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REVIEW ARTICLE
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Clin Pharmacokinet 2 0312-5963/06/
© 2006 Adis Data Information BV
Pharmacokinetic and Pharmacodynamic Characteristics of Medications Used for Moderate Sedation Tong J. Gan
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Optimal Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacokinetic Pr Properties of of Se Sedative Ag Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 AQUAVAN® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Re Rela lati tion onsh ship ip be betw twee een n Pha Pharm rmac acok okin inet etic ic Pa Para rame mete ters rs an and d Pha Pharm rmac acod odyn ynam amic ic Ef Effe fect ctss . . . . . 3.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 AQUAVAN® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Drug Co Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Safety Issues and Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Sign . . . up . . .to . .vote . . . .on . . .this . . .title . ... .... .... 5.5 AQUAVAN® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Useful .... ... . . . .Not . . .useful ........ ........ 6. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2 Propofol
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knowledge of the available drugs is required to choose the appropriate dr and/or combination regimen for individual patients. Midazolam, p ketamine and sevoflurane are the most frequently used agents, and all hav onset of action and rapid recovery. The primary drawback of midazola potential for accumulation of the drug, which can result in prolonged seda a hangover effect. The anaesthetics propofol and sevoflurane have recen used for sedation in procedures of short duration. Although effective, the require monitored anaesthesia care. Ketamine is an effective agent, partic children, but there is concern regarding emergence reactions. AQU injection (fospropofol disodium), a phosphorylated prodrug of propof investigational agent possessing a unique and distinct pharmacokinetic a macodynamic profile. Compared with propofol emulsion, AQUAVAN ciated with a slightly longer time to peak effect and a more p pharmacodynamic effect. Advances in the delivery of sedation, inclu development of new sedative agents, have the potential to further imp provision of moderate sedation for a variety of invasive procedures.
The use of sedation for interventional procedures ate for moderate sedation during interven cedures.[3,6,9,13-15] These agents have di has become commonplace in a number of settings, macokinetic and pharmacodynamic pro including endoscopic procedures (e.g. colonoscopy, how they may be optimally used, e bronchoscopy, gastroscopy), cardiac catheterisation, You're Reading affect a Preview or in combination with other agents. outpatient oral/maxillofacial surgery and the emerfull access free trial. article reviews the individua gency department. [1-3] For example, theUnlock increase in with aThis profiles and pharmacokinetic and pharma the number of patients undergoing screening for Download With Free Trial characteristics of the most commonly u colorectal cancer by endoscopy has been accompafor moderate sedation during interventi nied in most settings by an increased use of sedation dures. These include the benzodiazepin for control of pain and discomfort during colonosco[4] lam, the sedative/hypnotic agents pro py. Agents that deliver moderate sedation are apketamine, the inhalational agent sevoflu propriate for these procedures because they provide novel sedative hypnotic in clinical de quick recovery time, few sedation-related adverse AQUAVAN® 1 (fospropofol disodium events and greater overall patient satisfaction. [5,6] Important interactions of these agents The use of moderate sedation is also expanding to to incr sedation are on also include administration by nurse specialists and other Signagents up to vote thispresented title tioners’ understanding and use of sed non-anaesthesiologists in the endoscopy setting, and Useful Not useful niques and to improve patient satisfactio by the use of patient-controlled sedation (PCS). [7-11] comes. Moderate sedation is defined as that level of
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procedure. To this end, sedative drugs need to be pharmacodynamic profiles of inhalation titrated to effect to reach an optimal level of sedation primarily determined by their phys and to avoid complications. The ability to achieve properties; common pharmacokinetic the desired level of sedation is based on the charac(e.g. protein binding, metabolism, renal teristics of the various sedative drugs. However, the have little impact on the pharmacodynam wide variability in the temporal and dose-related of the drug. [22] The physiochemical pr response to various sedation agents dictates careful sevoflurane are summarised in table II. administration and monitoring of sedation in individual patients. 2.1 Midazolam The characteristics of an ideal agent for moderate Midazolam is highly lipophilic, resulti sedation have not been established by consensus opinion but are accepted to include rapid onset of distribution into the CNS and adipose These properties allow the drug to reach action, quick recovery of cognitive and physical action rapidly, producing an onset of act faculties following the procedure and a predictable minutes. However, the drug has a long pharmacokinetic/pharmacodynamic profile. [16] Each peak effect compared with propofol, m available sedation agent possesses characteristics drug less suitable for PCS. [39] Rapid rec that help dictate its best use and define its limitasedation with midazolam results from th tions.[17,18] A greater understanding of sedation distribution of the drug from the brain to agents will help physicians choose the correct drug, tissues.