Chapter 9: Local Anesthetics

Chapter 9: Local Anesthetics
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 9 Outline History Ideal local anesthetic Chemistry
Mechanism of action Pharmacokinetics Pharmacologic effects Adverse reactions Compositions of local anesthetic solutions Local anesthetic agents Vasoconstrictors Choice of local anesthetic Topical anesthetics Doses of local anesthetic and vasoconstrictor

Local Anesthetics Haveles (p. 112) No drugs are used more often in the dental office than local anesthetic agents Use can become routine, but these agents have a potential for systemic effects in addition to desired local effects

History Haveles (p. 112) (Figs. 9-1, 9-2) “Painless” dentistry through use of a local anesthetic is a relatively recent development Indigenous South American people chewed leaves that made them feel better Tasting it produced not only a loss of taste, but also of the sensation of pain cont’d…

History Koller noticed that cocaine in the eye produced complete anesthesia Sigmund Freud was also experimenting with cocaine and its effects on the central nervous system (CNS) CNS stimulation, toxicity, and the potential for abuse were quickly recognized as major problems with the widespread use of cocaine as a local anesthetic cont’d…

History Einhorn synthesized procaine in 1905; many years later, its use became common in dentistry The amide lidocaine (Xylocaine) was released in 1952 mepivacaine (Carbocaine) was released in 1960 More recently, bupivacaine (Marcaine) has been made available for dental use

Ideal Local Anesthetic
Haveles (pp ) Many local anesthetic agents are not clinically acceptable The ideal local anesthetic should possess certain properties No local anesthetic in use today meets all of those requirements, although many acceptable agents are available

Properties of the Ideal Local Anesthetic
Haveles (p. 113) (Box 9-1) Potent local anesthesia Reversible local anesthesia Absence of local reactions Absence of allergic reactions Rapid onset Satisfactory duration Adequate tissue penetration Low cost Stability in solution Sterilization by autoclave Ease of metabolism and excretion

Chemistry Haveles (pp ) (Table 9-1) Local anesthetic agents are divided chemically into two major groups—amides and esters A few agents fall outside these two groups The importance of this division is associated with potential allergic reactions Cross-hypersensitivity between amides and esters is unlikely cont’d…

Chemistry The structure of local anesthetic is composed of the following three parts Aromatic nucleus (R) Linkage (either an ester or amide, followed by an aliphatic chain, R) Amino group The aromatic nucleus (R) is lipophilic and the amino group is hydrophilic Esters are largely metabolized in the plasma and amides in the liver

Mechanism of Action Action on nerve fibers
Haveles (pp ) (Fig. 9-3; Box 9-2) Action on nerve fibers A resting nerve fiber has a large number of positive ions on the outside and a large number of negative ions on the inside The nerve action potential results in the opening of sodium channels and in inward flux of sodium This results in a change from the –90-mV potential to a +40-mV potential The outward flow of potassium ions repolarizes the membrane and closes the sodium channels cont’d…

Mechanism of Action Action on nerve fibers Haveles (p. 114)
Local anesthetics attach themselves to specific receptors in the nerve membrane After combining with the receptor, local anesthetics block conduction of nerve impulses by decreasing the permeability of the nerve cell membrane to sodium ions cont’d…

Mechanism of Action Decreasing permeability to sodium ions
Decreases the rate of depolarization of the nerve membrane Increases the threshold for excitability Prevents propagation of the action potential Local anesthetics may reduce permeability by competing with calcium for the membrane binding sites and by preventing the onset of nerve conduction cont’d…

Mechanism of Action Ionization factors
Haveles (pp ) (Fig. 9-4) Ionization factors Local anesthetic agents are weak bases occurring equilibrated between Fat-soluble (lipophilic) free base Water-soluble (hydrophilic) hydrochloride salt The proportion in each form is determined by The acid dissociation constant (pKa) of the local anesthetic The pH of the environment cont’d… Definition of pKa okay?

