sign in sign up
<<
Home , Barbital, Triazolam

4/15/2018

Oral Sedation Oral Sedation ➢ What is it good for??? ➢ Edwin Star 1970s ➢ “Absolutely nothin” ➢ Pediatric dentists Edward C. Adlesic, DMD – the experts in oral sedation – take uncontrollable patients a give them a University of Pittsburgh School of Dental “cocktail” and are able to provide care for 30 mins to Medicine an hour – specialty is dedicated to the safe practice of oral sedation

Oral Sedation in Adults Oral Sedation

➢ Questionable practice ➢ hydrate ( trichloroethanol ) – agents can provide safe anxiolysis when they work – synthesized in 1832 • but it is unpredictable – agent – CNS – moderate sedation with oral medications • respiratory as well • controversial on several levels – dose = 20 to 40 mg/kg • maximum dose of 1000 to 1500 mg – hypnosis in ~ 30 minutes – best use in children < 48 months old • decreased efficacy in older children

1 4/15/2018

Chloral Hydrate Oral

➢ + spirits ➢ Benadryl • Mickey Finn or knock out drops ➢ 1.5 mg/kg oral dose in children ➢ adverse effects – oral syrup: 12.5 mg/ 5 ml – myocardial sensitization with volatile agents ➢ 50 to 100 mg oral dose in adults – metabolite is carcinogen ➢ onset = 1 hour ➢ no analgesia ➢ duration = 4 to 6 hours ➢ purchase from compounding pharmacy ➢ was used in pediatric dentistry ➢ onset is slow & duration is too long – replaced by

Hydroxyzine ( Vistaril ) ( Vistaril )

➢ agent ➢ in children – , analgesic, & antiemetic properties – often combined with oral Demerol – side effect: dry mouth ➢ tablets: 10, 25, 50, & 100 mg ➢ dose in children ➢ syrup: 10 mg/5ml & 25 mg/ 5ml – 1 to 2 mg/kg PO maximum dose = 50 mg – onset = 15 to 30 minutes – working time = 45 minutes – duration = 2 to 4 hours

2 4/15/2018

Oral Sedation

➢ ➢ are the agents of choice for oral anxiolysis – in early 1900s ➢ compared to previous agents – Amytal, Seconal – equal or greater efficacy – Thiopental – greater margin of safety – CNS ➢ anxiolytic, sedative, & hypnotic effects – low margin of safety – dose dependent ➢ CNS effects are mediated by GABA system – benzodiazepines replaced this class of drugs

GABA GABA – A Receptor

➢ GABA is an inhibitory in the ➢ consists of 5 glycoprotein subunits CNS – a, b, g ( alpha, beta, gamma ) – counteracts the excitatory – subunits can also have subunits ➢ 3 GABA receptors on the post synaptic neuron • a 1 – 6 b 1 – 3 – GABA ➢ activation of GABA receptor increases Cl ion A transmembrane conduction • this is the target receptor for many general anesthetic agents – hyperpolarize the post synaptic membrane – inhibit post synaptic transmission – GABAB

– GABAC ➢ benzodiazepines bind to the GABAA a subunit

3 4/15/2018

Benzodiazepine Receptors

➢ benzodiazepines bind to a receptors – a 1 a 2 receptors – also called receptors ( BZ receptors )

• BZ1 BZ2 receptors ➢ BZ 1 receptors mediate ➢ benzodiazepine does not open the Cl channel – sedation & effects ➢ GABA must bind to its receptor for BZ to have an ➢ BZ 2 receptors mediate effect: No GABA – No response – anxiolysis, antegrade , & skeletal muscle ➢ Benzodiazepine then binds to its GABA receptor relaxation – this enhances GABA’s ability to open the Cl channel

Benzodiazepines Benzodiazepines

➢ dose dependent CNS depression ➢ high therapeutic index – concentration dependent receptor occupancy – dose required to achieve the desired effect is far less – 20% occupancy anxiolysis than the dose that produces adverse effects – 30 to 50% occupancy sedation – > 60% occupancy hypnosis ➢ shallow dose response curve ➢ all BZ agents have same efficacy for sedation – dose that produces mild to moderate sedation is far less than the dose for inducing hypnosis ➢ varying degrees of antegrade amnesia ➢ all reversible with

4 4/15/2018

Pharmacokinetics

➢ lipid soluble agents – h ability to diffuse from plasma to brain – more rapid onset – i duration of action by redistribution ➢ Effective dose (ED50) for BZ is far less than lethal dose ➢ metabolism is by hepatic phase I enzymatic (LD50) a death from overdose BZ very rare reactions – metabolite may be active a that will h duration of ➢ not so for barbiturates & other sedative hypnotic effect – these agents directly open Cl channels even in absence of GABA ➢ elimination half life does not predict anesthetic

