REVIEW URRENT C OPINION
Sedative medications outside the operating room and the pharmacology of sedatives Tom G. Hansen
Purpose of review There is a growing medical demand for suitable sedatives and analgesics to support the ongoing progress in diagnostic procedures and imaging techniques. This review provides an update of the pharmacology of the most commonly used drugs used for these procedures and shortly mention new drugs on the horizon. Recent findings There are many drugs available for procedural sedation; however, they all have drawbacks and shortcomings. Multiple adverse effects are associated with the use of these agents, hence monitoring is essential, and emergency equipment should be readily available. Newer drugs are on the horizon (e.g., remimazolam, fospropofol, and etomidate analogues) with a theoretical more predictable onset and offset; whether these will revolutionize the sedational practice sedation remains unknown. Summary Clinicians should be aware of the pharmacokinetic/pharmacodynamic differences of all agents in order to select appropriate medications for specific procedures and patients. Keywords a2-agonists, interventional pain management, midazolam, opioids, sedation: propofol
INTRODUCTION Sedation is used to facilitate diagnostic or therapeutic procedures requiring varying degrees of anxiolysis and/or analgesia. Sedation covers a continuum of stages from minimal sedation (‘anxiolysis’) through moderate sedation/analgesia (‘conscious sedation’), deep sedation, and ultimately general anesthesia. Each stage comprises a progressive degree of central nervous system (CNS) depression with impaired levels of consciousness, decreased responsiveness to stimuli, loss of protective reflexes, and progressive respiratory and cardiovascular depression [1–2]. The depth of sedation required and the agents used largely depend upon the anticipated degree of pain, the allowable amount of movements encountered during the procedure, and certain important patient factors [1,2] (Table 1). In this review, the pharmacology of these agents is reviewed. Pharmacokinetics of the agents is addressed in tabular form (Table 2), whereas pharmacodynamic aspects of each agent are described in more detail. This author does not recommend the use of chloral hydrate, and from a safety and efficacy point of view the route of administration www.co-anesthesiology.com
recommended is primarily intravenous (i.v.). Dosing of the reviewed drugs is listed in Table 3.
Propofol Propofol (2,6 di-isopropyl phenol) is a weak lipophilic acid unionized at pH 7.4. Because of its favorable pharmacokinetic profile it is commonly used for sedation for diagnostic procedures [3,4]. It acts by stimulation of the gamma-aminobutyric acid (GABAA)-receptor subunit b1 in which it activates chloride channels, thereby increasing inhibitory synaptic transmission. Propofol also inhibits N-methyl-D-aspartate (NMDA) receptors but to a much lesser extent. Its onset time is short (30– 60 s), and its duration of action is 5–10 min due Department of Anesthesiology and Intensive Care, Pediatric Section, Odense University Hospital, Odense, Denmark Correspondence to Tom G. Hasen, MD, PhD, Institute for Clinical Research – Anesthesiology, University of Southern Denmark, DK5000 Odense C, Denmark. E-mail: [email protected] or [email protected] Curr Opin Anesthesiol 2015, 28:446–452 DOI:10.1097/ACO.0000000000000202 Volume 28 Number 4 August 2015
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Sedative medications outside the operating room Hansen
KEY POINTS The demand for sedation to support the ongoing progress in diagnostic procedures and imaging techniques is growing. All available sedatives and analgesics have drawbacks and shortcomings. Well tolerated use of sedatives/analgesics require detailed pharmacological knowledge in order to select the appropriate drugs for specific procedures and patients. The new drugs on the horizon may be helpful in the future.
to redistribution. Propofol has a high clearance; total clearance exceeds liver blood flow. Metabolism is predominantly by sulphation and glucuronidation to a number of inactive metabolites excreted via the kidneys. The terminal elimination half-life is 3–9 h, which carries the risk of accumulation during long-term use. Propofol is highly plasma protein bound (98%), predominantly to albumin. Bolus dose is 1–5 mg/kg depending on age, comorbidity, and general condition. Pain at the site of injection is a problem, but can be minimized with the addition of lidocaine, pretreatment opioids, or use of the 0.5% propofol. Propofol is a negative inotropic and chronotropic drug, thus, any decrease in cardiac output is not compensated by an increase in heart rate. Further, propofol inhibits sympathetic tone, thus, cardiac output often drops significantly after a bolus dose. This is most pronounced in patients with impaired cardiac function, the elderly and neonates. Propofol induces a dose-dependent respiratory depression. Apnea occurs relatively frequently in young healthy individuals after an induction dose (25–30%). Incidence and duration depends on age, dose, and rate of injection, and coadministration of other sedatives/analgesics [3].
Table 1. Patient factors important for the choice of sedatives 1. Comorbidities (e.g., cardiopulmonary status, allergies, and comedication) 2. Degree of fasting 3. Age 4. Ability to cooperate 5. Degree of pain 6. Level of anxiety 7. Prior problems with previous sedation and sedatives
Propofol reduces brain metabolism, blood flow, and volume. Although propofol possesses clear dose-dependent anticonvulsant properties, it may act as a proconvulsant agent in certain individuals, but epilepsy as such is not a contraindication for propofol [3,4]. The propofol infusion syndrome (PRIS) is a rare condition described in patients exposed to propofol for a long time and in high doses. PRIS, first described in critically ill children undergoing longterm sedation in excessive doses, is characterized by quite: cardiac failure, rhabdomyolysis, metabolic acidosis, hepatomegaly, renal failure hyperkalemia, hypertriglyceridemia, and high mortality. PRIS has since been described in critically ill adults but also in anesthetized children and adults receiving high propofol doses. Treatment of PRIS is supportive with immediate cessation of propofol infusion and early initiation of dialysis. Long-term propofol infusion rates above 4 mg/kg/h should be avoided [5].