[23] Although midazolam is wel dose and combination to provide the best possible after oral administration, the relatively sedation for their patients. You're Readingpass a Preview hepatic metabolism of the drug res The availability of improved drug assay techbioavailability values ranging from 31% niques and pharmacokinetic modelling programmes Unlock full access with a free trial. Thus, oral doses of midazolam are app and the introduction of reliable infusion systems has twice those of the intravenous route. also led to an increased use of target-controlled Download With Free Trial Midazolam is eliminated by both h infusions (TCIs) of anaesthetic agents. [19] TCI sysrenal routes. [17] Hepatic metabolism is pr tems are pharmacokinetically based computer-conoxidation to three metabolites ( α-hydro trolled infusion systems designed to automatically lam, 4-hydroxymidazolam and α,4-hydro adjust the rate of infusion to maintain a desired lam) that are subsequently excreted as g (target) concentration. These systems can also be conjugates.[17] Midazolam has a relat combined into a patient-maintained sedation system clearance rate that is partially dependent in which target levels of the sedative agent are blood flow rate. [23] maintained via a computer-controlled infusion sys Sign up to vote on this parameters title [20] The pharmacokinetic of tem in response to patient demand. Because of its useful on the pa Useful Not are variable and are dependent short-acting pharmacokinetic profile, propofol has lation and the study design. [40,41] Age, b become the most frequently infused drug via TCI and hepatic and renal function influence th and a proprietary system for propofol is available. [21]
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Sheet Music Table II. Physical characteristics of sevoflurane and other inhalation anaesthetic agents[22,37] Parameter
Sevoflurane Desflurane Nitrous oxide
Boiling point (°C)
58.6
23.5
NR
Vapour pressure at 20°C 157 (mm Hg)
669
NR
Potency (MAC)[38]
6
104
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47.2–53.4
18.7
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0.68
0.42
0.47
MAC = minimum alveolar concentration (i.e. concentration that produced immobility in 50% of individuals exposed to a noxious stimulus); NR = not reported.
1 phase of elimination (t / 2α) of approxim minutes that represents the distribution into body tissues. The second phase is represents the metabolism of propofol (t minutes), while the third much longer variable phase represents the slow elimin drug from poorly perfused fat tissue (t hours).[17] As expected with a lipid-so pound, propofol has a very large volume tion (Vd).[24,44] Propofol initially distribu perfused tissue, then to lean tissue and fi deposits.[24]
lam compared with healthy controls (6.5% vs 3.9%) Propofol is primarily ( ≥88%) elim because of a reduction in serum albumin concentrasulphate and/or glucuronide conjugates i [17,23] tions. This is significant because an increased with <0.3% excreted as the parent com free fraction will result in greater pharmacodynamic The clearance of propofol (1.1–2.11 L/h effect. ally exceeds hepatic blood flow, sugg Important pharmacokinetic characteristics that trahepatic metabolism. [24] The pharmaco influence the duration of sedation with midazolam file of propofol can be altered with long include its relatively long elimination half-life periods, as evidenced by a larger V d and (1.8–6.4 hours) and its distribution to adipose tisYou're Reading a Preview compared with shorter infusi elimination [17] sue. With repeated administration, the adipose though most pharmacokinetic variables Unlock full access with a free trial. sites become saturated and the drug redistributes to between elderly patients and younger adu the blood. These properties can result in a prolongaelderly patients have a smaller V d an Free Trial tion of sedation and the potential for aDownload hangoverWithclearance compared with younger patien [17] effect. Although the drug is generally safe, reing that elderly patients will require low peated administration of midazolam in early studies the drug.[44] The clearance and V d of p resulted in fatal drug accumulation. [43] also significantly greater in obese than in
2.2 Propofol Propofol is a highly lipophilic sedative hypnotic agent that is structurally unrelated to other sedative agents. The pharmacokinetics of propofol are most commonly described using a three-compartment model (figure 1). This model describes the three dominant pharmacokinetic characteristics of pro-
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significantly alter the pharmacokinetics of propofol.[44]
2.5 AQUAVAN®
AQUAVAN®, a new sedative/hypno 2.3 Ketamine a water-soluble prodrug of propofol that in clinical development in the US. After Ketamine is an antagonist of N -methyl-D-asadministration, propofol is released partate (NMDA) receptors and is structurally related prodrug by the enzymatic action of alk to phencyclidine. [47] The drug is highly lipid soluble, phatases in the vascular endothelium. [51] resulting in extensive distribution to peripheral sites provides predictable and controlled rele (including the CNS) as evidenced by its relatively pofol with a smooth rise to therapeutic p large Vd.