Pharmacological Considerations for Implant Dentistry Jason H.

Goodchild, DMD

Pharmacological Considerations Local Anesthesia Pre-operative Antibiotics Peri-operative Corticosteroids Local Anesthesia Historical Perspective Cocaine was the first local anesthetic, discovered by Carl Koller in 1884 (eye drops) The first dental use was by Dr. William Halsted on Nov 26, 1884 The caines developed subsequent to cocaine have no relationship to cocaine other than an etymological and pharmacological one; that is they cause anesthesia. Structure-Activity Relationship 1. Aromatic portion Responsible for lipophilicity of compounds, i.e., lipid/water distribution and protein binding characteristics. 2. Intermediate linkage connected to aromatic residue via an ester or amide linkage. Type of linkage important in determining the route of metabolism and the allergic potential of the compounds. 3. Amine portion usually a secondary or tertiary amine and is associated with water solubility of the compounds, but is not necessary for anesthetic activity. Compounds lacking the amine portion are insoluble in water and useful only topically.

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Principles of Local Anesthetics Mechanism of Action: Local anesthetics block the sensation of pain by interfering with the propagation of impulses along peripheral nerve fibers. This is accomplished by a reduction in the permeability of the nerve cell membrane to sodium ions. This results in a decreased rate of rise in the depolariztion phase of the action potential causing a failure of a propagated action potential to develop.

Relative size and susceptibility to block of nerve fibers

Fiber Type Type A: Alpha Type A: Beta Type A: Gamma Type A: Delta Type B Type C: Dorsal Root Type C: Sympathetic Function
Proprioception, Proprioception, motor Touch, pressure

Myelination Heavy Heavy Heavy Heavy Light None None

Diameter (m) 1212-20 5-12 3-6 2-5 <3 0.40.4-1.2 0.30.3-1.3

Conduction ) Velocity (m/s (m/s) 7070-120 3030-70 1515-30 1212-30 3-15 0.50.5-2.3 0.70.7-2.3

Sensitivity to Block

+ ++ ++ +++ ++++ ++++ ++++

Muscle spindles Pain, temperature Preganglionic autonomic Pain

Postganglionic

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Factors affecting Local Anesthetic action: - pKa - Lipid Solubility - Protein Binding - Vasodilator Activity - Principles of Local Anesthetics pKa All LA are weak bases with a pKa range of 7.7-8.9. All LA molecules exist in 2 states: A free base (uncharged) that readily penetrates connective tissues and lipid-rich membranes; and a cation (positively charged species) that is unable to cross membranes. When the pH=pKa then the proportion of the two species is 50:50. If pKa increases, or the pH of the surrounding environment decreases then a greater proportion of the charged form will exist. Example Lidocaine pKa =7.8

Injected into an inflamed area with pH=6.0

98% Cationic species IMPERMEABLE 2% Uncharged species

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Relationships between pKa, Ionization, and Local Anesthesia onset at pH 7.4 Drug Mepivicaine Lidocaine Prilocaine Articaine Etidocaine Bupivicaine pKa 7.7 7.8 7.8 7.8 7.9 8.1 % Cationic 67 71 71 71 76 83 % Free Base Onset time (min) 33 29 29 29 24 17 2-4 2-4 2-4 2-4 2-4 5-8

Hersh EV. Local Anesthetics. In: Fonseca RJ. Oral and Maxillofacial Surgery, 2000

Lipid Solubility The major determination of potency for LA is their intrinsic lipid solubility. The general rule is: More lipid solubility = More potency. As a result, agents with lower solubility are generally marketed at higher concentrations.

Relationships between lipid solubility and clinically effective LA concentration Drug Articaine Mepvicaine Prilocaine Lidocaine Bupivicaine Etidocaine Lipid Solubility 40 42 55 110 560 1853 Concentration (%) 4 2-3 4 2 0.5 1.5

Adapted from: Jastak JT et al. Local Anesthesia of the Oral Cavity, 1995.

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Protein Binding Increased protein binding allows anesthetic molecules to be more firmly attached to proteins at receptor sites. The general rule is: Increased protein binding = longer duration of action. Duration of Local anesthesia is based on several factors: - Affinity of the LA to the nerve membrane (Lipid and protein components) - Type of injection - Presence or absence of vasoconstrictor - Pulpal vs. soft tissue anesthesia?

Protein Binding Characteristics and Duration of Action Agent Prilocaine Lidocaine Mepivacaine Etidocaine Bupivacaine Articaine Approx. Protein Binding 55 65 75 94 95 95 Duration of action (mins) 40-220 60-190 25-165 30-470 40-440 60-220

Adapted from: Malamed SF. Handbook of Local Anesthesia, 1990. and Jastak JT. Local Aneshesia of the Oral Cavity, 1995.

