Newer Drugs for Sedation: Soft Pharmacology




Etomidate analogsa




α2 adrenoceptor agonist


Propofol prodrug



α2 adrenoceptors



Sedative dose

0.1–0.2 mg/kg

1 mcg/kg over 10 min, then 0.2–0.7 mcg/kg/h infusion

To be determined

6.5 mg/kg followed by 1.6 mg/kg at 4 min intervals

Dose reduction for elderly



To be determined


Dose reduction for hepatic impairment



To be determined

Limited data but dose reduction advised

Dose reduction for renal impairment



To be determined- carboxylic acid metabolite may accumulate in renal impairment

No dose reduction with creatinine clearance > 30 ml/min

Limited data for patients with creatinine clearance < 30 ml/min


1.5–2.5 min

5–8 min

To be determined- rapid in animal models

4–8 min


Ester hydrolysis

Hepatic metabolism via cytochrome p450 and glucuronidation

Ester hydrolysis

Fospropofol metabolized to propofol by endothelial and hepatic alkaline phosphatases

Propofol metabolized by hepatic and erythrocyte dehydrogenases


6.8–9.9 min

6 min

To be determined- rapid in animal models

5–18 min

Active metabolite



Carboxylic acid metabolite


aEtomidate analogues such as MOC-etomidate and carboetomidate are currently under development and data available at time of publication comes from animal models

Benzodiazepine use for procedural sedation has two main limitations: the absence of analgesic properties, and persistence of sedative effects beyond the duration of the procedure. This latter feature relates to both diffuse drug distribution and prolonged elimination. The use of midazolam, which has the shortest half-life of any of the benzodiazepines, can lead to prolonged sedation and unpredictable recovery due to a half-life of 1.8–6.4 h and accumulation of an active metabolite, α-hydroxy-midazolam, which has a sedative effect [4, 5].

Remimazolam, in contrast, may bypass these limitations of benzodiazepines, and may indeed have many of the properties of the ideal sedative agent for use in the out-of-OR setting [6, 7]. In addition to producing dose-dependant sedation, remimazolam has a rapid offset when compared to midazolam. This is due to metabolism and clearance by tissue esterases, in addition to an inactive metabolite [8]. Another important feature of remimazolam for the out-of-OR setting is the lack of accumulation, with the context-sensitive half-time similar to that of remifentanil [9].



Pre-procedural premedication


Initiation and maintenance of procedural sedation

Rapid onset and offset sedation for procedural sedation [10]

Co-induction of anaesthesia

Benzodiazepine anaesthesia


Shorter duration of recovery from anesthetic/sedation, owing to reduction in intraoperative anesthetic andopioid requirements


The structures of midazolam and remimazolam are presented in Fig. 31.1. The significant difference between the two molecules is the introduction of a carboxylic ester linkage to remimazolam, which allows metabolism by non-specific tissue esterases in the blood- in a similar way to remifentanil.


Fig. 31.1
Structures of midazolam and remimazolam [11]


  • Sedative dose 0.1–0.2 mg/kg [10]

  • Due to organ-independent elimination, no dosage adjustments are required for patients with hepatic or renal impairment.

  • Age-related deterioration of hepato-renal drug handling is unlikely to have impact on remimazolam’s metabolism


  • Like other benzodiazepines, remimazolam acts on GABA receptors, specifically GABAA [8], modulating the effects of GABA at the GABA receptors

  • Onset 1.5–2.5 min [10]

  • Metabolized by dose-independent ester hydrolysis into inactive metabolite CNS 7054

  • Rapid clearance 70.3 ± 13.9 L/h (midazolam clearance 23 ± 4.5 L/h) [8]

  • Volume of distribution 23 ± 4.5 L/h (midazolam volume of distribution 81.8 ± 27.1 L/h) [8]

  • Half life 0.75 ± 0.15 h [8]

  • Mean offset time 6.8–9.9 min [10]

  • Minimal accumulation- context sensitive halftime 7–8 min after a 2-h infusion [9]

  • Slow clearance of inactive metabolite (4.22 ± 1.25 L/h) with terminal half-life of 2.89 ± 0.65 h

  • Reversed by flumazenil

Adverse Effects

At the time of publication, there was ongoing recruitment for a phase III trial investigating efficacy and adverse effects of remimazolam in patients undergoing colonoscopy [12]. From the results of the phase I and II trials of remimazolam, the adverse effects of remimazolam appear to be similar to those of other benzodiazepines, including hypotension, respiratory depression, and desaturation [9, 10].


Clonidine was the first α2-adrenoceptor agonist, and was formulated in the 1960s. It was initially marketed as a nasal decongestant but was subsequently recognized as an effective antihypertensive and sedative drug. Dexmedetomidine, which is also an α2-agonist, was approved by the Food and Drug Administration at the end of 1999 for short-term (<24 h) analgesia and sedation in the intensive care unit. Its use has since expanded to include the perioperative period.

Dexmedetomidine has greater specificity for the α2-adrenoceptor compared to clonidine (ratios of α2:α1 activity, 1620:1 for dexmedetomidine, 220:1 for clonidine) [13]. Presynaptic α2- adrenoceptors regulate the release of norepinephrine and adenosine trisphosphate through a negative feedback mechanism, which results in the analgesic effects of dexmedetomidine (Fig. 31.2). The sedative effects of dexmedetomidine result from agonism of central α2 receptors in the presynaptic neurons and subsequent inhibition of neuronal firing in the brain, particularly the locus coeruleus, and in the spinal cord [14].


