PHARMACOLOGY

Anxiolytics, sedatives and hypnotics

Caroline Meerts Anthony Absalom

Learning objectives
After reading this article, you should be able to: C discuss the inuence of anaesthetic agents on neurophysiology C list the most important drugs used for anxiolysis and sedation and their characteristics C list the most important drugs used for induction and maintenance of anaesthesia and their characteristics

Abstract
Anxiolytics and sedatives are used in current anaesthetic practice for two main reasons: for anxiolysis before surgery and as adjuvants during anaesthesia. A wide choice of agents are available. Their safety prole is dependent on their pharmacokinetic and pharmacodynamic proles, patient co-morbidity and the experience of the clinician using them. All sedative drugs have the potential to cause severe respiratory depression, and hence they should only be used with standard physiological cardiorespiratory monitoring. This is especially true of procedural sedation administered by non-anaesthetists in remote locations. Drugs used for anaesthesia vary in their pharmacology, but have broadly similar clinical effects. The choice of drug is usually a matter of individual preference, although pharmacokinetic and pharmacodynamic parameters do inuence the selection of anaesthetic agents, especially in day case surgery. Most intravenous agents are thought to alter consciousness by an effect at the GABAA or N-methyl-D-aspartate receptors or both. Our understanding of the mechanisms of action of anaesthetic drugs is incomplete, not least because of a lack of understanding of consciousness. Several theories have been proposed over the last century, but none of them have managed to comprehensively elucidate the processes involved. There is now a sense of expectation that with the use of modern imaging techniques, anaesthetic drug action can be better understood, and that this may help in our understanding of consciousness and cognitive functions.

sub-units enable considerable anatomical and functional diversity of the GABAA receptor, resulting in different spectra of effects with different agents. When activated, the receptor channel opens allowing an inux of chloride ions causing membrane hyperpolarization and inhibition of neural transmission. In recent decades, much research has been focussed on development of GABAA receptor subtype selective drugs, with the aim of nding drugs with more targeted physiologic effects as compared to currently available agents. The N-methyl-D-aspartate (NMDA) receptor is a glutamategated cation channel. Ketamine, nitrous oxide and xenon are thought to act predominantly as NMDA receptor antagonists, thereby inhibiting excitatory neurotransmission.

Keywords Anxiolytics; receptors, GABAA; receptors, NMDA; sedatives and hypnotics

Royal College of Anaesthetists CPD Matrix: A102

Mechanisms of action of anxiolytics, sedatives and hypnotics

Molecular mechanisms Growing evidence suggests that anaesthetic agents act by specic mechanisms on membrane proteins, especially ligand and voltagegated ion channels.1 Most hypnotic anaesthetic agents are reversible agonists at the GABAA receptor, a G-protein coupled chloride channel with ve sub-units. The diversity of these isoform

Caroline Meerts MD is a Resident in Anaesthesia and Intensive Care at the University Medical Center Groningen, The Netherlands. Conicts of interest: none. Anthony Absalom MBChB FRCA MD is Professor of Anaesthesia at University Medical Center Groningen, Groningen University, The Netherlands. Conicts of interest: none.

Inuence of anaesthetic agents on neurophysiology and neural correlates of consciousness The basic requirements for consciousness are wakefulness and awareness. The ascending reticular system controls wakefulness, while the thalamus is thought to have a central role in attention. Perception of external and internal sensory input alone is insufcient for awareness. For a person to be aware of an object in the external environment, the different attributes of that object, which are perceived via different sensory pathways and different areas of the cortex, have to be bound together before being passed to working memory. Binding is thought to be mediated in different relevant parts of the cortex. Anaesthetic agents may impair consciousness by preventing binding.2 The most consistent regional physiological effect produced by GABAA acting anaesthetics at (or near) loss of consciousness is a reduction of thalamic metabolism and blood ow. Ketamine, however, increases global metabolism, especially in the thalamus. Anaesthetic effects on the thalamus may be largely indirect. Spontaneous thalamic ring during anaesthesia is largely driven by feedback from cortical neurons. Anaestheticinduced unconsciousness is usually associated with deactivation of mesial parietal cortex, posterior cingulate cortex, and precuneus. Anaesthetics may disrupt cortical integration by acting on structures that facilitate long-range corticoecortical interactions.3 Anaesthesia involves inducing calmness, drowsiness, reducing anxiety and provides loss of consciousness. Ideally these different effects are produced by separate drugs to reduce unwanted side effects. Unfortunately sedatives, anxiolytics and hypnotics produce a dose-dependent spectrum of central nervous system (CNS) depressant effect. We have thus structured this review according to the indications for which the drugs are used.

