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Triazolam Triazolam Halcion™ Halcion™ Oral Oral Sedation Sedation 6/6/05 Copyright Quarnstrom Donaldson Is Halcion the Fred Quarnstrom, DDS theFADSA, ugly FAGD, Dirty FICD Duck Diplomate, American Dental Board of Anesthesionogy orDiplomate, beautiful Black Swan? National Dental Board of Anesthesiology 6/6/05 Certified, American Association of Dental Consultants Copyright Quarnstrom Donaldson patients - AAOMS - OCS Where is the ADA? 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 WouldCopyright youQuarnstrom please try to relax. Donaldson Mortality from Anesthesia 1970-1979 U. K. Dentists 1:260,000 Physicians 1:248,000 Single Operator / Anesthetist Anesthetist 1:143,000 One Operator One Anesthetist Anesthetist 1:598,000 Conscious sedation 1:1,000,000 (patient (patient died died on on aa motorcycle motorcycle later later the the same same day) day) note - this study was pre pre pulse pulse oximeter oximeter useage useage Dionne, Dionne, Pharmacologic Pharmacologic Considerations Considerations in in Training Training of of Dentists Dentists in in Anesthesia Anesthesia and and Sedation, Sedation, Anes Anes Prog Prog 36:113-116 36:113-116 1989 1989 6/6/05 Copyright Quarnstrom Donaldson The Spectrum of Anesthesia Normal Anxiolysis Conscious Sedation 1. Protective reflexes intact Patient can independently and continuously maintain an airway Patient can respond appropriately to verbal commands 6/6/05 Deep Sedation 2. Partial loss of protective reflexes Inability to independently maintain an airway May not respond to verbal commands Copyright Quarnstrom Donaldson General Anesthesia 3. Loss of protective reflexes Inability to independently maintain an airway No pain sensation or reflex withdrawal from stimuli Total unconsciousness Risks of Anesthesia high Deep Sedation Moderate Sedation Local Anesthesia Anxiolysis low 6/6/05 N20 Copyright Quarnstrom Donaldson General Anesthesia AGE VS ANESTHETIC-INDUCED, CARDIAC ARREST / DEATH incidence rate 0.05 0.04 0.03 0.02 0.01 << 11 1-10 60 1-10 11-20 11-20 21-30 21-30 31-40 31-40 41-60 41-60 >> 60 Marx, Marx,Anes., Anes., 39:54-58, 39:54-58, 1973 1973 6/6/05 Copyright Quarnstrom Donaldson AGE VERSUS SEVERE SEVERE MORBIDITY/MORTALITY MORBIDITY/MORTALITY 44 33 22 11 00 <10 <10 11-20 11-20 21-30 21-30 31-40 31-40 41-60 41-60 age range = 21 mo. - 59 yr. Jastak, Jastak,Anes Anes Prog Prog,, 38:39-44 38:39-44 1991 1991 6/6/05 Copyright Quarnstrom Donaldson AGE VERSUS SEVERE MORBIDITY/MORTALITY 44 33 22 11 00 <10 <10 11-20 11-20 21-30 21-30 31-40 31-40 41-60 41-60 age range = 21 mo. - 59 yr. Jastak, Jastak,Anes Anes Prog Prog,, 38:39-44 38:39-44 1991 1991 6/6/05 Copyright Quarnstrom Donaldson Standards for Conscious Sedation Level 1 minimal sedation - Anxiolysis Level 2 Moderate Sedation/Analgesia Conscious Sedation Level 3 Deep Sedation/Analgesia Level 4 Anesthesia Anesthesia Today vol.11 No. 2 Fall 2000 p. 2 6/6/05 Resek, Jayne, MS RN, Copyright Quarnstrom Donaldson Standards for Conscious Sedation Level 1 minimal sedation - Anxiolysis A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected. Level 2 Moderate Sedation/Analgesia Conscious Sedation Level 3 Deep Sedation/Analgesia Level 4 Anesthesia Anesthesia Today vol.11 No. 2 Fall 2000 p. 2 6/6/05 Resek, Jayne, MS RN, Copyright Quarnstrom Donaldson Standards for Conscious Sedation Level 1 minimal sedation - Anxiolysis Level 2 Moderate Sedation/Analgesia Conscious Sedation A drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patient airway and spontaneous ventilation is adequate. Cardiovascular function is usually maintained. Level 3 Deep Sedation/Analgesia Level 4 Anesthesia Anesthesia Today vol.11 No. 2 Fall 2000 p. 2 6/6/05 Resek, Jayne, MS RN, Copyright Quarnstrom Donaldson Standards for Conscious Sedation Level 1 minimal sedation - Anxiolysis Level 2 Moderate Sedation/Analgesia Conscious Sedation Level 3 Deep Sedation/Analgesia A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained. Level 4 Anesthesia Anesthesia Today vol.11 No. 2 Fall 2000 p. 2 6/6/05 Resek, Jayne, MS RN, Copyright Quarnstrom Donaldson Standards for Conscious Sedation Joint Commission on Accreditation of Healthcare Organizations (JCAHO) Level 1 - None Level 2 - conscious sedation - pulse oximeter and Blood Pressure, ability to resuscitate. Monitoring YES Patient assessment - ASA status YES - 1 OR 2 Staff - someone is always with the patient YES Equipment YES Informed consent YES Competent at least one level greater than where you6/6/05 normally if patients into level Resek, Jayne,practice MS RN, Anesthesia Today vol.11slip No. 2 Fall 2000next p. 2 Copyright Quarnstrom Donaldson NORMAL DISTRIBUTION CURVE mean freq. hyper hypo 11 S.D.= S.D.