Mechanism of Action In the acidic pH of the dental cartridge (4.5), the proportion of the drug in the ionized form increases, increasing solubility Once injected into tissues (pH 7.4), the amount of local anesthetic in the free-base form increases This provides for greater tissue (lipid) penetration cont’d…

Mechanism of Action In an acidic environment such as infection or inflammation (pH lower), the amount of free base is reduced (more in ionized form) This is one reason dental anesthesia with a local anesthetic is more difficult when infection is present Other reasons include dilution by fluid, inflammation, and vasodilation in the area The free base form is needed to penetrate the nerve membrane The cationic form exerts blocking action by binding to the specific receptor site

Pharmacokinetics Absorption depends on its route Haveles (p. 112)
When injected into tissues the rate depends on the vascularity of the tissues This is a function of the degree of inflammation present, the vasodilating properties of the local anesthetic agent, the presence of heat, or use of massage cont’d…

Pharmacokinetics Absorption
Haveles (p. 112) Absorption Reducing the systemic absorption of a local anesthetic is important when it is used in dentistry With reduced absorption, the chance of systemic toxicity is reduced cont’d…

Pharmacokinetics A vasoconstrictor is added to the local anesthetic to reduce absorption The vasoconstrictor Reduces the blood supply to the area Limits systemic absorption Reduces systemic toxicity cont’d…

Pharmacokinetics Absorption Haveles (p. 112)
With topical application, especially on mucous membranes or if the surface is denuded, absorption can approximate that produced by intravenous injection It is also determined by the proportion of the agent present in the free-base form (nonionized) cont’d…

Pharmacokinetics Distribution Haveles (p. 115)
After absorption, local anesthetics are distributed throughout the body Highly vascular organs have higher concentrations of anesthetics Local anesthetics cross the placenta and blood-brain barrier Lipid solubility affects the potency of the agent Bupivacaine 0.5% is about 10 times more lipid soluble than lidocaine used as a 2% solution cont’d…

Pharmacokinetics Metabolism Haveles (p. 115)
Local anesthetic agents are metabolized differently, depending on whether they are amides or esters Esters are hydrolyzed by plasma pseudocholinesterases and liver esterases Procaine is hydrolyzed to para-aminobenzoic acid (PABA), a metabolite that may be responsible for its allergic reaction cont’d…

Pharmacokinetics Metabolism Haveles (p. 115)
Amide local anesthetics are metabolized primarily by the liver In severe liver disease or with alcoholism, amides may accumulate and produce systemic toxicity A small amount of prilocaine is metabolized to orthotoluidine, which can produce methemoglobinemia if given in very large doses Cimetidine can interfere with metabolism of amides by reducing hepatic blood flow cont’d…

Pharmacokinetics Excretion Haveles (p. 115)
Metabolites and some unchanged drug of both esters and amides are excreted by the kidneys Both parent drug and metabolites can accumulate with end-stage renal disease

Pharmacologic Effects
Haveles (pp ) Peripheral nerve conduction (blocker) The main clinical effect of local anesthetic is reversible blockage of peripheral nerve conduction These agents inhibit movement of the nerve impulse along the fibers, at sensory endings, at myoneural junctions, and at synapses They do not penetrate the myelin sheath, but they affect myelinated fibers only at the nodes of Ranvier Local anesthetics affect small, unmyelinated fibers first and large; heavily myelinated fibers last

Common Order of Nerve Function Loss
Haveles (p. 116) (Box 9-3) Autonomic Cold Warmth Pain Touch Pressure Vibration Proprioception Motor

Pharmacologic Effects
Haveles (pp ) Antiarrhythmic Local anesthetics have a direct effect on cardiac muscle by blocking cardiac sodium channels and depressing abnormal cardiac pacemaker activity, excitability, and conduction They also depress strength of cardiac contraction and produce arteriolar dilation, leading to hypotension These properties make than useful in treatment of arrhythmias

Adverse Reactions Toxicity Haveles (p. 116) (Table 9-2)
Adverse reactions and toxicity are directly related to the plasma level of the drug Their potential for danger must be minimal Deaths from local anesthetics are difficult to document, dental-related mortality is even rarer cont’d…

Adverse Reactions Factors influencing toxicity include
Drug: inherent toxicity and amount of vasodilation Concentration Route of administration Rate of injection Vascularity Patient’s weight Rate of metabolism and excretion cont’d…

Adverse Reactions Toxicity Haveles (p. 116) CNS effects
CNS stimulation may occur before CNS depression CNS stimulation caused by depression of inhibitory fibers results in restlessness, tremors, and convulsions CNS depression caused by depression of both inhibitory and facilitative fibers results in respiratory and cardiovascular depression, and coma follows cont’d… Should CNS effects be expanded?