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Drugs used for anxiolysis and sedation

Premedication Although often not necessary, in some circumstances, such as in children and in patients who constitute a risk to themselves or healthcare staff, sedation might be necessary. For the average patient anxiolysis is sufcient and may assist the later conduct of anaesthesia. There is no evidence that accurate use of anxiolytic premedication delays discharge after day case adult surgery.4 Benzodiazepines Benzodiazepines (BZNs) are the most commonly used agents for preoperative anxiolysis and sedation. The properties and dosages of some typical agents, as well as some newer agents, are summarized in Tables 1 and 2. BZNs are potent anxiolytics, produce anterograde amnesia and have a favourable therapeutic index. They reduce induction dose requirements by several mechanisms including pharmacodynamic interactions with hypnotics. In most cases they are administered by the oral route, although the intranasal and rectal routes are also effective. Adverse effects include respiratory depression, impaired airway reexes, cardiovascular depression, and impaired consciousness and coma. BZNs should be avoided or used with caution in the elderly or frail, in which both pharmacokinetic and pharmacodynamic factors may greatly enhance cardio-respiratory depression. Patients with impaired consciousness are also very sensitive to sedative agents. This is especially important in neurosurgical patients with space-occupying lesions, where any resulting respiratory depression is likely to cause or exacerbate raised

intracranial pressure thereby amplifying the CNS depression and respiratory depression. Remimazolam is a new ester-linked benzodiazepine, which is rapidly metabolized by tissue esterase to an inactive metabolite.5 It has been developed to permit fast onset, a short predictable duration of sedation, and a more rapid recovery than currently available benzodiazepines. MR04A3 is a 1% aqueous formulation of JM-1232. JM-1232 is an iso-indoline, and although it is not a member of the benzodiazepine group, it acts at the same binding site as the benzodiazepines. In animals, it has been shown to have favourable anaesthetic and sedative properties, with wide safety margins, and appears to have potential as an analgesic adjunct. Early human studies are underway.6 Other agents Sedative doses of hyoscine are sometimes used for premedication, primarily for its anti-sialogogue effects. Barbiturates are seldom used for premedication, because of their narrow therapeutic index, and the availability of safer agents. Opioids are occasionally used for premedication, particularly in those with pain and with cardiac disease, in whom the anxiolytic and sedative properties, and the attenuation of the stress responses to endotracheal intubation are particularly benecial. In adults opioid premedication is often administered by the intramuscular route. In children oral transmucosal fentanyl citrate presented as a lolly produces reliable sedation. The disadvantage of using opioids for premedication is the common occurrence of adverse effects such as nausea and vomiting, blurred vision, pruritis and respiratory depression.

Doses of agents commonly used for anxiolysis and sedation

Intravenous (mg) (mg/kg) Adults Oral (mg) Intramuscular (mg) Oral (mg/kg) Children Other (mg/kg)

Benzodiazepines

Temazepam Midazolam Lorazepam Diazepam Remimazolam Zopiclone Morphine Fentanyl Hyoscine Chloral hydrate Triclofos Dexmedetomidine Melatonin MR04A3 2.5e5

Healthy: 20e30 Elderly, frail: 10 10e20a 2.5e5 10e20

1 (elixir) Nasal: 100e150 mg/kg 0.2

Other agents

0.01e0.3 7.5 mg 5e15 Oral transmucosal: w10 mg/kga 0.5e1.0 mg 1e1.5 mg/kg Continuous 0.2e0.7 mg/kg/h 0.05e0.8 mg/kga 2e6 0.2e0.4 50 mg/kg 50 mg/kg 0.5e1 mg/kg Intranasal 1e1.5 mg/kg

Not licensed for sedation in the UK.