= 66% 66% 22 S.D. S.D. == 95% 95% 33 S.D. S.D. == 99.7% 99.7% response Pallasch, Anes. Prog. 35:87-101,1988 6/6/05 Copyright Quarnstrom Donaldson Chloral Hydrate Response 100 ED50 LD50 50 Margin of Safety 0 Dose 6/6/05 Copyright Quarnstrom Donaldson Drug Distribution and Elimination Compartment models Volume of distribution First and zero kinetics Clearance and extraction ratios First pass effects Drug half lives 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 Compartment Models Simple one compartment model all drugs spread uniformly through the body Two and three compartment model - better varying blood flows changes in pH plasma protein binding tissue affinity for certain drugs Three compartment model is most accurate But two compartment is OK in most cases. central compartment- extra cellular fluid and organs peripheral tissue compartment - muscle and fat 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 Volume of Distribution Apparent volume of distribution (Vd) If Vd is small - drug is bound to plasma - little drug will be in tissues - higher blood concentrations If Vd is large it will be widely distributed through the tissues - but lower blood concentrations 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 First and Zero Order Kinetics First-order - a constant percentage crosses a membrane or is metabolized per unit of time - filtration of is determined by concentration. Zero-order - a constant amount of drug is metabolized per unit of time - independent of drug concentration. Ethanol metabolism is zero-order. There is a limited number of receptor cites to metabolize that drug 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 Clearance and Extraction Ratios Clearance is the amount of blood volume from which the drug is completely removed, cleared, per unit of time. ml./min. It is the total of all clearances of all organs. Extraction ratio is the difference in drug concentrations from the arterial to the venous blood of an organ from 0 to 1. If one, all drug is removed first pass if 0 non is removed by that organ. 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 First Pass Effects Some drugs have such high Extraction ratios that virtually all is removed First pass through the liver. If the drug is taken orally literally none of it reaches the tissue. Romazicon, flumazenil, is such a drug. It cannot be given orally as it is absorbed through the intestinal wall into the portal circulation and goes directly to the liver where it is almost 100% deactivated. 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 Drug Half Lives, T1/2 This is the time it take any drug concentration to fall 50%. It is based on a two-compartment model, first-order kinetics (constant % of drug concentration) and an exponential decline have the concentration for each fixed time increment. It is generally a reliable indicator of the rate of removal of a drug from the blood and body - duration of action. Exception high fat soluble drug - diazepam, valium Has a half life of 20 - 50 hours but it is very fat soluble so blood levels fall like a much shorter half life 6/6/05 Copyright Quarnstrom Donaldson Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 Drug Half Lives, T1/2 Oral I.V. 100 Distribution from blood to tissue distribution (alpha phase) 75 Half Lives, T1/2 50 Elimination via liver and kidneys Elimination (beta phase) 25 0 0 6/6/05 2 4 8 10 0 2 Copyright Quarnstrom Donaldson 4 8 10 Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 CHLORAL HYDRATE CL O H CL C C H CL O H chloral hydrate 6/6/05 CL H CL C C H CL O H trichloroethanol Copyright Quarnstrom Donaldson CHLORAL HYDRATE age age sex sex 15 15 O O 22 22 O O weight weight dose dose procedure procedure reaction reaction drugs drugs 115 115 33 g. g. ex ex 3rd molars vom vomit narcan narcan dopamine dopamine 120 120 2.5g. 2.5g. ex ex 3rd molars problem problem outcom outcome blood blood levels 6/6/05 epinephrine epinephrine c.a. c.a. c.a. c.a. revived died revived died 65 71 65 µg/m l 71 µg/m l (( normal normal 5 - 15 µg/ml after 1 gm dose) Copyright Quarnstrom Donaldson CHLORAL HYDRATE INDUCED ARRHYTHMIAS age age dose dose 22 99 17 17 19 19 21 21 29 29 32 32 33 33 1.5 1.5 0.6 0.6 14 14 17.5 17.5 20 20 10 10 20 20 40 40 arrhythmia arrhythmia c. c. a. a. PVC PVC SVT SVT PVC, PVC, VT VT PVC, PVC, Vfib Vfib VT VT PVC, PVC, VT VT PVC, PVC, Vfib Vfib PVC PVC no no no no no no yes yes no no no no yes yes yes yes antiarrhythmia antiarrhythmia outcome outcome drug drug resistance resistance no yes yes yes no yes survived survived survived survived survived survived survived survived survived survived survived survived survived survived died died In In large large doses, doses, it it shortens the cardiac refractory period. May May sensitize sensitize heart to circulating catecholamines. Jastak, J.A.D.A., vol 116, march 1988 6/6/05 Copyright Quarnstrom Donaldson Chloral hydrate vs Halcion Response 100 ED50 LD50 50 Margin of Safety Margin of Safety 0 Dose 6/6/05 Copyright Quarnstrom Donaldson LD50 NORMAL DISTRIBUTION CURVE mean freq. hyper hypo 11 S.D.