Anesth Progress. 2007;54:118-129 duration

Elimination of BZ CVS Effects of BZ

➢ , midazolam, & ➢ minimal CVS effects with therapeutic doses – phase I reactions form a hydroxy metabolite which ➢ high doses depress the CVS breaks down to inactive glucuronide compound – h HR i BP ➢ – 1 step conjugation reaction to form inactive ➢ BZ will decrease cardiovascular response to glucuronide compound stress ( anxiety & pain ) ➢ – form active metabolite then , another active metabolite, then inactive glucuronide compound for by

5 4/15/2018

Respiratory Effect of BZ Other Effects

➢ minimal respiratory depression ➢ disinhibitory reactions ➢ high doses can result in – dysphoria – idiosyncratic responses from BZ – depression of hypoxic respiratory drive – excitement, agitation, , & hostility – apnea – additional doses of BZ do not resolve the problem ➢ COPD & OSA patients • will delay recovery – BZ can cause airway obstruction by relaxation of • may make reaction worse airway ➢ IV route: venous irritation & phlebitis – in OSA anesthetics decrease arousal mechanism ➢ mild anticholinergic response – dry mouth h IOP

Oral Diazepam Oral Diazepam

➢ long acting agent ➢ lipid soluble drug ➢ onset 30 to 60 minutes – final redistribution compartment is fat ➢ peak plasma concentration 1 to 2 hours – prolonged drowsiness is due to slow release from fat ➢ duration of action 2 to 4 hours ➢ active metabolites – nordazepam 30 to 100 hours ➢ elimination half life 20 to 80 hours – oxazepam 5 to 15 hours – adds to drowsiness & “hang over” effects

6 4/15/2018

Oral Diazepam ( Adults ) Oral Diazepam ( Children )

➢ 10 to 30 mg PO ( 0.05 to 0.3 mg/kg ) ➢ usual dose 0.25 to 0.5 mg/kg PO – Child 2 to 5 yrs. 2 to 5 mg ➢ minimal sedation dose 5 to 10 mg PO – Child 6 to 10 yrs. 5 to 10 mg – Child 11 to 15 yrs. 5 to 15 mg ➢ moderate sedation dose 15 to 30 mg PO

➢ typical working time of 45 to 60 minutes ➢ no repeat dose given ➢ better alternative BZ available for use – triazolam

Oral Midazolam Oral Midazolam

➢ short acting BZ ➢ high degree of 1st pass effects ➢ onset of action 15 to 30 minutes – decrease midazolam plasma concentrations ➢ peak plasma level 20 to 50 minutes ➢ adult dose – 0.5 mg/kg PO ➢ t1/2b elimination 1.7 to 2.6 hours – maximum dose of 20 mg ➢ from oral route ➢ – 35 to 44% not a recommended BZ for adult sedation – due to gastric acidity in stomach ➢ used mostly in children – 0.5 mg/kg maximum of 15 mg – duration of 30 minutes

7 4/15/2018

Oral Lorazepam ( Ativan ) Oral Lorazepam ( Ativan )

➢ long acting BZ ➢ low lipid solubility agent ➢ onset of action 60 to 120 minutes – delayed onset of action • takes longer to leave plasma & enter CNS ➢ peak plasma level 1 to 2 hours – prolonged duration of action ➢ duration of action 2 to 4 hours • slow redistribution from CNS ➢ oral bioavailability 83 to 100% ➢ no active metabolite ➢ t1/2b elimination 10 to 20 hours – phase II hepatic metabolism • glucuronide conjugation • inactive metabolite excreted in urine

Oral Lorazepam ( Ativan ) Triazolam ( Halcion )

➢ adult dose 1 to 3 mg ( 0.02 mg/kg ) ➢ short acting sedative hypnotic ➢ profound amnesia with lorazepam ➢ Netherlands 1977 at maximum dose 1 mg – “ forget the entire day” – reports of hallucinations, amnesia, aggression, depression, & bizarre behavior ➢ not an agent for children ➢ introduced in US in 1983 – maximum dose 0.5 mg ➢ reports of adverse effects continued – 0.5 mg tablet removed from market – FDA review: 0.125 to 0.25 mg safe to use

Arch Int Med. 1991;151:2003

8 4/15/2018

Triazolam ( Halcion ) Triazolam ( Halcion )

➢ current indication for use is ➢ drug of choice for anxiolysis in adults – short term treatment only ➢ onset PO 30 minutes – 0.125 to 0.25 mg PO – maximum recommended dose ( MRD ) ➢ peak plasma levels ~ 75 minutes • in rare cases 0.5 mg is used – peak plasma levels occur 15 to 30 mins prior to CNS effects ➢ minimal sedation = anxiolysis – 0.125 to 0.25 mg ➢ minimal to moderate sedation in dentistry ➢ duration of action ~ 2 hours – 0.125 to 0.5 mg PO or SL

