Sedative and Anxiolytic Drugs

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Sedative and Anxiolytic Drugs

Sedation is best considered as a continuum between normal consciousness and general anaesthesia. The most frequently cited description of the varying levels of sedation utilized in clinical practice is that from the American Society of Anesthesiologists (Table 7.1).

TABLE 7.1

Continuum of Depth of Sedation: Definition of General Anaesthesia and Levels of Sedation/ Analgesia. American Society of Anesthesiologists, 2009

There is a seamless progression from minimal sedation to deep sedation, in which verbal contact and protective airway reflexes may be lost. It is very difficult to predict how an individual patient will respond to a sedative agent. The ability of the patient to maintain a patent airway independently is one characteristic of moderate or conscious sedation, but even at this level of sedation it cannot be assumed that protective airway reflexes are intact. Deep sedation may progress easily to be indistinguishable from general anaesthesia, and a higher level of skill is needed to ensure the safe management of the patient. The degree of apparent sedation is related to the stimulation from the procedure, and patients can move rapidly between levels of sedation due to procedural effects without any change in drug dosage. It is therefore important that healthcare professionals delivering sedation have the necessary skill set to cope with sedation which is deeper than intended. Similarly, patients having sedation should be fasted in an identical manner to patients having a general anaesthetic.

The difference between sedative and anaesthetic drugs is largely one of usage. Many anaesthetic drugs may be used at reduced dosage to produce sedation and, similarly, agents used primarily as sedatives will produce a form of anaesthesia if given in sufficiently high doses. The usual target is to produce conscious sedation, i.e. to titrate drug therapy so the patient is free of anxiety, free of pain and responding purposefully to command. In adults, this corresponds to the levels of sedation from anxiolysis to moderate sedation as described in Table 7.1.

Over recent years, there has been an increased focus of safe sedation practice by regulatory agencies. When sedation is used in areas outside the operating theatre environment, and by non-anaesthetic personnel, there is a particular need to ensure adequate provision of facilities, equipment and competent personnel. An audit of sedation for over 14 000 upper gastrointestinal endoscopies published in 1995 demonstrated a 30-day mortality of 1:2000 and a morbidity rate of 1:2003, primarily due to respiratory and cardiovascular problems. As a result, several practice guidelines have been published to address these issues. Examples include guidance on sedation for upper gastrointestinal endoscopy, procedures in the emergency department and dental surgery, and the sedation of children. Many of these documents share key messages: the requirement of a trained individual solely responsible for monitoring the patient during sedation; the mandatory use of pulse oximetry; the importance of supplementary oxygen therapy during sedation; the need for comprehensive resuscitation equipment which must be immediately available; and the need for personnel who are trained to recognize, and are competent to manage, cardiorespiratory complications. This guidance relates solely to conscious sedation. If deep sedation is required, the patient requires a level of care identical to that needed for general anaesthesia.

INDICATIONS FOR THE USE OF SEDATIVE DRUGS

Procedural Sedation

This is defined as the administration of sedative(s) (with or without analgesics) to induce a state which allows a patient to tolerate unpleasant procedures whilst maintaining cardiorespiratory function and the ability to maintain airway control independently and continuously. Procedural sedation may be used for a variety of interventions including radiological investigations, gastrointestinal endoscopy and transoesophageal echocardiography. However, there is no absolute indication for the use of sedation and many procedures for which sedation was felt previously to be mandatory can now be undertaken without the need for systemic drug therapy. The requirement for procedural sedation should be determined by a combination of patient, procedural and operator factors. It is always important to ensure that the benefits of procedural sedation (such as greater patient satisfaction and better tolerance of the procedure) outweigh the associated risks. Sedation should never be used for the convenience of the individual performing the procedure.

The commonest reasons for the use of procedural sedation are to provide anxiolysis for the concerned patient, analgesia for painful procedures and to allow longer procedures (e.g. interventional radiology) to be better tolerated. In individuals with significant cardiac comorbidity, sedation may also attenuate the cardiovascular stimulation (and increase in myocardial oxygen demand) associated with some procedures. It is important that the sedative agent used will target the specific undesirable symptom. For example, sedatives such as benzodiazepines have no analgesic action and will not provide effective sedation for painful procedures. Great care must be taken when co-administering sedative drugs and systemic opioids. The synergism between these two groups of drugs significantly increases the risks of airway obstruction and respiratory depression.

