Pharmacology of local anesthetics

Pharmacology of local anesthesiaByDr. Nermeen HassanienLecturer of Oral and Maxillofacial SurgeryCairo University

What is local anesthesiaLocal anesthesia is a local and temporary state of insensibility in an area without loss of consciousness.Properties of ideal local anesthesia1- Produce efficient anesthetic action2-Rapid onset with reasonable duration3- Selective action on sensory nerves4- Reversible reactions with nerve tissues5- Soluble in water6- Compatible with salts to form isotonic solutions7- Non-irritating to the tissues8- Can be sterilized without deterioration9-Not affect healing of tissues10-No systemic side effects after its absorption11- Should have vasoconstrictor action12- Stable chemical composition13- Not expensive

Chemistry

1- Aromatic (lipophilic) portion: composed of benzene ring, enable local anesthetic solution to diffuse through lipid rich nerves.2- Amine (hydrophilic) portion: enable anesthesia to diffuse through interstitial tissues.3- intermediate chain portion: connect between lipophilic and hydrophilic portions and divides local anesthesia into two chemical classes, ester and amide type.

RRAromatic portionAmine portionEster or Amide

1- Ester type (one I in scientific name)A- Benzoic-acid esters - Butacaine - Cocaine - Ethyl aminobenzoate(benzocaine) - Hexylcaine - Piperocaine - TetracaineB- Para-amino benzoic acid esters - Procaine - Propoxycaine - Chloroprocaine2- Amide type(2 Is in scientific name)- Lidocaine- Mepivacaine- Prilocaine- Bupivacaine- Etidocaine- Articaine- Dibucaine- Ropivcaine3- QuinolineCentbucridine

Mechanism of actionDifferent theories have been developed to explain :1- Acetylecholine theory-Stated that local anesthesia inhibit the release of acetylecholine at synaptic junction, result in inhibition of depolarization of cell membrane and nerve impulse conduction.2- Calcium displacement theory-Stated that local anesthetic nerve block was produced by displacement of Ca+ ions from some membrane sites that controlled permeability to Na+ ions which is necessary for nerve impulse conduction.

3- Surface charge theory-Stated that local anesthetic binding with nerve membrane and change electrical potential of nerve surface. This is because cationic portion are aligned at the membrane-water interface, and because some of local anesthetic molecules carried a net positive charge, they made the electrical potential at the membrane surface is more positive, thus decreasing the excitability of nerve by increasing the threshold potential.

-This theory not explain the activity of uncharged anesthetic molecules in blocking nerve impulses. Also conventional local anesthesia act within the membrane channels rather than at membrane surface.

4- Membrane expansion theory:-States that local anesthetic molecules diffuse to hydrophobic regions of excitable membrane, producing general disturbance of bulk membrane structure., expanding more critical regions of membrane(decrease diameter of Na channels). This prevent the increase of permeability to Na ions.-This theory explain local anesthetic activity of drugs that exhibit potent topical anesthetic activity.-There is no evidence that nerve conduction is not entirely blocked by membrane expansion per se.

ExtracellularchannelLipid membraneRNRNExtracellular

5- Specific receptor theory (most favored today)There is specific receptor site may exist within sodium channels for binding of local anesthetic molecules.Specific receptor sites for local anesthetic agents exist in Na channels either on its external or internal axoplasmic surface.Once local anesthesia has gained access to the receptors, permeability to Na+ ions is decreased or eliminated and nerve conduction is interrupted .

How do local anesthesia work-The primary action of local anesthetics in producing a conduction block is to decrease the permeability of ion channels to Na+ ions which is necessary for impulse conduction.-local anesthetic produce very slight, virtually insignificant decrease in K+ ions conductance through nerve membrane.-Ca+ ions exist in bound form within the cell membrane, are thought to exert a regulatory role on movement of Na ions across nerve membrane. S o local anesthetic molecules may act by competitive antagonism with Ca ions for some sites on nerve membrane

Sequence of events:1- Displacement of Ca ions from Na channel receptor sites2-Binding of local anesthetic molecule to this receptor sites3- Blockade of Na channels and decrease of Na conductance4- Decrease rate of depolarization

5-Failure to achieve threshold potential level6- Failure to develop propagated action potentials7- Conduction blockade

Dissociation of local anesthetics-Local anesthetics are available as salts(usually hydrochloride)for clinical use. These salts are water soluble and stable, is dissolved in sterile water or salineLocal anesthetic molecule exist in two chemical states:1- Free Base (uncharged form) : is the lipophilic portion, RN2- Cationic or positively charged form: is the hydrophilic portion, RNH+Free base can penetrate connective tissue barriers and lipid rich membranes.-The relative proportion of each ionic form in solution varies with the PH of solution or surrounding tissues.In low PH, the equilibrium is shifted to left and most of anesthetic solution exist in cationic form. RNH+ > RN+H+

-At higher PH, equilibrium shifts toward free base form RNH+ < RN + H+ -The relative proportion of ionic form is also depends on the Pka or dissociation constant of specific local anesthetic. The Pka is a measure of molecules affinity for hydrogen ions.-When PH of solution has the value as Pka of local anesthetic, exactly 50% of drug exists in the RNH+ form and 50% in the RN form. The percentage of drug existing in either form can be determined from the Henderson- Hasselbalch equation: Pka- PH =Log( cation conc./ free base conc.)