= S.D.= 66% 66% 22 S.D. S.D. == 95% 95% 33 S.D. S.D. == 99.7% 99.7% response Pallasch, Anes. Prog. 35:87-101,1988 6/6/05 Copyright Quarnstrom Donaldson APPREHENSION CONTROL sedation - mildly sleepy people are less likely to feel fearful barbiturates alcohol - trichloroethanol (chloral hydrate) anti anxiety medication mephenesin meprobamate - 1955 benzodiazepine librium - 1960 valium - 1965 Snyde, Drugs and the Brain, N.Y.,Scientific American Library, 1986 6/6/05 Copyright Quarnstrom Donaldson TRANQUILIZERS 1945 Frank Berger - While attempting to discover an antibacterial for penicillin resistant bacteria, discovered mephenesin which he noted quieted mice. An effect he referred to as "tranquilization." He developed a derivative meprobamate, which turned out to be a sedative not a tranquilizer. Snyde, Drugs and the Brain, N.Y.,Scientific American Libr ary, 1986 6/6/05 Copyright Quarnstrom Donaldson BENZODIAZEPINE DRUGS Roach was attempting to imitate the nonsedating nonaddicting antianxiety actions attributed to meprobamate. ( It turned out meprobamate was a simple sedative.) The goal was noble. The rational for the search was flawed as such an agent did not exist. to relieve anxiety Snyde, Drugs and the Brain, N.Y.,Scientific American Library, 1986 6/6/05 Copyright Quarnstrom Donaldson BENZODIAZEPINE TRANQUILIZERS Leo Sternbach 1930 - Cracow, Poland developed quinazolines. evaluated for Roach in 1955 saw no sedationturned chemicals over to Randall Lowell Randall found an active agent Sternbach reexamined chemical properties found it was not a quinazoline - named the new class benzodiazepines librium - 1960 valium - 1963 by 1975 15% of population 100,000,000 Rx / yr. Snyde, Drugs and the Brain, N.Y.,Scientific American Libr ary, 1986 6/6/05 Copyright Quarnstrom Donaldson BENZODIAZEPINE DRUGS relieve anxiety produce some drowsiness - patients became tolerant to this effect in a few days "vague uneasiness, generalized fear and associated physical symptoms of anxiety fade away." tolerance develops withdrawal occur advantage - overdoses are rarely fatal except with alcohol or barbiturates Snyde, Drugs and the Brain, N.Y.,Scientific American Libr ary, 1986 6/6/05 Copyright Quarnstrom Donaldson GABA NH2 - CH2 - CH2- CH2 - CO2 6/6/05 Copyright Quarnstrom Donaldson GABA Receptor Cl Cl Cl Cl cell wall Cl A B Cl 6/6/05 Copyright Quarnstrom Donaldson Cl Diazepam Alcohol Gaba Receptors Sedativeconvulsant Benzodiazepine Cl-- ion channel 6/6/05 Copyright Quarnstrom Donaldson Gaba Diazepam Alcohol Gaba Actions Cl Cl Cl Cl Cl 6/6/05 Cl Copyright Quarnstrom Donaldson Pharmacology Compare Compare to to valium valium Absorption Absorption Half Half life life Active Active metabolites metabolites Structure-activity Structure-activity relationship relationship Nitrogen Nitrogen atom atom prevents prevents water water solublity. solublity. Triazo Triazo ring ring alows alows quick quick metabolism metabolism Chlorine Chlorine atom atom is is responsible responsible for for potency. potency. Chlorine Chlorine atom atom is is responsible responsible for for benzodiazepine benzodiazepine action. action. 6/6/05 Copyright Quarnstrom Donaldson Halcion - Triazolam N N H C 3 N N Cl Cl 6/6/05 Copyright Quarnstrom Donaldson Triazolam Structure-Activity N triazo ring is responsible for ease of oxidation N N H C 3 nitrogen is responsible for lack of water solubility N N Cl Cl is responsible for potency Cl 6/6/05 Cl is responsible for benzodiazapine action Copyright Quarnstrom Donaldson Diazepam vs Triazolam H O H C 3 N N N N Cl H H C 3 N Cl Cl Diazepam 6/6/05 N Triazolam Copyright Quarnstrom Donaldson Benzodiazepine Elimination drug drug alprazolam alprazolam time time to peak plasm plasma conc. elim elimination ination half-life half-life m ajor active m etabolites 1-2 1-2 hr. hr. 12-15 12-15 hr. hr. -hydroxyalprazolam -hydroxyalprazolam 0.5 0.5 -- 4.0 4.0 hr. hr. 20-70 20-70 hr. hr. 1-6 1-6 hr. hr. 10-18 10-18 hr. hr. desmethyldiazepam desmethyldiazepam (oxepam) (oxepam) none none ** 2-5 2-5 hr. hr. none none 1-4 1-4 hr. hr. 5-15 5-15 hr. hr. none none 11- 22 hr. hr. §§ 1.5-5.0 1.5-5.0 hr.• hr.