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 Table of Contents  
REVIEW ARTICLE: REPUBLICATION
Year : 2017  |  Volume : 3  |  Issue : 3  |  Page : 63-66

Common sedative agents: An overview


OPUS 12 Foundation, Bethlehem, PA, USA

Date of Web Publication21-Apr-2017

Correspondence Address:
Stanislaw P Stawicki
Department of Research and Innovation, St. Luke's University Health Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJAM.IJAM_94_16

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  Abstract 


This article provides an overview of commonly utilized sedative agents, focusing on intensive care applications. High-yield information about ketamine, lorazepam, midazolam and propofol is presented. Fundamental mechanistic and drug safety details are discussed.
The following core competencies are addressed in this article: Medical knowledge, Patient care.
Republished with permission from: Stawicki SP. ABSITE Corner: Common sedative agents: An overview. OPUS 12 Scientist 2007;1(2):8-9.

Keywords: In-Training Examination, ketamine, lorazepam, midazolam, propofol, review, sedative agents


How to cite this article:
Stawicki SP. Common sedative agents: An overview. Int J Acad Med 2017;3, Suppl S1:63-6

How to cite this URL:
Stawicki SP. Common sedative agents: An overview. Int J Acad Med [serial online] 2017 [cited 2019 Jul 23];3, Suppl S1:63-6. Available from: http://www.ijam-web.org/text.asp?2017/3/3/63/204975




  Lorazepam Top


Lorazepam is an intermediate-acting benzodiazepine [1],[2]. It is used for short-term relief of anxiety. It is also useful as a first-line anticonvulsant in the setting of seizures and/or status epilepticus. Lorazepam is the preferred agent for long-term sedation in the Intensive Care Unit (ICU). Lorazepam's anticonvulsant and central nervous system (CNS) depressant effects are also useful for the prevention and treatment of alcohol withdrawal symptoms.[1],[2],[3],[4]

Lorazepam has a half-life of 10-20 h. It can be administered orally, intravenously, intramuscularly, or transdermally. It is metabolized through hepatic glucuronidation and undergoes renal excretion. Lorazepam has poor lipid solubility and a high degree of protein binding (85–90%). It is thought to have high affinity for gamma-aminobutyric acid (GABA) receptors, which helps explain its amnestic properties.

The recommended initial adult daily oral dosage is 2 mg in divided doses of 0.5–1.0 mg. The daily dose should be gradually increased or decreased by 0.5–1.0 mg based on patient response and tolerance. The usual daily dosage is between 2 and 3 mg. Dosages higher than 3 mg can be used, especially in long-term administration of lorazepam.[1],[2],[3],[4]

Lorazepam infusion can be useful in long-term ICU sedation. However, one must remember that renal impairment and advanced patient age may cause abnormally prolonged duration of action. The starting dose in the elderly (>65 years old) population should not exceed 0.5 mg and should be very carefully and gradually titrated. Lorazepam overdose can be treated with flumazenil.[1],[2],[3],[4]

The most common side effects associated with lorazepam use include (a) sedation reported in 1 of 6 people; (b) weakness; (c) unsteadiness/ataxia; (d) feeling of depression; (e) disorientation; (f) headache; (g) sleep disturbance – especially in the ICU; (h) respiratory failure; and (i) withdrawal. There are also case reports of renal toxicity and lactic acidosis related to propylene glycol, a component of the intravenous lorazepam formulation.[4] Concurrent use with alcohol may lead to fatal respiratory depression. Of note, lorazepam is classified as category D drug in the setting of pregnancy. Benzodiazepine use in pregnancy, especially in high doses, may result in significant perinatal problems.[3]


  Midazolam Top


Midazolam is a short-acting benzodiazepine used to relieve anxiety before operative procedures and to facilitate sedation in the acute procedural setting.[2] Midazolam can also be used to induce loss of consciousness before and during surgery. It has sedative, hypnotic, anxiolytic, and amnestic properties.