Actions on nerve membranes1- At normal tissue PH, 75% of local anesthetics molecules are present in cationic form (RNH+ ) and 25% in free base form (RN).RNH+ (750) RN(250)+ H+2- All 250 lipophilic RN molecules diffuse through nerve sheath to reach axoplasm of neuron.3- Extracellularly, the equilibrium between RNH+ and RN has been disrupted by the passage of free base forms into neuron. The remaining 750 extracellular RNH+ now reequilibrate according to tissue PH and the drug Pka RNH+ (570) RN(180)+ H+

4- The 180 newly created lipophilic RN molecules difffuse into the cell, starting the entire process again.This continues until all local anesthetic molecules diffuse into the axoplasm.5- The inside of nerve, reequillibriation of the lipophilic RN form of local anesthesia because local anesthesia cannot exists in only RN form at intracellular PH of 7.4. So 75% of RN molecules present within axoplasm revert to RNH+ form; the remaining 25% of molecules remain in uncharged RN form.6- Inside axoplasm, RNH+ ions enter into sodium channels and bind to channel receptor sites result in conduction blockade.

RNH+RNH+ RN +H+RNH+ RN

Extracellular (PH 7.4)Intracellular (PH 7.4)Sodium channelLipid bilayer75025018070

PH of extracellular fluid determine the ease with which local anesthetics move from administration site into axoplasm of nerve cell. PH of intracellular fluid remains stable and independent on extracellular PH.

If PH of extracellular fluid is low (inflamed or infected tissues), the following is occurred:1- 99% of local anesthesia present in charged cationic form and 1% present in lipophilic form2-10 RN molecules diffuse across nerve sheath to reach axoplasm ( contrasting with 250 RN molecules in health example)

3- Extracellularly, equilibrium between RNH+ and RN which has been disrupted, is reestablished. The relatively few newly created RN molecules diffuse into the cell, starting the entire process again.4- Intracellularly, 75% of free base molecules revert to cationic form , 25% remaining in the uncharged free base form (RN).5- Cationic molecules bind to receptor site of sodium channels, result in conduction blockade.

RNH+

Extracellular PH 6Intracellular PH 7.4RNH + RN

RNH+ RN

990107.52.5

Acidic products of inflammations can lower PH at injection site and lead to anesthetic failure WHY?

1- Because in acidic PH vast majority of local anesthetic molecule remain in the impermeable cationic form and few percentage in free base form which can penetrating nerve sheaths and nerve membrane, resulting in incomplete anesthesia.

2- Local mediators of inflammation such as prostaglandins and bradykinin can antagonize the effect of local anesthesia.3- Increase vascularity which accelerate rate of absorption of local anesthesia.

Onset of action of local anesthesiaFactors affect onset of action1- PH of tissue and Pka of the agent3 factors affect ratio between lipophilic and hydrophilic portions, are: Pka of L.A., PH of L.A., and PH of tissue in which anesthetic solution is deposited.Relation between Pka and PH is described by Henderson-Hasselbalch equation:Pka - PH of local anesthesia = log (Cation concentration/ Free base concentration)Pka of local anesthesia is defined as the PH at which half of local anesthetic particles are lipophilic and half are charged (hydrophilic)

The higher the Pka of local anesthesia, the slower its onset of action due to the fewer lipophilic particles initially available to cross the nerve sheath .

The closer the Pka of anesthesia to physiologic PH, the more rapid onset of action.

The low the PH of tissue and /or the local anesthetic solution, the slower its onset of action due to the fewer lipophilic particles initially available to cross nerve sheath.

2- The site of anesthetic depositionThe away from the nerve the local anesthetic is deposited, the longer it takes for onset of action. Thus the onset of infiltration technique is quite rapid.3- Nerve type and sizeThe C fibers are unmylinated and responsible for carrying sensations of pain and temperature. They are easily blocked by local anesthetic. Type A fibers are the largest and are responsible for carrying pressure and motor sensation. Local anesthesia are not as effective at blocking these fibers. This phenomenon is called Differential Nerve Block

4- ConcentrationThe effective concentration of local anesthesia depend partly on the agent and partly on the nerve to be blocked.Factors interfere with development of adequate concentration of anesthesia in the nerve fibers: a- Excessive dilution with blood or tissue fluid b- Too rapid absorption of anesthesia into circulation c- An infection in the injection site. 5- Lipid solubility The uptake of local anesthesia by nerve is facilitated with the more lipid soluble agents (lipophilic) this result in rapid onset of action. 6- Nonnervous tissue diffusibilityIncreased nonnervous tissue diffusibility decreased time of onset.