• -hydroxytriazolm -hydroxytriazolm Xanax Xanax diazepam diazepam Valium Valium lorazepam lorazepam Ativan Ativan midazolam midazolam Versed Versed oxazepam oxazepam Serax Serax triazolam triazolam Halcion Halcion §§ peak peak concentration concentration is is 28% 28% faster faster ifif given given sublingually sublingually • half life will be prolonged in the presence • half life will be prolonged in the presence of of erythromycin, erythromycin, cimethidine cimethidine (tagamet), (tagamet), isoniazid isoniazid and and possibly possibly oral oral contraceptives contraceptives ** not not available available as as an an oral oral agent agent 6/6/05 Copyright Quarnstrom Donaldson Diazepam vs Triazolam drug time to peak elim ination plasm a conc. half-life triazolam 1 - 2 hr. § diazepam 0.5 - 4.0 hr. 20 - 50 hr m ajor active m etabolites 1.5 -5.0 hr.• -hydroxytriazolm desm ethyldiazepam (oxepam ) § peak concentration is 28% faster if given sublingually • half life will be prolonged in the presence of erythromycin, cimethidine (tagamet), isoniazid and possibly oral contraceptives 6/6/05 Copyright Quarnstrom Donaldson Benzodiazepine Elimination drug drug alprazolam alprazolam time time to peak plasm plasma conc. elim elimination ination half-life half-life m ajor active m etabolites 1-2 1-2 hr. hr. 12-15 12-15 hr. hr. -hydroxyalprazolam -hydroxyalprazolam 0.5 0.5 -- 4.0 4.0 hr. hr. 20-70 20-70 hr. hr. 1-6 1-6 hr. hr. 10-18 10-18 hr. hr. desmethyldiazepam desmethyldiazepam (oxepam) (oxepam) none none ** 2-5 2-5 hr. hr. none none 1-4 1-4 hr. hr. 5-15 5-15 hr. hr. none none 11- 22 hr. hr. §§ 1.5-5.0 1.5-5.0 hr.• hr.• -hydroxytriazolm -hydroxytriazolm Xanax Xanax diazepam diazepam Valium Valium lorazepam lorazepam Ativan Ativan midazolam midazolam Versed Versed oxazepam oxazepam Serax Serax triazolam triazolam Halcion Halcion §§ peak peak concentration concentration is is 28% 28% faster faster ifif given given sublingually sublingually • half life will be prolonged in the presence • half life will be prolonged in the presence of of erythromycin, erythromycin, cimethidine cimethidine (tagamet), (tagamet), isoniazid isoniazid and and possibly possibly oral oral contraceptives contraceptives ** not not available available as as an an oral oral agent agent 6/6/05 Copyright Quarnstrom Donaldson Benzodiazepine Elimination drug drug alprazolam alprazolam time time to peak plasm plasma conc. elim elimination ination half-life half-life m ajor active m etabolites 1-2 1-2 hr. hr. 12-15 12-15 hr. hr. -hydroxyalprazolam -hydroxyalprazolam 0.5 0.5 -- 4.0 4.0 hr. hr. 20-70 20-70 hr. hr. 1-6 1-6 hr. hr. 10-18 10-18 hr. hr. desmethyldiazepam desmethyldiazepam (oxepam) (oxepam) none none ** 2-5 2-5 hr. hr. none none 1-4 1-4 hr. hr. 5-15 5-15 hr. hr. none none 11- 22 hr. hr. §§ 1.5-5.0 1.5-5.0 hr.• hr.• -hydroxytriazolm -hydroxytriazolm Xanax Xanax diazepam diazepam Valium Valium lorazepam lorazepam Ativan Ativan midazolam midazolam Versed Versed oxazepam oxazepam Serax Serax triazolam triazolam Halcion Halcion §§ peak peak concentration concentration is is 28% 28% faster faster ifif given given sublingually sublingually • half life will be prolonged in the presence • half life will be prolonged in the presence of of erythromycin, erythromycin, cimethidine cimethidine (tagamet), (tagamet), isoniazid isoniazid and and possibly possibly oral oral contraceptives contraceptives ** not not available available as as an an oral oral agent agent 6/6/05 Copyright Quarnstrom Donaldson Benzodiazepine Elimination drug drug alprazolam alprazolam time time to peak plasm plasma conc. elim elimination ination half-life half-life m ajor active m etabolites 1-2 1-2 hr. hr. 12-15 12-15 hr. hr. -hydroxyalprazolam -hydroxyalprazolam 0.5 0.5 -- 4.0 4.0 hr. hr. 20-70 20-70 hr. hr. 1-6 1-6 hr. hr. 10-18 10-18 hr. hr. desmethyldiazepam desmethyldiazepam (oxepam) (oxepam) none none ** 2-5 2-5 hr. hr. none none 1-4 1-4 hr. hr. 5-15 5-15 hr. hr. none none 11- 22 hr. hr. §§ 1.5-5.0 1.5-5.0 hr.• hr.• -hydroxytriazolm -hydroxytriazolm Xanax Xanax diazepam diazepam Valium Valium lorazepam lorazepam Ativan Ativan midazolam midazolam Versed Versed oxazepam oxazepam Serax Serax triazolam triazolam Halcion Halcion §§ peak peak concentration concentration is is 28% 28% faster faster ifif given given sublingually sublingually • half life will be prolonged in the presence • half life will be prolonged in the presence of of erythromycin, erythromycin, cimethidine cimethidine (tagamet), (tagamet), isoniazid isoniazid and and possibly possibly oral oral contraceptives contraceptives ** not not available available as as an an oral oral agent agent 6/6/05 Copyright Quarnstrom Donaldson Xanax -Alprazolam Dosage 0.25-1.0 mg adults Onset 1 hour Durration 1-2 hours 2004 SW Dental Conference Joseph Giovannitti JR, DMD QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. 6/6/05 Copyright Quarnstrom Donaldson QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 Copyright Quarnstrom Donaldson Effects Interaction with the Gama Amino Butyric Acid receptor complex. Potentiates GABA. Alters the Chloride ion channel to increase frequency of their opening. Interacts with the glycine receptors. Alters opiate peptide concentrations. 