Table 1

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Pharmacokinetic characteristics of benzodiazepines

Drug Bioavailability (oral) (%) 80 48 93 100 Vd (litres/kg) t1/2 a (minute) t1/2 b (hours) Clearance ml/min Active metabolites No No No Yes No

Temazepam Midazolam Lorazepam Diazepam Remimazolam Table 2

1.3e1.5 0.8e1.14 1.14e1.3 0.9e1.2

48e162 3e38 3e10 9e130 35e43

5.1e15.3 2.1e2.4 14.3e14.6 31.3e46.6

60.9 202e324 77.0 26e35 1213e1228

Other agents used for paediatric premedication include chloral hydrate (50 mg/kg orally) and triclofos (50 mg/kg orally). In unco-operative children intramuscular or rectal ketamine (2 mg/ kg) just before an intervention may be useful. Intravenous propofol, administered by a patient-maintained sedation system combining the benets of patient control with target-controlled infusion technology, has been shown to be a safe and effective method of providing instant anxiolysis and sedation during the preoperative period when respiratory and haemodynamic monitoring in present.7 The neurohormone melatonin has anxiolytic and analgesic effects and can be used as an anaesthetic adjunct. Although experience with it is limited, it is registered for use in the UK and recent studies suggest it may have a future role in clinical practice.8

Dexmedetomidine had been registered recently in the UK and has favourable properties for use during procedural sedation. In addition to rapid kinetics, it produces analgesia and rousable sedation similar in some aspects to natural sleep. It is associated with less respiratory depression than that with other sedatives. These properties may be responsible for demonstrated improved outcomes in intensive care patients.10 This agent is likely to nd a future role in procedural and intensive care sedation.

Hypnotics used for induction and maintenance of anaesthesia

Choice of agents In adults, induction of anaesthesia is usually achieved by administration of intravenous anaesthetic agents. In infants and young children the inhalational route has traditionally been used, but in recent years the availability of topical local anaesthetic creams has resulted in increased popularity of intravenous induction. The availability of sevourane has meant that single breath or gradual inhalational induction of anaesthesia in adults is now not uncommon. Anaesthesia is maintained by administration of a volatile anaesthetic agent or an intravenous agent. The advantage of volatile agents is the dependable pulmonary route of elimination versus the comparatively slow routes of elimination of some intravenous agents. The use of total intravenous anaesthesia for maintenance of anaesthesia is becoming more popular due to the availability of drugs with favourable pharmacokinetic proles and better delivery systems. The choice of individual agents, either intravenous or inhalational is dictated by personal preference as much as it is by clinical indications. Intravenous anaesthetics The salient features of commonly used intravenous anaesthetics are summarized in Table 3. Propofol: propofol is commonly used for induction of anaesthesia due to its favourable recovery prole. Its antiemetic and antipruritic properties at subanaesthetic concentrations are particularly valuable in the day case setting. Propofol causes a signicant reduction in arterial blood pressure by decreasing systemic vascular resistance, preload and myocardial contractility. These effects are more prominent in patients with compromised cardiac function and the elderly. Following an induction dose, propofol causes apnoea, inhibits hypoxic ventilatory drive and impairs the response to hypercarbia. It also causes rapid reductions in

Procedural sedation
Sedation during procedures such as endoscopy is commonly administered by the operator, or by a non-medically trained person supervised by the operator. Mortality rates for these procedures are several orders of magnitude greater than for general anaesthesia. One factor likely to be responsible for this is the common practice of using drug combinations. Common combinations include intravenous bolus doses of fentanyl and midazolam, which have potent but variable synergism in terms of sedation and respiratory depression. Even when used alone, the pharmacokinetics of midazolam are sub-optimal, as the peak effect after an intravenous bolus dose only occurs at around 13 min, by which time many patients are already in the recovery area. In the UK anaesthetists commonly administer sedation during surgical procedures performed under local or regional anaesthesia. Bolus doses of midazolam are often used, but have the disadvantage that repeat doses can be associated with prolonged sedation and recovery. Infusions of propofol offers several pharmacokinetic and dynamic benets. These include potent anxiolysis, a rapid and pleasant onset of sedation, easy titration of sedation level, and a rapid clear-headed recovery. Targetcontrolled infusion (TCI) propofol is popular and has the benets of ease-of-use, easy titration to clinical effect and stable blood concentrations. Patient-maintained propofol sedation may improve patient satisfaction, and has been shown to result in reduced propofol consumption and fewer adverse effects than anaesthetist-administered propofol sedation.9

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Induction dose (mg/kg)