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Average Durations of Local Anesthesia after Intraoral Injection (mins) Maxillary Inferior Alveolar Infiltration Block Soft Soft Pulpal Pulpal Tissue Tissue 2% Lidocaine w/ 1:100K or 1:50k epi 3% Mepivacaine 4% Prilocaine 0.5% Bupivacaine w/ 1:200k epi 1.5% Etidocaine w/ 1:200k epi 4% Articaine w/ 1:100k or 1:200k epi 60 25 20 40 30 60 170 90 105 340 280 170 85 40 55 240 240 90 190 165 190 440 470 220

Jastak JT et al. Local Aneshesia of the Oral Cavity, 1995.

Local Anesthetic Lidocaine Mepivacaine Prilocaine Bupivacaine Etidocaine Articaine

Elimination Half-life (mins) 96 114 96 210 156 27 mins (Hepatic 108 mins)

Malamed SF. Handbook of Local Anesthesia. 4th Ed, 1997. Drug Information Handbook for Dentistry. 6th Ed, 2001.

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Relative Vasodilating Values of Amide-Type Local Anesthetics Vasodilatory Activity Articaine Bupivacaine Etidocaine Lidocaine Mepivacaine Prilocaine 1 2.5 2.5 1 0.8 0.5

Maximum Recommended Dosages of Common Local Anesthetics # of # of Carpules Carpules Adult 50 lb Child
13.8 5.5 8.3 7.4 11.1 8.3 8.3 4.6 NR 2.8 2.5 3.7 2.8 2.8

Local Anesthetic

Maximum Dose

Lidocaine w/ 1:100k epii (2%-36 mg) 3.3 mg/lb (500 mg) 3.3 mg/lb (500 mg) Lidocaine w/ 1:50k epi 2.0 mg/lb (300 mg) Lidocaine w/o epi Mepivacaine (3% - 54 mg) Mepivacaine (2% w/ 1:20k levo) Prilocaine plain (4% - 72 mg) Prilocaine w/ 1:200k epi 2.6 mg/lb (400 mg) 2.6 mg/lb (400 mg)

4.0 mg/lb (600 mg)

Bupivacaine (0.5%)

0.6 mg/lb (90 mg)

10

NR

Articaine (4% - 72 mg)

3.3 mg/lb (500mg)

6.9

2.3

Dent Clin N Am 2010;54:587599.

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Maximum Recommended Dosages of Vasoconstrictors Concentration mg/mL Epinephrine 0.02 0.01 0.005 Levonordefrin 0.05 Parts / Thousand 1:50,000* 1:100,000 1:200,000 1:20,000 Maximum Recommended Dosage mg 0.2 0.2 0.2 1.0 mL 10 20 40 20 # of Carps 5 11 11 11

* 1:50,000 should be reserved for local hemostasis Max no. of carps is limited by the LA

Hersh EV. Local Anesthetics. In: Fonseca RJ. Oral and Maxillofacial Surgery, 2000

Concentrations of Lidocaine
2% lidocaine 2 gm/100 mL 2,000 mg/100 mL 20 mg/1 mL 1 cartridge = 1.8 mL 20 mg/mL x 1.8 = 36 mg/cartridge Remains the safest local anesthetic for children is lidocaine with 1:100,000 epi Maximum dose is 1 cartridge per 25 pounds (~10kg)

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RULE of 25?
and easy way to estimate maximum local anesthetic doses Calculation yields a dose that will always be less than the MRD
In Quick

healthy patients, the Rule of 25 states a practitioner can use 1 carpule of any local anesthetic formulation for every 25 lbs of body weight
Dent Clin N Am 2010;54:587599.

Pregnancy and Breastfeeding Risk Classification of Local Anesthetics Drug Lidocaine Mepivacaine Prilocaine Bupivacaine Etidocaine Articaine Pregnancy Category B C B C B C JADA 2012;143:858-71. Use during breastfeeding? Yes Yes Yes* Yes Yes With Caution

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Pregnancy and Breastfeeding Risk Classification of TOPICAL Local Anesthetics Use during Drug Pregnancy Category breastfeeding? Lidocaine Dyclonine Benzocaine Tetracaine B C C C JADA 2012;143:858-71. Yes Yes With Caution With Caution