5-HT decreases - a precursor of Seratonin. 6/6/05 Copyright Quarnstrom Donaldson Effects Central nervous system system Antianxiety, sedative-hypnotic, sedative-hypnotic, anticonvulsant and skeletal skeletal muscle muscle relaxant All depress CNS to some some degree. degree. These These tend tend to be more antianxiety as as compared compared with with barbiturates and other other sedative-hypnotics. sedative-hypnotics. Depress the limbic limbic system system and and areas areas of of brain brain associated with emotion emotion and and behavior behavior particularly the hippocampus hippocampus and and the the amygdaloid nucleus. 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular system Benzodiazepines cause few alterations in cardiac output or blood pressure when administered intravenously to healthy persons. Slightly greater than normal doses cause slight decreases in blood pressure, cardiac output, and stroke volume in normal subjects and patient with cardiac disease, but are not usually clinically significant. Triazolam did not affect cardovascular dymanics in doses 4 to 8 times normal. 6/6/05 Copyright Quarnstrom Donaldson Absorption Rapid peak within 2 hours Faster in elderly and young women Faster in daytime than at night due to longer predose fasting period 2 times faster after a 12 hour fast. 85% absorbed 15% passed through. 6/6/05 Copyright Quarnstrom Donaldson Distribution No difference in obese and normal patients. Plasma potient binding at 89%. 49% to to serum serum proteins. Crosses readily into central nervous system system because of high lipid solubility. solubility. Crosses the placental barrier and milk of rats. rats. 6/6/05 Copyright Quarnstrom Donaldson Metabolism Halcion is oxidized first pass in liver and lining of gut by the cytochrome P450 mono-oxygenase system The P450 is made up of many enzymes. The majority of drug metabolism is by seven enzymes, 1A2, 3A4, 2c8, 2C9/10, 2C19, 2C19, 2D6, 2F1. Halcion is metabolized by the 3A4 enzyme. The presence or absence of an enzyme can be idiosyncratic or associated with certain patient subsets 6/6/05 Copyright Quarnstrom Donaldson Metabolism The absence of an enzyme can be idiosyncratic or associated with certain patient subsets CYP 2D6: 2-10% of the total population 5-10% of Caucasians 6% of Afro-Americans 0-1% of Asians CYP 2C19: 18-25% of Afro-Americans and Asians 2-5% of Caucasians S.E. Asians may have less 3A4 enzyme Giving the drug a longer half life 6/6/05 Copyright Quarnstrom Donaldson Elimination Half life averages 1.2 to 3.3 hours. Slower at night. Longer - elderly - lower liver oxidixing capacity. No change with kidney dialysis. Slower with cirrhosis. 91% eliminated in urine 9% in feces within 72 hr. 6/6/05 Copyright Quarnstrom Donaldson Benzodiazepine Elimination CNS. CNS. conc. conc. drug drug blood blood brain brain barrier barrier plasma plasma conc. conc. plasma plasma binding binding liver liver portal portal circulation circulation (metabolism) (metabolism) excretion excretion 6/6/05 fat fat stores fat partition fatpartition stores time time 00 1hr. 1hr. Copyright Quarnstrom Donaldson 66 hr. hr. 11 d. d. 66 d. d. Bioavailability Fraction of unchanged drug reaching the systemic circulation after administration by any route 6/6/05 IV Dose Oral Dose Target Organ Systemic Circulation Portal Circulation Cytochrome Excretion Copyright Quarnstrom Donaldson P450 metabolism Inhalation N2O Side effects .5 mg. 8% sleepiness 4% headach, dizzyness, neuritis, dry mouth Reproduction In rats slightly reduced fertility but did not affect postnatal development in rats. 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular system Benzodiazepines cause few alterations in cardiac output or blood pressure when administered intravenously to healthy persons Slightly greater than normal doses cause slight decreases in blood pressure, cardiac output and stroke volume in normal subjects and patients with cardiac disease, but are not usually clinically significant. Triazolam did not affect cardovascular dynamics in doses 4 to 8 times normal. 