[48] The drug exhibits a biphasic plasma pofol concentrations. The pharmacok concentration-time curve characterised by a rapid AQUAVAN® are best described by a tw elimination phase lasting approximately 45 minutes, ment model, [51] while AQUAVAN ®-de 1 which corresponds to the analgesia period (t / 2α ≈ 10 pofol (once converted) is best described minutes). This is followed by a longer elimination compartment model. [26] The parent comp half-life that represents redistribution from the CNS relatively fast distribution to the peripher 1 and hepatic metabolism (t / 2–3 hours). [25] 2β = ment, a small V d and a short terminal hal Ketamine is primarily eliminated via hepatic metab38–46 minutes), whereas AQUAVAN olism with conversion to an active metabolite propofol, as expected, is lipophilic and (norketamine). Elderly patients appear to have a peripheral compartments (as described lower clearance and prolonged duration of action [26,51] ly). compared with younger adult patients. [49] There are You're Reading a Preview modest pharmacokinetic differences between the S + Despite producing the same active Unlock full access with a free trial. and R+ enantiomers, with the clearance of the S + AQUAVAN®-delivered propofol has enantiomer being somewhat greater than that of the pharmacokinetic and pharmacodynamic Download With Free Trial R+ enantiomer. [25] propofol emulsion. For example, in ex animals AQUAVAN ®-delivered propo 2.4 Sevoflurane longer elimination half-life, a larger delayed onset of action compared wit Sevoflurane has a low blood : gas solubility that emulsion.[52] Differences between prop produces a rapid uptake and elimination of the sion and AQUAVAN ®-delivered propo agent.[22,37] In healthy volunteers, the alveolar F A /FI so seen in healthy volunteers, although of sevoflurane (the rate at which fractional end-tidal differences varied from those seen in an alveolar concentration [F A] approaches the fraction® had pofol Sign fromupAQUAVAN a longe to vote on this title al inspired concentration [F I]) was 0.85 (i.e. ‘washtime, larger V d, higher clearance and sh Useful Not useful in’).[37] This increase was more rapid than that seen nation half-life than propofol emulsion. with isoflurane or halothane but somewhat slower than that seen with nitrous oxide and desflurane. [37]
The time course of plasma propofol
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a
10
10 1
8
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tinct hysteresis between plasma concent CNS effects, [55] and the greater sensit CNS depressant effects of midazolam am ly patients that is not explained by pharmacokinetics.[55] In addition, midazo so been shown to have both stimulatory a properties,[60,61] with stimulatory effects after infusion in small percentages of This effect may explain why the drug is with rebound adverse effects and toleran
As noted earlier, protracted admin midazolam can produce prolonged seda accumulation of midazolam and its acti lite in adipose tissue from which it is leased.[17,63] The risk of such accumulati est in patients with renal impairment b 480 960 1440 occur in those with normal renal fun benzodiazepine antagonist flumazenil for reducing the residual effects (espec tion) of midazolam, although the duratio 100 120 a single dose of flumazenil may be s You're Reading aofPreview the hangover effect of midazolam. [64,65]
Fig. 2. Plasma concentration-time curve for (a) propofol Unlockemulsion full access with a free trial. ® and (b) AQUAVAN -delivered propofol in healthy volunteers. The insets show the complete plasma concentration-time courses (reproduced from Fechner et al., [26] with permission). Download With Free 3.2Trial Propofol
3. Relationship between Pharmacokinetic Parameters and Pharmacodynamic Effects
3.1 Midazolam Most, but not all, evidence suggests that there is a wide range of midazolam blood levels associated with adequate sedation. [54-57] The level of sedation
The plasma concentration of propof for sedation depends on the desired dep tion and whether concomitant agents are general, propofol produces sedation in pendent fashion, with lower plasma con (0.5–1.5 µg/L) needed for sedation and s Sign up to vote on this title higher plasma concentrations (3–16 µ [44] Useful Not useful for surgical anaesthesia. Loss of cons typically reported at concentrations ra 3.5 to 10.5 µg/L.[24] There is also an inve
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3.3 Ketamine Ketamine has general anaesthetic properties most prominently characterised by profound analgesia, acting as an antagonist on the NMDA receptor. Unlike opioid analgesics, ketamine does not adversely affect respiratory or cardiovascular stability.[49] However, tachycardia was reported in 27.9% of children sedated with ketamine and midazolam who were undergoing minor surgical procedures. [67] The drug has a rapid onset of action (0.5 minute) and a short duration of action. The CNS depressant effects of ketamine are dose dependent, with concentrations of 0.6–2.0 µg/mL associated with general anaesthesia. [68] In children receiving postoperative analgesia and sedation following cardiac surgery, the children were arousable when ketamine concentrations fell below 1.0–1.5 µg/mL.[69]
two patients with 1.3%–1.5% end-tidal concentrations were responsive to vo scores of 41 and 52. [71]
3.5 AQUAVAN®
In rats, AQUAVAN ®-delivered prop sociated with a delayed onset, a sustain of action and greater potency compare pofol emulsion with respect to plasma tion.[52] Initial studies in healthy volun that propofol from AQUAVAN ® had a tency than propofol emulsion with respec concentration and did not show a hystere plasma concentrations and effect. [26] H other study found that when corrected f concentration of propofol, the pharmacod fect of AQUAVAN ®-delivered propofo lar to that of propofol emulsion. [72] 3.4 Sevoflurane Fechner et al. [27] demonstrated in hea teers that continuous infusions of AQ Sevoflurane has been investigated for providing You're Reading a Preview dose-dependent sedation, as m produced, sedation because of its rapid onset and offset as well the BIStrial. and the Modified Observer’s As as its non-pungent property, which makes inhalation Unlock full access with a free Alertness/Sedation (MOAA/S) scale. of this agent tolerable. Sevoflurane produces dosefrom logistic regression analysi dependent depressant effects on the central nervous,With curves Download Free Trial [37,50] that an AQUAVAN ®-delivered propo respiratory and cardiovascular systems. In genconcentration of 1.85 µg/mL or an ini eral, sedation with sevoflurane is associated with nous bolus dose of about 10 mg/kg of AQ more rapid recovery and faster return of cognitive [70] had the highest probability of producing function than with midazolam. In a randomised, S score of 3, corresponding to a moder comparative study in patients receiving sedation for sedation.