Arch Int Med. 1991; 151: 2003 Dent Clin N America. 2002; 46: 781

Triazolam ( Halcion ) Sublingual Triazolam

➢ oral bioavailability 44% ➢ avoids liver 1st pass effect ➢ significant liver 1st pass effect ➢ increases bioavailability by 28% ➢ metabolized in liver to inactive metabolite ➢ greater anxiolytic effect than PO route ➢ anxiolytic effect of 0.25 to 0.5 mg – no h in adverse side effects by this route – equivalent to 10 to 20 mg of IV diazepam – no h in psychomotor impairment ➢ not well studied in children ➢ no detectable amnesia ➢ 0.5 mg SL triazolam should be used cautiously – potential h in side effects & recovery

JADA. 2006;137: 502-13 OOO. 1997; 84:119 J Clin Pharmacology. 1986; 26:208

9 4/15/2018

Triazolam prior to Sedation Triazolam Oral Sedation

➢ 0.25 mg PO (45 to 60 min) prior to IV sedation ➢ single dose of agent 1 hour prior to surgery ➢ reduced anxiety at time of venipuncture ➢ 0.125 to 0.25 mg PO ➢ reduced doses of intra operative IV drugs – sublingual route more effective

➢ MRD maximum recommended dose 0.5 mg – manufacturer of drug a unusual circumstances – used for moderate sedation in dentistry 0.25 to 0.5 mg

➢ like any oral medication: unpredictable results Anesth Progress. 1993;40: 117-121

Triazolam Mutiple Dosing Triazolam Mutiple Dosing

➢ 188 patients for 270 procedures over 15 years ➢ after 30 minutes: assess the level of sedation ➢ age 7 to 78 – if inadequate a give ½ the initial dose ➢ weight based dose triazolam – based upon sedation scores from 1st treatment ➢ procedure started after 60 minutes – 0.25 mg for 1st 40 lbs – if not sedate a add 30 to 50% – additional 0.125 mg for each 70 lbs – if that fails a reschedule for IV sedation – given 1 hour prior to scheduled appointment

– medical literature a usually not weight based ➢ SpO2 mean range a 96.5 to 96% dose – multiple patients 90 to 96% • use either 0.125 or 0.25 mg

10 4/15/2018

Triazolam Mutiple Dosing Triazolam & Implant Surgery

➢ CVS system stable ➢ usual dose 0.125 to 0.25 mg for insomnia ➢ dose range was 0.25 mg to 0.75 mg ➢ dental sedation: 0.125 to 0.25 mg PO or SL ➢ 98.4% success rate – give a dose the evening before ➢ only 9% needed the second dose – anxiolytic dose 1 hour before surgery ➢ not a weight based dose ➢ Question: if only 9% required a second dose, ➢ do not exceed 0.5 mg why not limit the oral sedation to just a single preoperative dose and refer the others for IV J Oral Implantology. 2004; 30(2): 93-97

General Dentistry. 2004 Nov-Dec; 496-501

Incremental Triazolam Incremental Triazolam

➢ 0.25 mg PO 1 hour before procedure ➢ at end of treatment ➢ reassess in 30 minutes – give the patient 6 to 8 ounces of clear carbohydrate – if sedation inadequate a 0.25 mg SL by dentist to speed recovery – additional doses are used a time interval not explained – give the patient additional carbohydrate fluids for the ride home to prevent hypoglycemia & dehydration ➢ during xrays, bite adjustment, or restroom breaks where – REALLY????? you need patient cooperation – 2.0 ounces of clear fruit juice ( do not use grapefruit ) through a straw • lightens sedation by physiologic stimulation General Dentistry. 2005 Jan-Feb: 22-26 • REALLY?????

11 4/15/2018

2007 Oral Sedation Survey 2007 Oral Sedation Survey

➢ oral sedation in 1686 cases ➢ adverse side effects – at home dosing 10.9% of cases – 78.2% no adverse effects • triazolam 50.4% diazepam 46.9% – 16% DBP decrease > 25% baseline

– in office dosing 81.8% of cases – 4% SpO2 < 90 • triazolam used 82.9% of the time – 54.8% used 1 additional dose ➢ based on the survey the conclusion was – 32.3% used 2 additional doses – triazolam used at 1 to 3 doses of 0.125 or 0.25 mg – 15.9% used 3 additional doses appear to be safe ( dose up to 0.75 mg ) – 6.2% used 4 additional doses – rare to see more than 4 additional doses

Gen Dentistry. 2007 Sep-Oct: 410-415

Justifying Total Anxiolytic Justifying Total Anxiolytic Dose of Triazolam Dose of Triazolam

➢ attempt to recommend oral doses for sedation ➢ previous oral sedation literature set maximum anxiolytic dose of triazolam to be 0.625 mg ➢ compared lorazepam to triazolam – far below the 2.0 max 24 hour dose – statement in paper: lorazepam to triazolam ratio is 4:1 ➢ arbitrarily picked 200 lbs as maximum weight to ➢ used lorazepam doses in ETOH withdrawal dose triazolam & set that dose as 0.5 mg – ETOH withdrawal: lorazepam total dose PO 8 mg day – 0.25 mg for 1st 40 lb then 0.125 mg for each 70 lb – statement in paper: triazolam max dose could be 2 mg ➢ divide weight by 400 for triazolam & 100 for a day since it is 4X as potent as lorazepam lorazepam to get max weight based dose for ages ➢ flawed conclusion 41 to 64 – ETOH withdrawal symptoms including can not be compared to procedural sedation Gen Dentistry. 2006 Jan-Feb: 54-57

12 4/15/2018

Maximum Cumulative Dose

➢ paper claims maximum cumulative dose of triazolam is 2.0 mg in 24 hr ➢ use their weight based formula to set initial dose ➢ additional doses are given every 90 min as needed – no additional dose to exceed 0.25 mg ➢ weight calculations are for age 41 to 64 ➢ no scientific research to validate the above ➢ age 18 to 40 increase dose by 25% ➢ Question: should 90 min be the interval for ➢ age 65 and older decrease by 50% dosing???