Premedication

Sedative drugs may be given in the preoperative period to reduce the apprehension experienced before undergoing anaesthesia and surgery. Sedation may be particularly useful in young children, patients with learning difficulties and individuals who are very anxious. Sedative drugs given in this way augment the actions of anaesthetic agents. The choice of drug depends on the patient, the proposed surgery and the prevailing circumstances; for example, requirements for patients undergoing ambulatory surgery are different from those scheduled for major surgery as an inpatient. The oral route of administration is preferred and benzodiazepines are the drugs used most commonly for this purpose. Nasal administration may be useful in children.

Supplementation of General or Regional Anaesthesia

The synergy between sedative drugs and intravenous induction agents is used in the technique of co-induction. The administration of a small dose of sedative may result in a significant reduction in the dose of induction agent required, and therefore in the frequency and severity of side-effects. Patients undergoing regional anaesthetic techniques (e.g. for joint arthroplasty) may also receive supplemental sedation to help alleviate anxieties regarding hearing or seeing parts of the surgery, or to help maintain comfort for prolonged surgery. A target-controlled infusion of propofol is used increasingly for this purpose. Studies in the elderly have found that sedation regimens can relatively frequently produce a deeper level of sedation than intended, resulting in unplanned general anaesthesia.

Awake Fibreoptic Tracheal Intubation

Sedation is often used to supplement the use of topical local anaesthesia when awake fibreoptic intubation is necessary. Because mask ventilation or tracheal intubation may be difficult or indeed impossible in some of these cases, great caution must be taken not to depress consciousness or respiratory drive. For this reason, an infusion of remifentanil (either manual or target-controlled) is used frequently for sedo-analgesia.

Critical Care

Most critically ill patients require sedation to facilitate mechanical ventilation and other therapeutic interventions in the intensive care unit (ICU). With the increasing sophistication of mechanical ventilators, the modern approach is to titrate adequate analgesia with sufficient sedation to maintain the patient in a tranquil but rousable state. The pharmacokinetic profiles of individual drugs should be considered because sedatives are inevitably given by infusion for prolonged periods in patients with potential organ dysfunction and impaired ability to metabolize or excrete drugs. Many different drugs and regimens have been used to provide short-term and long-term sedation in the ICU, including benzodiazepines, anaesthetic agents such as propofol, opioids, and most recently, α₂-adrenergic agonists. There is no evidence supporting the use of any particular regimen or combination of agents.

The value of sedation titration by such measures as the Ramsay Sedation Score or Richmond Agitation Sedation Scale during critical care has been recognized for many years, but more attention has focused recently on the importance of daily sedation ‘holds’. These daily interruptions in the sedative and analgesic infusions of selected patients help avoid the accumulation of these agents and this now forms part of the ventilator care bundle package. This has been shown to decrease the incidence of some complications associated with mechanical ventilation during critical illness, such as ventilator-associated pneumonia. In addition, sedation ‘holds’ may facilitate weaning from mechanical ventilation, thereby decreasing the length of stay in critical care and the need for tracheostomy.

Administration Techniques

The administration of sedative drugs requires skill and vigilance, not least because of the seamless progression from light sedation to general anaesthesia. Traditionally, sedative drugs have been administered by intermittent intravenous bolus doses titrated to effect. There is considerable variability in the individual response to a given dose and there are many circumstances in which medical practitioners without anaesthetic training administer sedatives. Recent technological advances in microprocessor-controlled infusion pumps have improved the safety of administration of sedatives. Patient-controlled analgesia systems have been programmed for patient-controlled sedation, usually to maintain sedation after an initial bolus dose administered by the physician. When the system is wholly patient-controlled, the mean dose of sedative drug decreases while the range increases. In target-controlled infusion (TCI), an adapted syringe driver is programmed with the pharmacokinetic model of a drug and designed to rapidly achieve (and subsequently maintain) a prescribed ‘target’ plasma concentration. The individual using a TCI system is able to set (and alter) the desired concentration based on the clinical assessment of the patient. There are several different pharmacological models, each specific for an individual drug. Examples include Marsh and Schnider (propofol), Minto (remifentanil) and Maitre (alfentanil). All these models adjust for variations in pharmacokinetics due to gender, age and weight.

Sedative Drugs

Most sedative drugs may be categorized into one of three main groups: benzodiazepines, antipsychotics and α₂-adrenoceptor agonists. Drugs classified more usually as intravenous anaesthetic agents, particularly propofol and ketamine, are also used as sedatives in subanaesthetic doses; the pharmacology of these drugs is discussed in Chapter 3. Similarly, remifentanil, which is used increasingly as part of a sedative regimen, is described fully in Chapter 5. Inhaled anaesthetics (see Ch 2) are also used occasionally as sedatives (e.g. sevoflurane to an end-tidal concentration of 0.3–0.5 kPa, or nitrous oxide).

