
  30. 30. MEMBRANE EXCITATION : Depolarization : Excitation of nerve segment to an increase in permeability of the cell membrane to sodium ions. This is accomplished by a transient widening of transmembrane ion channels sufficient to permit the unhindered passage of hydrated sodium ions. The rapid influx of sodium ions to the interior of the nerve cell causes a depolarization of the nerve membrane from its resting level to its firing threshold of approximately 50- 70mV. (Exposure of the nerve to a local anesthetic basis its firing threshold). When firing threshold is reached, permeability of the membrane to sodium increases dramatically, and sodium ion rapidly enters the axoplasm. At the end of depolarization (the plate of action potential), the electrical potential of the nerve is actually reversed; an electrical potential of +40mV exists. The entire depolarization requires 0.3msec.
  31. 31. Depolarization : The action potential is terminated when the nerve repolarises. This is caused by extinction or inactivation of increased permeability to sodium. In many cells permeability to potassium also increases, resulting in the efflux of K+ , leading to a more rapid membrane repolarization and return to its resting potential. The movement of sodium ions into the cell during depolarization and subsequent movement of potassium ions out of the cell during repolarization are passive  not requiring the expenditure of energy, river the ions moves along their concentration gradient. Active transfer of sodium ion out of the cell occur via the “sodium pump”. An expenditure of energy is needed to move sodium ions out of the nerve cell against their concentration gradient, this energy comes from the oxidative metabolism of ATP. The entire process of repolarization requires 0.7msec Immediately after a stimulus has initiated an action potential, a nerve is unable, (for a time) to respond to another stimulus, regardless of its strength. This is termed the absolute refractory period. This is followed by a relative refractory period, during which a new impulse can be initiated bout only by a stronger their normal stimulus. The relative refractory period continuous to decrease until the normal level of excitability returns, at which point the nerve is said to be repolarised. The nature of nerve conduction is summarized as a depolarization – repolarization process. Membrane channels : Discrete aqueous pores through the excitable nerve membrane, called sodium (or ion) channels, are molecular structures that mediate its sodium permeability. The channel is a lipoglycoprotein firmly situated in the membrane. It consists of an aqueous pore spanning the membrane that is
  32. 32. narrow enough at least at one point to discriminate between sodium and other ions. (Na+ posses through 12 times more easily than K+ ) the channel also includes a portion that changes configuration in response to change in membrane potential, thereby gating the passage of the ions through the pore. Sodium channels have an internal diameter of approximately 0.3 x 0.5 nm. A sodium ion is “thinner” than either a potassium or chloride ion and should therefore diffuse feely down its concentration gradient thought membrane channels into the nerve cells. This does not occur, however, because all these ions attract water molecules and thus become hydrated. Hydrated sodium ions have a radius of 3.4 A0 , which is greater than 2.2A0 radius of potassium and chloride ions. Sodium ions are therefore too charge to pass through the narrow channels when a nerve is at rest. Recent evidence indicates that channel specificity exists, in that the sodium channels differ from potassium channels. The gates on the sodium channels are located near the external surface of the nerve membrane, whereas those an the potassium channel are located near the internal surface of the nerve membrane. IMPULSE PROPAGATION : Following the initiation of an action potential by a stimulus, the impulse must move along the surface of the axon. Energy for impulse propagation is derived from the nerve membrane is the following manner: The stimulus disrupts the resting equilibrium of the nerve membrane, the trans membrane potential is recurred momentarily – the interior of the cell changing from negative to positive and the exterior changing from positive to negative. This now electrical equilibrium in this segment of nerve produces local currents that begin flouring between the depolarized segment and the adjusting resting area. These local currents flow from positive to negative, extending for several mm along the nerve membrane.
