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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 Mepivacaine Lidocaine Articaine Etidocaine Prilocaine Bupivacaine Procaine pKa 7.7 7.8 7.8 7.9 7.9 8.1 9.1 ONSET (MIN) 2-4 min 2-4 min 2-4 min 2-4 min 2-4 min 5-8 min 14-18 min Local Anesthetics: Protein Binding vs. Duration Bupivacaine RELATIVE PROTEIN BINDING 95 Etidocaine 94 LONG Mepivacaine 75 MODERATE Lidocaine 65 MODERATE Prilocaine 55 MODERATE Procaine 5 SHORT AGENT DURATION LONG Manufacturers’ Recommended Dose AGENT Lidocaine +Epinephrine Mepivacaine+/- Vaso Prilocaine +/- Epi Articaine + Epi Bupivacaine + Epi ADULT ABSOLUTE DOSE MAXIMUM (mg/lb) (mg) 2 300 3 500 3 400 3.6 400 3.2 500 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) SIGNS – – – – 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 lightheadedness – Dizziness – Visual and auditory disturbances – Disorientation Local Anesthetics: PaCO2 vs. Convulsant Threshold (Cats) AGENT Procaine PaCO2 (25-40 torr) 35 PaCO2 (68-81 torr) 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 4 Opio id Dose (Multip le sofMRD) 3 Re c o v e ry Bra in Da m age/ De a th 2 1 Redrawn from Moore & Goodson, Anesth Prog 32:129 (1985) 0 0 1 2 3 L o c a lAn e s th e tic Do s e (Mu ltip le s o fMRD) 4 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 Not significant between the two groups – Vital sign changes and adverse events 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 – 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 – 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 – 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 – 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. 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 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. 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