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Local Anesthesia: Minimizing Complications and Maximizing Success Considerations for Mandibular Local Anesthetic Failures Anxiety & Fear Infection Too little volume of anesthetic Central Core Theory Lack of understanding of technique or local anatomy Variations in anatomy Sphenomandibular Ligament Nerve of the Mylohyoid Gonial Angle of the Mandible Highly Anxious Patients Factors such as fear are clearly capable of influencing patient response to painful or other stimuli applied after administration of a local anesthetic. The relationship between these variables may be reciprocal: fear can lead to inadequate anesthesia and being treated with inadequate anesthesia can increase fear Source: Milgrom P, Weinstein P, Getz T. Treating Fearful Dental Patients. 2nd Ed. Seattle, WA: University of Washington Press; 1995:p219. There is a direct relationship between anxiety and acute pain. Increases in anxiety increase sensitivity to pain. Conversely, reductions in anxiety reduce the perception of pain Source: Anesth Prog. 1991;38:120-127. Apprehension is learned but pain is perception. For patients who would otherwise experience no stimulus after an effective anesthetic injection, even the slightest perception is painful. A feeling of pressure or touch can create an expectation of pain, eliciting a response from the patient. Source: Feck AS. Goodchild JH. Compendium 2005;26(3):81-7. Infection

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Volume of Anesthetic In general the volumes of local anesthetic should be: (Br Dent J 1999;186(1):15-20.) Infiltrations: approximately 1.0mL IANB: approximately 1.5mL Palatal or long buccal: 0.2-0.5mL Local Anesthetics Preferably

Block Small Nerve Fibers

Coverage of 3 nodes is needed to stop conduction

Relative size and susceptibility to block of nerve fibers Diameter (m) 12-20 5-12 3-6 2-5 <3 0.4-1.2 0.3-1.3 Conduction Sensitivity to Velocity Block (m/s) 70-120 30-70 15-30 12-30 3-15 0.5-2.3 0.7-2.3 + ++ ++ +++ ++++ ++++ ++++

Fiber Type Type A: Alpha Type A: Beta Type A: Gamma Type A: Delta Type B Type C: Dorsal Root Type C: Sympathetic

Function Proprioception, motor Touch, pressure Muscle spindles Pain, temperature Preganglionic autonomic Pain Postganglionic

Myelination Heavy Heavy Heavy Heavy Light None None

Source: Morgan GE, et al. Clinical Anesthesiology. 4th Ed. 2005.

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What about injection speed? Does injection speed impact efficacy? Kanna MD, et al (2006) 38 subjects Crossover Design (1 week apart) 27ga long needle Slow IANB (delivered over 60 secs) Rapid IANB (delivered over 15 secs)

Central Core Theory?

Onset of Pulpal Anesthesia Slow IANB (60 secs) secs) First Molars Premolars Lateral Incisors
Central Core Theory Nerves on the outside of the nerve bundle (mantle fibers) supply molar teeth. More centrally located nerve fibers (core fibers) innervate the incisors. Local anesthetic placement near to the IAN may diffuse and block the outermost fibers but will not block the inner fibers. May lead to incomplete mandibular anesthesia Incisors may not achieve complete anesthesia. May require mental or incisive block in addition to IANB. Or buccal + lingual infiltration Source: JADA 2011;142(suppl 9):3S-7S. Anesthesiology 1976;45:421-44.

Rapid IANB (15 secs) secs) 6.7mins 7.1mins 11.1mins 9.7mins 11.6mins 10.1mins
J Endod 2006;32:919-23.

5.4mins 3.2mins 8.9mins 8.2mins 13.3mins 9.8mins

Consequences of improper needle placement during traditional IANB Too Low: An injection too far below the lingula will result in lingual anesthesia with inadequate anesthesia of the teeth or bony structures

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Position of the lingula in comparison to the occlusal plane (Oral Surg Oral Med Oral Pathol 1952;5:96688.) In 16% of mandibles, the lingula was less than 1 mm above the occlusal plane 48% were from 1 to 5 mm above the occlusal plane 27% were from 9 to 11 mm above the occlusal plane 4% were from 11 to 19 mm above the occlusal plane A needle inserted 5 mm above the occlusal plane and parallel to it would lie above the lingula in 64% of mandibles and below it in 36%. A needle placed 11 mm above the occlusal plane would be above the lingula in 96% of mandibles

Too Deep (posteriorly): If an injection is made too deeply, the solution may be deposited into the parotid gland resulting in facial nerve anesthesia and paralysis, without mandibular nerve anesthesia Too Mesial: An injection too far mesially will cause anesthetic failure because the solution will be deposited into the media lpterygoid muscle. In addition to anesthetic failure it may cause muscle inflammation and trismus

Direction of IANB

Too Superficial: The solution may be deposited too distant from the lingula and the inferior alveolar nerve. May result in lingual anesthesia but inadequate anesthesia to the teeth Too High: Solution may be deposited into the sigmoid notch, inadequate/no anesthesia would be the result

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Intravascular: If all of part of the local anesthetic solution is deposited intravascularly, local anesthesia may be inadequate. Possible complications include: Hematoma Pain Trismus (also the result of penetrating the medial pterygoid muscle) Effects 2 to the drugs itself (local anesthetics and/or vasoconstrictor) Positive aspiration is infrequent during IANB (2.6-30%). Technique of alternating injection/aspiration is recommended (JADA 1992;123:69-73.) Lack of understanding of local anatomy, variations in anatomy Anatomy of the pterygomandibular space

Source: JADA 2003;134:888-93.