  33. 33. As a result of this current flow, the interior of the adjacent area becomes less negative and its exterior less positive. Trans membrane potential decreases, approaching firing threshold for depolarization. When the trans membrane potential is decreased by 1.5mV from resting potential, firing threshold is reached and complete depolarization occurs. The newly depolarized segment sets up local current in adjacent resting membrane, and the entire process starts anew. Conditions in the segment that has first depolarized return to normal following the absolute and relation refractory periods. Because of this the wave of depolarization can spread in only one direction. Backward (retrograde) movement is presented by the unexcitable refractory segment. IMPULSE SPREAD :
  34. 34. The propagated impulse travels along the nerve membrane toward the CNS. The spread the impulse differs depending on whether or not a nerve is myelinated. Unmyelinated nerves : An unmyelinated nerve fiber is basically a long cylinder with a high- electrical resistance cell membrane surrounding a low resistance conducting core of axoplasm, all of which is bathed in low resistance extracellular fluid. The high resistance cell membrane and low resistance intracellular and extracellular media produce a rapid decrease in the density of current within a short distance of the depolarized segment. In areas immediately adjacent to this depolarized segment, local current flow may be adequate to initiate depolarization in the resting membrane. Further among it will prove to be inadequate to achieve firing threshold. The spread of an impulse is can unmyelinated nerve filers is therefore characterized as a relatively slow forward – creeping process. Myelinated nerves : Impulse conduction in myelinated nerve occurs by means of current leap from node to node – a process termed as salutatory conduction. (salt are is the latin verb “to leap”. This from of impulse conduction process to be much faster and more energy efficient than that which is employed in unmyelinated nerves. MODE AND SITE OF ACTION OF LOCAL ANESTHETIC :
  35. 35. It is possible for the local anesthetic agents to interfere with the excitation process in a nerve membrane in one or more of the following ways: i) Altering the basic resting potential for the nerve ii) Altering the threshold potential iii) Decreasing the rate of depolarization iv) Prolonging the rate of repolarization It has been established that the primary effects of local anesthetic occur during the depolarization phase of the action potential. These effects include a decrease in the rate of depolarization, particularly in the phase of slow depolarization. Because of this, cellular depolarization is not sufficient to reduce the membrane potential to firing level, and a propagated action potential does not develop. Site : The nerve membrane is the site at which local anesthetic agent exert their pharmacologic actions. Mechanism of action : The local anesthetic is a weak base which must be combined with a strong acid in order to makes the acid salt that is soluble for use in solution. RNHOH + HCl  RNHCL + H2O Weak strong acid water Base acid salt To act as local anesthetic, it must dissociate into a free base, for which a basic environment found in normal tissue is necessary.
  36. 36. RNHCI  RNH+ + CI- This positively charged (RNH+ ) molecules is called certain and is hydrophilic. It further dissociated outside the nerve sheath resulting in an unionized lipophillic molecule called the base RNH+ RN + H+ The relative proportion of each ionic form in the solution caries with the pH of the surrounding tissues. In a acidic environment (low pH) the equilibrium shifts to the left and most of the anesthetic solution exists in cationic form RNH+ > RN + H+ As hydrogen ion concentration decreases (higher pH), the equilibrium shift toward the free base form: RNH+ < RN + H+
  37. 37. The relative proportion of the ionic forms also depends on the pKa or dissociation constant of the specific local anesthetic. The pKa is a measure of a molecules affinity for hydrogen ions (H+ ). When the pH of a solution has the same value as the pKa of the local anesthetic drug, exactly half the drug will exist in the RNH+ form and half in RN form. The percentage of drug existing in either form can be determined for the Henderson – Hasselbalch equation : This non ionize lipophillic local anesthetic molecules (RN) diffuses readily through the lipid composed nerve sheath. After his molecules passage into the interstitial fluid between the nerve sheath and the nerve cell membrane. Here it undergoes another reaction will the for hydrogen found here. This free hydrogen ion is liberated from the buffer system reaction according in the area. The reaction results in the formation of an ionized hydrophilic form of local anesthetic molecule. RN + H+ RNH+ This molecule in nerve call membrane displaces calcium ions for the sodium channel receptor site. ↓ Binding of the local anesthetic molecules to this receptor site ↓ Blockade of sodium channel ↓ Decrease in sodium conduction ↓ Log Base Acid = pH – pKa
  38. 38. Depression of the rate of electrical depolarization ↓ Failure to achieve the threshold potential level ↓ Lack of development of propagated action potentials ↓ Conduction blockade THEORIES OF MECHANISM OF ACTION OF L.A. Many theories have been proposed over the years to explain the mechanism of action of local anesthetics. i) Acetyl chorine theory : According to this theory, liberation of acetyl chorine at synaptic function alters the permeability of plasma membrane, and permits depolarization which is responsible for continuous pulse-transmission. The local anesthetic agents prevents the depolarization and pulse transmission by their effect on acetyl chorine.
  39. 39. This theory is not accepted because acetyl chorine is the neurotransmitter at the synaptic function, there is no evidence that acetyl chorine is involved in neural transmission along the body of the neuron. ii) Calcium displacement theory : This theory was once quite popular and maintained that local anesthetic nerve block was produced by the displacement of calcium from some membrane sites that controlled permeability to sodium. Evidence that varying the concentration of calcium ions bathing a nerve does not effect local anesthetic potency has diminished the credibility of this theory. iii) Surface charge (repulsion) theory : This theory proposed that local anesthetic acted by binding to nerve membrane and changing the electrical potential at the membrane surface. Cationic (RNH+ ) drug molecules were aligned at the membrane water
  40. 40. interfere, and since some of the local anesthetic molecules carried a not positive charge, they made the electrical potential at the membrane surface more positive, thus decreasing the excitability of the nerve by increasing the threshold potentials. Current evidence indicates that the resting potential of the nerve membrane is unaltered by local anesthetics (they do not become hyperpolarized) and that conventional local anesthetics act within the membrane channels rather than at the membrane surface. Also the surface charge theory cannot explain the activity of uncharged anesthetic molecules in blocking in blocking nerve impulses (e.g. benzocaine). iv) Membrane expansion theory : This theory states that local anesthetic molecules diffuse to hydrophobic regions of excitable membrane, producing a general disturbance of the bulk membrane structure, expanding some critical regions in the membrane, and thus preventing an increase in the permeability to sodium ions. Local anesthetics that are highly lipid soluble can easily penetrate the lipid portion of the cell membrane, producing a charge in configuration of the lipoprotein matrix of the nerve membrane. This results in decreased diameter of sodium channels, which leads to an inhibition of both sodium conductance and neural excitation.