[27,28] Gibiansky et al. [53] fou surgery, 76% of patients receiving sevoflurane had dose-response relationship for AQUAV return of cognitive function 30 minutes postoperaered propofol was curvilinear, with a line tively compared with 35% of midazolam-treated Sign up to at vote on this ship observed doses uptitle to 20 mg/kg. patients.[70] Useful Not useful The concentrations of sevoflurane required to A physiological model was used to produce sedation are variable. In patients who were pharmacokinetics and pharmacody slowly titrated to a moderate level of sedation with analysis) of propofol produced after
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of consciousness. However, AQUAVAN ® was associated with a longer time to peak BIS and a more prolonged pharmacodynamic effect. [73] This was probably related to a slower decrease in concentrations of AQUAVAN ®-delivered propofol. In addition, AQUAVAN ®-delivered propofol plasma concentrations were predictive of effect-site concentrations and clinical effect, although there were concentration-related differences in the equilibration time (K e0 = 1.2 minute–1 at AQUAVAN ® 30 mg/kg dose) between plasma and effect-site concentrations.[73]
4. Drug Combinations
meperidine) achieved a moderate leve and measures of recovery that were com those of standard-dose propofol. [6] Benz are frequently added to ketamine to red gence reactions but may be associate creased risk of hypoxaemia. [77] Initial studies also suggest that AQUA be effectively combined with other agen nous bolus administration of AQ (7.5–12.5 mg/kg) following pretreatmen venous fentanyl (0.5–1.5 µg/mL) induc adequate for colonoscopy within 2 min ministration. Recovery to fully alert occu 11 minutes (median time) after end of pr
5. Safety Issues and Adverse Ev Sedation regimens for moderate sedation frequently include the use of more than one agent, such In addition to the normal concerns wit as a hypnotic/anxiolytic (e.g. propofol, midazolam) tion and the associated cardiopulmonary plus an opioid (e.g. fentanyl, remifentanil, meperquate and safe sedation in critically ill o idine) for the purpose of anaesthesia and analgesia. patients is the primary measure of a goo These combinations have been used with different [78] agent. High-risk patients may include You're Reading a Preview degrees of patient satisfaction and procedural sucend-stage renal disease, chronic liver cess, and there are limited definitive data demonUnlock full access with a free trial. compromised cardiac or pulmonary func strating the superiority of combination regimens patient factors such as age and weight sho over single agents. For example, in a randomised Download Withtaken Free Trial into account when calculating dos study comparing propofol plus remifentanil with Dexmedetomidine, a highly selectiv propofol alone in patients undergoing colonoscopy, noceptor agonist with sedative and analg the addition of remifentanil resulted in a decreased used for sedating patients in the inte requirement for propofol. [74] However, patients in unit,[79] has a limited role in providing s the combination group experienced more respiratory analgesia for colonoscopy because of and blood pressure depressant effects and had a complicated administration regimen, pro lower recovery and lower patient satisfaction than covery time, pronounced haemodynamic with propofol alone. [80] A dos and distressing adverse Sign up to vote on thiseffects. title A number of trials have attempted to quantify the to produce sedation during useful colonoscop Useful Not optimal concentrations of sedation agents that are profound hypotension and bradycardia. used in combination (e.g. propofol emulsion/various opioids),[75] or compared sets of different drug com-
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(e.g. elderly, critically ill, those with hepatic dysfunction) who have decreased clearance of midazolam. These patients should receive reduced doses and should be monitored for excessive sedation.[38,42]
5.2 Propofol
propofol is injected into the dorsum o compared with the forearm or antecubita has been suggested that the lipid solvent induces the release of bradykinin by ac plasma kallikrein-kinin system, resulting fication of the local vein that increases between the aqueous phase of propofol nerve endings of the vessel. [87] Concomi local anaesthetic agent (e.g. lidocaine [l is commonly used to reduce local pain. include the administration of lidocaine i prior to propofol, the mixing of propofo caine or the use of topical EMLA ® crea mixture of local anaesthetics). [86] Other reducing local pain included administr opioid, metoclopramide, cold saline or to glycerin prior to propofol. [86]