Gen Dentistry. 2007 March-Apr: 143-148

Adult Minimal Oral Sedation However

➢ triazolam initial dose PO 0.125 to 0.375 mg ➢ following statements are of concern ➢ if sedation not adequate ➢ afternoon cases encourage intake of small amount of – redose after 2 hours clear liquids + dry toast or crackers to – use SL route a greater bioavailability – “absorb gastric secretions” – maximum total dose 0.5 mg ➢ DM patients should take their medications – in operatory give them small amounts of apple juice to stabilize ➢ limit treatment time to 4 hours blood sugars ➢ avoid multiple incremental dosing ➢ SpO2 < 92%: take 1 to 2 deep breaths & reverses in few seconds ➢ may be reasonable approach ➢ Flumazenil 0.2 mg SL will reverses BZ??????

Gen Dentistry. 2012 Jan-Feb: 31 - 43 Gen Dentistry 2012

13 4/15/2018

Pharmacokinetics of Pharmacokinetics Triazolam PO

➢ PO & SL dose have short half life: 2 to 4 hours ➢ dose of triazolam determines – intensity of anxiolysis – duration of effect ➢ dose of 0.5 mg SL can have sustained sedation beyond 8 hours ➢ IV route: immediate plasma levels – full recovery can not occur at the completion of a 4 hour appointment – refer back to 2012 paper on time ➢ PO route: slower to absorb; bioavailability issues; lower plasma concentrations Anest Progress.2011;58:166 J Clin Psychopharmacol. 2006; 26(1): 1-3

Time-0 dose 0.25 mg

Time-60 dose 0.25 mg Triazolam: single SL dose of 0.25 mg Time-90 dose 0.25 mg 0.25

➢ 1st dose at 0; 2nd dose at 60 min; 3rd dose at 90 min ➢ demonstrates effect-site equilibration effect ➢ maximum pharmacologic effects at 3 hours ➢ still exceed 2 ng/ml at 8 hours – time for triazolam to leave plasma & cross blood brain barrier – Cmax for 0.25 mg triazolam is 2 ng/ml ➢ expect some sedation past 8 hours – clinical effect of drug delayed 30 mins after Tmax of 1 hour J Clin Psychopharm 2006

14 4/15/2018

Pharmacokinetics Stacked Doses

Dose T min C ng/ml ➢ healthy volunteers age 21 to 39 max max 0.25 60 ( 1 hr ) 2.1 + 0.8 ➢ 3 Groups of SL triazolam 0.25, 0.50, 0.75 mg 0.50 150 ( 2+ hr ) 4.0 + 1.6 ➢ evaluate sedation by BIS & Observer Assessment of Alertness/Sedation ( OAA/S ) 0.75 240 to 300 ( > 4 hr ) 5.1 + 1.6 scale 2009 Study

Pharmacokinetics Stacked Pharmacokinetics Stacked Doses Doses Dose Plasma concentration at end of Dose Lowest BIS at min Max OAA/S at min 6 hours ng/ml 0.25 mg 80 at 90 min 3.6 at 120 min 0.25 mg 0.9 + 0.3 0.50 mg 67 at 210 min 3.2 at 150 min 0.50 mg 2.9 + 1.5 0.75 mg 60 at 180-210 min 2.7 at 150 min 0.75 mg 4.1 + 1.6 ➢ after six hours ➢ level of consciousness in 0.25 mg group returned to – groups 0.5 mg & 0.75 mg still had plasma concentrations baseline at 360 min

exceeding the Cmax of 0.25 mg of triazolam

15 4/15/2018

Pharmacokinetics Stacked Summary for Triazolam Doses

➢ patients should be monitored at least 360 min if ➢ no pharmacology data to support the concept of the total stacked dose is given in 60 to 90 min “oral titration” – unpredictable ➢ total stacked doses of 0.5 to 0.75 mg of triazolam ➢ 0.5 mg dose at 90 min had a plasma – unsafe to discharge a patient earlier than 6 hours after concentration of ~ 2.5 ng/ml the first dose – it did not reach Tmax until 150 minutes & the Cmax was 4.0 + 1.6 ng/ml ➢ larger doses will require even longer recovery – at 6 hours the plasma conc is still 2.9 ng/ml periods – you can not re-dose at 60 min intervals and 90 min intervals will not allow for a significant reduction J Clin Psychopharmaco. 2009