  41. 41. This theory serve an a possible explanation for the local anesthetic activity of a drug such as benzocaine, which does not exist in cationic form yet still exhibits potent topical anesthetic activity. It has been demonstrated that nerve membrane do, infect, expand and become more ‘fluid’ when exposed to local anesthetics. However, there is no direct evidence that nerve conduction is entirely blocked by membrane expansion per se. v) Specific receptor theory : It is the most forward theory today and proposes that local anesthetics act by binding to specific receptors on the sodium channel. The action of the drug is direct and not medicated by some charge in the general properties of
  42. 42. the cell membrane. Both biochemical and electrophysiological studies have indicated that a specific receptor site for local anesthetic agents exist in the sodium channel either on its external surface or on the internal axoplasmic surface. Once the local anesthetic has gained access to the receptors, permeability to sodium ions is decreased or eliminated and nerve conduction is interrupted. KINETICS OF LOCAL ANESTHETICS When a local anesthetics drug is injected and deposited about the nerve bundle, drug movement into the nerve bundle and into individual nerve cells follows a regular series of steps to achieve a state of nerve block. Fours aspect are to be considered with respect to onset and maintenance of the state of block. The require of movement is as follows: ii) Diffusion to the nerve and into the nerve bundles. This depends on the aqueous solubility.
  43. 43. iii) Process of penetration into the nerve cell. This depends on non ionized (base) form. iv) Retribution of the agent in a nerve fiber cell. This depends on aqueous solubility v) The fixation to the nerve cell components. This depends on the affinity of cation form to channel receptors. As the anesthetic state is being established, the process of removal of the drug from the site of injection into the vascular space begin. The processes become more prominent with their and four aspects of recovery from block and disposition of drug may be considered: i) Absorption : Extracellular drug enters the vascular spaces and continuous during anesthetic block. ii) Release process : The nerve fiber releases the fixed drug as the gradient of concentration reverses with time. iii) Redistribution to other organs and tissues occurs after absorption iv) Destruction and elimination. DIFFUSION OF LOCAL ANESTHETICS : Following the administration of a local anesthetic into the soft tissues near a nerve, (local anesthetic solution should be deposited as near to the nerve as possible without penetrating or spearing the nerve sheath. An injection into the perineural space will compress the nerve bundles and also cause ischemia) the molecules of the local anesthetic transverse the distance from one site to another according to their concentration gradient.
  44. 44. During the induction phase of anesthesia, the local anesthetic moves from its extraneural site of deposition toward the nerve (as well is in all the other direction). This process is termed as diffusion. It is the unhindered migration of molecules or ions through a fluid medium under the influence of the concentration gradient penetration of an anatomical barrier to diffusion occurs when a drug passes through a tissue that tends to restrict the molecular movement. The perineurium is the greatest barrier to penetration of local anesthetics. Diffusion an penetration are relatively slow process and speed of overt of anesthetic action is essentially proportional to the log of concentration of the drug i.e. the rate of diffusion is governed by the concentration gradient ( the greater the initial concentration of the local anesthetic, the faster will be the diffusion. Mantle bundles one the first ones reached by local anesthetic and are exposed to a higher concentration of it. They are usually blocked completely shortly after the injection of a local anesthetic. Core bundles are contacted by the drug only after much delay and by a lower anesthetic concentration
  45. 45. because of the greater distance that the solution must transverse and the greater number of barrier it must cross. As the local anesthetic diffuses into the nerve, it becomes increasingly diluted by tissue fluids and is absorbed by capillaries and lymphatics; ester anesthetics undergo almost immediate enzymatic hydrolysis. Thus the core fibers are exposed to a decreased concentration of local anesthetic, a fat that may explain the clinical situation of inadequate Pulpal anesthesia developing in the presence of subjective symptoms of adequate oft tissue anesthesia. Fibers near the surface of the nerve (mantle fibers) tend to innervate more proximal regions (e.g. molar area with an inferior alveolar nerve block), whereas fibers in the care bundles innervate the more distal points of nerve distribution (e.g. incisors). Lipid solubility of a local anesthetic appears to be related to its intrinsic potency. Local anesthetics with greater lipid solubility produce more effective conduction blockade at lower concentrations than do the less lipid soluble solutions. The degree of protein binding of the anesthetic molecule is responsible for the duration of local anesthetic activity. Vasoactivity affect both the anesthetic potency and the duration of anesthesia provided by a drug. Absorption : After injection of a local anesthetic agent and exposure of a grain nerve to its effect, the agent is diluted in the extracellular fluid and taken up by capillaries. Ultimately, all of the agents enters the blood steam. The blood supply to a tissue is a crucial factor in determining rate of absorption. Direct i.v. injection provides the most rapid absorption rate and produces high plasma levels. Topical application to many mucous
