4.4 Pharmacology
4.4.1 Introduction
The most commonly used drugs for sedation in gastrointestinal endoscopy are benzodiazepines, opioids, and propofol. Propofol use has increased enormously in the last decade after several studies demonstrated advantages over traditional benzodiazepine/opioid combinations, including faster recovery, and with the same safety profile.29,30,31 The pharmacologic profiles of the drugs most commonly used for sedation in endoscopy are listed in
4.4.2 Benzodiazepines
Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), which results in sedative, hypnotic, anxiolytic, anticonvulsant, and amnesic action.32 The benzodiazepines diazepam and midazolam are the most commonly used sedatives in gastrointestinal endoscopy, and have comparable efficacy and safety.32,33 Because benzodiazepines do not have an analgesic effect, addition of an opioid is often necessary. Midazolam is frequently the drug of choice over diazepam for endoscopic procedures because of its rapid onset, short duration of action, 1.5 to 3.5 times higher sedation potency, and lack of associated phlebitis.34 In addition, midazolam has less respiratory depression and superior patient satisfaction compared to diazepam.34,35 However, the potency of midazolam increases in patients older than 60 years, with an increased potential for causing respiratory depression. Therefore, the dose of midazolam should be decreased and the intervals between administrations should be longer in such patients.35
An advantage of benzodiazepines is temporary reversibility through the antagonist flumazenil (0.1–0.3 mg intravenous bolus). Because the half-life of action of flumazenil is shorter than that of midazolam/diazepam, resedation may occur after flumazenil reversal.3
4.4.3 Opioids
Introduction
Opioids have a high analgesic effect, in addition to a mild sedative effect. The two most commonly used opiates for gastrointestinal endoscopy are meperidine/pethidine and fentanyl.9,10 They are often used in combination with benzodiazepines during endoscopic procedures, which is important as the sedation effect is quite pronounced. Because of the increased central nervous system depression, the opioid dose should be reduced when combination therapy is used, especially in the elderly and in patients with significant renal or liver dysfunction. Moderate sedation with a benzodiazepine/opioid combination results in high levels of physician and patient satisfaction, with a low risk of serious adverse events.3,29
Pethidine Hydrochloride (Meperidine)
Pethidine hydrochloride (meperidine) should be used primarily in procedures lasting longer than 30 minutes, because of its half-life of 3 to 4 hours. It is metabolized in the liver to normeperidine, an active metabolite with a half-life of 15 to 20 hours. Therefore, the clearance of meperidine may be significantly prolonged in patients with renal and hepatic insufficiency.3 In addition, the combination of meperidine with monoamine oxidase inhibitors is contraindicated due to the potential for life-threatening complications.36
Fentanyl
Because of its high degree of fat solubility fentanyl has a rapid onset and brief duration of action. In addition, it reduces the incidence of nausea as compared to meperidine and has analgesic properties approximately 100 times more potent than morphine, with relatively little effect on the cardiovascular system. Fentanyl has a shorter overall procedure duration during upper endoscopy and colonoscopy due to faster recovery.
A dose reduction of 50% or more is recommended in the elderly.3 Fentanyl has a narrow therapeutic range with a high risk of respiratory depression, which may persist longer than the analgesic effect.3 In addition, it must be injected slowly to avoid chest-wall rigidity associated with rapid administration.3
The central nervous effects of all described opioids can be reversed by intravenous administration of naloxone. The onset of action is only 1 to 2 minutes but its half-life is 30 to 45 minutes, and patients receiving naloxone should be monitored for at least 2 hours.3
4.4.4 Propofol
Pharmacology
Propofol, a phenol derivate, is a short-acting hypnotic agent. It has a rapid onset of action and a rapid elimination, which leads to significantly faster time to sedation and shorter recovery times compared to other agents.3,29,37 Propofol is significantly more efficacious than the combination of midazolam and meperidine for therapeutic endoscopies.31,37,38
Propofol has a weaker amnesic effect than midazolam, and has virtually no analgesic effects. However, the lack of analgesia is somewhat compensated when deeper sedation is reached. Dose reduction is not necessary for patients with moderately severe liver disease or renal failure, whereas a dose reduction is mandatory in patients with cardiac dysfunction and in the elderly.3 For interventional endoscopic procedures, propofol has been shown to be at least as safe as midazolam/pethidine, even when used in high-risk octogenarians.39 Furthermore, previously published randomized controlled studies demonstrate that propofol does not cause acute or transient deterioration of minimal encephalopathy in patients with liver cirrhosis and is associated with an improved recovery in those patients.40,41,42 Therefore, propofol is preferred instead of midazolam for sedation in patients with hepatic cirrhosis.3,4,5,6
While propofol can induce and maintain all levels of sedation, ranging from moderate sedation to general anesthesia, it has a narrow therapeutic window, so that sedation might become more deeply than intended, and reversal agent exists.3 However, data from the world-wide safety registry of 646,080 patients who received propofol sedation administered by gastroenterologists showed a mortality rate of 1 per 161,515, lower than that seen when standard sedation (opioids and benzodiazepines) is used (1 per 10,000),43,44 and comparable to published data on general anesthesia administered by anesthesiologists (1 per 10,000–50,000).44,45 The most common severe complications are dose-dependent hypotension, particularly in volume-depleted patients, and transient apnea following induction doses.
The wide variability in patient response to propofol should be considered. In some patients, only small doses of propofol induce deep sedation or even anesthesia. Because it is lipophilic, it should be handled in an aseptic fashion and measures should be taken to minimize the risk of bacterial contamination. Propofol contains soybean and egg lecithin and is therefore contradicted in patients with egg or soybean allergy.3
Administration Techniques
Propofol might be administered intravenously as repeated bolus injection, continuous infusion, or a combination. For gastrointestinal endoscopy sedation, propofol is most commonly administered by an initial bolus, adapted to patient’s weight, age, and comorbidities, followed by repeated boluses (10–20 mg), or by a continuous propofol infusion adapted to the desired sedation and patient conditions. The latter technique of continuous infusion is most commonly used by anesthesiologists, whereas the bolus application is currently used when nonanesthesiologist-administered propofol (NAAP) sedation is used. Another mode for the administration of propofol is the so-called balanced propofol sedation (BPS). This is achieved by a small induction dose of a benzodiazepine and/or an opioid, followed by small incremental doses of propofol. BPS might