PotencyPotency of local anesthesia is its ability to provide complete analgesia under almost all circumstances.Factors affecting potency of local anesthesia:1- Lipid solubilityThe major potency determinant for local anesthetics is their intrinsic lipid solubility. Agents with low lipid solubility coefficients are marketed at higher concentrations than those with higher lipid solubility coefficients.2- ConcentrationMLAC: is a term used to determine the relative potency for local anesthesiaMLAC(minimum local anesthetic concentration), determine the amount of drug at which 50% of patients will have the desired effect. For enhancing potency of local anesthesia by addition of carbon atoms to key points on local anesthetic molecule.3- Vasodilator activity of anesthesia- Increased vasodilator activity, decrease the potency.

Duration of actionIs the length of time the drug is within the nerve.It depend primarily on the redistribution of the drug away from the site of action.This redistribution can be altered by several factors:1- Protein bindingThe more highly protein bound the drug, the longer duration of action, because the degree of plasma protein binding of local anesthesia correlates with the degree of binding to the receptor site in the ion channels.2- Status of tissue in the injection site(vascularity & PH)-Increased vascularity in the injection site results in more rapid absorption of local anesthesia. This most notable in areas of infection and inflammation.

3- Concentration-Doubling the dose increases duration by about one half-life.4- Individual variation in response to the drug5- Anatomical variation6- Type of injection technique7- Presence of vasoconstrictorThe presence of vasoconstrictor prolong duration of action of L.A. because it decrease rate of absorption of L.A.8- Type of local anesthetic drug (short, medium, or long acting drugs)9- Accuracy of anesthetic deposition10- Vasodilator activity of anesthesia

Local anesthetics could be classified according to their duration into:1- Short acting(5-40 min):Without vasoconstrictors:- Lidocaine HCL 2%Prilocaine HCL 4% (by infiltration)Mepivacaine HCL 3%2- Medium acting(45-90 min)Lidocaine HCL 2% + epinephrin 1:50,000Lidocaine HCL 2%+ epinephrine 1:100,000- Mepivacaine HCL 2% + epinephrin(1:100,000) or levonordefrinPrilocaine HCL 4% + epinephrin 1:200,000Articaine HCL 4%+ epinephrine 1:100,000Articaine HCL 4%+ epinephrine 1:200,0003- Long acting(>90 min)- Bupivacaine HCL 0.5% with epinephrin 1:200,000- Etidocaine 1.5% with epinephrin

Pharmacokinetics of local anesthesiaIt describes the processes by which drugs are absorbed, distributed, metabolized, and excreted by the body.I- Uptake(absorption)Absorption of anesthesia is affected by:Blood flow in the injected site, Affinity of anesthetic for local tissues, Effect of anesthetic on circulation, and Presence or absence of vasoconstrictors.Rate of absorption of anesthesia into the blood is related to:A- Vasoactivity of the drugB- Vascularity of injection site

A- Vasoactivity of L.A.- L.A. have different vasodilating activities. Ester L.A. are potent vasodilating drugs, Procaine is the most potent vasodilator and is often used clinically for vasodilatation when peripheral blood flow has been compromised due to intra-arterial injection of drug.

- Tetracaine, chloroprocaine, and propoxycaine posses vasodilating properties to varying degrees but not to the degree of procaine.Cocaine is the only L.A. that produces vasoconstriction. Its initial action is vasodilation, which is followed by intense and prolonged vasoconstriction.

The clinical effect of vasodilatation is an increase in the rate of absorption of local anesthetics into blood, thus decreasing the duration of pain control while increasing blood level of L.A. and the potential for overdose.

B- Vascularity of injection siteIncreased vascularity at the site of injection results in a more rapid absorption of local anesthesia. This most notable in areas of infection and inflammation.

II- Distribution of L.A.Once L.A. absorbed into blood, they are distributed throughout the body to all tissues.The blood level of L.A. is affected by the following factors:1- Rate of absorption of L.A. into cardiovascular system2- Rate of distribution of L.A. from vascular compartment into the tissues.3- Elimination of L.A. through metabolic and/or excretory pathway.The rate at which L.A. is removed from blood is described as The elimination half-life of the drug.