0.2e0.7 mg/kg

1.5e2.5

3e7 0.3

1.2

intracranial and intraocular pressure, but will reduce cerebral perfusion pressure if the mean arterial pressure decreases signicantly. Pain during injection, bacterial contamination of preparations and unexplained excitatory phenomena remain important concerns with the use of propofol. Some clinicians routinely avoid propofol in poorly controlled epileptic patients and those with a current driving licence, although it has been used as an adjunct in patients with status epilepticus.11 A rare but serious complication is the propofol infusion syndrome, associated with prolonged infusion (>48 hours) of higher doses (>4 mg/kg/hour) in children and young adults.12 Thiopentone: thiopentone is the only barbiturate in common use. It is mainly used for rapid sequence induction or in patients who are allergic to propofol or its constituents. Nausea and vomiting, a prolonged recovery period and accumulation with repeated doses or infusions, are some of the factors responsible for its declining popularity. The organ system effects are generally similar to those caused by propofol. There is a higher incidence of laryngospasm and bronchospasm in lightly anaesthetized patients. Burst suppression usually follows large doses of thiopentone; these effects are considered to be protective in focal brain injury and might be of use in patients with status epilepticus. Etomidate: etomidate is most commonly used in emergency situations where propofol or thiopentone are likely to precipitate marked hypotension. The classic example is rapid sequence induction for emergency repair of an abdominal aortic aneurysm. Etomidate causes inhibition of 11b-hydroxylase and 17a-hydroxylase resulting in reversible adrenocortical suppression. As a result continuous infusions increase morbidity and mortality in the critically ill.13 Methoxycarbonyl (MOC) etomidate is the ultra-short-acting etomidate analogue. In animals it does not produce adrenocortical suppression after bolus administration, probably because of its rapid hydrolysis to a relatively inactive carboxylic acid metabolite.14 MOC etomidate might be valuable in hemodynamically unstable and septic patients. Further human studies are required. It is not registered in the UK. Ketamine: ketamine is a phencyclidine derivative that produces analgesia, a dissociative anaesthetic state, and unpleasant postoperative psychomimetic effects including hallucinations and nightmares. It is associated with bronchodilation, cardiorespiratory stability, and relative preservation of airway reexes, making it ideal for use in battleeld surgery and in septic and hypovolaemic patients. Sympathetic stimulation can be troublesome in patients with ischaemic heart disease. It causes an increase in cerebral metabolic rate, blood ow and intracranial pressure which precludes its use in patients with intracranial hypertension. In contrast recent studies have shown a benet of ketamine in the treatment of status epilepticus. In the UK ketamine is more commonly used for sedation during regional techniques, sedation of uncooperative patients, analgesia during change of burns dressings, and for postoperative pain relief in patients with chronic pain. S-Ketamine is more potent and associated with fewer adverse effects than

50e200 mg/kg/min; Target-controlled infusion: 2e8 mg/ml Not routinely used for maintenance

Hepatic and extra-hepatic. Inactive metabolites

Hepatic oxidation to inactive metabolites Hydrolysis by plasma esterase and liver microsomal enzymes. Inactive metabolites

Clearance (ml/kg/ minute)

18e40

2.7e4.1 12.5e26

17

9.3e69.3 min

Summary of important characteristics of intravenous anaesthetic agents

3.4e22 1e4.7

tb (hours)

2.5

ta (minutes)

1.0 1.2e4.5

1.3e4.1

Protein binding (%)

20e50

Vd (litres)

700e1500

130 140e340

210

Barbiturate Imidazole derivative

Chemical group

Phenol derivative

Methoxycarbonyl etomidate Ketamine

Drug

Propofol

Thiopentone Etomidate

Demetomidine

Selective a2 agonist Table 3 358

Etomidate derivate

Phencyclidine derivative

118

94

80 76

97

6.2

11

2.0

39

Norketamine e active metabolite Hepatic enzyme induction Hepatic extraction ratio 0.9 None

Metabolism

0.6e0.7 mg/kg/hour

Maintenance dose (infusion)

