LOCAL ANESTHESIA

Ester Local Anesthetics Cocaine Benzocaine Procaine Tetracaine Chloroprocaine

Amide Local Anesthetics Lidocaine Mepivacaine Prilocaine Bupivacaine Etidocaine Articaine

Metabolism of Amide Local Anesthetics Biotransformation by hepatic microsomal enzyme system Drugs may increase metabolism via enzyme induction Liver disease may decrease metabolism via decreased functional tissue Decreased metabolism secondary to decreased hepatic blood flow

Metabolism of Ester Local Anesthetics Hydrolyzed by plasma cholinesterase Factors which may lead to decreased plasma esterase activity Liver dz—decreased protein synthesis Pregnancy—decreased pseudocholinesterase activity Atypical pseudocholinesterase

Excretion of Local Anesthetics Active metabolites excreted by kidney Severe renal disease may result in accumulation of active metabolites and produce toxicity

Local Anesthetics: pKa vs. Onset of Action AGENT pKa ONSET (MIN) Mepivacaine 7.7 2-4 min Lidocaine 7.8 Articaine Etidocaine 7.9 Prilocaine Bupivacaine 8.1 5-8 min Procaine 9.1 14-18 min

Local Anesthetics: Protein Binding vs. Duration AGENT RELATIVE PROTEIN BINDING DURATION Bupivacaine 95 LONG Etidocaine 94 Mepivacaine 75 MODERATE Lidocaine 65 Prilocaine 55 Procaine 5 SHORT

Manufacturers’ Recommended Dose AGENT ADULT DOSE (mg/lb) ABSOLUTE MAXIMUM (mg) Lidocaine +Epinephrine 2 3 300 500 Mepivacaine+/- Vaso 400 Prilocaine +/- Epi 3.6 Articaine + Epi 3.2 Bupivacaine + Epi 0.6 90

Local Anesthetics: Adverse Effects Central Nervous System Cardiovascular System Respiratory System Local Toxicity (skeletal muscle)

Local Anesthetics: CNS Effects Anticonvulsant Properties Procaine, lidocaine, mepivacaine Low dose; 1-4.5 ug/ml CNS depression; preconvulsant 4.5-7 ug/ml CNS depression; tonic-clonic seizures 7.5-10 ug/ml Generalized CNS depression >10 ug/ml

Preconvulsant: Signs and Symptoms (4.5-7 ug/ml) Slurred speech Shivering Muscular twitching Tremor in muscles of face and distal extremities SYMPTOMS Numbness of tongue and circumoral region Warm, flushed feeling of skin Pleasant dream-like state Generalized light-headedness Dizziness Visual and auditory disturbances Disorientation

Local Anesthetics: PaCO2 vs. Convulsant Threshold (Cats) AGENT PaCO2 (25-40 torr) (68-81 torr) Procaine 35 17 Prilocaine 22 12 Mepivacaine 18 10 Lidocaine 15 7 Bupivacaine 5 2.5

Local Anesthetics: CV Effects Decreased electrical excitability, conduction rate and force of myocardial contraction (1.8-5 ug/ml) .5-2 ug/ml—normal blood level following intraoral injection (no CV effects) 5-10 ug/ml—myocardial depression and peripheral vasodilation >10 ug/ml—massive peripheral vasodilation, intensive myocardial depression, arrest

Local Anesthetics: Drug Interactions Tricyclic antidepressants Cocaine Beta-adrenergic blocking agents Phenothiazines alpha blocking effect

Local Anesthetic Toxicity: Interaction w/ Opioids Redrawn from Moore & Goodson, Anesth Prog 32:129 (1985)

Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults.Hersh E,et al. JADA; 139 August 2008; 1080-1093 Objective To determine the efficacy of soft tissue reversal Phentolamine mesylate Non-selective alpha-adrenergic blocking agent used for the treatment of HTN associated with pheo. 1.7 ml carpule with 0.4 mg phentolamine mesylate Methods Four different locals with epi utilized All injections resulted in soft tissue anesthesia to the lower/upper lip 244 subjects

Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults.Hersh E,et al. JADA; 139 August 2008; 1080-1093 Methods Randomized to phentolamine or sham injection Subjective analysis of numbness q 5 min and function testing (speech, drooling, etc)

Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults.Hersh E,et al. JADA; 139 August 2008; 1080-1093 Results Tongue function Phentolamine group; 60 min Sham group; 125 minutes Lower lip Phentolamine group; 70 min Sham group; 155 min Upper lip Phentolamine group; 50 min Sham group; 133 min Vital sign changes and adverse events Not significant between the two groups

Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults.Hersh E,et al. JADA; 139 August 2008; 1080-1093 Conclusions “...safe and efficacious in reducing the duration of soft tissue anesthesia and function” Studies have also found the drug to be safe and efficacious in children 6-12 Children 4-6 were not included secondary to poor historians in determining level of soft tissue anesthesia, but the drug was found to be safe with no adverse events

ANALYSIS OF N2O/O2 SEDATION

N2O/O2 ADVANTAGES… Analgesia: variable Sedation Amnestic Rapid Onset 20% = 15mg morphine Sedation Calm, relaxed, and tolerant Amnestic Passage of time becomes unclear Rapid Onset Clinical effects < 30 seconds, peak effects < 5 minutes