III- Metabolism (biotransformation) of L.A.1- Ester L.A.They are hydrolyzed by pseudocholinestrase enzyme in plasmaRate of hydrolysis has an impact on the potential toxicity of L.A.Chloroprocaine the most rapidly hydrolyzed, is the least toxic, whereas tetraciane hydrolyzed 16 times more slowly than chloroprocaine, so has the greatest toxicity.PABA(para-aminobenzoic acide) is the byproduct result from biotransformation of ester type. PABA excreted unchanged in the urine.The allergic reactions from ester group are not related to the parent compound but rather to PABA.

2- Amide L.A-They are hydrolyzed in liverPrilocaine undergoes primary metabolism in liver, with some also occurring in lung.Administration of large doses of prilocaine and articaine produce methmoglobenimia which appears clinically as cyanosis of mucous membrane and nail beds, and brown color of arterial blood.

- In case of poor liver function, biotransformation occurs at slower rate than normal lead to increased anesthetic blood levels, and potentially increased toxicity.

IV- Excretion of L.A.- All local anesthesia and their metabolites are excreted through kidney.Esters appear in small concentration as the parent compound in the urine, but amides are present in urine as parent compound in a greater % than are esters.Patients with renal dysfunction unable to eliminate L.A. and its metabolites. This lead to increase its blood level and increased potential toxicity.

Systemic actions of local anesthesiaI- Central nervous system1- Anticonvulsant properties- All L.A. in normal doses producing generalized CNS depression, but overdose cause increase excitability of CNS.Some L.A. such as procaine, lidocaine, mepivacaine have anticonvulsant properties and can be used intravenously to terminate or decrease duration of grand mal and petit mal seizures.2- AnalgesiaIn past procaine was injected intravenously for management of chronic pain and arthritis.

II- Cardiovascular system1- Direct action on myocardiumL.A. produce depression of myocardium related to anesthetic level in blood. So it decrease rate of conduction and force of contraction.Overdose of L.A. cause different signs and symptoms :1- Low to moderate overdose Elevated blood pressure, heart rate, and respiratory rate . 2- Moderate to high overdose levels decreased blood pressure, heart rate , and respiratory rate.

2- Direct action on peripheral vasculatureCocaine is the only L.A. that produce vasoconstriction at normal dosage.Ropivacaine cause cutaneous vasoconstriction.All other L.A. produce peripheral vasodilatation, through relaxation of smooth muscle in wall of blood vessels.At normal dose, L.A. slight increase or no change in blood pressureAt levels approaching, yet still below overdose level mild degree of hypotension is notedAt overdose levels profound hypotension- At lethal levels cardiovascular collapse is noted.

III- Local tissue toxicitySkeletal muscles are more sensitive to local irritant properties of local anesthesia than other tissuesIV- Respiratory systemNormal dose have direct relaxant action on bronchial smooth muscles, at overdose levels respiratory arrest as a result of generalized CNS depression.V- Drug interactionAdministration of CNS depressants in conjunction with L.A. lead to potentiation of the CNS depressant actions of local anesthesia.

VI- Neuromuscular blockadeL.A. block neuromuscular transmission in humans. This is a result of inhibition of sodium diffusion through a blockade of sodium channels in the cell membrane.VII- Malignant Hyperthermia(MH)- Is a pharmacogenic disorder in which genetic variant in individual alter that persons response to certain drugs. MH appears clinically as tachycardia, cyanosis, respiratory and metabolic acidosis, fever, unstable blood pressure, muscle rigidity, and death. Recently, amide L.A. were thought to be capable of provoking MH , so it is contraindicated in MH susceptible patients.

Contraindications of local anesthesiaI- Absolute contraindications

Medical problem Avoid May useAnesthetic allergySame chemical classDifferent chemical classBisulfite allergyAnesthetics with vasoconstrictorsPlain anesthesiaSulfur allergy ArticaineNon-sulfur types

2- Relative contraindications

Medical problem Avoid May useAtypical cholinestrase esters AmidesMethemoglobinemiaPrilocaine& articaineOthersSevere liver disease &congestive heart failure(ASA III-IV)AmidesEsters, or amides(reduce the dose)Severe kidney disease(ASA III-IV)Amides &estersEither(reduce the dose)Severe cardiovascular disease(ASA III-IV)Excess vasoconstrictorsPlain anesthesia, or with vasoconstrictor(low dose)Severe thyrotoxicosis(ASA III-IV)Excess vasoconstrictorsPlain anesthesia, or with vasoconstrictors(low dose)

Factors affect selection of local anesthetic1- The anticipated duration of dental procedure for pain control-For long lasting procedures, long- duration local anesthetics are selected to provide adequate pain control period2- Potential need for posttreatment pain control- long acting anesthesia is selected when postoperative pain is thought to be a factor.3- Possibility of self-mutilation in the postoperative period4- Presence of any contraindications to local anesthetic administration5- The need for hemostasis- Anesthetic solution containing epinephrine in 1:50,000 or 1:100,000 conc. are recommended via local infiltration into surgical site.6- Practitioner's knowledge of the anesthetic agents