Adverse Reactions Toxicity Haveles (pp. 116-117)
Cardiovascular effects Local anesthetic agents can produce myocardial depression and cardiac arrest with peripheral vasodilation Usual concentrations that are achieved with administration of dental anesthesia would not be expected to result in any of these adverse reactions It is postulated that the effect of these agents on heart conduction may produce a fatal arrhythmia cont’d…

Adverse Reactions Local effects Haveles (pp. 116-117)
Most commonly the result of physical injury caused by injection technique or administration of an excessive volume too quickly to be accepted by the tissues Occasionally a hematoma may be produced cont’d…

Adverse Reactions Malignant hyperthermia Haveles (p. 117)
An inherited disease that is transmitted as an autosomal-dominant gene with reduced penetration and variable expression Symptoms include an acute rise in calcium, which produces muscular rigidity, metabolic acidosis, and extremely high fever Mortality is above 50% Treatment includes supportive measures and the administration of dantrolene cont’d…

Adverse Reactions In the past, it was thought that amide local anesthetics might precipitate malignant hyperthermia, but they are currently no longer implicated Patients with a family history of malignant hyperthermia can be given amide local anesthetic agents cont’d…

Adverse Reactions Pregnancy and nursing considerations
Haveles (p. 117) Pregnancy and nursing considerations Elective dental treatment should be rendered before a patient becomes pregnant Most sources suggest that lidocaine may be administered to a pregnant woman if dental treatment is needed cont’d…

Adverse Reactions Pregnancy and nursing considerations
Fetal bradycardia has been reported when larger doses are administered to the mother near term Lidocaine and prilocaine are U.S. Food and Drug Administration (FDA) pregnancy category B Mepivacaine, articaine, and bupivacaine are FDA pregnancy category C cont’d…

Adverse Reactions Allergy Haveles (p. 117)
Allergic reactions that result from local anesthetics have been reported They range from rash to anaphylactic shock An allergy history should be elicited from each patient before a local anesthetic agent is chosen Esters have a much greater allergic potential; some question has surfaced about whether amides can produce allergic reactions at all cont’d…

Patients giving a history of allergies to all local anesthetic agents may be “tested” by giving them an amide by injection Use of skin testing is unreliable; it can give both false-positive and false-negative results cont’d…

Another approach is to use the antihistamine diphenhydramine (Benadryl) as a local anesthetic Antihistamines, because of their similarity in structure to local anesthetics, have some local anesthetic action diphenhydramine (Benadryl) in a concentration of 1% plus 1:100,000 epinephrine is recommended to be given by injection to produce a block No prepared product is available; this combination must be prepared from its constituents cont’d…

Adverse Reactions Allergy
Local anesthetics with vasoconstrictors also contain a sulfite that serves as an antioxidant In sulfite-sensitive patients, the sulfites may produce a hypersensitivity reaction that exhibits itself as an acute asthmatic attack The reaction is the same as the “salad bar” syndrome, a hypersensitivity reaction to sulfites

Composition of Local Anesthetic Solutions
Haveles (pp ) Local anesthetic usually contains several other ingredients such as the following Vasoconstrictor: to retard absorption, reduce systemic toxicity, and prolong duration of action Antioxidant: to retard oxidation of epinephrine Sodium hydroxide: to adjust the pH between 6 and 7 Methylparaben and propylparaben: preservatives added to multidose parenteral solutions No dental cartridge contains methylparaben

Local Anesthetic Agents
Haveles (p. 118) Amides Many local anesthetic agents are available with similar pharmacologic and clinical effects and systemic toxicity Dental issues associated with local anesthetics are listed in Box 9-4 Table 9-3 lists the local anesthetics available in dental cartridges cont’d…

Haveles (p. 118) Amides The only class of anesthetics used parenterally Esters are occasionally used topically The relative lack of allergenicity of the amides is probably responsible for this cont’d…

Haveles (pp ) Amides: lidocaine Introduced in 1948, it became an anesthetic standard to which other local anesthetics were compared Rapid onset related to its tendency to spread well through the tissues Lidocaine 2% with vasoconstrictor provides profound anesthesia of medium duration The local anesthetic solution most commonly used in dental offices cont’d…