Barbiturates For all practical purposes, thiopental is the only sedative barbiturate used clinically. Thiopental is a core medication according to the WHO’s Essential Drug List (http://whqlibdoc.who.int/hq/2005/ a87017_eng.pdf). However, because it was used for lethal injections (in combination with other drugs) in the USA, the US manufacturer ceased manufacturing it and exportation of it outside Europe was banned by the European Union. Hence, it is no longer used in the USA, but remains widely used in many other countries. Following an i.v. bolus dose it is an ultra-short-acting barbiturate due to rapid redistribution. However, with repeated dosing or continuous infusion the duration of action increases significantly due to a long terminal halflife. Barbiturates mechanism of action is by stimulation of the GABAA receptors [4,6]. Allergic reactions to barbiturates are occasionally seen in varying severity. Barbiturates are contraindicated in patients with porphyria, and thiopental may trigger bronchospasm and should be used cautiously in asthmatic patients. Thiopental Thiopental is a lipophilic drug; at pH 7.40, 60% is present in an unionized form. After an induction dose (2–5 mg/kg, up to 7 mg/kg in children) the onset of action is rapid (10–30 s) and the duration of action is, approximately, 7–10 min due to redistribution. Thiopental undergoes hepatic metabolism, and many metabolites are pharmacologically active. At high dosages the drug exhibits zero order kinetics. Thiopental is a low-clearance drug with a relatively
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Anesthesia outside the operating room Table 2. Pharmacokinetic parameters for the most commonly used sedatives and analgesics Vss (l/kg)
Cl (ml/kg/min)
t1/2 –el (h)
CSHT1 (min)
CSHT3 (min)
1.0–8.5
30–39
3–9
10
21
Thiopental
1.4–3.3
1.6–4.3
5–12
80
120
75
Etomidate
2.0–4.5
12–20
1–5
4
8
76
S-ketamine
3.0
16–18
2–3
5
22
50
Midazolam
1.0–1.5
4–8
1–4
32
60
95
Fentanyl
4.0
12.6
2–4
25
105
Clonidine
1.7–2.5
3.2
6–24
Dexmedetomidine
1.7
9.0
2–3
Alfentanil
0.7
5.1
1.0–1.5
Sufentanil
1.7
11.8
2.7
Remifentanil
0.4
44.0
0.1
Flumazenil
1.0
5–20
0.7–1.3
Propofol
Naloxone
F (%) 98
43 20–40 94
32
56
85
18
22
70
0.1
0.1
70
30–60
Cl, clearance; CSHT1, context-sensitive half-time after 1 h; CSHT3, context-sensitive half-time after 3 h; F, protein binding; t1/2-el, elimination half-time; Vss, volume of distribution at steady state.
large volume of distribution and a long elimination half-life (5–12 h), hence the risk of accumulation is high with repeated dosages and continuous infusion. Thiopental is highly plasma protein bound (75%) mainly to albumin. Quantitative and qualitative changes in binding proteins seen in the elderly, neonates, and patients with compromised cardiac, renal, or hepatic function requires a considerable reduction in induction dose (2.0–2.5 mg/kg). Thiopental is an alkaline solution (pH 10–11) and tissue damaging when administered paravenously. A minor proportion of thiopental undergoes placental transfer and a modest amount is excreted via breast milk [4,6].
Thiopental possesses negative inotropic properties and it reduces the sympathetic tone, thus, reducing venous pressure and venous return. The net effect is a significant decrease in cardiac output; hence thiopental should be used cautiously in patients with significant cardiac failure or hypovolemia [4,6]. Thiopental also induces a dose-dependent respiratory depression. An induction dose is accompanied by a few irregular deep breaths followed by brief apnea, in which the patient’s breathing might need support by mask ventilation. Coadministration of opioids synergistically increases the respiratory depressant effects of thiopental.
Table 3. Recommended intravenous dosing of sedative and analgesics Bolus dose
Continuous infusion (ml/kg/min)
Propofol
1.0–1.5 mg/kg
10–50 mg/kg/min
Thiopental
2–5 mg/kg
n/a
Etomidate
0.2–0.4 mg/kg
n/a
S-ketamine
0.1–0.3 mg/kg
10–20 mg/kg/min
Midazolam
0.025–0.05 mg/kg
0.3–1.5 mg/kg/min
Clonidine
1.0–5.0 mg/kg
0.2 mg/kg/h
Dexmedetomidine
1.0 mg/kg over 20 min
0.2–1.0 mg/kg/h
Fentanyl
0.5–1.5 mg/kg
n/a
Alfentanil
5–15 mg/kg
n/a
Sufentanil
1.7
n/a
Remifentanil
n/a
0.02–0.25 mg/kg/min
Flumazenil
0.1–0.2 mg (max 1 mg)
0.5–1.0 mg/kg/min
Naloxone
1–2 mg/kg every 2–3 min
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Sedative medications outside the operating room Hansen
Additionally, thiopental lowers the brain’s metabolism, decreases brain blood flow, thereby reducing intracranial pressure (ICP) [4,6].
Etomidate Etomidate is a carboxylated imidazole derivate. Following an induction dose (0.2–0.4 mg/kg) the onset of action is 30–60 min and the duration of action is 5–10 min, even though the elimination half-life is, approximately, 75 min due to redistribution. The volume of distribution of etomidate is 2–4.5 l/kg and protein binding is 76%. Etomidate is metabolized by the liver and plasma esterases; less than 2% is excreted unchanged in the urine. Etomidate possesses little negative inotropic effects and breathing is minimally affected, thus it is often used in patients with reduced cardiac function. Nausea and vomiting is common in the recovery phase as are myoclonic twitches. The main concern regarding etomidate is its suppression of adrenal steroid synthesis. This was first described in critically ill patients receiving continuous etomidate infusions, but is also seen after a bolus dose, albeit the latter does not appear to be associated with increased mortality [4,7].