Constituents of anesthetic carpule1- Anesthetic drugThe main substance contained in carpule2- Vasoconstrictors3- Vehicle to make isotonic solution: 0.9% Na CL,to avoid hypotonic or hypertonic solution.4- PreservativeSuch as: - Sodium meta bisulfite (0.5mg/ml) and Methylparaben (1 mg/ml) are antioxidants, prevent oxidation of vasoconstrictors which cause deterioration of solution.- Methylparaben (1 mg/ml) used as preservative with articaine local anesthesia. It may cause allergic reaction, so patient with para- group allergy should not take local anesthesia that contain this preservative.

ItemLidocaine(Xylocaine)Mepivacaine(Carbocaine)Prilocaine(Citanest)Nature1st amide to be used in dentistry as L.A.Is an amide L.A. drugAmide L.A. drugPotency & toxicityTwice potent compared with procaine- twice toxic compared with procaineTwice potent as procaine- twice toxic as procaineTwice potent as procaine- its 40% less toxic than lidocaineMetabolismIn liverIn liver, by microsomal fixed-function oxidasesIn liver, kidney, and lung- undergo biotransformation more rapidlyExcretionVia kidney- Via kidney Via kidneys, faster than any amides

Amide types of local anesthesia

ItemlidocaineMepivacainePrilocaineVasodilating propertiesLess than procaine & more than prilocaine and mepivacaineGives slight vasodilatationMore than mepivacaine and less than lidocaine and procaineOnset of actionRapid onset of action (2-3 min)Rapid onset of action(1.5-2 mint.)Its onset of action is slightly slower than lidocaine(2-4 mint.)Dental concentration2%- 3%- Both conc. Can be used with or without V.C.- V.C. used is epinephrin 1:50,000 or 1:100,0003% without V.C.-2% with V.C.- Two V.C. levonordephrin(1:20,000) & epinephrin(1:100,000) are available with mepivacaine4% with or without V.C.- V.C. used with it is epinephrine 1:200,000Maximum dose- With or without V.C. is 4.4 mg/kg body weight-4.4 mg/kg body wt. for adults or children- 6 mg/kg body wt. for adults

itemsLidocaineMepivacainePrilocainePKa7.97.67.9PH of plain solution6.54.54.5PH of vasoconstrictor-contained soln.5.0-5.53.0-3.53.0-4.0Anesthetic half-life90 mint.1.9 hour1.6 hoursTopical anesthetic actionYes, in conc. 5%Not in clinically acceptable concentration-Not in clinically acceptable concentration

- Prilocaine in its uncharged base form , is an integral part of EMLA cream used to provide topical anesthesia of skin

ItemLidocaineMepivacainePrilocaineNotes- 2% lidocaine with epinephrin 1:50,000 can be used safely with max. epinephrin dose (0.2mg) for healthy pt.For cardiac or hyperthyroid pt. max. safe dose is 0.04mg(1 cartridge)2 % lidocaine with epinephrin 1:100,000 ,2 catridges can be used for cardiac or hyperthyroid pt..For hemostasis, 2% lidocaine + epinephrine 1:50,000 is recommendedFor duration & depth of pain control, 2% lidocaine with 1:100,000 or 1:50,000 epinephrine is recommended.-It is the least vasodilating L.A. , so best for short proceduresIt has the least concentrated epinephrine dilution 1:200,000Therefore cardiac or hyperthyroid pt. may receive up to 4 cartridges in one appointment.

Its relatively contraindicated in pt. with idiopathic or congenital methmoglobinemia, sickel cell anemia, cardiac or respiratory failure because methmoglobine level is elevated.

50

ItemAtricaine(Ultracaine)Bupivacaine(Marcaine)EtidocaineNatureIt is amide L.A. agentIt s amide L.A. agent its structurally related to mepivacaine- Its long acting L.A. drug-It is amide and long acting L.A. drugPotency & toxicityIt is 1.5 times that of lidocaine Its equally toxic to lidocaine & procaine4 times potent that of lidocaine,mepivacaine, prilocaine 4 times less toxic than lidocaine4 times that of lidocaine4 times as toxic as lidocaine after rapid IV injectionMetabolismIn plasma(by plasma estrase) & liverIn liver by amidasesIn liverExcretionVia kidneysVia kidneysVia kidneys