  46. 46. membranes results in the next highest plasma levels. indeed, application to the pharynx and tracheo-bronchial tree may produce blood levels comparable to slow i.v. injection. I.m. infection of local anesthetics provide the next highest levels. The lowest levels occurs after subcutaneous and intracutaneous infections. vasoconstrictor agents further limit the absorption of agents from there sites. No absorption occurs through unbroken skin, but if the skin is abraded, significant plasma levels are attained. In burn site, the absorption depends on the degree of the burn. Disposition : Little or no destruction of local anesthetics occurs in situ at the tissue sites of injection. This can be explained by an example. Chlorprocaine provides a local block for more than 1hours, while the agent undergo complete hydrolysis in plasma within 5 minutes. Redistribution : A redistribution to other organs and tissues remote from the site of injection ensues. Concentration in these is dependent on regional blood flow. Those organs that are usual rich with a high blood flow, such as the ling, liver and kidney, concentrate more amount of drug. The greatest percentage of an injected dose distributes to skeletal muscle due to its large mass. Destruction : Detoxification is primarily dependent on liver enzymes. Breededown of esters occurs in the plasma. The primary site of amide metabolism is the liner.
  47. 47. REINJECTION OF LOCAL ANESTHETIC Not infrequently a dental procedure will outlast the duration of clinically effective pain control and a repent infection of local anesthetic will be required. Recurrence of immediate propound anesthesia : At the this of reinjection, the concentration of local anesthetic in the mantle fibers is below that in the more centrally located core fibers. The partially recovered mantle fibers still contain some local anesthetic, although not enough to provide complete anesthesia. After deposition of a new high concentration of anesthetic the nerve, the mantle fibers are once again exposed to a concentration gradient directed inward toward the nerve. This combination of residual local anesthetic and the newly deposition supply results in a rapid onset of profound anesthesia with a small volume of local anesthetic drug bring administered. Difficultly in re-achieving profound anesthesia : In this situation, effective control of pain does not occur even after reinjection of local anesthetic agent. This is explained by following phenomenon. Tachyphylaxis : Is defined as an increasing tolerance to a drug that is administered repeatedly. Although difficult to explain, tachyphylaxis is probably brought about through some or all of the following factors: edema, localized hemorrhage, clot formation, transudation, hypernatremia, and decreased pH of tissues. the first form factors isolate the nerve from contact with the local anesthetic
  48. 48. solution. Hypernatremia, raises the sodium ion gradient, thus counteracting the decrease in sodium ion conduction brought about by the local anesthetic. The last factor, a decrease in pH of the tissues, is brought about by the first infection of the acidic local anesthetic, the ambient pH in the area of injection may be somewhat lower, so that fever local anesthetic molecules are transformed into the free base (RN) on reinjection. POTENTIATION OF ACTION OF LOCAL ANESTHESIA It is a common practice to old various agents to anesthetic solutions in order to increase the intensity or duration of action. VASOCONSTRICTORS : The value of vasoconstrictors in prolonging local anesthetic action has been well established. As a result of local vasoconstriction the absorption of the local anesthetic is delayed, and the effect of the anesthetic is allowed to continue at the local site. Role of vasoconstrictor in local anesthetic solution is as follows  - By constricting blood vessels, vasoconstrictors decrease blood flow (perfusion) to the site of injection. - Absorption of the local anesthetic into the cardiovascular system is slowed, resulting in lower anesthetic blood levels - Lower local anesthetic blood levels decrease the risk of local anesthetic toxicity. - Higher volumes of the local anesthetic agent remain in and around the nerve for longer periods, thereby increasing the duration of action of most local anesthetics