BORDERS OF THE PTERYGOMANDIBULAR SPACE Inferior and Medial: medial pterygoid muscle Anterior: pterygomandibular raphe Superior: lateral pterygoid muscle Lateral: mandibular ramus Posterior: parotid gland

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CONTENTS OF THE PTERYGOMANDIBULAR SPACE Inferior alveolar nerve IA artery and vein Lingual Nerve Sphenomandibular ligament Buccal nerve Mylohyoid nerve Mylohyoid artery and vein

Anatomy of the pterygomandibular space

Diagrammatic representation of a transverse section of the right mandibular ramus at the level at which an IANB would be given Source: Clin Anat 2010;23:936944.

Diagrammatic representation of the right inferior alveolar neurovascular bundle at the level of the lingual Source: Clin Anat 2010;23:936944.

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IAN

8.5mm 7.3mm

Masseter

3.9mm

LN

Recommended insertion of needle for traditional IANB is 1 inch (25.4mm) Average length of short needles: 21.5 mm (hub to tip) Average length of long needles: 33 mm (hub to tip) Summary of Statistics Position of the NVB in relation to the anterior border of the ramus expressed as a ratio of total ramal anteroposterior diameter Direct distance between IAN and LN (mm) 0.60 0.07

8.5 2.4

Anterior displacement of the LN from the IAN (mm) Mediolateral displacement of the LN from the IAN (mm) Source: Clin Anat 2010;23:936944

7.3 2.5 3.9 1.6

Sphenomandibular Ligament Upper attachment on the sphenoid spine, sometimes extending to the petrotympanic fissure and malleus Lower attachment is to the mandibular lingula May be a septum of the pterygomandibular space Barrier against LA!

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Sphenomandibular Ligament: Lower attachment is to the mandibular lingula There is significant variation regarding the lower attachment: The SML may also attach to the inferior margin of the mandibular foramen, extending superiorly and posteriorly to the posterior border of the mandible, up the condyle where it can merge with stylomandibular ligament The mylohyoid nerve passes medially and behind the ligament before passing into the mylohyoid groove of the ramus In one study, 60% of SML studied extended from the anterior border of the lingula to the posterior border of the ramus Source: Cranio 2007;25(3):160-5. Dent Clin N Am 2012;56:133148.

Mylohyoid Nerve (MN) The nerve to the mylohyoid is derived from the mandibular division of the trigeminal nerve It provides motor supply to the mylohyoid and digastric muscles MN splits superiorly to the mandibular foramen (~13-14mm), and passes along the mylohyoid groove (which is parallel to the mandibular canal) It has long been suspected that the mylohyoid nerve is a mixed motor and sensory nerves supplying accessory innervation to the mandibular teeth It may join with the lingual nerve It also may enter the mandible through foramen in the symphysis or premolars, in this case it may terminate directly into the mandibular teeth or join with the incisive nerve Source: Clin Anat 2010;21:591-5. Aust Endod J 2001;27(3);109-11.

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Inferior Alveolar Nerve Mylohyoid Nerve

Lingual Nerve

Anesthetizing the Mylohyoid Nerve (MN) The nerve may be anesthetized by infiltrating the soft tissue over the disto-lingual root surface of the tooth requiring treatment; or simply under the lingual mucosa adjacent to the tooth requiring treatment

Goal is to bathe the nerve as branches of it enter the lingual surface of the mandible

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Gonial Angle of the Mandible Several studies have looked at the relationship between the gonial angle and the position of the mandibular foramen Average gonial angle among the publications was 120.4 Gonial angle was inversely related to the anterior-posterior width of the ramus and the distance from the mandibular foramen to the mandibular border For patients with a wide gonial angle, the IANB is accomplished lower and possibly with a smaller needle. For patients with a narrow gonial angle, the IANB is accomplished higher and possibly with a larger needle Effect of Age on Gonial Angle: Gonial angle decreased significantly with age (approximately 140 to 120) . Also, with increasing age the mandibular foramen moves anteriorly approximately 5.5mm. Mandibular foramen increases in size by 40% from childhood to adulthood. Source: Int J Morphol 2009;27(4):1305-11. Anat Rec 1985;212(1):110-2. West Ind Med J 2002;51(12):14.

26mm 14mm

30mm 16mm 22mm 124

19mm 131

Smaller Gonial Angle corresponds with a thicker width of ramus Larger Gonial Angle corresponds with a thinner width of ramus

Eur J Orthodond 2009;31:59-63. Int J Morphol 2009;27(4):1305-11.

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