Dentist Disciplined for 8 fold Summary for Triazolam Dose of Triazolam

➢ using current data ➢ West Virginia dentist administered 17 tablets of – an oral triazolam dose of 0.25 to 0.5 mg for adults triazolam ( 4.25 mg ) for a 5 hour case should be safe ➢ Patient admitted to hospital for 3 days for – repeat dosing schedules still need clinical testing to identify a “safe” increment of time & dose flumazenil treatment – even at 0.5 mg there are still significant plasma levels ➢ According to officials from DOCS after 6 hours – maximum dose of triazolam is 0.5 mg – overdose may occur at > 2.0 mg ➢ the most conservative approach would be to

limit the dose to 0.125 to 0.5 mg http://www.drbicuspid.com/index.aspx?sec=nws&sub=rad&pag=dis&ItemID=303149 – if that is not sufficient a refer for IV Case report 2009

16 4/15/2018

Flumazenil Flumazenil

➢ flumazenil is a competitive pharmacologic ➢ FDA approval for IV route only – reports of intranasal, rectal, and down ET tube antagonist of BZ at the BZ receptor ➢ reverse BZ sedation – 0.2 mg IV at 1 minute intervals as needed – most patients will respond to 0.6 to 1 mg ➢ in sufficient doses it will compete for the BZ ➢ overdoses of BZ receptor to displace the BZ from the receptor – will need cumulative dose of 1 to 3 mg IV

➢ anesthetic situation where patient is hypoxic, apneic, & ➢ reverses unconsciousness before hypoxic brain can not be ventilated damage from , upper airway – 1 to 3 mg IV bolus of flumazenil should be safe – research in volunteers showed no adverse effects from 100 mg obstruction, or apnea occurs

Flumazenil Flumazenil

➢ 0.1 to 0.2 mg yield plasma conc of 3-6 ng/ml ➢ t ½ a distribution half life 4 to 11 min – partial antagonism of BZ ➢ t 1/2b elimination half life 40 to 80 min ➢ 0.6 to 1 mg yield plasma conc of 12-28 ng/ml ➢ 99% metabolism to inactive metabolites – complete antagonism for typical BZ sedation ➢ 1% excreted unchanged in urine

➢ onset 1 to 2 minutes ➢ resedation is unlikely if used < 10 mg midazolam ➢ 80% response 3 minutes – > 10 mg midazolam or equivalent may see resedation in ~ 40 minutes ➢ peak effect 6 to 10 minutes – monitor patients for at least 1 hour before discharge

17 4/15/2018

Flumazenil SM Flumazenil Study

➢ study used 3 doses of 0.25 mg SL triazolam – 1st at 0 min; 2nd at 60 min; 3rd at 90 min ➢ at 120 min a inject 0.2 mg flumazenil in 2 ml fluid into posterior maxillary vestibule (submucosal) injection

➢ at 150 min ( 30 min after flumazenil ) – transient h in BIS lasting 30 min then return to baseline – transient h in sedation score for 30 min then returned to baseline JADA 2009

SM Flumazenil Study Fallacy of SL Flumazenil

➢ demonstrates that moderate to deep sedation ➢ 0.2 mg flumazenil IV will incompletely reverse from incremental SL triazolam conscious sedation – get incomplete and transient reversal – do not expect it to reverse unconscious patient – reversal lasted no longer than 30 min – resedation occured ➢ SL flumazenil will eventually work to a degree – dose of flumazenil 0.2 mg submucosal injection – light sedation may be partially reversed by 0.2 mg – deeper sedation requires h dose of flumazenil ➢ 0.2 mg submucosal is inappropriate for rescue – will not have enough time to prevent hypoxic brain injury in apneic, obstructed, unconscious patient JADA. 2009;140(5): 559-566

18 4/15/2018

Fallacy of SL Flumazenil Ketamine

➢ BZ overdosed & unconscious patient ➢ Structural analog of phencyclidine ( angel dust – – IV route is still the best & only approved route PCP ) synthesized in 1962 – no IV skills a give 0.6 to 1 mg flumazenil IM ➢ NMDA: N-methyl-D-aspartate receptor • volume is 6 to 10 ml antagonist • too much volume for SL injection • IM in divided doses in both deltoid muscles ➢ IV, IM, PO, or rectal anesthetic agent • Anest Progress. 2011; 58: 1-2 ➢ Analgesic, amnestic, & cataleptic effects ➢ Been used in anesthesia since 1970’s ➢ Personally, SL is unproven a if you want to use stacked doses learn how to start an IV

Dissociative Anesthesia Anesthesia

➢ ketamine produces a functional dissociation ➢ patient remains still during the surgery between thalamocortical & limbic systems ➢ eyes may be open – depresses neuron function in cerebral cortex while – vacant stare, glassy eyes, & horizontal nystagmus simutaneously activating the limbic system ➢ may see involuntary movements – blocks perception of visual, auditory, and pain by higher centers of the brain – at low doses: patients may be trying to reach out & touch imaginary objects – result is a cataleptic state