Haveles (p. 118) (Fig. 9-5) Amides: lidocaine No cross-allergenicity among the amide lidocaine, other available amides, or esters has been documented In toxic reactions, one is likely to observe CNS depression initially rather than the CNS stimulation characteristic of other local anesthetics Adverse reactions include hypotension, positional headache, and shivering cont’d…

Haveles (p. 119) Amides: lidocaine In dentistry, lidocaine 2% with 1:100,000 epinephrine is used for infiltration and block anesthesia Lidocaine is used for topical anesthesia as a 5% ointment, a 10% spray, and a 2% viscous solution Lidocaine with epinephrine 1:100,000 provides a 1.0- to 1.5-hour duration of pulpal anesthesia Soft-tissue anesthesia is maintained for 3 to 4 hours cont’d…

Haveles (p. 119) Amides: lidocaine A new dose form of lidocaine is a patch applied to mucosal membranes for local anesthesia Its maximal effect occurs after about 10 minutes, which is probably too long to wait cont’d…

Haveles (p. 119) Amides: mepivacaine Introduced in 1960, its rate of onset, duration, potency, and toxicity are similar to those of lidocaine Mepivacaine is not effective topically; however, it is used for infiltration, block, spinal, epidural, and caudal anesthesia The usual dose form in dentistry is a 2% solution with addition of 1:20,000 levonordephrin (Neo-Cobefrin) as a vasoconstrictor cont’d…

Haveles (p. 119) Amides: mepivacaine Because mepivacaine produces less vasodilation than lidocaine, it can be used as a 3% solution without a vasoconstrictor Can be used for short procedures when a vasoconstrictor is contraindicated cont’d…

Haveles (p. 119) Amides: prilocaine Prilocaine is related chemically and pharmacologically to both lidocaine and mepivacaine Chemically, lidocaine and mepivacaine are xylidine derivatives, whereas prilocaine is a toluidine derivative Prilocaine appears to be less potent and less toxic than lidocaine and has a slightly longer duration of action cont’d…

Haveles (p. 119) Amides: prilocaine Although toxicity of prilocaine is 60% that occurring with lidocaine, several cases of methemoglobinemia have been reported after its use Prilocaine is metabolized to orthotoluidine and in large doses can induce some methemoglobinemia Prilocaine should not be administered to patients with any condition in which problems of oxygenation may be especially critical cont’d…

Haveles (p. 119) Amides: prilocaine Drugs that affect the hemoglobin, such as acetaminophen, may exacerbate the adverse reaction Prilocaine is used for infiltration, block, epidural, and caudal anesthesia It is available in dental cartridges as a 4% concentration both with and without 1:200,000 epinephrine cont’d…

Haveles (p. 119) Amides: prilocaine Prilocaine’s niche in dentistry involves situations in which the desired duration of action is somewhat longer than that obtained with mepivacaine both without and with vasoconstrictor Prilocaine plain has a duration of action slightly longer than mepivacaine plain, and prilocaine with epinephrine has a duration of action slightly longer than lidocaine with epinephrine The other potential advantage of prilocaine is that the concentration of epinephrine (1:200,000) is lower than in other local anesthetic amide combinations cont’d…

Haveles (p. 119) Amides: bupivacaine Bupivacaine is related to lidocaine and mepivacaine More potent but less toxic than the other amides The major advantage is its greatly prolonged duration of action Indicated in lengthy dental procedures when pulpal anesthesia of greater than 1.5 hours is needed or when postoperative pain is expected cont’d…

Haveles (p. 119) Amides: bupivacaine Available in dental cartridges as a 0.5% solution with 1:200,000 epinephrine Should not be used in patients prone to self-mutilation Bupivacaine has been used for infiltration, block, and peridural anesthesia cont’d…

Haveles (p. 119) Amides: articaine Articaine was approved for use in the United States in 2000 Its delay in the United States was a result of the addition of methylparaben to both multidose vials and single-dose cartridges Articaine is derived from thiophene This allows for greater lipid solubility and ability to cross lipid barriers such as nerve membranes This mechanism may account for its enhanced action compared with other local anesthetics cont’d…

Haveles (p. 119) Amides: articaine Articaine also differs from other amide local anesthetics because it has an extra ester linkage This extra linkage causes articaine to be hydrolyzed by plasma esterase Only 5% to 10% of articaine is metabolized by the liver; the other 90% to 95% is metabolized in the blood cont’d…