Some of the limitations of propofol emulsion and its adverse effects include the risk of extraneous microbial contamination of the emulsion formulation, lipidaemia induced by repeated administration of the agent over time, intravenous injection site pain, oversedation and risk of hypotension/cardiopulmonary complications. Although short-term infusions of propofol emulsion ( ≤3 days) have no effect on lipid levels, longer infusions produce progressive increases in serum lipid levels, particularly Several recent studies demonstrated t triglycerides.[44] Green discoloration of the urine can ty and safety of propofol sedation admi also be seen after long-term administration, algastroenterologists, nurses and patient though its significance is not known. [81] There are endoscopic procedures. [8,9,89-92] Fo You're Reading aterm Preview also concerns about the safety of propofol for procenurse-administered propofol was asso dural sedation because of possible problems with Unlock full access with a freerecovery, trial. faster quicker discharge and be hypoxaemia, hypotension and decreased cardiac erative neuropsychological test scores output when administered by non-anaesthesioloDownload With midazolam Free Trial plus fentanyl in patients unde gists.[82] Propofol has well established respiratory patient colonoscopy. [90] Similarly, PCS f depressant effects, particularly at anaesthetic doses copy with propofol plus alfentanil prod and when used in combination with opioids; [74,83,84] recovery, quicker discharge and similar however, comparative studies have found that proisfaction than with physician-administer pofol does not induce greater changes in arterial lam and meperidine. [9] [44] blood gases than midazolam. Propofol infusions Propofol also appears to be a safe an may also decrease cardiac output, particularly in sedation agent in critically ill or high-ri conjunction with the coadministration of opioids those with end-stage disease and the Sign up to vote onrenal this title (e.g. fentanyl). [16] Propofol-induced decreases in For example, high-risk patients (Amer Not useful Useful in blood pressure are generally dose- and infusion-rate ty of Anesthesiologists [ASA] physical s dependent, an effect at least partially related to IV) undergoing colonoscopy, propofol p decreases in peripheral vascular resistance. Notwith-
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tion, time to full recovery and greater overall patient satisfaction than combination sedation with midazolam and meperidine. [95] In elderly patients undergoing outpatient colonoscopy, patient-controlled administration of propofol produced faster recovery time and significantly less hypotension than intravenous sedation with diazepam and meperidine. [10]
5.3 Ketamine Ketamine has a narrow therapeutic window. Emergence reactions such as disorientation, dreamlike experiences, vivid imagery, hallucinations and delirium are among the most important adverse reactions. These reactions are particularly common in adults.[77] These reactions are reduced when ketamine is used in conjunction with a benzodiazepine or propofol. It can also increase the incidence of nausea and vomiting. [96]
label, dose-ranging trial evaluating AQU patients undergoing colonoscopy, transi moderate pelvic/perianal tingling, itchi sensation was noted in 85% of patients. of AQUAVAN ® in high-risk patients choscopy and intensive care unit sedat rently under evaluation.
6. Drug Interactions 6.1 Midazolam
Midazolam is metabolised via CY dases. Therefore, coadministration of with CYP inhibitors (e.g. azole macrolide antibacterials, grapefruit juice in excess sedation because of decre ance.[97-99] For example, coadministratio nous midazolam with azole antifu itraconazole, fluconazole) decreased 5.4 Sevoflurane clearance by 50–70%. [99] The interacti You're Reading amidazolam Preview and azoles is even more As with other inhalational anaesthetics, sevofluwhen midazolam is administered orally rane can be associated with airway complications Unlock full access with a free trial. result in 3- to 15-fold increases in mida such as breath holding, coughing, excitement and [37,50] exposure (as measured by the AUC). laryngospasm. Changes in haemodynamics are Download With Free be Trial may explained by the potentially grea generally small and the risk of fluoride-induced ry effect of azoles on the CYP3A4-depe nephrotoxicity appears to be minimal. In a comparapass metabolism of midazolam that occu tive trial in patients undergoing moderate sedation, nantly in the gut mucosa, [100] resulting sevoflurane was associated with significantly more breakdown and clearance of midazolam disinhibition excitement (70%) than with propofol [71] tered by the oral route in the presence o (36%) or midazolam (5%). azoles. 5.5 AQUAVAN® 6.2Sign Propofol up to vote on this title Some of the concerns associated with the use of useful Useful isNotmetabolised propofol emulsion may be mitigated with the use of Since propofol via ® AQUAVAN , which has not been reported to inpathway, drugs that inhibit this pathw [73] duce injection site pain and does not have safety ly could alter the clearance of propof
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approximately 20%. [102] Furthermore, combination of propofol and these opioids has synergistic sedative and analgesic effects, with fentanyl and alfentanil concentrations of 3 ng/mL and 122 ng/mL, respectively, reducing the propofol blood concentration associated with loss of consciousness in 50% of patients (EC 50) by 40%.[75]
6.3 Sevoflurane The minimum alveolar concentration of sevoflurane is reduced by the concomitant administration of nitrous oxide and opioids. Sevoflurane also potentiates the pharmacological activity of neuromuscular blocking agents. Since sevoflurane is metabolised by CYP2E1, agents that induce this isozyme (isoniazid, alcohol [ethanol]) may increase the metabolism of the drug. [37,50]
Properties of an ideal agent for mode include rapid onset, rapid recovery, c recovery, ease of use, safety and no requ monitored anaesthesia care. The current agents most commonly used in short-ter sedation (e.g. midazolam, propofol, ke generally effective sedative agents and but not all, of these characteristics. For e benzodiazepine midazolam is an effe when administered alone or in combin other agents (e.g. opioids) for providin sedation during short procedures. Th drawback of this agent is the prolongati tion and hangover effects induced by th long half-life of midazolam and its meta their slow release from adipose tissue af administration.