ItemAtricaineBupivacaineEtidocaineVasodilation propertiesEqual to lidocaineMore than lidocaine,mepivacaine,prilocaine and less than procaineAs bupivacaineOnset of actionRapid onset equal to lidocaine-Similar to that of lidocaine,mepivacaine,prilocaine(6-10 mint.)-Less than etidocaineRapid onset equal to lidocaine(1.5-3 mint.) and more than bupivacaineDental concentration- 4% conc. With 1:200,000 or 1:100,000 epinephrine not available in plain solution-0.25%-0.5% conc. With 1:200,000 epinephrine- 1.5% conc. With 1:200,000 epinephrineMaximum dose7 mg/kg body wt. for adults 5 mg/kg body wt. for children between 4-12 years- 1.3 mg/kg body wt. for adults- 8 mg/kg body wt. for adults

itemsArticaineBupivacaineEtidocainePKa7.88.17.7PH of plain solutionNot available4.5-6.04.5PH of vasoconstrictor containing solution4.4 to 5.2 for 1:100,000 and 4.6 to 5.4 for 1:200,0003.0-4.53.0-3.5Anesthetic half life0.5 hour2.7 hour2.6 hoursTopical anesthetic actionNot in clinically acceptable concentrationNot in clinically acceptable concentrationNot in clinically acceptable concentrationNotes-It is the only anesthetic agent of amide type contain thiophene ring as its lipophilic portion- It cause methmoglobinemia if given in large doses-Not recommended for younger pt. or in those postoperative soft tissue injury caused by self-mutilation is increased

ItemArticaineBupivacaineEtidocaineNotes-Should not be used in pt. with para -group (sulfur containing drug) allergy, because it contains hydroxyl gp. In para position- Articaine is able to diffuse through soft and hard tissues more reliably than other local anesthetics. So in max. buccal infiltration can provide palatal anesthesia.indicated for :1- lengthy dental procedures for which deep anesthesia in excess of 90 mint. is necessary.2- management of postoperative pain following oral surgical procedure giving pain free period up to 12 hours (long acting L.A.)As bupivacaine, is long acting local anesthetic agent with same clinical indications of bupivacaine. But only different in onset of action and duration for infiltration anesthesia because of different Pka.

Ester types of local anesthesia1- Procaine HCL (Novocaine)- Nature: ester type- Potency= 1, weak anesthetic agent- Toxicity= 1, low- Metabolism: in plasma by pseudocholinestrase enzymes- Excretion: by kidney, more than 2% unchanged in urine.- Vasodilating properties: produce the greatest vasodilation of all currently used L.A.Pka= 9.1PH of plain anesthesia=5.0 to 6.5PH of vasoconstrictor-containing solution=3.5-5.5Dental conc.: 2% or 4%2% solution gives from 12-15 min of anesthesiaAddition of 1:100,000 adrenaline prolong duration to 30-45 minAddition of 1:50,000 adrenaline prolong duration to 60-90 min* Maximum dose: 1000 mg

2- Propoxycaine HCLNature : ester typePotency=7-8 (procaine=1)Toxicity= 7-8 (procaine=1)Metabolism: metabolized in both plasma and liver.Excretion: via kidneys; almost entirely hydrolized.Vasodilating properties: yes, but not as profound as those of procaine.Onset of action: rapid (2-3 minutes)Dental concentration: 0.4%Combined with procaine in solution to provide a more rapid onset & profound anesthesia than can be obtained by procaine alone.Propoxycaine is not available alone due to its high toxicity (7-8 times that of procaine).Maximum recommended dose: 6.6 mg/kg of body weight for adults. For children a dose of 3.0 mg/Ib is recommended up to a maximum of five cartridges.

Local anesthesiamg/kgmg/lbMRD(mg)Articaine(with vasoconstrictor)7.03.2500Bupivacaine(with vasoconstrictor)1.30.690LidocaineNo vasoconstrictor-with vasoconstrictor4.46.62.03.0300500Mepivacaine-no vasoconstrictor-with vasoconstrictor6.66.63.03.0400400Prilocaine-no vasoconstrictor-with vasoconstrictor6.06.02.72.7400400

Manufactures(MRD-m)Maximum recommended doses of L.A.

Local anesthesiaPercent concentrationmg/mlX 1.8 ml= mg/cartridgeArticaine44072Bupivacaine0.559Lidocaine22036Mepivacaine2320303654Prilocaine44072

Calculation of milligrams of local anesthesia per dental cartridge(1.8ml cartridge)

Calculation of maximum dosagesand numbers of cartridges1- Patient 22 yr. old, healthy,110LBS-lidocaine 2%= 36mg/cartridge-lidocaine HCL+ epinephrine 1:100,000Lidocaine:3.0mg/Ib=3.0x110=330mg(MRD-m)-Number of cartridges :330/36=9 cartridges per appointment