Midazolam has a short elimination half-life (1.8-6.4 h). Its metabolism is primarily hepatic, with renal excretion. Midazolam is metabolized mostly by cytochrome P450-3A4, and agents that affect this system will affect midazolam action. Midazolam acts on benzodiazepine receptors, which enhance the binding of GABA to GABA-A receptor, causing CNS inhibition. It can be administered orally, intramuscularly, or intravenously.[5]

Midazolam is indicated for (a) preoperative sedation, anxiolysis, and amnesia; (b) treatment of seizures and/or status epilepticus; (c) sedation, anxiolysis, and amnesia before endoscopic procedures; (d) general anesthesia in combination with other agents. Continuous intravenous infusion of midazolam has been used for sedation of intubated patients in the ICU.[2],[5]

Preoperative sedation with midazolam is given intramuscularly at 70–80 mcg/kg approximately 30–60 minutes before general anesthesia. For conscious sedation, intravenous midazolam can be administered starting with doses of 0.5 mg and titrating slowly to desired effect. Total doses >2.5 mg should not be exceeded over any 2-min period. For induction of general anesthesia, intravenous midazolam (150–350 mcg/kg) should be given over 30 s and may be followed with additional 25% of the initial dose, if needed, few minutes after the initial injection.[2],[5]

Midazolam dosage should be reduced for patients who are older than 55 years, premedicated, debilitated, or have severe systemic disease. In the pediatric population, preoperative sedation may require anywhere between 80 and 200 mcg/kg and general anesthesia may require anywhere between 50 and 200 mcg/kg.

Side effects of midazolam include hypotension, bradycardia, respiratory depression, impaired motor function, coma, and withdrawal symptoms. Midazolam overdose can be treated with flumazenil. Midazolam administered regularly during pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations, and withdrawal symptoms. Newborns may show hypotonia, poor feeding, apnea, cyanosis, floppy infant syndrome.[2],[5]


  Propofol Top


Propofol (2,6-diisopropylphenol) is a short-acting intravenous anesthetic agent. It can be used for induction and/or maintenance of general anesthesia. It is also used in the ICU as a sedative agent for intubated, mechanically ventilated patients. It can be utilized in the short procedure setting, including endoscopic procedures. Propofol provides no analgesia or muscle relaxing properties.[6],[7],[8]

The commercial preparation consists of 1% propofol, 10% soybean oil, 1.2% purified egg phospholipid (emulsifier), 2.25% of glycerol as a tonicity agent, and sodium hydroxide to adjust the pH. Propofol emulsion is an opaque white fluid (i.e., the “milk of anesthesia”). Propofol is highly protein bound in vivo. It is metabolized by hepatic glucuronidation. Its rapid rate of clearance suggests nonhepatic metabolism as well. Its mechanism of action is not precisely known, but the primary effect may be potentiation of GABA-A receptor, possibly by slowing the channel closing time. The endocannabinoid system may also contribute to propofol's anesthetic action. The elimination half-life is 2-24 h, but the duration of action is much shorter (minutes) because propofol is rapidly distributed into peripheral tissues.

Propofol is perfectly suited as a quick “on/off” agent in the setting of head injury, where it allows for periodic “awakenings” followed by rapid reinstitution of sedation. It may also offer some neuroprotection. In terms of dosing, anesthesia induction in adults (<55 years old) is given at 2.0–2.5 mg/kg. In elderly patients (>65 years old), propofol induction is given at 1.0–1.5 mg/kg. Propofol maintenance anesthesia is dosed at 100–200 mcg/kg/min in adults and 50–100 mcg/kg/min for geriatric patients. For ventilated ICU patients, the dose is titrated between 5 and 50 mcg/kg/min.[6],[7],[8],[9]

Side effects of propofol include (a) hypotension; (b) transient apnea following induction doses; (c) pain at the injection site can be mitigated by pretreatment with lidocaine; (d) significant variability in dose-response among patients; (e) rare dystonia; (f) mild myoclonic movements; (g) pancreatitis due to the high-lipid content of the propofol carrier medium seen in chronic administration; (h) hallucinations; (i) seizures – very rare; (j) thrombophlebitis. A rare, but serious, side effect of propofol is the propofol infusion syndrome. This potentially lethal metabolic disorder (severe metabolic/lactic acidosis) has been reported in the ICU patients after prolonged high-dose infusion of propofol, usually in conjunction with catecholamines and/or corticosteroids.[6],[7],[8],[9]


  Ketamine Top


Ketamine is a unique sedative agent – a dissociative anesthetic.[10],[11],[12],[13],[14] Ketamine does not induce significant respiratory depression. It has hypnotic, analgesic, and amnestic effects – a unique combination of clinical features. Ketamine is a coanalgesic, being most effective when combined with low-dose opioids.