N2O/O2 ADVANTAGES… Titration Recovery In combination Sedation depth is easily controlled Recovery Complete recovery in < 3-5 minutes In combination Sophrology, distraction techniques, premedication, local anesthesia

DISADVANTAGES N2O/O2… Weak anesthetic Air space expansion MAC 104-105% Air space expansion N2O is 35 times as soluble as N2 Diffusion hypoxia HA, N/V, and lethargy Need for cooperative patient

Contraindications to N2O/O2 sedation… Absolute Respiratory tract infection Craniofacial deformity Relative Severe emotional and behavior problems Clinically significant COPD Pregnancy Drugs: potentiating effects of N2O/O2

Properties of N2O… Manufacturing NH4NO3  N2O + 2H2O 99.5-99.9% pure Major contaminant is nitrogen Sweet smelling and nonflammable Will support combustion in the proper concentration

Properties of N2O… Stored as a liquefied compressed gas Full cylinder = 95% liquid, 5% vapor 35 times more soluble than N2 Stable, does not react with soda lime, anesthetic drugs, or metal anesthesia equipment

PHARMACOLOGY OF NITROUS OXIDE

Pharmacokinetics N2O… Relatively insoluble in blood N2O replaces N2 Quick onset N2O replaces N2 35 times more soluble than N2 Rigid body spaces—increase pressure Non-rigid spaces—increase volume

Pharmacokinetics N2O… Tissue concentrations Gas solubility Blood flow to tissue Conc. of gas in arterial blood Factors for elimination of N2O Same as uptake factors Diffusion hypoxia Metabolism N2O not metabolized 99% eliminated through lungs

Central Nervous System… Mechanism of action: unknown Cerebral cortex: depression of all forms of sensation. Memory and concentration minimally affected Cerebellar functions: ataxia and uncoordinated movements, nystagmus Chronic exposure Pneumocephalus

Hematopoietic System… Megaloblastic bone marrow changes: primarily seen with abuse cases

Drug Reactions/Interactions No reported allergies to N2O in 150 years of use Drug interaction: no direct interactions reported, but may enhance other CNS depressants

OCCUPATIONAL EXPOSURE

History of Controversial Literature… Vaisman 1967 Cohen et al 1970 Bruce, Bach, and Arbit 1970 OSHA standards Clark 1995

Specific Biologic Issues and Health Concerns

Biochemical and Metabolic … Inactivation of Vit. B12 Enzyme Systems Blocked Methionine synthase Methylmalonyl-CoA mutase Leucine 2,3-aminomutase Studies and clinical significance

Health Concerns… Nunn et al Deoxyuridine Supression Test—detects early signs of inactivation of the enzyme methionine synthase No alteration if this enzyme occurred in anesthetists exposed to between 150-400 ppm

Health Concerns… Because of the demands for folic acid during organogenesis (first trimester) postponement of N2O sedation is recommended. Pregnant females employed in a setting using N2O– important to know the exposure levels of N2O Safe use of scavenging systems.

Biochemical and Metabolic.. Hematological Effects Megaloblasic anemia Leukopenia Thrombocytopenia

Biochemical and Metabolic Inactivation of Vit. B12 Enzyme Systems Blocked Methionine synthase Methylmalonyl-CoA mutase Leucine 2,3-aminomutase Studies and clinical significance

Biochemical and Metabolic Hematological Effects Megaloblasic anemia Leukopenia Thrombocytopenia

Health Concerns… Abuse: chronic—MS like symptoms and myloneuropathies Paresthesia of extremities Loss of dexterity Loss of balance Muscle weakness in legs Gait ataxia Impotence

3,187 patients scheduled for GA for abdominal procedure Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery. A Randomized Controlled Trial Myles P, Leslie K et al Anesth. 2007; 107:221-31 3,187 patients scheduled for GA for abdominal procedure One group received 70% nitrous and 30% oxygen with anesthetic One group received 80% oxygen and 20% nitrogen with anesthetic End-points included: N/V, complications, arousal, quality of recovery, etc

Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery. A Randomized Controlled Trial Myles P, Leslie K et al Anesth. 2007; 107:221-31 Results Nitrous group had a lower incidence of major complications and N/V No difference in length of hospital stay Shorter time spent in ICU Conclusions Avoidance of nitrous oxide and concomitant increase in oxygen decreased the incidence of complications after major surgery

CONTROL OF OCCUPATIONAL EXPOSURE

Detection and Monitoring Establish base-line and monitor exposure Limit legal liability Techniques of monitoring Infrared spectrophotometry Time-weighted average dosimetry

Dosimetry Devices

ADA Recommendations… Monitor office with N2O analyzer Use scavenging mask Vent gases outside of building Minimize patient conversation Test equipment for leaks monthly Employ air sweep ventilation Achieve levels of < 50ppm

Sexual Phenomena with N2O… Euphoric effects associated with N2O: hallucinations, visualizations, auditory illusions, and sexual stimulation Legal and personal consequences Common sense approach to N2O administration Concentration < 50%, 3rd person, No suggestive language