Fig. 31.2
The action of dexmedetomidine at a synapse

The analgesic effects of dexmedetomidine are a result of:

  1. 1.

    direct α2-adrenoceptor agonism and inhibition of norepinephrine release


  2. 2.

    α2-adrenoceptor modulation of G-protein-gated potassium channels, resulting in membrane hyperpolarization and decreased firing rate in excitable cells in the CNS


  3. 3.

    G protein coupled reduction in calcium conductance through cell membranes and inhibition of neurotransmitter release [15]


There are many advantages to dexmedetomidine as an out-of-OR sedative. Because its actions are not mediated by the GABA-mimetic system, it has sedative, analgesia, and antishivering properties, but does not cause respiratory depression [16]. ‘Cooperative sedation’ is a term used to describe the sedative effect of dexmedetomidine, whereby the patient can be deeply sedated yet rousable and able to interact with healthcare providers [17].



Pre-procedural premedication [18]


Initiation and maintenance of procedural sedation

Reduction of anaesthetic requirements [19, 20]

Dose-dependant sedation without respiratory depression [21]

Arousability maintained at deep levels of sedation [22]

Attenuation of sympathoadrenal effects of surgical stimulationand endotracheal intubation [23]

Analgesia, in addition to reduction of opioid requirements [23, 24]


Reduced duration of recovery from anesthetic/sedation,owing to reduction in intraoperative anesthetic and opioidrequirements

Reduction in analgesic requirements [24]


Initiation and maintenance of intensive care sedation [25, 26]


Dexmedetomidine is an imidazole compound and is the pharmacologically active dextroisomer of medetomidine, which displays selective α2-agonism.


Dexmedetomidine is presented in 200 mcg/2 mL (100 mcg/mL) glass vial to be used after dilution. Dexmedetomidine must be diluted with 48 ml 0.9 % sodium chloride injection to achieve a concentration of 4 mcg/ml.


  • Initial loading dose 1 mcg/kg over 10 min, followed by continuous IV infusion of 0.2–0.7 mcg/kg/h [27]

  • For patients >65 years a loading infusion of 0.5 mcg/kg over 10 min and a reduction in the maintenance infusion should be considered [27]

  • Hepatic impairment- dose reduction recommended [27]

  • Renal impairment- no dose reduction required [28]


  • Time to onset of action 5–8 min [27]

  • Peak effect 10–20 min [27]

  • Peak plasma concentrations achieved within 1 h after continuous infusion [27]

  • Distribution half-life (t1/2) of approximately 6 min; a terminal elimination half-life (t1/2) of approximately 2 h [27]

  • Highly bound to plasma proteins (94 %) [27]

  • Lipophilic- Steady-state volume of distribution (Vss) of approximately 118 l

  • Metabolism by the liver via cytochrome P450 & glucuronidation [13]

  • Clearance is approximately 39 L/h [27]

  • Mean offset time after single dose 6 min [27]

  • Context sensitive halftime increases, depending on duration of infusion- ranging from 4 min after a 10 min infusion to 250 min after an 8 h infusion [29]

  • No active metabolites

  • Inactive metabolites excreted in urine (~95 %) and faeces (4 %) [27]

Adverse Effects [27]


  • Hypotension incidence (56 %) and bradycardia incidence (42 %), both of which are due to inhibition of central sympathetic outflow [30, 31]

  • Hypertension on initial bolusing, owing to peripheral α2B-adrenoceptor stimulation of vascular smooth muscle incidence (16 %) [30, 31]

  • Arrhythmias including atrial fibrillation (4 %), extrasystoles, supraventricular tachycardia, ventricular arrhythmia and heart block


  • Respiratory depression incidence (37 %)

  • Respiratory failure incidence (6 %)

  • Acute respiratory distress syndrome incidence (3 %)

  • Pleural effusion incidence (2 %)


  • Agitation incidence (8 %)

  • Anxiety incidence (5 %)


  • Nausea incidence (11 %)

  • Constipation incidence (6 %)

  • Dry mouth incidence (4 %)


  • Hypokalaemia incidence (9 %)

  • Pyrexia incidence (7 %)

  • Hyperglycaemia incidence (7 %)

  • Anemia incidence (3 %)

  • Oliguria incidence (2 %)

Etomidate Analogs- MOC-Etomidate & Carboetomidate

Etomidate is a rapidly acting imidazole-based intravenous sedative-hypnotic agent that is used to induce general anesthesia through potentiation of GABAA receptor activation. As is the case with other intravenous anaesthetic agents, etomidate’s hypnotic action ceases following bolus delivery when it is redistributed from the brain to other tissues. Etomidate undergoes elimination by the liver with a half-life of several hours [32]. One of the main advantages of etomidate over other induction agents is its ability to maintain hemodynamic stability even in the setting of cardiovascular compromise [33]. The predominant issue surrounding the use of etomidate however, is adrenocortical suppression [34]. Etomidate potently inhibits 11β-hydroxylase, an enzyme in the biosynthetic pathway leading to adrenocortical steroid synthesis [35, 36]. Alternative etomidate analogs are currently under investigation in the hopes of developing a rapidly metabolized hypnotic agent with the haemodynamic stability of etomidate but without the adrenocortical suppression characteristic of the parent compound. At the time of publication, these agents were under development and had not yet undergone human testing.

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Aug 26, 2017 | Posted by in Uncategorized | Comments Off on Newer Drugs for Sedation: Soft Pharmacology

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