Ketamine Ketamine is a unique phencyclidine derivate that differs from other sedatives in several ways. It possesses analgesic properties and can, therefore, be used as the sole agent for painful procedures. Ketamine seems to induce a dissociative anesthetic state with functional and electrophysiological separation between the limbic system and hypothalamus. Ketamine is primarily an NMDA receptor antagonist, but also interacts with other receptors [e.g., opioid (m-, k-, and s-) and muscarinic receptors] [4,8]. For many years ketamine was available as a racemate; but currently it is mainly marketed as S-ketamine, which is believed to be about three times as potent as R-ketamine, and with fewer sideeffects. S-ketamine is a highly lipophilic drug. After an i.v. dose of 0.5–1.5 mg/kg the onset of action is 30–60 s and the duration of action is 10–20 min due to rapid redistribution. (S)-Ketamine has analgesic properties at lower dosage (0.25 mg/kg) [9 ]. In the absence of i.v. lines (children) – ketamine can be administered IM (4–10 mg/kg), but the onset of action is delayed (5–10 min). S-ketamine is metabolized primarily in the liver via the cytochrome P450 system (CYP3A4, CYP2B6, and CYP2C9) resulting in the production of dehydro-nor-ketamine and nor-ketamine; the latter has one-third of S-ketamine’s activity. In plasma S-ketamine is &
bound to a1-acid glycoprotein (50%), it has a large volume of distribution (3 l/kg) and a terminal elimination half-life of 2–3 h [4,8,9 ]. S-ketamine itself is a negative inotropic, but because it stimulates the sympathetic nervous system via inhibition of catecholamine reuptake, the net effect is that ketamine increases blood pressure (BP) and heart rate. Ketamine is also a bronchodilator but sympathetic stimulation may contribute here too. Because of the cardiovascular stimulation ketamine should be used cautiously in patients with ischemic heart disease [4,8,9 ]. S-ketamine’s effect on respiration is minimal, and pharyngeal/laryngeal reflexes are essentially preserved, which has made it very popular in certain prehospital settings and in third world countries with financial constraints. Overall, S-ketamine’s side-effect profile limits its clinical usage. Unlike thiopental and propofol, S-ketamine increases CNS blood flow and oxygen consumption, and its use in neurosurgical patients is controversial. Although, psychomimetic side-effects (hallucinations) may be less after S-ketamine than after racemic ketamine, they remain a problem [4,8,9 ]. &
&
&
Benzodiazepines Benzodiazepines were previously used widely, but nowadays their use has declined. They act primarily as hypnotic/sedative and anxiolytic, but are also used as anticonvulsants, muscle relaxants, and for amnesia. Benzodiazepines have dose-dependent cardiorespiratory depressant properties. They act via stimulation of the GABAA receptor. A plethora of different types of benzodiazepines have been marketed, they mainly differ pharmacologically in terms of speed of onset and duration of action. This review only describes midazolam [4,10]. Midazolam Midazolam’s onset of action is dose dependent. After an i.v. bolus dose of 0.05–0.15 mg/kg onset of action is 30–60 s, maximum effect is reached after 3–5 min and the duration of action is 20–80 min due to redistribution. For long-term sedation, a continuous infusion of midazolam 0.5–1.0 mg/kg/min has been recommended. Midazolam is metabolized in the liver by oxidation (CYP3A4) to a number of active metabolites (including 1-hydroxy-midazolam-glucuronide), which subsequently are excreted renally. Midazolam has a high protein binding (95%), mainly to albumin. Midazolam clearance is 4–8 ml/kg/min and the elimination half-life is 1–4 h. Midazolam has been used for a number of shorter procedures including prolonged infusions. However, as with many other sedatives, the
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pharmacokinetics of midazolam is context sensitive. Further, it should be used cautiously in the elderly and patients with significant comorbidity and is not recommended in premature infants and neonates. Paradoxical reactions to midazolam particularly in children are common [10]. Flumazenil is a specific benzodiazepine antidote that may antagonize benzodiazepine intoxication/ overdose (Table 2). Flumazenil may trigger seizures and arrhythmias in some individuals [4].
a2-agonists Two a2-agonists (clonidine and dexmedetomidine) are used for sedation in clinical practice [11–13]. Of the three subgroups of adrenoceptors (a2A, a2B, and a2C), the a2A adrenoceptor is responsible for analgesia, sedation, and anxiety including blockade of the sympathetic nervous system. Contrary to most sedatives, a2-agonists seem to have minimal effect on respiration. However, a 10–20% reduction in heart rate and BP is common. Interestingly, a transient increase in BP is seen after i.v. clonidine (peripheral a1- receptor effect) [11].
Clonidine Clonidine is a highly lipophilic drug with low plasma protein binding (20–40%). Onset time following i.v. administration is typically 5–10 min, and the duration of action is 5–8 h. Clonidine is eliminated unchanged via both the kidneys (70%) and liver (no active metabolites). The terminal elimination half-life is highly variable (6–24 h), but can be doubled in patients with compromised renal function. In adults, an i.v. bolus dose of 1.5– 5.0 m/kg i.v. and continuous infusion 0.2 mg/kg/h is recommended. For children, a bolus dose of 0.5–2.0 mg/kg is recommended [11]. Dexmedetomidine Dexmedetomidine is a new a2-agonist with a higher selectivity for a2 adrenoceptors than clonidine (dexmedetomidine, 1600 : 1 versus Clonidine, 200 : 1). This explains its more linear dose-response curve and allows more liberal dosing than with clonidine. Dexmedetomidine is a lipophilic drug, and its plasma protein binding is high (94%). It is eliminated by the liver (via both cytochrome P450 and glucuronidation) and there are no active metabolites. Onset time after i.v. administration is 5–8 min with max effect after 10–20 min, and the duration of action is 2–4 h. Its elimination half-life is 2–3 h. The recommended loading dose is 1 mg/kg over 20 min (to minimize cardiovascular side-effects) 450
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followed by a continuous infusion of 0.2–1.0 mg/kg/h. Dexmedetomidine is used increasingly for pediatric sedation (MRIs) despite a paucity of pharmacological studies [12,13].
Opioids For painful procedures analgesics are required and the use of opioids often remains the only viable clinical option. Opioids comprise a mixed group of potent analgesics, and although morphine is the reference drug, synthetic opioids such as fentanyl, alfentanil, sufentanil, and remifentanil are more useful to supplement sedatives for painful procedures. Opioids interact with the m-receptor subtypes. The different pharmacokinetic properties of opioids determine the onset, duration, and disposition of effects, whereas the individual opioid’s receptor specificity and affinity determine the type and quality of effect [14 ]. &
Cardiovascular effects In general, the synthetic opioids have minimal effects on the cardiovascular system. Myocardial contractility is only modestly reduced without significant effects on preload, afterload, coronary blood flow, and baroreceptors. However, they inhibit the sympathetic tone increasing the parasympathetic tone and the propensity for bradycardia. Opioids also have a minor vasodilator effect. The cardiovascular effects are accentuated by concomitant use of other sedatives [14 ]. &
Respiration All opioids trigger a dose-dependent respiratory depression mediated via m-2-receptors. Peripheral and central chemoreceptors respond to hypoxia or hypercapnia by increasing respiratory rate and tidal volume. Although both hypercapnia and hypoxia increase (primarily) respiratory rate and tidal volume, PaCO2 influences respiratory drive more than PaO2 does. The CO2-response curve describing the relationship between minute ventilation and PaCO2 is an expression of respiratory drive. Whenever this curve is shifted to the right, or the slope is flattened, it reflects respiratory depression. Relevant doses of opioids for acute pain management significantly inhibits the CO2-response curve, but with no or minor increase in PaCO2. Even moderate opioid doses administered to awake individuals can affect the ventilatory response to hypoxia. This is important in patients who are dependent on the hypoxic respiratory drive (COPD), neonates and the elderly. Opioids cause a dose-dependent effect on consciousness from slightly blurred sensorium to deep coma. Depressed consciousness in patients receiving Volume 28 Number 4 August 2015
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opioids is an important indication for the need for increased monitoring. Brain metabolism is only modestly reduced by opioids, but because ICP may markedly be increased in patients with intracranial pathologies, such an increase would obviously be exacerbated by hypercapnia [14 ]. &
Fentanyl Fentanyl is, approximately, 100 times more potent than morphine. Its use is generally associated with very stable cardiovascular conditions. To supplement painful procedural sedation the dose is usually 0.5–1.5 mg/kg i.v. The onset of action is 2–3 min, with maximum effect after 15–20 min. The effect then decreases rapidly due to redistribution and the elimination half-life is 2–4 h. However, following repeated doses/or a continuous infusion, the context-sensitive half-life of fentanyl increases significantly, due to accumulation (Fig. 1) [15]. Alfentanil Alfentanil is only one of five to one of three as potent as fentanyl. Following a bolus dose of 10– 15 mg/kg, its onset time is slightly faster (2 min) and the duration of action slightly shorter (10–20 min) due to redistribution. The elimination half-life of alfentanil is shorter than fentanyl (60–90 min). Following repeated doses/or a continuous infusion, the context-sensitive half-life of alfentanil increases, albeit not as pronounced as with fentanyl [14 ]. &
Sufentanil Sufentanil is 5–10 times as potent as fentanyl. After an IV bolus dose of 0.25–0.50 mg/kg, the onset time is slightly faster than fentanyl, but a little slower than alfentanil. Similarly, sufentanil’s elimination half-life of 2.7 h is also slightly shorter than fentanyl, but significantly longer than alfentanil. Although the context-sensitive half-life of sufentanil is slightly increased during a continuous infusion, it is significantly less than with fentanyl and alfentanil [14 ]. &
Remifentanil Remifentanil has a unique pharmacokinetic. It has a short onset time and a short elimination half-life independent of the duration of a continuous infusion. Remifentanil is eliminated rapidly and completely by nonspecific plasma and tissue esterases. Its elimination half-life (¼ context-sensitive halflife) is, approximately, 5–7 min and interindividual variation in esterase activity is very modest even in the extreme of ages. Remifentanil’s pharmacokinetic profile enables the clinicians to ensure the patient’s level of analgesia regardless of age and concomitant diseases without the risk of prolonged recovery and reduces the need for the other sedatives significantly. Because of the risk of side-effects (bradycardia, hypotension, apnea, rigidity) bolus doses are not recommended but only a continuous infusion at a rate of 0.1–0.4 mg/kg/min [16].