Ketamine is classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, along with phencyclidine (PCP).[10],[11],[12],[5] There are two stereoisomers of ketamine, (S)-ketamine and (R)-ketamine. The (S)-ketamine has a stronger affinity for the PCP site on NMDA receptor as well as greater analgesic effect than (R)-ketamine. Ketamine is usually given intravenously or intramuscularly, but it can be effective when insufflated, smoked, or taken orally. Its half-life is approximately 2.5–3.0 h and excretion is 90% renal. The usual intravenous dose of ketamine is 1.0–4.5 mg/kg, which produces surgical anesthesia within 30 s after injection. Intramuscular doses, from primarily pediatric experience, produce surgical anesthesia within 3–4 minutes in doses of 6.5–13 mg/kg. Intravenous ketamine anesthetic effect usually lasts 5–10 min and intramuscular ketamine effect usually lasts 12–25 min.[10],[11],[12],[13],[14]

Ketamine has a variety of clinical effects, including (a) analgesia, (b) anesthesia, (c) hallucinations, (d) neurotoxicity, (e) arterial hypertension, and (f) bronchodilation. In contrast to the smooth induction of anesthesia, the patient may be agitated on recovery – a phenomenon called emergence delirium

(disorientation, restlessness, and crying). Patients may experience unpleasant, vivid dreams up to 24 h postketamine administration. The use of benzodiazepines as premedication and providing an undisturbed recovery may help reduce these side effects. Ketamine infusion may be used in small doses (0.1–0.5 mg/kg/h) in the setting of regional pain syndromes (including reflex sympathetic dystrophy). Here, ketamine provides selective pain relief without prolonged sedation or respiratory depression. Ketamine causes elevations in intracranial pressure and should not be used in patients who sustained a head injury. There may be an increased risk of cardiac ischemia with ketamine use. Ketamine may also lower the seizure threshold.[10],[11],[12],[13],[14]

Acknowledgement

Justifications for re-publishing this scholarly content include: (a) The phasing out of the original publication after a formal merger of OPUS 12 Scientist with the International Journal of Academic Medicine and (b) Wider dissemination of the research outcome(s) and the associated scientific knowledge.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy 1998;18:57-62.  Back to cited text no. 1
    
2.
Lader M. Short-term versus long-term benzodiazepine therapy. Curr Med Res Opin 1984;8 Suppl 4:120-6.  Back to cited text no. 2
    
3.
McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994;8:461-75.  Back to cited text no. 3
    
4.
Yaucher NE, Fish JT, Smith HW, Wells JA. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy 2003;23:1094-9.  Back to cited text no. 4
    
5.
Munro A, Machonochie I. Midazolam or ketamine for procedural sedation of children in the emergency department. Emerg Med J 2007;24:579-80.  Back to cited text no. 5
    
6.
Iwersen-Bergmann S, Rösner P, Kühnau HC, Junge M, Schmoldt A. Death after excessive propofol abuse. Int J Legal Med 2001;114:248-51.  Back to cited text no. 6
    
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Miner JR, Burton JH. Clinical practice advisory: Emergency department procedural sedation with propofol. Ann Emerg Med 2007;50:182-7, 187.e1.  Back to cited text no. 7
    
8.
Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: A simple name for a complex syndrome. Intensive Care Med 2003;29:1417-25.  Back to cited text no. 8
    
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Wilbur K, Zed PJ. Is propofol an optimal agent for procedural sedation and rapid sequence intubation in the emergency department? CJEM 2001;3:302-10.  Back to cited text no. 9
    
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Bergman SA. Ketamine: Review of its pharmacology and its use in pediatric anesthesia. Anesth Prog 1999;46:10-20.  Back to cited text no. 10
    
11.
Bonanno FG. Ketamine in war/tropical surgery (a final tribute to the racemic mixture). Injury 2002;33:323-7.  Back to cited text no. 11
    
12.
Elia N, Tramèr MR. Ketamine and postoperative pain - A quantitative systematic review of randomised trials. Pain 2005;113:61-70.  Back to cited text no. 12
    
13.
Ketalar. Indications & Dosage. Available from: http://www.rxlist.com/cgi/generic/ketamine_ids.htm. [Last accessed on 2007 Oct 17].  Back to cited text no. 13
    
14.
Lubenow T, Kirkpatrick A, Friedberg B. Two-hour Ketamine Infusion with Video Demonstration. Available from: http://www.rsdfoundation.org/en/Ketamine_Treatment.html. [Last accessed on 2007 Oct 18].  Back to cited text no. 14
    




 

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  In this article
Abstract
Lorazepam
Midazolam
Propofol
Ketamine
References

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