Recent studies have also shown tha acting agent propofol, an anaesthetic/hyp Preliminary data indicate that coadministration used previously for deep sedation, can b Reading acessfully Previewand safely for moderate sedati of AQUAVAN ® with fentanyl provides You're satisfactory sedation with an acceptable safety profile in patients variety of interventional procedures. Co Unlock full access with a free trial. undergoing colonoscopy. [28] In the dose-ranging of propofol and other sedation agents c study of AQUAVAN ® by Pruitt et al.[28] (<619 to DownloadinWith excellent Free Trialresults in sedation and patient >931mg), hypoxaemia (<90% O 2 saturation) while providing many of the character creased modestly at the higher doses of this agent in ‘ideal’ procedural sedation agent for co combination with fentanyl pretreatment, but reIn addition, the availability of ‘open’ T solved quickly with the administration of oxygen or precluding the use of prefilled syringes repositioning. Transient apnoea was observed in 7 for nearly no propofol wastage has re of 93 (7%) volunteers in this study, 5 of whom had technique economically attractive as w received the highest dose of AQUAVAN ® plus cally efficient. However, the use of pro fentanyl at doses >1 µg/kg. One episode of apnoea sion is limited by injection sitepain, o was a serious adverse event requiring a 3-minute Sign up to vote on this title and the risk of hypotension/cardiopulm [28] interval of mechanical ventilation. Useful Not useful plications. Possibly of most importance ling requirement for monitored anaest 7. Conclusions
6.4 AQUAVAN®
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15. Stewart RD. Nitrous oxide sedation/analgesia medicine. Ann Emerg Med 1985; 14: 139-48 16. Skues MA, Prys-Roberts C. The pharmacol Clin Anesth 1989; 1: 387-400 17. Horn E, Nesbit SA. Pharmacology and pharm Acknowledgements sedatives and analgesics. Gastrointest Endos 2004; 14: 247-68 Editorial assistance was provided on this manuscript 18. Karan SB, Bailey PL. Update and review of mo through an unrestricted grant from MGI Pharma. The author sedation. Gastrointest Endosc Clin N Am 2004 is grateful for editorial assistance provided by Nexus Com19. Gepts E. Pharmacokinetic concepts for TCI anae thesia 1998; 53 Suppl. 1: 4-12 munications, Inc., North Wales, PA, USA. 20. Rodrigo MR, Irwin MG, Tong CK, et al. A The author serves on the advisory board of MGI Pharma over comparison of patient-controlled sedatio and has received grant support related to research activities. maintained sedation using propofol. Anaesth 333-8 21. Egan TD. Target-controlled drug delivery: prog References intravenous "vaporizer" and automated anesthe 1. Bahn EL, Holt KR. Procedural sedation and analgesia: a review tion. Anesthesiology 2003; 99: 1214-9 and new concepts. Emerg Med Clin North Am 2005; 23: 22. Behne M, Wilke HJ, Harder S. Clinical pharm 503-17 sevoflurane. Clin Pharmacokinet 1999; 36: 132. Javorski JJ, Hansen DD, Laussen PC, et al. Paediatric cardiac 23. Fragen RJ. Pharmacokinetics and pharmac catheterization: innovations. Can J Anaesth 1995; 42: 310-29 midazolam given via continuous intravenous in 3. Cillo Jr JE. Propofol anesthesia for outpatient oral and maxilsive care units. Clin Ther 1997; 19: 405-19 lofacial surgery. Oral Surg Oral Med Oral Pathol Oral Radiol 24. Kanto J, Gepts E. Pharmacokinetic implicati Endod 1999; 87: 530-8 use of propofol. Clin Pharmacokinet 1989; 17: 4. Heuss LT, Froehlich F, Beglinger C. Changing patterns of 25. Persson J, Hasselstrom J, Maurset A, et al. Ph sedation and monitoring practice during endoscopy: results of and non-analgesic effects of S- and R-ketam a nationwide survey in Switzerland. Endoscopy 2005; 37: volunteers with normal and reduced metabolic 161-6 Clin Pharmacol 2002; 57: 869-75 5. Froehlich F, Schwizer W, Thorens J, et al. Conscious You'resedation Reading a Preview 26. Fechner J, Ihmsen H, Hatterscheid D, et for gastroscopy: patient tolerance and cardiorespiratory parampharmacokinetics and pharmacodynamics of th eters. Gastroenterology 1995; 108: 697-704 Unlock full access with a free trial. prodrug GPI 15715 and propofol emulsion. A 6. Cohen LB, Hightower CD, Wood DA, et al. Moderate level 2004; 101: 626-39 sedation during endoscopy: a prospective study using low27. Fechner J, Ihmsen H, Schiessl C, et al. Seda dose propofol, meperidine/fentanyl, and