3- Patient,6 yr. old, healthy,male, 40 LBS- Mepivacaine 3%=54 mg/cartridge- Mepivacaine HCL with no vasoconstrictor- Mepivacaine: 3.0 mg/Ib= 3.0x40= 120 mg(MRD-m)- Number of cartridges: 120/54= 2 cartridges per appointment

Vasoconstrictors - Are sympathomimetic or adrenergic drugs.Two main types according to presence or absence of catechole nucleus:1- Catecholamines a- epinephrine b- nor-epinephrine c- levonordephrine d- isoproterenol e- dopamine

2- Non-catecholamines, include a- phenylephrine b- ephidrine c- amphetamine d- methamphetamine e- mephentermine f- metaraminol g- hydroxyamphetamine

* Felypressine, is synthetic analogue of polypeptide vasopressin and is available as vasoconstrictors.

Mode of action of vasoconstrictors1- Direct acting drugsAre directly acting on adrenergic receptors: EpinephrineNorepinephrineLevonordephrineDopaminePhenylephrineIsoproterenolMethoxamine2- Indirect actingWhich act by releasing norepinephrine from adrenergic nerve terminals:TyramineAmphetamineMethamphetamineHydroxyamphetamine3- Mixed- actingActing both directly and indirectly:Metaraminolephedrine

Selection of vasoconstrictors1- Length of dental procedurePrilocaine 4% provides pulpal anesthesia of about 40-60 minutes duration, the addition of a 1:200,000 epinephrine dilution increasing duration but slightly (to about 60-90 minutes)Lidocaine 2% last 10 minutes, addition of 1:50,000,1:100,000, or 1:200,000 of epinephrine prolong the duration to 60 minutes.2- Requirement for hemostasisEpinephrine has hemostatic effect in conc. 1:50,000 and at 1:100,000(but to a lesser extent), but with rebound vasodilation.

Phenylephrine is long-acting pure alpha- stimulating vasoconstrictors, dont produce rebound beta effect because its beta actions are minimal, so it is not as potent vasoconstrictors as epinephrine. Its long duration of action cause lesser postoperative bleeding than epinephrine.Norepinephrine is potent alpha stimulator and vasoconstrictor that produce cases of tissue necrosis and slough.3- Medical status of patient- Include contraindications of vasoconstrictors

Pharmacology of vasoconstrictors1- Epinephrine (adrenaline)Is available in following concentrations 1:200,000, 1:100,000. and 1:50,000. Its affinity to alpha and beta receptors is equivalent(50:50)Systemic action: Increase heart rate and cardiac output, Peripheral vasodilation in skeletal muscle beds, Increase systolic blood pressure but decrease diastolic pressure. Increase irritability of pacemakers causing dysrhythmias. Produce dilation of coronary arteries. Produce constriction of vessels of skin and mucous membrane.Produce dilation of smooth muscles of bronchioles (used in management of bronchospasm).- Normal dose not stimulant for CNS, but overdose cause CNS stimulation.

Termination of action and elimination-By its reuptake by adrenergic nerves. -Epinephrine that escape reuptake,is inactivated in blood by catechol-O-methyletransferase(COMT) and monoamine oxidase(MAO), Both are present in liver.

Metabolism-Is metabolized by glycogenolysis in liver and skeletal muscles.Clinical applicationManagement of allergic reactionsManagement of bronchospasmManagement of cardiac arrestAs vasoconstrictor and for hemostasis

Maximum doses1:50,000 and 1:100,000 for pain control1:50,000 for hemostasisFor normal healthy patients, use 0.2 mg per appointmentFor patient with clinically cardiovascular disease (ASA III or IV): 0.04 mg per appointment

2- Nor-epinephrine(Levarterenol, Levophed)-Available in concentration of 1:30,000 solution.Its affinity for alpha receptors greatly exceeds that for beta receptors (90:10)Systemic action: Increase systolic ,diastolic, and mean arterial blood pressure with reflex slowing heart rate.Stimulate pacemaker cells and increase its irritabilityVasodilation of coronary arteries and increase its blood flow.Constriction of cutaneous blood vesselsNot relax bronchial smooth muscle as epinephrine(produce alpha-induced constriction of lung arteriols), so not used for management of bronchospasm.Normal dose not stimulating CNS, but occur at overdose.

MetabolismIn same manner as epinephrine.Termination of action and eliminationBy reuptake at adrenergic nerve terminals and its oxidation by MAO. Exogenous nor-epinephrine inactivated by COMT.Clinical applicationsAs vasoconstrictors in L.A.Management of hypotension.Maximum dosesFor normal healthy patients: 0.34 mg per appointment (10 ml of a 1:30,000 solution.)For cardiovascular diseased patients(ASA III or IV):0.14 mg per appointment (4ml of a 1:30,000 solution).