JOMS. 2007;19:454-47 JOMS. 2006; 64:693

19 4/15/2018

NMDA Receptor NMDA Receptor

➢ glutamate & NMDA are excitatory amino acids ➢ ketamine binds to the PCP site ➢ glutamate binds to NMDA receptors – opens ion channel to influx of Na, K, and Ca – depolarizes the post synaptic neuron ➢ ketamine binds to the NMDA receptor – it blocks the ion channel – get inhibition of the post synaptic neuron

Ketamine Pharmacokinetics

➢ no GABA activity ➢ rapid onset due to high lipid solubility ➢ peak plasma concentrations ➢ does bind to other sites – IV 60 seconds – nicotinic – IM 5 minutes ( range of 5 to 15 ) – muscarinic – PO ~ 30 minutes – kappa receptors ➢ Redistribution in 7 to 15 minutes with IV route – expect to see anesthetic effects wear off during that time if you only use a single IV bolus ➢ IM route: see effects start to wear off in 30 to 120 minutes after the IM injection

➢ t 1/2b = 2 to 3 hours ( elimination half life )

20 4/15/2018

Metabolism Ketamine CVS Effects

➢ clinical effects wane not because of elimination ➢ acts as a sympathomimetic agent – due to redistribution – expect to see an h heart rate, blood pressure, & CO ➢ ketamine metabolism liver P450 enzymes – creates an imbalance in myocardial oxygen supply & – metabolite is active drug: norketamine demand • h in myocardial oxygen consumption • one third to one fifth as potent as ketamine – not a good drug to use in patients with long standing • responsible for some of analgesia seen CAD, uncontrolled HTN, or CHF

Ketamine & Respiratory Ketamine: Other Effects

➢ preserves spontaneous respirations ➢ myoclonus but no focus ➢ laryngeal & pharyngeal reflexes are intact – ketamine has been used to terminate status ➢ respiratory depression is rare epilepticus ➢ functional residual capacity is increased ➢ h ICP secondary to h in cerebral blood flow & ➢ bronchodilator cerebral perfusion pressures – direct smooth muscle dilation, h catecholamine ➢ h IOP levels in plasma, & inhibition of vagal conduction ➢ hypersalivation ➢ h airway secretions a possible but rare laryngospasm

21 4/15/2018

Emergence Reactions Emergence Reactions

➢ emergence delirium ➢ contributing factors – pleasant or unpleasant reactions – age > 10, psychiatric disorders, female – “body floating in air”, vivid dreaming, nightmares, & – high dose + rapid IV bolus hallucinations ➢ agents that prevent or decrease incidence – may be crying but are still under control – benzodiazepines, , & dexmeditomidine – may become violent ➢ usually a short lived reaction – incidence with ketamine – traumatic for parents of children & escorts for adults • adults: 0 to 50% children: 0 to 10% – may be traumatic for the staff

Nausea & Vomiting Ketamine Isomers

➢ reported incidence 0 to 43% ➢ Racemic ketamine used in US ➢ most likely after emergence during recovery – S + R isomer ➢ antiemetics ➢ S isomer of ketamine ( dextro isomer ) – intra operative propofol – 2X as potent as racemic ketamine – high risk patients: use ondansetron – 3X more potent than R isomer – high doses of ketamine ( especially if solo agent ) – faster elimination & less psychomimetic reactions • use ondansetron ➢ R isomer is likely cause of emergence reactions

Can J Anesth. 2003;50: 470-75

22 4/15/2018

Ketamine General Anesthesia Pediatric Patients

➢ IM injection adults ➢ IM dosing in children – 4 to 6 mg/kg IM – 2 to 4 mg/kg – onset ~ 5 minutes – duration = 20 minutes of working time – consider starting an IV for maintenace by ketamine or another ➢ IV 1.0 to 2 mg/kg IV anesthetic agent – onset ~ 1 minute ➢ maintenance dose ➢ Oral ketamine – 0.1 to 0.3 mg/kg IV Q 10 to 15 minutes – can be used as a solo agent – 5 to 20 mg IV as needed – most current studies combine ketamine + midazolam – infusion 50 mcg/kg/min • decrease incidence of ketamine emergence delirium • deeper sedation than midazolam alone

Oral Ketamine Pediatric Dental Procedures

➢ oral ketamine has been used in children ➢ 6 mg/kg PO – more use in Europe than US ➢ onset of sedation: 20.5 minutes ➢ extensive 1st pass metabolism in liver – bioavailability has been as low as 17% ➢ duration of sedation: 36.4 minutes – reports of 59% bioavailability ➢ all patients needed at least 1 hour of recovery prior to • ketamine + metabolite ( norketamine ) discharge ➢ sedation onset range 17 to 25 mins