midazolam. Gas-With Free Download Trial 15715, a water-soluble prodrug of propofol trointest Endosc 2004; 59: 795-803 controlled infusion in volunteers. Anesth An 7. Kulling D, Bauerfeind P, Fried M, et al. Patient-controlled 701-6 analgesia and sedation in gastrointestinal endoscopy. Gas28. Pruitt RE, Cohen LB, Gibiansky E, et al. A ran trointest Endosc Clin N Am 2004; 14: 353-68 label, multicenter, dose-ranging study of 8. Heuss LT, Drewe J, Schnieper P, et al. Patient-controlled versus AQUAVAN ® injection (GPI 15715) during c nurse-administered sedation with propofol during colonoscoDigestive Disease Week; 2005 May 14-19, Chi py: a prospective randomized trial. Am J Gastroenterol 2004; 29. Greenblatt DJ, Ehrenberg BL, Culm KE, e 99: 511-8 EEG effects of midazolam during and after 1-m 9. Bright E, Roseveare C, Dalgleish D, et al. Patient-controlled and 3-hour intravenous infusions. J Clin Pharm sedation for colonoscopy: a randomized trial comparing pa605-11 tient-controlled administration of propofol and alfentanil with 30. Wehrmann T,vote Kokabpick Lembcke B, e physician-administered midazolam and pethidine. Endoscopy Sign up to on thisS, title safety of intravenous propofol sedation during r 2003; 35: 683-7 Useful Not useful prospective, controlled study. Gastrointest En 10. Lee DW, Chan AC, Sze TS, et al. Patient-controlled sedation 677-83 versus intravenous sedation for colonoscopy in elderly pa31. Zakko SF, Seifert HA, Gross JB. A comparison tients: a prospective randomized controlled trial. Gastrointest
fulfil many unmet needs in the provision of moderate sedation for invasive procedures.
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35. Hijazi Y, Boulieu R. Protein binding of ketamine and its active wide interpatient variability? Clin Pharmac metabolites to human serum. Eur J Clin Pharmacol 2002; 58: 263-9 37-40 55. Albrecht S, Ihmsen H, Hering W, et al. The effe 36. Sipe BW, Rex DK, Latinovich D, et al. Propofol versus midazopharmacokinetics and pharmacodynamics of m lam/meperidine for outpatient colonoscopy: administration by Pharmacol Ther 1999; 65: 630-9 nurses supervised by endoscopists. Gastrointest Endosc 2002; 56. Short TG, Young KK, Tan P, et al. Midazolam 55: 815-25 pharmacokinetics and pharmacodynamics foll 37. Patel SS, Goa KL. Sevoflurane: a review of its pharmacodynamneous administration to human volunteers. Ac ic and pharmacokinetic properties and its clinical use in generScand 1994; 38: 350-6 al anaesthesia. Drugs 1996; 51: 658-700 57. Tolia V, Brennan S, Aravind MK, et al. Pharm 38. MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics pharmacodynamic study of midazolam in chil and pharmacodynamics of intravenous midazolam in patients ophagogastroduodenoscopy. J Pediatr 1991; 11 with severe alcoholic cirrhosis. Gut 1986; 27: 190-5 58. Volkow ND, Wang GJ, Hitzemann R, et al. Dec 39. Cook LB, Lockwood GG, Moore CM, et al. True patientresponse to inhibitory neurotransmission in al controlled sedation. Anaesthesia 1993; 48: 1039-44 Psychiatry 1993; 150: 417-22 40. Maitre PO, Funk B, Crevoisier C, et al. Pharmacokinetics of 59. Abi-Dargham A, Krystal JH, Anjilvel S, et midazolam in patients recovering from cardiac surgery. Eur J benzodiazepine receptors in type II alcoholic Clin Pharmacol 1989; 37: 161-6 sured with SPECT and [123I]iomazenil. Am 41. Zomorodi K, Donner A, Somma J, et al. Population 1998; 155: 1550-5 pharmacokinetics of midazolam administered by target con60. Lau CE, Wang Y, Ma F. Pharmacokinetic-pha trolled infusion for sedation following coronary artery bypass modeling of the coexistence of stimulatory and grafting. Anesthesiology 1998; 89: 1418-29 ponents for midazolam. Eur J Pharmacol 1998 42. Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinet61. Golparvar M, Saghaei M, Sajedi P, et al. Parad ics of midazolam following intravenous and oral administrafollowing intravenous midazolam premedicati tion in patients with chronic liver disease and in healthy patients: a randomized placebo controlled trial subjects. J Clin Pharmacol 1989; 29: 272-7 rapid tranquilization. Paediatr Anaesth 2004; 1 43. Bell GD, Spickett GP, Reeve PA, et al. Intravenous midazolam 62. Massanari M, Novitsky J, Reinstein LJ. Paradox for upper gastrointestinal endoscopy: a study of 800 consecuchildren associated with midazolam use duri tive cases relating dose to age and sex of patient. Br J Clin Clin Pediatr (Phila) 1997; 36: 681-4 You're Reading a Preview Pharmacol 1987; 23: 241-3 63. Bauer TM, Ritz R, Haberthur C, et al. Prolong 44. Fulton B, Sorkin EM. Propofol. An overview of its pharmacoloaccumulation of conjugated metabolites of mid full access gy and a review of its clinical efficacy inUnlock intensive care with a free trial. 