Time to 50% drop in concentration at effect site (min)
THE FUTURE
Fentanyl
100
Alfentanil Sufentanil 75
Remifentanil
50
25
0 0
100
200
300
400
500
600
Duration of infusion (min)
FIGURE 1. This figure shows the context-sensitive half-time of four different synthetic opioids demonstrating the relative cost in sensitivity of remifentanil compared with, for example, fentanyl. The context-sensitive half-time indicates the time necessary for drug plasma concentration to decrease by 50% following discontinuation of an infusion of a particular duration.
New and promising sedatives are on the horizon (e.g., remimazolam, fospropofol, and etomidate analogues) with a theoretical more predictable onset and offset [17,18]. Remimazolam is an ester-based benzodiazepine designed to be rapidly hydrolyzed in the body by tissue esterases (similar to remifentanil) resulting in short onset and offset of action [19]. Several watersoluble prodrugs of propofol have been developed, of which (at this point) fospropofol appears to be the most promising for clinical development. It is metabolized to propofol by endothelial alkaline phosphatases. Theoretically, the delayed onset time and resulting lower peak plasma concentration should improve safety including less severe cardiorespiratory depression. Moreover, because fospropofol is not formulated in a lipid emulsion, pain at the injection site may also be less severe and the risk of intralipid-related complications eliminated [18]. Of the etomidate analogues, cyclopropyl-methoxycarbonyl metomidate (CPMM) is currently the most promising. Similar to remifentanil and remimazolam, CPMM contains a metabolically labile ester
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moiety facilitating rapid metabolism by esterases. CPMM has half the potency, a faster onset and offset of action and less adrenocortical suppression compared with etomidate [20 ]. Whether these drugs will revolutionize sedational practice remains to be demonstrated [17,18]. &
CONCLUSION A variety of sedative agents are used for procedures requiring sedation and analgesia. Multiple adverse effects are associated with their use, hence monitoring is essential, and emergency equipment should be readily available. Clinicians should be aware with the pharmacokinetic/pharmacodynamic differences of all agents in order to select appropriate medications for specific procedures and patients. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Delgado M, Gempeler F, Rodriguez N. Analgo-sedation for diagnostic and therapeutic endoscopic or radiologic procedures in adults (Protocol). The Cochrane Database of Syst Rev 2003; Issue 4. Art. No. CD004582. doi: 10.1002/14651858.
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2. Gross JB, Bailey PL, Connis RT, et al., The American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by nonanesthesiologists. Anesthesiology 2002; 96:1004–1017. 3. McCaughey W, Clarke RSJ, Fee JPH, Wallace WFM. Anaesthetic physiology and pharmacology. 1st ed. New York: Churchill Livingstone; 1997. 4. Smith I, White PF, Nathanson M, Gouldson R. Propofol: an update on its clinical use. Anesthesiology 1994; 81:1005–1043. 5. Hansen TG. Propofol infusion syndrome in children. Ugeskr Laeger 2005; 167:3672–3675. 6. Olsen RW. Barbiturates. Int Anesthesiol Clin 1988; 26:254–261. 7. Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology 2011; 114:695–707. 8. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119–136. 9. Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacody& namics, molecular aspects, recent findings). CNS Neurosc Ther 2013; 19: 370–380. An interesting historical review about most aspects regarding NMDA-receptor inhibition, ketamine, and s-ketamine including new psychiatric indications and neurotoxicity. 10. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985; 62:310–324. 11. Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet 1988; 14:287–310. 12. Venn RM, Karol MD, Grounds RM. Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive care. Br J Anaesth 2002; 88:669–675. 13. Hoy SM, Keating GM. Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation. Drugs 2011; 30:1481–1501. 14. Drewes AM, Jensen RD, Nielsen LM, et al. Differences between opioids: & pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol 2013; 75:60–78. A recent and well written pharmacological review article about all (most) clinically available opioids including some interesting views on pharmacoeconomic aspects. 15. Bailey JM. Context-sensitive half-times: what are they and how valuable are they in anesthesiology? Clin Pharmacokinet 2002; 41:793–799. 16. Westmoreland CL, Hoke JF, Sebel PS, et al. Pharmacokinetics of remifentanil and its major metabolite in patients undergoing elective inpatient surgery. Anesthesiology 1993; 79:893–903. 17. Gin T. Hypnotic and sedative drugs: anything new on the horizon. Curr Opin Anesthesiol 2013; 26:409–413. 18. Sneyd JR, Rigby-Jones AE. New drugs and technologies, intravenous anaesthesia is on the move (again). Br J Anaesth 2010; 105:246–254. 19. Borkett KM, Riff DS, Schwartz HI, et al. A phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg 2015; 120:771–720. 20. Campagna JA, Pojasek K, Grayzel D, et al. Advancing novel anesthetics: & pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs. Anesthesiology 2014; 121:1203–1216. A fascinating recent study demonstrating the superiority of CPMM compared with etomidate in dogs.