6/6/05 Copyright Quarnstrom Donaldson Contraindications to Traizolam absolute relative known known hypersensitivity hypersensitivity lack lack of of knowledge knowledge inability inability to to initiate resuscitation myasthemia myasthemia gravis gravis glaucoma glaucoma first first trimester trimester lactation lactation concurrent concurrent CNS CNS depressants depressants Cimethadine Cimethadine (tagamet) (tagamet) Erythromycin Erythromycin Isoniazid Isoniazid 6/6/05 pediatric pediatric patients patients geriatric geriatric patients patients psychiatric psychiatric patients patients no no FDA FDA approval approval for for dental dental sedation sedation Copyright Quarnstrom Donaldson Patient Assessment ASA Classification American Society of Anesthesiologists ASA I: ASA II: ASA III: ASA IV: ASA V: ASA E: 6/6/05 normal healthy mild systemic disease – does not effect the way the live severe systemic disease – effects the way they live incapacitating systemic disease moribund, 24 hours to live emergency Copyright Quarnstrom Donaldson Patient Assessment Much the same as for doing dentistry Cardiovascular Disease Pregnancy – benzodiazepines are known teratogens Elderly Patients on Steroids 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular Disease Hypertension Ischemic heart disease Valvular heart disease Congestive heart disease Dysrhythmia 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular Disease Hypertension Systolic <140 140 160-200 200 &/or 6/6/05 Diastolic <90 &/or 90-95 Effect on Treatment none none: reassess BP next 2 appt. &/or 95-115 reassess in 5 min., refer to MD >115 reassess in 5 min., refer to MD immediately Copyright Quarnstrom Donaldson Cardiovascular Disease Hypertension Protocol Vital signs Stress reduction Chairside manner Profound Local Anesthesia Conscious sedation Limit epinephrine to 0.04 mg. – 2 cartridges - 1:100,000 epi. Retraction cord with epi. ??? 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular Disease Hypertension Ischemic heart disease stable Treatment? Yes? Valvular heart disease Congestive heart disease Dysrhythmia 6/6/05 Copyright Quarnstrom Donaldson unstable No Cardiovascular Disease Hypertension Ischemic heart disease stable unstable Treatment? Yes? No Valvular heart disease Consider SBE prophylaxis Medical consultation Congestive heart disease Medical Consultation Dysrhythmia 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular Disease Hypertension Ischemic heart disease stable unstable Treatment? Yes? No Valvular heart disease Consider SBE prophylaxis Medical consultation Congestive heart disease Medical Consultation Dysrhythmia 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular Disease Hypertension Ischemic heart disease stable unstable Treatment? Yes? No Valvular heart disease Consider SBE prophylaxis Medical consultation Congestive heart disease Medical Consultation Dysrhythmia 6/6/05 Copyright Quarnstrom Donaldson Cardiovascular Disease Dysrhythmia Vital signs Stress reduction Chairside manner Profound local anesthesia Conscious sedation Limit epi to 0.04 mg. – 2 cartridges 1:100,000 No epi. in retraction cord 6/6/05 Copyright Quarnstrom Donaldson Elderly Physiologic changes with age Concomitant disease Polypharmacy – review medication list Drug interactions Decrease initial dose 6/6/05 Copyright Quarnstrom Donaldson Patients on Steroids Physiologic release 20-30 mg of cortisol daily equivalent to: 20-30 mg of hydrocortisone daily 5-7.5 mg. Of prednisone daily Coverage is required if: Stressful procedure On physiologic dose, at least 1 week in past year Double daily dose or 100 mg I.M. Hydrocortisone 6/6/05 Copyright Quarnstrom Donaldson Metabolism The absence of an enzyme can be idiosyncratic or associated with certain patient subsets CYP 2D6: 2-10% of the total population 5-10% of Caucasians 6% of Afro-Americans 0-1% of Asians CYP 2C19: 18-25% of Afro-Americans and Asians 2-5% of Caucasians S.E. Asians may have less 3A4 enzyme Giving the drug a longer half life 6/6/05 Copyright Quarnstrom Donaldson Drug interactions Cimethedine - for ulcer treatment Erythromycin - an antibiotic Isoniazid - an antitubercular agent Reduce the first pass liver clearance by decreased metabolism and reduction in hapatic blood flow. Due to decrease in cytochrome P450-mediated oxidatative system. 6/6/05 Copyright Quarnstrom Donaldson Halcion Study 6/6/05 Patients 173 Treatments 269 Age average 31.2 +/- 19.7 range 1.5 - 71 Sex male female Weight average 135 +/range 23-286 54 119 75 Copyright Quarnstrom Donaldson Drug Record Forms 6/6/05 Copyright Quarnstrom Donaldson Patient information and consent forms 6/6/05 Copyright Quarnstrom Donaldson Medical History and Sedation Record 6/6/05 Copyright Quarnstrom Donaldson AGE count 30 20 10 10 6/6/05 20 30 40 Copyright Quarnstrom Donaldson 50 60 70 AGE count 30 20 10 10 20 30 40 50 60 With new ADA Guidelines 6/6/05 Copyright Quarnstrom Donaldson 70 6/6/05 Copyright Quarnstrom Donaldson Apprehension Level terrified terrified panicked panicked very very afraid afraid afraid afraid tense tense nervous nervous calm calm start start 6/6/05 30 30 min. min. 60 60 min min Copyright Quarnstrom Donaldson finish finish 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 Copyright Quarnstrom Donaldson Amnesia 100% 100% % % of of patients patients remembering remembering symbol symbol 80% 80% 60% 60% 40% 40% 20% 20% pre pre med med 6/6/05 30 30 min min 60 60 min min