Haveles (p. 120) Amides: articaine Articaine is excreted by the kidneys The average patient can tolerate twice as much lidocaine as compared with articaine before the maximal dose is reached Articaine, similar to prilocaine, may cause methemoglobinemia in very high doses Articaine rarely causes paresthesia after a mandibular block when the 4% solution is used cont’d…

Haveles (p. 120) Amides: articaine Articaine is used for local, infiltrative, and conductive anesthesia Available as a 4% concentration with 1:100,000 epinephrine in a 1.7 ml cartridge unlike the more common 1.8 ml dental cartridge cont’d…

Haveles (p. 120) Esters No esters are currently available in a dental cartridge Esters, such as benzocaine, are commonly used topically cont’d…

Haveles (p. 120) Esters: procaine Procaine is a PABA ester Procaine is used as an antiarrhythmic agent and is combined with penicillin to form procaine penicillin G Procaine is not used in dentistry today because of the high rate of allergic reaction The allergic reaction is usually a result of PABA and not procaine cont’d…

Haveles (p. 120) Esters: propoxycaine Propoxycaine, another ester of PABA, is not available in a dental cartridge cont’d…

Haveles (p. 120) Esters: tetracaine Tetracaine, an ester of PABA, has a slow onset and long duration, and is generally estimated to have at least 10 times the potency and toxicity of procaine Great care must be exercised if used for topical anesthesia Tetracaine is available in various sprays, solutions, and ointments for topical application

Other Local Anesthetics
Haveles (p. 120) Dyclonine Dyclonine is a topical local anesthetic that is neither an ester nor an amide Its side effects involving the cardiovascular system and CNS are similar to those of the other local anesthetics The onset of local anesthesia is 2 to 10 minutes, and its duration is 30 to 60 minutes cont’d…

Other Local Anesthetics
Haveles (p. 120) Benzonatate Benzonatate is a tetracaine congener indicated in the management of nonproductive cough A topical anesthetic that acts on the respiratory stretch receptors, which produces its antitussive properties

Vasoconstrictors Overview Haveles (p. 120) (Box 9-5)
Vasoconstricting agents are included in local anesthetic solutions for many reasons Vasoconstrictors are members of the autonomic nervous system drugs call the adrenergic agonists or sympathomimetics When a local anesthetic solution does not contain a vasoconstrictor, the anesthetic drug is more quickly removed from the injection site and distributed into systemic circulation than if the solution contained a vasoconstrictor Any anesthetic given without a vasoconstrictor is more likely to be toxic than those given without a vasoconstrictor cont’d… Please verify the last point; a contradiction appears to exist; both sided of the comparison have “without a vasoconstrictor”

Vasoconstrictors Overview Haveles (p. 121) (Figs. 9-6, 9-7)
The decision about whether epinephrine should be used in a patient is made by weighing the risks and benefits A sufficient concentration must be used to keep the local anesthetic localized at its site of action and provide adequate depth, duration, and low systemic toxicity of the anesthetic 1:100,000 and 1:200,000 produce about the same amount of vasoconstriction and the same distribution of the local anesthetics cont’d…

Vasoconstrictors Overview Haveles (p. 121) (Fig. 9-7)
Research shows that a patient can produce endogenous epinephrine far in excess of that administered in dentistry in the presence of inadequate anesthesia, which sometimes occurs when vasoconstrictors are avoided Patients with uncontrolled high blood pressure, hyperthyroidism, angina pectoris, and cardiac arrhythmias and those who have had a myocardial infarction or cerebrovascular accident in the past 6 months should make an appointment for elective dental treatment after their medical condition is under control cont’d…

Vasoconstrictors Overview Haveles (p. 122) (Table 9-4)
Patients with cardiovascular disease who are able to withstand elective dental treatment can receive epinephrine-containing local anesthetic agents Anesthetic should be administered in the lowest possible dose by means of the best technique, including aspiration and a very slow injection rate to minimize systemic absorption The maximal safe dose of epinephrine for the healthy patient is 0.2 mg and for the cardiac patient is 0.04 mg cont’d…