  49. 49. - Vasoconstrictors decrease bleeding at the site of their administration and are useful, when increased bleeding is anticipated. The actions of the vasoconstrictors so resemble the response of adrenergic nerves to stimulation that they are classified as sympathomimetic a adrenergic drugs. There drug have many clinical actions brides vasoconstriction. Sympathomimetic drug many also be classified according to their chemical structure. I. According toChemical structure : Catecholamines : • Epinephrine • Norephinephrine • Dopamine • Levonordefrin • Isoproterenol Non catecholamines • Amphetamine • Methamphetamine • Hydroxy-amphetamine • Ephedrine • Mephetermine • Metaraminol • Phenyl ephrine Natural
  50. 50. II. According to Modes of action : i) Direct – acting drugs : They exert their action directly on adrenergic receptors. • Epinephrine • Nor epinephrine • Levonordefrin • Isoproterenol • Dopamine • Methoxamine • Pheylephrine ii) Indirect – acting drugs : They act by releasing norepinephrine from adrenergic nerve terminals. • Tyramine • Amphetamine • Methamphatamine • Hydroxynphetamine iii) Mixed – Acting Drugs : with both direct and indirect actions. • Metaraminal • Ephedrine. ADRENERGIC RECEPTORS : The concept of adrenergic receptors was proposed by ahlquist in 1948 and is well accepted today. Adrenergic receptors are found in most tissues of the body. Ahlquist recognized two types of adrenergic receptors. Non catecolamines
  51. 51. • Alpha (α) • Beta (β) Activation of α receptors causes vasoconstriction. α1  excitatory – post synaptic α2  inhibitary – post synaptic. Activation of β receptors produces smooth muscle relaxation (vasodilation and brondiodilation) and cardiac stimulation (increased heart rate and strength of contractions). β1 Found in heart and small intestines and are responsible for cardiac stimulation and lipolysis β2  found in bronchi, vascular beds, and uterus and produces brondiodilation and vasodilation. Dilutions of vasoconstrictors: The dilution of vasoconstrictors in commonly referred to as a ratio. Dilution Mg/ml Therapeutic use 1:1,000 1.0 Emergency medicine (IM/Sc anaphylaxis) 1:2,500 0.4 Phenylephrine 1:10,000 0.1 Emergency medicine (IV cardiac arrest) 1:20,000 0.05 Levonordefrin 1:30,000 0.033 Norepinephrine 1:50,000 0.02 Local anesthesia 1:80,000 0.0125 Local anesthesia 1:100,000 0.01 Local anesthesia 1:2000,000 0.005 Local anesthesia Based on the inhibitory or excitatory actions of catecolamines on smooth muscle.
  52. 52. 1. Epinephrine • Most potent and widely used vasoconstrictor in dentistry • Source: 80% of medullary secretion, also available as a synthetic • Mode of action is both a and b , with b being predominate Systemic Effects of Epinephrine • Myocardium -Increase heart rate and cardiac output • Pacemaker -Increase risk of dysrhythmia • Coronary Artery-Dilation of coronary artery • Blood Pressure -Increased systolic pressure, effect on diastolic pressure is dose related • Cardiovascular -Decrease cardiac efficiency • Vasculature -Vasoconstriction in skin, mucous membrane & kidneys -Vasodilation in skeletal muscle in small doses, vasoconstriction in large doses • Respiratory - Bronchodilator • CNS - Not a potent CNS stimulant • Metabolism - Increase oxygen consumption Termination of Epinephrine • Reuptake • COMT and MAO • Excreted unchanged in urine (1%) Clinical Manifestations of Epinephrine Overdose • CNS stimulation - fear, anxiety, tremor, pallor, dizziness
  53. 53. • Cardiac dysrhythmia • Ventricular fibrillation • Drastic increase in BP - can cause cerebral hemorrhage • Angina in patients with coronary insufficiency Maximum Dose for Dental Appointment • Normal healthy patient 0.2 mg. per appointment • Significant cardiovascular impairment 0.04 mg per appointment Clinical Applications for Epinephrine • Acute allergic reaction • Bronchospasm • Cardiac arrest • Hemostasis • Produce mydriasis • Vasoconstrictor • Norepinephrine Source: 20% of adrenal medulla secretion, also available in synthetic form Mode of action - almost exclusively a , b effect in heart
  54. 54. 2. Norepinephrine • 1/4 potency of epinephrine Systemic Effects of Norepinephrine • Myocardium - increase force of contraction • Pacemaker - increase stimulation causing dysrhythmia • Heart rate - decrease heart rate • Coronary artery - increase coronary flow • Blood Pressure - increase both systolic and diastolic • Cardiovascular - increase stroke volume, decrease cardiac output • CNS - no effect at therapeutic doses • Metabolism - increase basal metabolic rate, increase blood sugar Elimination of Norepinephrine • Reuptake • COMT and MAO • Excreted unchanged in urine Overdose of Norepinephrine • Same as epinephrine • Can cause sloughing of tissue due to a effect Availability in Dentistry
  55. 55. • With mixture of procaine and propoxycaine, in a concentration of 1:30,000 MaximumDosefor Dental Appointment • Healthy patient 0.34 mg. per appointment • Medically compromised 0.14 mg. per appointment 3. Levonordefrin Proprietary name - Neo-Cobefrin Source: synthetic Mode of action - mostly a , 25% b Systemic action - same as epinephrine, but to a smaller degree Termination - COMT and MAO Availability - 1:20,000 concentration with Mepivacaine or mixture of Propoxycaine/Procaine Maximum dose for all patients 1 mg. per appointment