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Sedative medications outside the operating room and the pharmacology of sedatives Tom G. Hansen
Purpose of review There is a growing medical demand for suitable sedatives and analgesics to support the ongoing progress in diagnostic procedures and imaging techniques. This review provides an update of the pharmacology of the most commonly used drugs used for these procedures and shortly mention new drugs on the horizon. Recent findings There are many drugs available for procedural sedation; however, they all have drawbacks and shortcomings. Multiple adverse effects are associated with the use of these agents, hence monitoring is essential, and emergency equipment should be readily available. Newer drugs are on the horizon (e.g., remimazolam, fospropofol, and etomidate analogues) with a theoretical more predictable onset and offset; whether these will revolutionize the sedational practice sedation remains unknown. Summary Clinicians should be aware of the pharmacokinetic/pharmacodynamic differences of all agents in order to select appropriate medications for specific procedures and patients. Keywords a2-agonists, interventional pain management, midazolam, opioids, sedation: propofol
INTRODUCTION Sedation is used to facilitate diagnostic or therapeutic procedures requiring varying degrees of anxiolysis and/or analgesia. Sedation covers a continuum of stages from minimal sedation (‘anxiolysis’) through moderate sedation/analgesia (‘conscious sedation’), deep sedation, and ultimately general anesthesia. Each stage comprises a progressive degree of central nervous system (CNS) depression with impaired levels of consciousness, decreased responsiveness to stimuli, loss of protective reflexes, and progressive respiratory and cardiovascular depression [1–2]. The depth of sedation required and the agents used largely depend upon the anticipated degree of pain, the allowable amount of movements encountered during the procedure, and certain important patient factors [1,2] (Table 1). In this review, the pharmacology of these agents is reviewed. Pharmacokinetics of the agents is addressed in tabular form (Table 2), whereas pharmacodynamic aspects of each agent are described in more detail. This author does not recommend the use of chloral hydrate, and from a safety and efficacy point of view the route of administration www.co-anesthesiology.com
recommended is primarily intravenous (i.v.). Dosing of the reviewed drugs is listed in Table 3.
Propofol Propofol (2,6 di-isopropyl phenol) is a weak lipophilic acid unionized at pH 7.4. Because of its favorable pharmacokinetic profile it is commonly used for sedation for diagnostic procedures [3,4]. It acts by stimulation of the gamma-aminobutyric acid (GABAA)-receptor subunit b1 in which it activates chloride channels, thereby increasing inhibitory synaptic transmission. Propofol also inhibits N-methyl-D-aspartate (NMDA) receptors but to a much lesser extent. Its onset time is short (30– 60 s), and its duration of action is 5–10 min due Department of Anesthesiology and Intensive Care, Pediatric Section, Odense University Hospital, Odense, Denmark Correspondence to Tom G. Hasen, MD, PhD, Institute for Clinical Research – Anesthesiology, University of Southern Denmark, DK5000 Odense C, Denmark. E-mail: [email protected] or [email protected] Curr Opin Anesthesiol 2015, 28:446–452 DOI:10.1097/ACO.0000000000000202 Volume 28 Number 4 August 2015
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Sedative medications outside the operating room Hansen
KEY POINTS The demand for sedation to support the ongoing progress in diagnostic procedures and imaging techniques is growing. All available sedatives and analgesics have drawbacks and shortcomings. Well tolerated use of sedatives/analgesics require detailed pharmacological knowledge in order to select the appropriate drugs for specific procedures and patients. The new drugs on the horizon may be helpful in the future.
to redistribution. Propofol has a high clearance; total clearance exceeds liver blood flow. Metabolism is predominantly by sulphation and glucuronidation to a number of inactive metabolites excreted via the kidneys. The terminal elimination half-life is 3–9 h, which carries the risk of accumulation during long-term use. Propofol is highly plasma protein bound (98%), predominantly to albumin. Bolus dose is 1–5 mg/kg depending on age, comorbidity, and general condition. Pain at the site of injection is a problem, but can be minimized with the addition of lidocaine, pretreatment opioids, or use of the 0.5% propofol. Propofol is a negative inotropic and chronotropic drug, thus, any decrease in cardiac output is not compensated by an increase in heart rate. Further, propofol inhibits sympathetic tone, thus, cardiac output often drops significantly after a bolus dose. This is most pronounced in patients with impaired cardiac function, the elderly and neonates. Propofol induces a dose-dependent respiratory depression. Apnea occurs relatively frequently in young healthy individuals after an induction dose (25–30%). Incidence and duration depends on age, dose, and rate of injection, and coadministration of other sedatives/analgesics [3].
Table 1. Patient factors important for the choice of sedatives 1. Comorbidities (e.g., cardiopulmonary status, allergies, and comedication) 2. Degree of fasting 3. Age 4. Ability to cooperate 5. Degree of pain 6. Level of anxiety 7. Prior problems with previous sedation and sedatives
Propofol reduces brain metabolism, blood flow, and volume. Although propofol possesses clear dose-dependent anticonvulsant properties, it may act as a proconvulsant agent in certain individuals, but epilepsy as such is not a contraindication for propofol [3,4]. The propofol infusion syndrome (PRIS) is a rare condition described in patients exposed to propofol for a long time and in high doses. PRIS, first described in critically ill children undergoing longterm sedation in excessive doses, is characterized by quite: cardiac failure, rhabdomyolysis, metabolic acidosis, hepatomegaly, renal failure hyperkalemia, hypertriglyceridemia, and high mortality. PRIS has since been described in critically ill adults but also in anesthetized children and adults receiving high propofol doses. Treatment of PRIS is supportive with immediate cessation of propofol infusion and early initiation of dialysis. Long-term propofol infusion rates above 4 mg/kg/h should be avoided [5].