➢ SpO2 > 95; no airway issues; no emergence delirium ➢ no oral form so use parenteral drug and mix with a liquid carrier – 5 to 30 ml of carbonated drink, kool-aid, honey & water ➢ better sedation than meperidine 2mg/kg + 0.5 mg/kg PO ➢ dose range: 4 to 10 mg/kg PO Pediatr Dent. 1993

23 4/15/2018

Pediatric Dental Procedure Pediatric Dental Procedure

➢ age 21 to 43 months ➢ age < 36 months ➢ ketamine 10 mg/kg PO ➢ midazolam 0.5 mg/kg + ketamine 3 mg/kg PO ➢ onset 25 minutes ➢ onset: 20 minutes ➢ procedure time 33 minutes ➢ ketamine was S isomer of ketamine – study done in Brazil where isomer available ➢ no intraoperative complications ➢ no emergence delirium ➢ after discharge: slept at home on average 3 hrs ➢ better sedation than midazolam 1.0 mg/kg – range of 15 minutes to 6 hours – no maximum limit on midazolam: weight based only

Anest Progress. 2002;49:14-18 Int J Pediatr Dent. 2013;23:207-215

Intellectually Disabled Patients: Primary Teeth Excision Oral Agents ( Adults )

➢ 0.75 mg/kg midazolam + 5 mg/kg ketamine PO ➢ age group: 35 + 2.06 years old ➢ age group: 5.4 + 1.6 years ➢ ketamine 5 mg/kg + midazolam 0.3 mg/kg ➢ inject local anesthesia 30 min after ketamine ➢ onset of sedation: 12 minutes ➢ if sedation insufficient for local – IM injection 2 mg/kg ketamine + atropine 10 mcg/kg ➢ maximum sedation: 25 minutes – in M + K group: 3 of 15 patients needed IM ➢ BP 123.6 + 5.3 / 74.6 + 3.2 – in M ( 0.75 mg/kg ): 13 of 15 patients needed IM ➢ HR 94.2 + 5.4 ➢ M + K group tolerated excision better than M ➢ SpO 95.4 + 0.07 ➢ time to discharge: 108 + 10.8 minutes 2 ➢ no N/V or hallucinations ➢ sedation produced cooperative patient for dental procedures Eur J Paediatr Dent. 2010;11: 19 Neuoendocrinology Letters. 2012;33: 380-384

24 4/15/2018

Other Oral Dosing ER: Oral Dose for Lacerations

➢ combinations of ketamine + midazolam for ➢ midazolam 0.5 mg/kg + ketamine 5 mg/kg pediatric dentistry a oral route ➢ onset of sedation: 14.59 + 6.3 minutes ➢ laceration repair time: 15.75 + 6.53 mins Midazolam + Ketamine ➢ time of discharge 0.35 mg/kg + 5 mg/kg – administration of drug until discharge from ER 0.75 mg/kg + 5 mg/kg – 186.79 + 93.10 minutes 0.25 mg/kg + 3 mg/kg ➢ more effective sedation than midazolam 0.5 mg/kg

Emerg Med J. 2013; 00: 1-5

Additional PO References

J Indian Med Assoc. 2011;109:386 ➢ highly selective a2 adrenergic agonist – a2 to a1 ratio: 200 to 1 Pediat Anest. 2010;20:330 ➢ produces sedation, anxiolysis, & analgesia J Clin Pediatr Dent. 2011;35:415 Emerg Med J. 2001;18:30 ➢ improves separation anxiety in children Anest Analg. 2000; 90:299 ➢ i anesthetic agent requirements by 40 to 60% Br J Anest. 2000;84:335 – i MAC of volatile agents & i opioid doses Dent Res J. 2012;9:36 ➢ attenuates reflex & hypertension response to Pediatr Anest. 2005;15:554 intubation

25 4/15/2018

Clonidine Alpha 1 Receptors

➢ oral dosing: peak plasma level 60 to 90 minutes ➢ oral bioavailability: 75 to 95% ➢ highly lipid soluble

➢ t1/2b 6 to 23 hours – approximately 50% is metabolized in liver – excreted by kidney ➢ a1 receptors have 2 subunits: a1A a1B • ~ 50% is excreted unchanged ➢ IV form is available ➢ no presynaptic receptor identified – mostly used outside of the United States ➢ post synaptic receptors only ➢ h inotrope heart, h vasoconstriction, i urine output

Alpha 2 Receptors Alpha 2 Receptors

➢ presynaptic a2 receptor activity – inhibits the release of NEpi from presynaptic neuron into the synaptic cleft – acts as a negative feedback for further release of NEpi • together you get inhibition of the post synaptic neuron – reduction in sympathetic outflow – enhance parasympathetic outflow

– result = i SVR, i cardiac output, i myocardial inotropic effect, i heart rate

➢ at least 4 subtypes of a receptors ➢ post synaptic a2 receptor activity 2 – vasoconstriction – alpha 2A, 2B, 2C, & 2D

26 4/15/2018

Synaptic Cleft Alpha 2 Receptors

➢ a2A receptors – cause sedation, analgesia, and sympatholysis – brain & spinal cord ➢ a2B receptors – cause vasoconstriction by stimulating peripheral Clonidine receptors – may be responsible for antishivering ➢ i BP & HR during anesthesia – a2A receptors predominate over a2B receptors