  56. 56. 4. Phenylephrine Hydrochloride Proprietary name - Neo-Synephrine Source : synthetic Mode of action - 95% a Systemic Action of Phenylephrine Hydrochloride • Myocardium - little effect • Pacemaker - little effect • Coronary artery - increase blood flow • Blood Pressure - increase systolic and diastolic • Heart rate - bradycardia • Respiratory - bronchodilator, but not effective for bronchospasm • CNS - minimum effect • Metabolism - some increase in metabolic rate Termination - hydroxylation to epinephrine Clinical application - vasoconstrictor, nasal decongestant Availability - 1:2500 with 4% procaine Maximum Dose for Phenylephrine Hydrochloride • Normal healthy patient 4 mg. per appointment
  57. 57. • Medically compromised 1.6 mg. per appointment Factors in selection of Vasoconstrictor • Length of the dental procedure • The need for hemostasis during and following procedure • The medical status of the patient Vasoconstrictor Factors to Consider • High BP, Cardiovascular disease • Hyperthyroidism • MAO Inhibitors (anti-depressant) • Tricyclic antidepressants • Patient using cocaine-never use epinephrine !! RECENT ADVANCES AND FUTURE TRENDS IN PAIN CONTROL Through local anesthesia remains the backbone of pain control in dentistry, research has continued, in both medicine and dentistry, to seek new and bester means of managing pain associated with many surgical treatments. i) Centbucridine : It is a quinalone derivative with five to eight times the potency of lidocaine and with an equally rapid onset and an equivalent duration of action. Significantly is does not effect central nervous system or
  58. 58. cardiovascular system adversely except when administered in very large doses. It has been used in subarachnoid and epidural anesthesia and in intravenous regional anesthesia. Vacharejani et al compared the efficacy of 0.5% Centbucridine concentration with that of 2% lidocaine for dental extraction in 120 patients. They reported that a degree of analysis attained with Centbucridine that compared well to that obtained with lidocaine. Centbucridine was well to related, with no significant parameters and no serious side effects. when administered to overdose, Centbucridine function as a true stimulant of the CNS unlike lidocaine. ii) Ropivacaine : It is a long- acting amide anesthetic, similar to bupivacaine and etidocaine in duration of activity. It is structurally similar to mepivacaine and bupivacaine, but is unique in that it is prepare as a isomer rather than as a racemic mixture. Data indicate that it has a greater margin of safety between convulsive and lethal doses than does bupivacaine. The elimination ½ life of ropivacaine is 25.9 minutes which is considerably shorter than that of other amides. Ropivacaine has demonstrated decreased cardio-toxicity relation to bupivacaine, but its clinical duration of action is approximately 20% shorter. The primary use of ropivacaine in anesthesiology has been for regional nerve block (especially epidural). Its potential for use in dentistry as another long-acting local anesthetic appears great, but awaits clinical evaluation. iii) EMLA :
  59. 59. Intact skin is an imperious barrier to the penetration of drugs, including topical anesthetics. Yet once skin is damaged, as occurs in sunburn or injury, anesthetic drugs such as solarcaine could be applied topically for the relief of pain. For years a drug or a technique was sought that would permit needles to be inserted painlessly through intact skin. The development of oil-in-water emulsion containing high concentrations of lidocaine and prilocaine in base form resulted in EMLA (eutectic mixture of local anesthetics), which has been shown to provide anesthesia of intact skin profound enough to permit venipunture to be performed painlessly. EMLA consists of a 5% cream containing 25mg/g lidocaine and 25mg/g prilocaine. It is applied to the skin for at least 1 hour before the anticipated procedure. The cream is covered with an occlusive dressing. Research has demonstrated the effectiveness of EMLA in many aspects of pediatrics, including venepuncture, vaccination, suture removal, lumbar puncture, minor otological surgery. It is also effective in minor gynecological and ecological procedures, and dermatological surgery including split-thickness, post herpetic neuralgia, debridement of infected ulcers, and inhibition of itching and burning in adults.
  60. 60. The potential for toxic local anesthetic blood levels developing with EMLA is minimal. Peak plasma anesthetic concentrations occurring 180 minutes after application have been quite low. The use of EMLA in infants under the age of 6 months is contraindicated because of the possibility of a metabolite of prilocaine inducing methemoglobinemia. Adverse responses noted included transient and mild skin bleeding and Erythema. Several studies have reported on the intra-oral use of EMLA cream. EMLA decreased patient reports of pain to needle insertion and anesthetic administration significantly in both the greater palatine and nasopalatine injection compared to placebo application. However, the use of EMLA in an attempt to obtain Pulpal anesthesia has provided conflicting reports.