Barbiturates For all practical purposes, thiopental is the only sedative barbiturate used clinically. Thiopental is a core medication according to the WHO’s Essential Drug List (http://whqlibdoc.who.int/hq/2005/ a87017_eng.pdf). However, because it was used for lethal injections (in combination with other drugs) in the USA, the US manufacturer ceased manufacturing it and exportation of it outside Europe was banned by the European Union. Hence, it is no longer used in the USA, but remains widely used in many other countries. Following an i.v. bolus dose it is an ultra-short-acting barbiturate due to rapid redistribution. However, with repeated dosing or continuous infusion the duration of action increases significantly due to a long terminal halflife. Barbiturates mechanism of action is by stimulation of the GABAA receptors [4,6]. Allergic reactions to barbiturates are occasionally seen in varying severity. Barbiturates are contraindicated in patients with porphyria, and thiopental may trigger bronchospasm and should be used cautiously in asthmatic patients. Thiopental Thiopental is a lipophilic drug; at pH 7.40, 60% is present in an unionized form. After an induction dose (2–5 mg/kg, up to 7 mg/kg in children) the onset of action is rapid (10–30 s) and the duration of action is, approximately, 7–10 min due to redistribution. Thiopental undergoes hepatic metabolism, and many metabolites are pharmacologically active. At high dosages the drug exhibits zero order kinetics. Thiopental is a low-clearance drug with a relatively
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Anesthesia outside the operating room Table 2. Pharmacokinetic parameters for the most commonly used sedatives and analgesics Vss (l/kg)
Cl (ml/kg/min)
t1/2 –el (h)
CSHT1 (min)
CSHT3 (min)
1.0–8.5
30–39
3–9
10
21
Thiopental
1.4–3.3
1.6–4.3
5–12
80
120
75
Etomidate
2.0–4.5
12–20
1–5
4
8
76
S-ketamine
3.0
16–18
2–3
5
22
50
Midazolam
1.0–1.5
4–8
1–4
32
60
95
Fentanyl
4.0
12.6
2–4
25
105
Clonidine
1.7–2.5
3.2
6–24
Dexmedetomidine
1.7
9.0
2–3
Alfentanil
0.7
5.1
1.0–1.5
Sufentanil
1.7
11.8
2.7
Remifentanil
0.4
44.0
0.1
Flumazenil
1.0
5–20
0.7–1.3
Propofol
Naloxone
F (%) 98
43 20–40 94
32
56
85
18
22
70
0.1
0.1
70
30–60
Cl, clearance; CSHT1, context-sensitive half-time after 1 h; CSHT3, context-sensitive half-time after 3 h; F, protein binding; t1/2-el, elimination half-time; Vss, volume of distribution at steady state.
large volume of distribution and a long elimination half-life (5–12 h), hence the risk of accumulation is high with repeated dosages and continuous infusion. Thiopental is highly plasma protein bound (75%) mainly to albumin. Quantitative and qualitative changes in binding proteins seen in the elderly, neonates, and patients with compromised cardiac, renal, or hepatic function requires a considerable reduction in induction dose (2.0–2.5 mg/kg). Thiopental is an alkaline solution (pH 10–11) and tissue damaging when administered paravenously. A minor proportion of thiopental undergoes placental transfer and a modest amount is excreted via breast milk [4,6].
Thiopental possesses negative inotropic properties and it reduces the sympathetic tone, thus, reducing venous pressure and venous return. The net effect is a significant decrease in cardiac output; hence thiopental should be used cautiously in patients with significant cardiac failure or hypovolemia [4,6]. Thiopental also induces a dose-dependent respiratory depression. An induction dose is accompanied by a few irregular deep breaths followed by brief apnea, in which the patient’s breathing might need support by mask ventilation. Coadministration of opioids synergistically increases the respiratory depressant effects of thiopental.
Table 3. Recommended intravenous dosing of sedative and analgesics Bolus dose
Continuous infusion (ml/kg/min)
Propofol
1.0–1.5 mg/kg
10–50 mg/kg/min
Thiopental
2–5 mg/kg
n/a
Etomidate
0.2–0.4 mg/kg
n/a
S-ketamine
0.1–0.3 mg/kg
10–20 mg/kg/min
Midazolam
0.025–0.05 mg/kg
0.3–1.5 mg/kg/min
Clonidine
1.0–5.0 mg/kg
0.2 mg/kg/h
Dexmedetomidine
1.0 mg/kg over 20 min
0.2–1.0 mg/kg/h
Fentanyl
0.5–1.5 mg/kg
n/a
Alfentanil
5–15 mg/kg
n/a
Sufentanil
1.7
n/a
Remifentanil
n/a
0.02–0.25 mg/kg/min
Flumazenil
0.1–0.2 mg (max 1 mg)
0.5–1.0 mg/kg/min
Naloxone
1–2 mg/kg every 2–3 min
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Sedative medications outside the operating room Hansen
Additionally, thiopental lowers the brain’s metabolism, decreases brain blood flow, thereby reducing intracranial pressure (ICP) [4,6].
Etomidate Etomidate is a carboxylated imidazole derivate. Following an induction dose (0.2–0.4 mg/kg) the onset of action is 30–60 min and the duration of action is 5–10 min, even though the elimination half-life is, approximately, 75 min due to redistribution. The volume of distribution of etomidate is 2–4.5 l/kg and protein binding is 76%. Etomidate is metabolized by the liver and plasma esterases; less than 2% is excreted unchanged in the urine. Etomidate possesses little negative inotropic effects and breathing is minimally affected, thus it is often used in patients with reduced cardiac function. Nausea and vomiting is common in the recovery phase as are myoclonic twitches. The main concern regarding etomidate is its suppression of adrenal steroid synthesis. This was first described in critically ill patients receiving continuous etomidate infusions, but is also seen after a bolus dose, albeit the latter does not appear to be associated with increased mortality [4,7].