CNS Effects of Clonidine CVS & Respiratory Effects

➢ Brainstem g pontine locus ceruleus ➢ CVS effects of clonidine – clonidine binding to a2A receptor – i heart rate, i SVR, i systolic blood pressure • produces sedation – dose dependent ➢ Brainstem g medullary vasomotor center – clonidine stimulates inhibitory neurons in medulla ➢ Respiratory effects – a2A receptors – minimal respiratory depression at best • i sympathetic outflow resulting in i BP, HR, and CO

➢ Spinal Cord a2A receptor – inhibits the release of substance P – analgesia

27 4/15/2018

Other Effects Clonidine PO in children

➢ i post operative shivering ➢ 4 mcg/kg PO: maximum 200 mcg PO ➢ dry mouth – took 1 mcg tablet crushed in fixed volume fluid ➢ hypertensive patients using clonidine to control ➢ administer 90 minutes pre op BP ➢ time from drug adminstration to induction of – abrupt withdrawal will lead to acute, severe general anesthesia hypertension – no episodes of hypotension, bradycardia, or

SpO2 < 95%

Clonidine Premedication in Clonidine PO in children Children

➢ sedation describes as drowsy or asleep ➢ superior to midazolam for pre induction sedation ➢ for venipuncture 33% were sedate ➢ superior to midazolam post operatively – less post operative pain reported ➢ for mask induction 26.6% were sedate – lower incidence of emergence delirium ➢ better results than 0.5 mg/kg midazolam – maximum dose 15 mg PO

Saudi J Anesth. 2012;6: 1-4 & 8-11

Acta Anaesthesiol Scand. 2010;54:397

28 4/15/2018

Clonidine & Third Molars Clonidine for Adults

➢ 150 mcg clonidine PO vs midazolam 7.5 mg PO ➢ PO dose range: 100 to 200 mcg PO ➢ age group: 18 to 40 yrs old – 100 mcg dose: bradycardia & hypotension rare ➢ anxiolytic dose of drug then local anesthesia – 150 mcg dose: stable hemodynamics only for surgery – 200 mcg: more episodes of bradycardia & hypotension ➢ give 150 mcg clonidine PO 60 mins prior to Sx • some case studies show stable hemodynamic – 1 patient fell asleep after 45 minutes • others show i in heart rate & BP ➢ no change in blood pressure reported – especially in medically compromised patients ➢ equal anxiolytic effects for 2 drugs ➢ 1.5 mcg/kg rare to see adverse hemodynamics

Oral Maxillofac Surg. 2012;16:341-347 Plast Reconst Surg. 2001;108:637

Clonidine for Adults Use for Clonidine

➢ optimal dose for 70 kg adult: 200 mcg PO ➢ patient for local anesthesia but has “white coat” – 60 to 90 minutes for peak hypertension verified by PCP – single dose will not cause rebound hypertension – documented normotensive outside healthcare office – rare to cause i BP or heart rate ➢ anxiolytic useful to try & calm patient • if it does occur a usually responds to fluids – lorazepam, diazepam, triazolam • small decreases in BP & HR have no clinical consequences – clonidine 100 mcg to 200 mcg PO ➢ 200 mcg used pre operatively in Friedberg • anxiolysis, sedation, analgesia Technique • attenuate heart rate & BP response to stress – office plastic surgery: clonidine, ketamine, propofol • improves myocardial oxygenation status Anesth Prog. 2006;53:34-42

29 4/15/2018

Non Benzodiazepine ( Ambien )

➢ chemical structure different from BZ ➢ approved in 1993 for insomnia ➢ are BZ receptor agonists ➢ sedative hypnotic at 5 to 10 mg – GABA a 1 subunit – h dose to get & anticonvulsant A effect ➢ reversible by flumazenil – need ~ 20 mg to see antegrade amnesia ➢ some selective binding to receptor ➢ onset 30 minutes t 1/2b 1-3 hours – limits cognitive impairment & abuse ➢ no active metabolites – less anxiolysis but more hypnosis ➢ side effects: headache & muscle pain ➢ do not use the controlled release compound

Zolpidem a Potential ( Sonata ) Problems

➢ FDA warning ➢ non BZ agonist – drowsiness day after use for sleep aid ➢ more hypnosis but less amnesia than BZ – patients engaged in “activities while asleep” ➢ onset 15 to 20 minutes t 1 hour • walking, driving, eating, sex 1/2b • all with no recall of events ➢ duration of action 4 hours – patients with behavioral changes ➢ 10 mg PO dose • h depression, suicidal thoughts, hallucinations ➢ 1 study 3rd molars under local + Sonata – patients engaging in at risk behavior without fear of danger – anxiolysis similar to triazolam – women at greater risk lower the dose to 5 mg for sleep – no amnesia faster recovery

Anest Progress. 2005;52:128

30 4/15/2018

Thank you

31