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PHARMACOLOGY

R-ketamine, but unfortunately the racemic mixture is the only formulation available in the UK. Dexmedetomidine: dexmedetomidine is a specic a-2 agonist, with potency eight times greater than clonidine. It properties of sedation, anxioloysis and analgesia together with its favourable pharmacokinetics make it a valuable adjunct for procedural and intensive care sedation. For light and moderate sedation, dexmedetomidine is associated with a shorter duration of mechanical ventilation and decreased incidence of delirium, when compared with benzodiazepines.10 There was no difference between duration of intensive care unit or hospital stay. Inhalational anaesthetics The physicochemical properties of commonly used inhalational anaesthetic agents are summarized in Table 4. Among the volatile anaesthetic agents, potency, assessed by the minimum alveolar concentration (MAC50) concentration, is generally proportional to the lipid solubility. Uptake of a volatile agent depends on the inspired concentration, alveolar minute ventilation, cardiac output and blood gas solubility. Rate of onset and offset of clinical effects depends on the concentration gradient from the alveoli to the pulmonary capillaries and the brain, and also on the bloodebrain equilibration rate (determined by the lipid solubility). The alveolarecapillary concentration gradient is proportional to minute ventilation, and inversely proportional to cardiac output and bloodegas solubility co-efcient. Nitrous oxide: nitrous oxide is the only commonly used nonvolatile inhalational anaesthetic. A MAC of 105 precludes its use as a sole anaesthetic, but it has unique advantages when used as a carrier gas. N2O reduces the MAC of concomitantly administered

volatile agents, has analgesic properties and partially reverses the cardiorespiratory effects of volatile agents through its indirect sympathomimetic effects. These advantages are offset by the potential for adverse clinical effects including the expansion of closed air spaces, an increase in pulmonary vascular resistance and postoperative nausea and vomiting. Prolonged exposure may result in megaloblastic anaemia and peripheral neuropathy by inhibition of vitamin B12-dependent enzymes. It may also impair chemotactic responses and neutrophil motility, thus adversely affecting the immunological response to infection. Though the teratogenic effects of nitrous oxide have never been unequivocally proven, it is avoided in pregnant patients. Isourane: isourane is a volatile agent commonly used for maintenance of anaesthesia. It causes minimal cardiac depression, but it may cause coronary steal in susceptible patients. There is an insignicant risk of causing hepatic dysfunction, as it is metabolized only to a small extent. Sevourane: the physicochemical characteristics of sevourane (non-pungent, non-irritant to airways, low blood gas partition coefcient) make it the agent of choice for inhalational induction of anaesthesia. Cardiovascular effects are minimal, and respiratory and cerebral effects are similar to those caused by isourane. Rapid emergence from anaesthesia is benecial in the day case setting, although this can precipitate emergence delirium in the paediatric population. Concerns about compound A are now widely considered to be theoretical, although fresh gas ows greater than 2 litres/minute are recommended. Desurane: the unique physical properties of desurane (low boiling point, high saturated vapour pressure, low potency) mean

Summary of important characteristics of volatile anaesthetic agents

Isourane Physical properties Structure Molecular weight Boiling point ( C) SVP (kPa at 20 C) Oil gas solubility Blood gas solubility Systemic effects MAC (in air/70% N2O) Metabolism (hepatic) Excretion Sevourane Desurane Halothane Enurane

Halogenated methyl ether 184.5 48.5 32 174 1.4 1.15/0.50 0.2% (oxidation and dehalogenation) 0.2% in urine as nonvolatile compounds; remainder exhaled unchanged

Halogenated ether 200 58.5 21.3 53 0.6 1.7e2/0.7e2 3% Exhaled predominantly unchanged

Halogenated ether 168 23.5 88.5 18.7 0.42 5.7e10.6/1.7e7.7 0.02% (triuoroacetic acid) Traces of triuoroacetic acid in urine; remainder exhaled unchanged

Halogenated hydrocarbon 198 50.2 32 220 2.4 0.75/0.29 20% (oxidation and dehalogenation) 60e80% exhaled unchanged; urinary metabolites excreted for up to 3 weeks

Halogenated methyl ethyl ether 184.5 56.5 23.3 120 1.91 1.68/0.57 2.4% (oxidation and dehalogenation) 2.4% in urine as non volatile compounds; 80% exhaled unchanged; high plasma uoride concentrations

MAC, minimun alveolar concentration; SVP, saturated vapour pressure.

Table 4

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that it cannot be delivered by conventional vaporizers e electrically heated blended vaporizers are required. It is not suitable for induction of anaesthesia due to its pungent smell, propensity to cause laryngospasm and breath-holding, and activation of the sympathetic nervous system if the inhaled concentration is increased rapidly. Very low blood gas solubility results in rapid emergence. A

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