Ketamine Ketamine is a unique phencyclidine derivate that differs from other sedatives in several ways. It possesses analgesic properties and can, therefore, be used as the sole agent for painful procedures. Ketamine seems to induce a dissociative anesthetic state with functional and electrophysiological separation between the limbic system and hypothalamus. Ketamine is primarily an NMDA receptor antagonist, but also interacts with other receptors [e.g., opioid (m-, k-, and s-) and muscarinic receptors] [4,8]. For many years ketamine was available as a racemate; but currently it is mainly marketed as S-ketamine, which is believed to be about three times as potent as R-ketamine, and with fewer sideeffects. S-ketamine is a highly lipophilic drug. After an i.v. dose of 0.5–1.5 mg/kg the onset of action is 30–60 s and the duration of action is 10–20 min due to rapid redistribution. (S)-Ketamine has analgesic properties at lower dosage (0.25 mg/kg) [9 ]. In the absence of i.v. lines (children) – ketamine can be administered IM (4–10 mg/kg), but the onset of action is delayed (5–10 min). S-ketamine is metabolized primarily in the liver via the cytochrome P450 system (CYP3A4, CYP2B6, and CYP2C9) resulting in the production of dehydro-nor-ketamine and nor-ketamine; the latter has one-third of S-ketamine’s activity. In plasma S-ketamine is &
bound to a1-acid glycoprotein (50%), it has a large volume of distribution (3 l/kg) and a terminal elimination half-life of 2–3 h [4,8,9 ]. S-ketamine itself is a negative inotropic, but because it stimulates the sympathetic nervous system via inhibition of catecholamine reuptake, the net effect is that ketamine increases blood pressure (BP) and heart rate. Ketamine is also a bronchodilator but sympathetic stimulation may contribute here too. Because of the cardiovascular stimulation ketamine should be used cautiously in patients with ischemic heart disease [4,8,9 ]. S-ketamine’s effect on respiration is minimal, and pharyngeal/laryngeal reflexes are essentially preserved, which has made it very popular in certain prehospital settings and in third world countries with financial constraints. Overall, S-ketamine’s side-effect profile limits its clinical usage. Unlike thiopental and propofol, S-ketamine increases CNS blood flow and oxygen consumption, and its use in neurosurgical patients is controversial. Although, psychomimetic side-effects (hallucinations) may be less after S-ketamine than after racemic ketamine, they remain a problem [4,8,9 ]. &
&
&
Benzodiazepines Benzodiazepines were previously used widely, but nowadays their use has declined. They act primarily as hypnotic/sedative and anxiolytic, but are also used as anticonvulsants, muscle relaxants, and for amnesia. Benzodiazepines have dose-dependent cardiorespiratory depressant properties. They act via stimulation of the GABAA receptor. A plethora of different types of benzodiazepines have been marketed, they mainly differ pharmacologically in terms of speed of onset and duration of action. This review only describes midazolam [4,10]. Midazolam Midazolam’s onset of action is dose dependent. After an i.v. bolus dose of 0.05–0.15 mg/kg onset of action is 30–60 s, maximum effect is reached after 3–5 min and the duration of action is 20–80 min due to redistribution. For long-term sedation, a continuous infusion of midazolam 0.5–1.0 mg/kg/min has been recommended. Midazolam is metabolized in the liver by oxidation (CYP3A4) to a number of active metabolites (including 1-hydroxy-midazolam-glucuronide), which subsequently are excreted renally. Midazolam has a high protein binding (95%), mainly to albumin. Midazolam clearance is 4–8 ml/kg/min and the elimination half-life is 1–4 h. Midazolam has been used for a number of shorter procedures including prolonged infusions. However, as with many other sedatives, the
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pharmacokinetics of midazolam is context sensitive. Further, it should be used cautiously in the elderly and patients with significant comorbidity and is not recommended in premature infants and neonates. Paradoxical reactions to midazolam particularly in children are common [10]. Flumazenil is a specific benzodiazepine antidote that may antagonize benzodiazepine intoxication/ overdose (Table 2). Flumazenil may trigger seizures and arrhythmias in some individuals [4].
a2-agonists Two a2-agonists (clonidine and dexmedetomidine) are used for sedation in clinical practice [11–13]. Of the three subgroups of adrenoceptors (a2A, a2B, and a2C), the a2A adrenoceptor is responsible for analgesia, sedation, and anxiety including blockade of the sympathetic nervous system. Contrary to most sedatives, a2-agonists seem to have minimal effect on respiration. However, a 10–20% reduction in heart rate and BP is common. Interestingly, a transient increase in BP is seen after i.v. clonidine (peripheral a1- receptor effect) [11].
Clonidine Clonidine is a highly lipophilic drug with low plasma protein binding (20–40%). Onset time following i.v. administration is typically 5–10 min, and the duration of action is 5–8 h. Clonidine is eliminated unchanged via both the kidneys (70%) and liver (no active metabolites). The terminal elimination half-life is highly variable (6–24 h), but can be doubled in patients with compromised renal function. In adults, an i.v. bolus dose of 1.5– 5.0 m/kg i.v. and continuous infusion 0.2 mg/kg/h is recommended. For children, a bolus dose of 0.5–2.0 mg/kg is recommended [11]. Dexmedetomidine Dexmedetomidine is a new a2-agonist with a higher selectivity for a2 adrenoceptors than clonidine (dexmedetomidine, 1600 : 1 versus Clonidine, 200 : 1). This explains its more linear dose-response curve and allows more liberal dosing than with clonidine. Dexmedetomidine is a lipophilic drug, and its plasma protein binding is high (94%). It is eliminated by the liver (via both cytochrome P450 and glucuronidation) and there are no active metabolites. Onset time after i.v. administration is 5–8 min with max effect after 10–20 min, and the duration of action is 2–4 h. Its elimination half-life is 2–3 h. The recommended loading dose is 1 mg/kg over 20 min (to minimize cardiovascular side-effects) 450
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followed by a continuous infusion of 0.2–1.0 mg/kg/h. Dexmedetomidine is used increasingly for pediatric sedation (MRIs) despite a paucity of pharmacological studies [12,13].
Opioids For painful procedures analgesics are required and the use of opioids often remains the only viable clinical option. Opioids comprise a mixed group of potent analgesics, and although morphine is the reference drug, synthetic opioids such as fentanyl, alfentanil, sufentanil, and remifentanil are more useful to supplement sedatives for painful procedures. Opioids interact with the m-receptor subtypes. The different pharmacokinetic properties of opioids determine the onset, duration, and disposition of effects, whereas the individual opioid’s receptor specificity and affinity determine the type and quality of effect [14 ]. &
Cardiovascular effects In general, the synthetic opioids have minimal effects on the cardiovascular system. Myocardial contractility is only modestly reduced without significant effects on preload, afterload, coronary blood flow, and baroreceptors. However, they inhibit the sympathetic tone increasing the parasympathetic tone and the propensity for bradycardia. Opioids also have a minor vasodilator effect. The cardiovascular effects are accentuated by concomitant use of other sedatives [14 ]. &
Respiration All opioids trigger a dose-dependent respiratory depression mediated via m-2-receptors. Peripheral and central chemoreceptors respond to hypoxia or hypercapnia by increasing respiratory rate and tidal volume. Although both hypercapnia and hypoxia increase (primarily) respiratory rate and tidal volume, PaCO2 influences respiratory drive more than PaO2 does. The CO2-response curve describing the relationship between minute ventilation and PaCO2 is an expression of respiratory drive. Whenever this curve is shifted to the right, or the slope is flattened, it reflects respiratory depression. Relevant doses of opioids for acute pain management significantly inhibits the CO2-response curve, but with no or minor increase in PaCO2. Even moderate opioid doses administered to awake individuals can affect the ventilatory response to hypoxia. This is important in patients who are dependent on the hypoxic respiratory drive (COPD), neonates and the elderly. Opioids cause a dose-dependent effect on consciousness from slightly blurred sensorium to deep coma. Depressed consciousness in patients receiving Volume 28 Number 4 August 2015
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opioids is an important indication for the need for increased monitoring. Brain metabolism is only modestly reduced by opioids, but because ICP may markedly be increased in patients with intracranial pathologies, such an increase would obviously be exacerbated by hypercapnia [14 ]. &
Fentanyl Fentanyl is, approximately, 100 times more potent than morphine. Its use is generally associated with very stable cardiovascular conditions. To supplement painful procedural sedation the dose is usually 0.5–1.5 mg/kg i.v. The onset of action is 2–3 min, with maximum effect after 15–20 min. The effect then decreases rapidly due to redistribution and the elimination half-life is 2–4 h. However, following repeated doses/or a continuous infusion, the context-sensitive half-life of fentanyl increases significantly, due to accumulation (Fig. 1) [15]. Alfentanil Alfentanil is only one of five to one of three as potent as fentanyl. Following a bolus dose of 10– 15 mg/kg, its onset time is slightly faster (2 min) and the duration of action slightly shorter (10–20 min) due to redistribution. The elimination half-life of alfentanil is shorter than fentanyl (60–90 min). Following repeated doses/or a continuous infusion, the context-sensitive half-life of alfentanil increases, albeit not as pronounced as with fentanyl [14 ]. &
Sufentanil Sufentanil is 5–10 times as potent as fentanyl. After an IV bolus dose of 0.25–0.50 mg/kg, the onset time is slightly faster than fentanyl, but a little slower than alfentanil. Similarly, sufentanil’s elimination half-life of 2.7 h is also slightly shorter than fentanyl, but significantly longer than alfentanil. Although the context-sensitive half-life of sufentanil is slightly increased during a continuous infusion, it is significantly less than with fentanyl and alfentanil [14 ]. &
Remifentanil Remifentanil has a unique pharmacokinetic. It has a short onset time and a short elimination half-life independent of the duration of a continuous infusion. Remifentanil is eliminated rapidly and completely by nonspecific plasma and tissue esterases. Its elimination half-life (¼ context-sensitive halflife) is, approximately, 5–7 min and interindividual variation in esterase activity is very modest even in the extreme of ages. Remifentanil’s pharmacokinetic profile enables the clinicians to ensure the patient’s level of analgesia regardless of age and concomitant diseases without the risk of prolonged recovery and reduces the need for the other sedatives significantly. Because of the risk of side-effects (bradycardia, hypotension, apnea, rigidity) bolus doses are not recommended but only a continuous infusion at a rate of 0.1–0.4 mg/kg/min [16].