Copyright Quarnstrom Donaldson mid end mid end procedure procedure 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 Copyright Quarnstrom Donaldson 6/6/05 Copyright Quarnstrom Donaldson Weight vs. Dose of Halcion .75 .75 .625 .625 .5 .5 .375 .375 n n == 100 100 .25 .25 suggested suggested dose dose .125 .125 minimum minimum dose dose 00 6/6/05 50 100 150 50 100 150 tended tended to to sleep sleep good good sedation sedation 200 250 300 200 250 300 difficult difficult but but possible possible uncontrolable uncontrolable Copyright Quarnstrom Donaldson ADA Guidelines Except for unusual circumstances, the maximum recommended dose (mrd) shall not be exceded. Only one dose can be given. You may not titrate for effect. “In accord with this particular definition, titration of oral medication for the purposes of sedation is unpredictable. Repeated dosing of orally administered sedative agents may result in an alteration of the state of consciousness beyond the intent of the practitioner. Except in unusual circumstances the Maximum Recommended Dose (MRD) of an oral mediation should not be exceeded” The FDA stated there is no mrd for halcion used as an oral sedative. 6/6/05 Copyright Quarnstrom Donaldson Weight vs. Dose of Halcion .75 .75 no sedation .625 .625 .5 .5 .375 .375 n n == 100 100 .25 .25 suggested suggested dose dose .125 .125 minimum minimum dose dose 00 6/6/05 50 100 150 50 100 150 tended tended to to sleep sleep good good sedation sedation 200 250 300 200 250 300 difficult difficult but but possible possible uncontrolable uncontrolable With new ADA Guidelines Copyright Quarnstrom Donaldson Weight vs. Dose of Halcion no sedation .75 .75 .625 .625 .5 .5 .375 .375 .25 .25 suggested suggested dose dose .125 .125 minimum minimum dose dose 00 6/6/05 50 100 150 50 100 150 tended tended to to sleep sleep good good sedation sedation 200 250 300 200 250 300 difficult difficult but but possible possible uncontrolable uncontrolable With new ADA Guidelines Copyright Quarnstrom Donaldson Dose Dose of = 0.25mg + 0.125mg Halcion ( weight - 40 70 ) (weight in pounds) If at 30 minutes the patient notices NO sedation and the dentist observes NO Weight vs. Dose of Halcion sedation, half the original dose is administered sublingually. .75 .75 .625 .625 .5 .5 .375 .375 n n == 100 100 .25 .25 suggested suggested dose dose .125 .125 minimum minimum dose dose 00 6/6/05 Copyright Quarnstrom 50 100 150 50 100 150 tended tended to to sleep sleep good Donaldson good sedation sedation 200 250 300 200 250 300 difficult difficult but but possible possible uncontrolable uncontrolable Drug Half Lives, T1/2 Oral I.V. 100 Distribution from blood to tissue distribution (alpha phase) 75 Half Lives, T1/2 50 Elimination via liver and kidneys Elimination (beta phase) 25 0 0 6/6/05 2 4 8 10 0 2 Copyright Quarnstrom Donaldson 4 8 10 Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988 Titration of Halcion half first dose? Halcion Second 1/2 dose active conc. halcion Population study of triaazolam pharmacokinetics B.J.Clin.Pharmc (1986) 22, 639-642 Triazolam pharmacodynamics in obesity, J. Clin Psychopharmacol Vol 15/no3, June 1995 6/6/05 time 1Copyright Quarnstrom 2 3 Donaldson 4 5 Aggressive Titration of Halcion - guess 3rd dose 2nd dose active conc. First dose n 6/6/05 time 1Copyright Quarnstrom 2 3 Donaldson 4 5 Nitrous Oxide Supplementation second second dose dose at at 30 30 min min -- 1/2 1/2 original original dose apprehension level nitrous nitrous oxide oxide effect effect sedation sedation level level halcion halcion effect effect sedation sedation level level 11 time time in in hours hours 6/6/05 22 33 Copyright Quarnstrom Donaldson 44 Flumazenol COOCH CH 3 N H C 3 N N N C H3 N H C 3 N N Cl O Cl Cl Flumazenol 6/6/05 Copyright Quarnstrom Donaldson Triazolam Flumazenil ethyl 6 - fluoro - 6, 6 - dihydro - 5 methyl - 6 - oxo - 4h - imidazo (l,5-a) (1,4) benzodiazepine - 3 carboxylate 6/6/05 Copyright Quarnstrom Donaldson Dose .007 and .014 mg/kg. Lethal dose in mice and rats is 62.5 and and 125 125 mg mg / kg. One study suggested lethal dose is 3000 3000 times times theraputic dose. It has been tested up to 200 mg. IV IV and and oral. oral. In In the case of oral dosages only 18% is active active as it is oxidized in first pass through through the the liver liver 6/6/05 Copyright Quarnstrom Donaldson Elimination and Side Effects Eliminated completely in first pass through liver by P-450 system. Not effective orally for this reason. Side effects are infrequent. These include mild headache, loss of pupil reactivity to light, mild hypotension. 