1995; 346: 145-7 sedation. Drugs 1995; 50: 636-57 64. The Flumazenil in Intravenous Conscious 45. Frenkel C, Schuttler J, Ihmsen H, et al. Pharmacokinetics and Diazepam Multicenter Study Group I. Reve Download With Free Trial pharmacodynamics of propofol/alfentanil infusions for sedabenzodiazepine effects by flumazenil after con tion in ICU patients. Intensive Care Med 1995; 21: 981-8 produced by intravenous diazepam. Clin Ther 46. Servin F, Farinotti R, Haberer JP, et al. Propofol infusion for 909 maintenance of anesthesia in morbidly obese patients receiv65. Short TG, Galletly DC. Residual psychomotor ef ing nitrous oxide: a clinical and pharmacokinetic study. Anesreversal of midazolam sedation with flumazen thesiology 1993; 78: 657-65 tensive Care 1989; 17: 290-7 47. Peyton SH, Couch AT, Bost RO. Tissue distribution of 66. Doufas AG, Bakhshandeh M, Bjorksten AR, e ketamine: two case reports. J Anal Toxicol 1988; 12: 268-9 speed is not a determinant of propofol pharm 48. Xie H, Wang X, Liu G, et al. Analgesic effects and Anesthesiology 2004; 101: 1112-21 pharmacokinetics of a low dose of ketamine preoperatively 67. Cheuk DK, Wong WH, Ma E, et al. Use o administered epidurally or intravenously. Clin J Pain 2003; 19: ketamine as sedation for children undergoing m 317-22 Sign up to vote on this title procedures. Support Care Cancer 2005; 13: 10 49. Tsui BC, Wagner A, Finucane B. Regional anaesthesia in the Useful Not useful 68. Ketamine 2005 [online]. Available from URL: h elderly: a clinical guide. Drugs Aging 2004; 21: 895-910 trohealthanesthesia.com/edu/ivanes/ketamine5. 50. Goa KL, Noble S, Spencer CM. Sevoflurane in paediatric anaes2005 Aug 29] thesia: a review. Paediatr Drugs 1999; 1: 127-53
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Sheet Music 73. Struys MM, Vanluchene AL, Gibiansky E, et al. AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 2): pharmacodynamics and safety. Anesthesiology 2005; 103: 730-43 74. Moerman AT, Struys MM, Vereecke HE, et al. Remifentanil used to supplement propofol does not improve quality of sedation during spontaneous respiration. J Clin Anesth 2004; 16: 237-43 75. Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions. Acta Anaesthesiol Belg 2001; 52: 445-51
tion by nurses supervised by endoscopists. Cl Hepatol 2003; 1: 425-32
91. Seifert H, Schmitt TH, Gultekin T, et al. Sedatio plus midazolam versus propofol alone for inter scopic procedures: a prospective, randomized Pharmacol Ther 2000; 14: 1207-14
92. Koshy G, Nair S, Norkus EP, et al. Propofol ve and meperidine for conscious sedation in GI en Gastroenterol 2000; 95: 1476-9
76. Kucukyavuz Z, Cambazoglu M. Effects of low-dose midazolam with propofol in patient-controlled sedation (PCS) for apicectomy. Br J Oral Maxillofac Surg 2004; 42: 215-20
93. Knibbe CA, Zuideveld KP, DeJongh J, pharmacokinetic and pharmacodynamic model for long-term sedation in critically ill patients between propofol 6% and propofol 1%. Clin P 2002; 72: 670-84
77. Mason KP, Michna E, DiNardo JA, et al. Evolution of a protocol for ketamine-induced sedation as an alternative to general anesthesia for interventional radiologic procedures in pediatric patients. Radiology 2002; 225: 457-65
94. Heuss LT, Schnieper P, Drewe J, et al. Safety conscious sedation during endoscopic procedu patients: a prospective, controlled study. Am J 2003; 98: 1751-7
78. Walder B, Tramer MR. Analgesia and sedation in critically ill patients. Swiss Med Wkly 2004; 134: 333-46
95. Weston BR, Chadalawada V, Chalasani N, et tered propofol versus midazolam and meperi endoscopy in cirrhotic patients. Am J Gastroen 2440-7
79. Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs 2000; 59: 263-8
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Effects 101. Ibrahim A, Park S, Feldman J, et al. Sign up to vote on this title parenteral COX-2-specific inhibitor, on the ph Useful Not useful and pharmacodynamics of propofol. Anesthesio 88-95
102. Vuyk J. Pharmacokinetic and pharmacodynam
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