Vasoconstrictors Drug interactions Haveles (p. 122)
The two epinephrine drug interactions that are most likely to be clinically significant Tricyclic antidepressants Administration of epinephrine may produce an exaggerated increase in pressor response Nonselective β-blockers Hypertension and reflex bradycardia may be exhibited cont’d…

Vasoconstrictors Drug interactions
Haveles (p. 122) Drug interactions The two drug interactions commonly mentioned but not usually clinically significant are Monoamine oxidase inhibitors (MAOIs) Epinephrine can be given to patients taking MAOIs, because epinephrine is eliminated primarily by reuptake and secondarily by catechol-O-methyltransferase (COMT) rather than by monoamine oxidase (MAO) Indirect acting sympathomimetic agents should be avoided in patients taking MAOIs Phenothiazines Phenothiazines are α-blockers, and when an α- and β-agonist is given, the beta effects predominate

Choice of Local Anesthetic
Haveles (pp ) (Figs. 9-8, 9-9; Box 9-6; Table 9-6) Local anesthetic should be chosen depending on the duration of local anesthesia desired and the side effects that must be avoided pKa is related to duration of action With lower pKa, the local anesthetic is distributed more in the base form and so is better absorbed Duration of action is primarily related to its protein-binding capacity Duration is unrelated to the local anesthetic’s half-life Lipid solubility determines the potency of a local anesthetic agent cont’d…

Choice of Local Anesthetic
Haveles (pp. 123, 125) (Table 9-7) The vasodilating property can affect both the potency and duration of action The dental practitioner should become familiar with a short-, an intermediate-, and a long-acting agent The duration of the procedure and any patient-specific information will determine the anesthetic of choice

Topical Anesthetics Haveles (p. 123) (Table 9-8) Benzocaine, an ester, is the most commonly used topical anesthetic Lidocaine, an amide, is the second most commonly used Comparison should take into account their onset, duration of action, and allergenic potential The patient should be instructed to avoid eating for 1 hour after application to oral mucosa so that the gag reflex can become fully functional cont’d…

Topical Anesthetics Amides: lidocaine Haveles (pp. 123-124)
Lidocaine is available as the base or hydrochloride salt The base is preferred when large areas of the mucosal surface are ulcerated, abraded, denuded, or erythematous Base is available as a jelly and an oral topical solution The hydrochloride salt is water soluble and penetrates the tissue better Hydrochloride is available as an ointment, an oral topical, and an oral aerosol cont’d…

Topical Anesthetics Haveles (p. 124) Amides: lidocaine and prilocaine (injection-free local anesthesia) The combination of lidocaine and prilocaine gel (Oraqix) applied into the periodontal pocket offers pain relief during scaling and root planing procedures Lidocaine provides rapid anesthesia, and prilocaine has a slower onset of action The more common side effects include pain, soreness, irritation, edema or redness at the area of application, and taste changes cont’d…

Topical Anesthetics Esters: benzocaine Haveles (p. 124)
Benzocaine, an ester of PABA, cannot be converted to a water-soluble form for injection Poorly absorbed and lacks significant systemic toxicity Benzocaine is used in many dental offices, although a hypersensitivity reaction is possible cont’d…

Topical Anesthetics Esters: cocaine Haveles (pp. 124-125)
Cocaine is a naturally occurring ester of benzoic acid that is potent and extremely toxic Although cocaine has ideal pharmacokinetics, the systemic absorption and subsequent CNS stimulation and its great potential for abuse make the use of cocaine as a local anesthetic untenable cont’d…

Topical Anesthetics Precautions in topical anesthetics
Haveles (p. 125) (Box 9-7) Precautions in topical anesthetics Some local anesthetics are absorbed rapidly when applied topically to mucous membranes To avoid toxic reactions from surface anesthesia, the dental health care provider should consider many factors

Doses of Local Anesthetic and Vasoconstrictor
Haveles (pp ) The amounts of local anesthetic and vasoconstrictor contained in a certain volume of solution can be calculated from the concentration of that solution The dental health care provider should be able to determine the number of milligrams of both local anesthetic and vasoconstrictor given in any clinical situation The maximal safe dose for each component should not be exceeded cont’d…

Doses of Local Anesthetic and Vasoconstrictor
Haveles (p. 126) Each dose should be recorded in the patient’s chart as soon as possible after the injection Information recorded should include the strength of both ingredients and the volume of solution used or the number of milligrams of each given

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