6/6/05 Copyright Quarnstrom Donaldson Half life At 54 minutes (.7 to 1.3 hr. hr. 50 50 min. min. average) average) is is less than midazolam and valium valium so so you you may may see some rebound. Worked within 2 to 5 minutes. minutes. One author saw no improvment improvment after after 15 15 minutes. Another showed improvment improvment at at 15, 15, 30 30 but but not not 60 60 minutes. 1 mg. will last for about 2 hours. 6/6/05 Copyright Quarnstrom Donaldson Flumazenol Reversal of Halcion flumazenol active conc. 6/6/05 time halcion without reversal 1Copyright Quarnstrom 2 3 Donaldson 4 5 Reversal of Triazolam by Romazicon, IV reversal SL reversal Flumazenil, Much effect An unpublished from the needle stick study Min. 6/6/05 5 10 Copyright Quarnstrom Donaldson 15 20 Successful Nitrous Oxide / Oxygen Sedation apprehension level sedation sedation level level nitrous nitrous oxide oxide effect effect time time in in minutes minutes 6/6/05 Copyright Quarnstrom Donaldson Inadequate Nitrous Oxide / Oxygen Sedation apprehension level sedation sedation level level nitrous nitrous oxide oxide effect effect 15 15 time time in in minutes minutes 6/6/05 30 30 45 45 Copyright Quarnstrom Donaldson 60 60 Inadequate Halcion Sedation second second dose dose at at 30 30 min min -- 1/2 1/2 original original dose dose apprehension level sedation sedation level level halcion halcion effect effect 11 time time in in hours hours 6/6/05 22 33 Copyright Quarnstrom Donaldson 44 Nitrous Oxide Supplementation second second dose dose at at 30 30 min min -- 1/2 1/2 original original dose apprehension level nitrous nitrous oxide oxide effect effect sedation sedation level level halcion halcion effect effect sedation sedation level level 11 time time in in hours hours 6/6/05 22 33 Copyright Quarnstrom Donaldson 44 Deaths from Halcion Impaired driving Sexual Assault Death due to drugs Death Drug related Death drug involved 17 4 45 20 8 Cases from 1979-1990 in Canada of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Deaths from Halcion Impaired driving 17 9 combination with other drugs Sexual Assault 4 Death due to drugs 45 Death Drug related 20 Death drug involved 8 Cases from 1979-1990 in Canada of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Deaths from Halcion Impaired driving 17 Sexual Assault 4 male and female - “love drug” Death due to drugs 45 Death Drug related 20 Death drug involved 8 Cases from 1979-1990 in Canada of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Deaths from Halcion Impaired driving Sexual Assault Death due to drugs 4 were halcion alone 1 10 ng/ml 3 40 ng/ml Death Drug related Death Drug involved 17 4 45 20 8 Cases from 1979-1990 in Canada of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Deaths from Halcion Death due to drugs 45 4 were halcion alone 1 10 ng/ml 3 40 ng/ml Peak conc. 0.125 = 1.08 +-0.08 ng/ml 1.67+-0.16 ng/ml elderly 0.25 = 2.02 +-0.15 ng/ml 3.06+-0.22 ng/ml elderly 1.0 = 7.47 +-1.51ng/ml at .83 hr +-0.32 hr of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Deaths from Halcion Death due to drugs 45 41 were halcion + other drugs 9 - 190 ng/ml Peak conc. 0.125 = 1.08 +-0.08 ng/ml 1.67+-0.16 ng/ml elderly 0.25 = 2.02 +-0.15 ng/ml 3.06+-0.22 ng/ml elderly 1.0 = 7.47 +-1.51ng/ml at .83 hr +-0.32 hr of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Deaths from Halcion Impaired driving Sexual Assault Death due to drugs Death Drug related Death drug involved 17 4 45 20 8 Most appear to be self inflicted suicide, an error in patient compliance or the result of foul play of Analytical Toxicology, 6/6/05 Joynt, Brian, Journal Copyright Quarnstrom Donaldsonvol.17 May/June 1993 p171-177 Q’s Recommendations This refers only to the use of halcion MRD is for use as a sleep aid - elderly with no monitoring ED60 equals about the LD5 of chloral hydrate. No use on patients under 40 lbs. (5 years of age). Titration is possible It is very slow. Can be used to adjust initial dose. Secondary doses should be no more than the predicted amount that has been metabolized (1/2 original dose at 2 hr. intervals) 6/6/05 Copyright Quarnstrom Donaldson Q’s Recommendations Administered in the office assistant in the room Dr. in the office Monitoring Pulse oximeter monitoring - constant BP monitoring (q. 15 min.) No multiple drugs Single drug plus nitrous oxide OK. Staff and Dentist must have BLS every year. The Dentist should be trained and current in the use of nitrous oxide. 6/6/05 Copyright Quarnstrom Donaldson Solution Research Education Education Good courses will drive out Or cause bad courses to be altered. It is the responsibility of the ADA to educate and publish when so many are using a drug in 6/6/05 Copyright Quarnstrom Donaldson potentially dangerous techniques. Halcion Oral Sedation Drugs make the world go round. To get really high Free online Halcion manual http://faculty.washington.edu/quarn select “oral halcion” 6/6/05 takes a telescope. Copyright Quarnstrom Donaldson