Time to 50% drop in concentration at effect site (min)
THE FUTURE
Fentanyl
100
Alfentanil Sufentanil 75
Remifentanil
50
25
0 0
100
200
300
400
500
600
Duration of infusion (min)
FIGURE 1. This figure shows the context-sensitive half-time of four different synthetic opioids demonstrating the relative cost in sensitivity of remifentanil compared with, for example, fentanyl. The context-sensitive half-time indicates the time necessary for drug plasma concentration to decrease by 50% following discontinuation of an infusion of a particular duration.
New and promising sedatives are on the horizon (e.g., remimazolam, fospropofol, and etomidate analogues) with a theoretical more predictable onset and offset [17,18]. Remimazolam is an ester-based benzodiazepine designed to be rapidly hydrolyzed in the body by tissue esterases (similar to remifentanil) resulting in short onset and offset of action [19]. Several watersoluble prodrugs of propofol have been developed, of which (at this point) fospropofol appears to be the most promising for clinical development. It is metabolized to propofol by endothelial alkaline phosphatases. Theoretically, the delayed onset time and resulting lower peak plasma concentration should improve safety including less severe cardiorespiratory depression. Moreover, because fospropofol is not formulated in a lipid emulsion, pain at the injection site may also be less severe and the risk of intralipid-related complications eliminated [18]. Of the etomidate analogues, cyclopropyl-methoxycarbonyl metomidate (CPMM) is currently the most promising. Similar to remifentanil and remimazolam, CPMM contains a metabolically labile ester
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moiety facilitating rapid metabolism by esterases. CPMM has half the potency, a faster onset and offset of action and less adrenocortical suppression compared with etomidate [20 ]. Whether these drugs will revolutionize sedational practice remains to be demonstrated [17,18]. &
CONCLUSION A variety of sedative agents are used for procedures requiring sedation and analgesia. Multiple adverse effects are associated with their use, hence monitoring is essential, and emergency equipment should be readily available. Clinicians should be aware with the pharmacokinetic/pharmacodynamic differences of all agents in order to select appropriate medications for specific procedures and patients. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Delgado M, Gempeler F, Rodriguez N. Analgo-sedation for diagnostic and therapeutic endoscopic or radiologic procedures in adults (Protocol). The Cochrane Database of Syst Rev 2003; Issue 4. Art. No. CD004582. doi: 10.1002/14651858.
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2. Gross JB, Bailey PL, Connis RT, et al., The American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by nonanesthesiologists. Anesthesiology 2002; 96:1004–1017. 3. McCaughey W, Clarke RSJ, Fee JPH, Wallace WFM. Anaesthetic physiology and pharmacology. 1st ed. New York: Churchill Livingstone; 1997. 4. Smith I, White PF, Nathanson M, Gouldson R. Propofol: an update on its clinical use. Anesthesiology 1994; 81:1005–1043. 5. Hansen TG. Propofol infusion syndrome in children. Ugeskr Laeger 2005; 167:3672–3675. 6. Olsen RW. Barbiturates. Int Anesthesiol Clin 1988; 26:254–261. 7. Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology 2011; 114:695–707. 8. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119–136. 9. Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacody& namics, molecular aspects, recent findings). CNS Neurosc Ther 2013; 19: 370–380. An interesting historical review about most aspects regarding NMDA-receptor inhibition, ketamine, and s-ketamine including new psychiatric indications and neurotoxicity. 10. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985; 62:310–324. 11. Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet 1988; 14:287–310. 12. Venn RM, Karol MD, Grounds RM. Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive care. Br J Anaesth 2002; 88:669–675. 13. Hoy SM, Keating GM. Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation. Drugs 2011; 30:1481–1501. 14. Drewes AM, Jensen RD, Nielsen LM, et al. Differences between opioids: & pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol 2013; 75:60–78. A recent and well written pharmacological review article about all (most) clinically available opioids including some interesting views on pharmacoeconomic aspects. 15. Bailey JM. Context-sensitive half-times: what are they and how valuable are they in anesthesiology? Clin Pharmacokinet 2002; 41:793–799. 16. Westmoreland CL, Hoke JF, Sebel PS, et al. Pharmacokinetics of remifentanil and its major metabolite in patients undergoing elective inpatient surgery. Anesthesiology 1993; 79:893–903. 17. Gin T. Hypnotic and sedative drugs: anything new on the horizon. Curr Opin Anesthesiol 2013; 26:409–413. 18. Sneyd JR, Rigby-Jones AE. New drugs and technologies, intravenous anaesthesia is on the move (again). Br J Anaesth 2010; 105:246–254. 19. Borkett KM, Riff DS, Schwartz HI, et al. A phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg 2015; 120:771–720. 20. Campagna JA, Pojasek K, Grayzel D, et al. Advancing novel anesthetics: & pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs. Anesthesiology 2014; 121:1203–1216. A fascinating recent study demonstrating the superiority of CPMM compared with etomidate in dogs.
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