  61. 61. iv) pH alterations : The administration of local anesthetics into skin and to a lesser degree, oral mucous membranes is frequently uncomfortable. Though many factors are involved in this including the speed of injection, volume of solution, density of the tissues, and a lot of psychology, the acidic pH of the anesthetic solution play a significant role in provoking discomfort during local anesthetics injections. The pH of a “plain” local anesthetic solution is approximately 5.5, whereas that of a vaso-presser-containing solution is about 4.5. The addition of substance to the anesthetic that alkalinize the solution should make the drugs administration more comfortable. in addition, the anesthetic drug, at a higher pH, should have a more rapid onset of action and greater potency. Two strategies have been used to achieve this effect : the addition of sodium bicarbonate to the anesthetic solution, and the addition of carbon dioxide. Carbonation of local anesthetics is not really new, their use being described as early as 1965. The addition of sodium bicarbonate to a local anesthetic solution immediately prior to injection alkalinizes the solution, increasing the number of uncharged base molecules (RN). This uncharged ionic form is lipid soluble and able to diffuse through the nerve membrane, a formulation of lidocaine with epinephrine plus sodium bicarbonate (pH 7.2) provide a more rapid onset of anesthetic block (onset = 2 min) than commercially prepared pH 4.55) lidocaine plus epinephrine (onset = 5 min). However if the pH of the solution is too high, local anesthetic will precipitate out as the drug base, thereby decreasing their shelf life. Alkalinization of epinephrine pre anesthetic solution proffers no benefit. Recommendation for preparation of the local anesthetic with bicarbonate after divided between part 4.2% bicarbonate with 10 parts local anesthetic, and 1 part 8.4% bicarbonate in 5 parts local anesthetic.
  62. 62. Carbon dioxide enhances diffusion of local anesthetic through nerve membranes, providing a more rapid onset of nerve block. As Co2 diffuses through the nerve membrane, intracellular pH is decreased, raising the intracellular concentration of charged cations (RNH+ ), the form of anesthetic that attaches to receptor site in sodium channels. Since the cationic form of the drug does not readily diffuse out of the nerve, the anesthetic becomes concentrated within the nerve trunk (termed “ion trapping”, providing a longer duration of anesthesia. The problem clinically has been that of the carbonated anesthetic agent is not injected almost immediately after opening of the vial, the Co2 will diffuse out of solution, significantly diminishing the solution’s effectiveness. The anesthetic drug must be administrated within a short time after preparing the syringe. v) Hyaluronidase : hyaluronidase is an enzyme that breaks down intracellular cement. It has been advocated as an additive to local anesthetics because if permits injected solutions to spread and penetrate tissues. The primary use of hyaluronidase has been in plastic surgery, dermatology and ophthalmologic procedure, primarily in retero bulbar nerve blocks, where it has been demonstrated to seep both the onset of anesthesia and the area of anesthesia significantly when compared with non- hyaluronidase containing anesthetic solutions. The duration of anesthesia is slightly decreased when hyaluronidase is added, but the benefits associated with its addition more than out weigh this minor inconvenience. Hyaluronidase is available as hydase in a lyophilized powder, as well as in a stabilized solution. It is added to the anesthetic cartridge just before
  63. 63. administration by removing approximately one third of the anesthetic solution and refilling the cartridge with hyaluronidase. Allergic reactions have been reported following hyaluronidase administration. vi) Ultra –long acting local anesthetics : Tetradotoxin and saxitoxin are classified as biotoxins. Tetradotoxin is found in puffer fish and saxitoxin is found in certain species of dinoflagehlates. They specifically block the sodium channel on the outer membranes surface and thus produce conduction blockade. Though these agents are about 250,000 times as potent as procaine in providing conduction blockade of isolated nerve preparations, they both are highly toxic and will not pass readily through the epineurium surrounding peripheral nerves; they therefore provide little or no conduction blockade of the sciatic nerve. However, when administered via sub-arachnoid block in sheep, they induced spinal anesthesia of almost 24 hours duration. Unfortunately , there biotoxins are difficult to synthesize and are not very stable in aqueous solutions, thereby significantly limiting their usefulness. vii) Felypressin : It is an analogue of vasopressin (the antidiuretic hormone), has been available in dental local anesthetic cartridges in many European countries, most often in combination with prilocaine. It is a direct stimulator of vascular smooth muscle (primarily venous), having little direct effect on the heart or on adrenergic nerve transmissions. It may be used safely in patients in whom a medical problem (e.g., hypertension). Hypothyroidism / contraindicates the administration of epinephrine. Because it acts primarily on the venous circulation, felypressin is not as