3- Levonordephrin (Neo-cobefrin)Is the least potent catecholamine vasoconstrictorIts concentration is 1:20,000Its affinity for alpha and beta receptors is 75% alpha and 25% betaSystemic action: resemble nor-epinephrin, but to lesser degree.MetabolismSame as epinephrineTermination of action and eliminationThrough actions of COMT and MAO.Clinical applicationAs vasoconstrictor in local anesthesiaMaximum dosesFor healthy patients: 1 mg per appointment (20ml of a 1:20,000 dilution= 11 cartridges)For cardiovascular patients: 0.2 mg per appointment or 2 cartridges.

4- Phenylephrine hydrochloride(Neo-synephrine)-Available concentration is 1:2500 dilution- Mode of action: 95% for alpha, and 5% for betaSystemic actions:-little inotropic and chronotropic effect on heart and cause bradycardia.Little effect on pacemakersIncrease blood flow by dilation of coronary arteriesIncrease both systolic and diastolic blood pressureBronchial dilation but to lesser degree than epinephrineIt has minimum effect on CNSMetabolismBy glycogenolysis similar to epinephrineTermination of action and elimination-- It undergo hydroxylation to epinephrine which then eliminated as epinephrine.

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Clinical applicationAs vasoconstrictors in L.A.Nasal decongestantManagement of hypotensionMaximum doses-For healthy patients: 4 mg per appointment (10ml of a 1:2500 solution)- For cardiovascular patients(ASA III or IV): 1.6 mg per appointment (4ml of a 1:2500).

5- Felypressin(Octapressin)Available dose is 0.03 IU/mlMode of Action: act as a direct stimulant of vascular smooth muscle, which is more pronounced on venous than arteriolar microcirculation.Systemic actionsNo direct effect on myocardiumNondysrhythmogenic (no effect on pace maker cells)High doses may impair blood flow through coronary arteriesHigh doses may cause constriction of cutaneous blood vesselsHas no effect on CNSIt has antiduretic and oxytocic actions , so contraindicated in pregnantClinical applicationsAs vasoconstrictors in L.A. Maximum doses- For cardiovascular patients(ASA III or IV): 0.27 IU (9ml of 0.03 IU/ml)

Dilutions of vasoconstrictorsIs indicated to produce clinically safe and effective vasoconstrictors and is referred as ratio.- 1:1000 means that there is 1 gm (1000mg) of the drug contained in 1000 ml of solution, or 1.0 mg/ml of solution.- Vasoconstrictors used in local anesthetic solutions are much less concentrated than 1:1000 to be more clinically safer and effective. * Dilution of:1:50,000= 0.02 mg/ml1:100,000= 0.01 mg/ml1:200,000= 0.005 mg/ml1:2,500 (phenylephrine)=0.4 mg/ml1:20,000 (levonordephrine)=0.05 mg/ml1:30,000 (nor-epinephrine)=0.033 mg/ml

Potenial benefits of vasoconstrictors1- Increase duration of action2- Hemostatic effect:The hemostatic effect of vasoconstrictors may lead to higher postoperative bleeding and delayed healing of extraction sockets. This rebound vasodilation is mediated by beta-2-adrenergic receptors effect.

3- Vasoconstrictors can delay and reduce in peak blood levels of local anesthesia so decrease systemic toxicity.

4- Decrease amount of local anesthetic solution needed

Maximum recommended dosage of vasoconstrictors 1- For healthy patientsMaximum recommended dose of epinephrine is 0.2 mg per appointment (5.5 cartridges) of 1:50,000, 11 cartridges of 1:100,000, and 22 cartridges of 1:200,000. Maximum recommended dose of levonordephrine , 1:20,000 is 1 mg per appointment (11 cartridges)Maximum No. of cartridges of levonordephrine: Maximum recommended dose / concentration of V.C 1.8 1 mg/0.05 1.8= 11 cartridges

2- For cardiovascular patientsMaximum recommended dose of epinephrine for cardiac patient is 0.04 mg per appointment (1 cartridge) of a 1:50,000, and 2 cartridges of a 1:100,000 solution, or 4 cartridges of a 1:200,000 solution.Maximum recommended dose for levonordephrin is 0.2 mg per appointment or 2 cartridges of a 1:20,000 solution.

Conditions in which vasoconstrictors should be avoided or used in minimum doses1- Heart diseases - Hypertension(>200mm Hg systolic or >115mm Hg diastolic) - Myocardial infarction within 6 months - Cerebrovascular accident within 6 months - Daily episodes of unstable angina - Coronary artery bypass surgery within 6 months - Uncontrolled cardiac arrhysmias - Uncontrolled congestive heart failure2- Uncontrolled hyperthyroidism3- Sulfite-sensitive asthma or true sulfite allergy.