  64. 64. effective as conventional vasoconstrictors in providing hemostasis during surgical procedures. It is marketed under the trade name octapressin and is used in concentration of 0.03 10/ml. viii) Electronic dental anesthesia : The use of electricity as a therapeutic modality in medicine and dentistry is not new. The first recorded report of electrotherapy dates from 46 A.D., when Scribonius Largus, used the torpedo fish to relieve the pain of gout. The use of transcutaneous electrical nerve stimulation (TENS) and more recently, its dental progeny, electronic dental anesthesia (EDA), has developed since. The mid 1960’s into techniques that appear to have utility in the battle against pain. Mechanism of action : At the low frequency setting of 2 Hz, which is most often used in the management of chronic pain, TENS produces measurable changes in the blood level of L-tryptophan, serotonin and β-endorphins. L-tryptophan, a precursor of serotonin, is present in the blood in decreasing amounts as the duration of TENS increased. By contract, serotonin levels in the blood increase with times serotonin possesses analgesia actions, elevating the pain reaction threshold. At the same time, levels of beta –endorphins and enkephains in the cerebral circulation also increase, Beta-endorphin and enkephalins are potent analgesics produced by the body in response to certain types of stimulation. Because blood levels of serotonin end beta – endorphins remain elevated for several horns following the terminated of
  65. 65. TENS therapy, patients benefit from this residual analgesic action in the immediate post-treatment period. In mechanism by which EDA operates to prevent acute pain during surgery / dentistry is somewhat different. It is feet that the Melzack and wall gate control theory of pain provides an adequate explanation for the precaution of acute pain provided by EDA. Used at high frequency (120 Hz or greater), EDA causes the patient to experience a sensation most often described as “vibrating”, “throbbing”, “pulsing” or “twitching”. This involves the stimulation of larger diameter (A fibers), which transmit the sensations of touch, presence and temperature now, pain impulse which is transmitted to the CNS along the smaller A-delta and C fibers, will come upon a “closed” gate and be unable to reach the brain, where it is translated into physical pain. Thus, larger-fiber is said to inhibit central transmission of the overall effects of small-fiber input, when the pain impulse fails to reach the brain, the sensation of pain does not occur. Blood levels of serotonin and endorphins are likewise elevated during high-frequency stimulation and probably play a secondary role in providing acute pain control during most dental treatment. Today TENS is an accepted treatment modality in the management of an overgrowing variety of chronic pain disorders: - Causalgia - Phantom limb pain - Post herpetic neuralgia - Intractable cancer pain - Lower back pain - Spinal cord injury - Ileus - Peripheral nerve injury - Bursitis
  66. 66. - Parturition - Polycythemia vera - Cervical back pain - Post operative pain - Diabetic ulceration. The application of a low frequency electrical current to an area that has recently been injured can be of benefit to the patient in two ways  i) It acts to increase tissue perfusion produced capillary and arteriolar dilation while stimulating the contraction of skeletal muscles. The net effect of there two process is to provide a pumping action in the area of application of the current. Therapeutically, a 1-hour treatment at a low frequency (2.5 H2) helps to decreased edema and the increased perfusion and skeletal muscle stimulation act to “dense” the area of tissue injury breakdown products. This spreads up the recovery process. ii) A second benefit in the secondary from injury is the analgesic action it possesses. EDA Indications : i) TMJ/MPD (chronic pain) ii) Administration of local anesthesia iii) Nonsurgical periodontal procedure iv) Restorative dentistry v) Fixed prosthodontic procedures EDA Contraindications : • Cardiac pacemakers Acute pain
  67. 67. • Neurological disorders - Status post – cerebrovascular accident - History of transient ischemic attacks - History of epilepsy • Pregnancy • Immaturity (in ability to understand) the concept of patient control of pain) - Very fond pediatric patient - Older patients with senile dementia - Language communication difficulties. EDA advantages : • No need for needle • No need for injection of drug • Patient is in control of the anesthesia • No residual anesthetic effect at the end of procedure • Residual analgesic effect remain for several hours EDA disadvantages : • Cost of the unit • Training • Learning curve  initial success may be low but will increase with experience. • Intra oral electrodes – weak link in the entire system.
  68. 68. CONTENTS 1) Introduction 2) Historical background 3) Definition 4) Ideal properties of L.A. 5) Pharmacology of LA. - Classification - Pharmacokinetics – uptake, distribution, metabolism excretion - Individual drugs 6) Rating of drugs - Safety
  69. 69. 7) Anatomic consideration - Structure of nerve fibers - Schwann cells and myelin sheath - Myelinated nerve fibers - Anatomy of mixed nerve. 8) Physiologic considerations - Electrophysiology of nerve conductive - Electrochemistry of nerve conductive - Impulse propagation - Impulse spread 9) Mode and site of action of local anesthetic - Mechanism of action - Effect of pH - Theories of L.A. 10) Kinetics of L.A. - Diffusion, absorption, redistribution, elimination - Reinjection 11) Potentiation of action of local anesthetics- vasoconstrictors 12) Surgical consideration - Pre block evaluation - Asepsis - Skin preparation 13) Recent advances and future trends in pain control 14) References
  70. 70. REFERENCES 1. Principles of anesthesiology, 3rd edition, vol- 2, Vincent J. Collins 2. Local anesthesia- mechanism of action and clinical use- Benjamin G Cohino 3. Handbook of local anesthesia, 5th edition, Stanley F. Malamed 4. Monehim”s local anesthesia and pain control, Benett 5. Current trends in pain research and therapy, Vol 4, chronic pain reactions, mechanism and modes of therapy 6. Local anesthesia- M. L. Kuzin