BENZODIAZEPINES

The term benzodiazepine originates from the structure of the molecule, which consists of the fusion of a benzene and diazepine ring. These drugs were developed initially for their anxiolytic and hypnotic properties and largely replaced oral barbiturates in the 1960s due to their favourable pharmacological profile: minimal cardiorespiratory effects, the production of anterograde amnesia and a lower incidence of physical dependence. As parenteral preparations became available, they rapidly became established in anaesthesia and intensive care. All benzodiazepines have similar pharmacological effects; their therapeutic use is determined largely by their potency and the available pharmaceutical preparations. Benzodiazepines are often classified by their duration of action as long-acting (e.g. diazepam), medium-acting (e.g. temazepam) or short-acting (e.g. midazolam).

Benzodiazepines exert their actions by high-affinity binding to a specific benzodiazepine binding site, which is part of the γ-aminobutyric acid (GABA) receptor complex. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS), with most neurones undergoing GABA-ergic modulation. The benzodiazepine site is an integral part of the GABA_A receptor subtype. Binding of the agonist increases the affinity of the GABA_A receptor to GABA, producing an increased frequency of the opening of the chloride ion channel, and thus an increase in intracellular chloride transmission. This causes hyperpolarization of the postsynaptic membrane, which makes the neurone resistant to excitation. Benzodiazepine binding sites are found throughout the brain and spinal cord, with the highest density in the cerebral cortex, cerebellum and hippocampus, and with a lower density in the medulla. The absence of GABA_A receptors outside the CNS is consistent with the good cardiovascular safety profile of these drugs.

The GABA_A receptor is a large structure which also contains separate binding sites for other drugs including barbiturates, alcohol and propofol. The binding of other compounds to the benzodiazepine binding site explains the synergistic effects seen with some other drugs. This synergy may lead to dangerous depression of the CNS if drugs are used in combination and also results in pharmacological cross-tolerance, e.g. with alcohol. It is also consistent with the use of benzodiazepines to manage the symptoms associated with acute withdrawal or detoxification from alcohol or other drugs. Elderly patients are particularly sensitive to the effects of benzodiazepines and dosage should be reduced accordingly.

The benzodiazepine antagonist flumazenil occupies the benzodiazepine binding site but produces no activity. Benzodiazepine compounds have been developed which are ligands at the benzodiazepine binding site but have inverse agonist activity, resulting in cerebral excitement. These compounds are also antagonized by flumazenil. This mirrors the way in which paradoxical reactions to benzodiazepines in the elderly are reversed by flumazenil and exacerbated by increasing the dose of the original drug. Other more sinister causes of restlessness, such as hypoxaemia and local anaesthetic toxicity, should always be excluded first.

Physical Properties

Benzodiazepines are relatively small lipid-soluble molecules. Unlike diazepam and lorazepam, which are dissolved in solvents (polyethylene and propylene glycol previously, now lipid emulsions), midazolam is water-soluble. This is due to the presence of an imidazole ring in its structure, which allows midazolam to act as a structural isomer demonstrating tautomerism (isomerism triggered by a change in the physical environment). Midazolam is prepared in a solution buffered to a pH of < 4. At this pH, the imidazole ring is open and the molecule is ionized and therefore water-soluble. When the molecule is exposed to the higher pH of the body, the molecule forms the unionized ring, resulting in high lipid solubility.

Systemic Effects

The characteristic CNS effects seen with all benzodiazepines are anxiolysis, sedation, anterograde amnesia and antiepileptic activity. The degree to which individual benzodiazepines produce these effects is variable, and is thought to be related to their affinity for particular subunits of the GABA_A receptor. For example, benzodiazepines with high activity at the α₁ and/or α₅ subunits tend to have more sedative and amnesic effects, whilst those with activity at α₂ and/or α₃ subunits produce more anxiolysis.

Anxiolysis occurs at low dosage and these drugs are used extensively for the treatment of acute and chronic anxiety states. It is these anxiolytic properties which make benzodiazepines so useful in premedication and during unfamiliar or unpleasant procedures. Longer-acting oral drugs such as diazepam and chlordiazepoxide have a place in the management of acute alcohol withdrawal states.

Chronic administration of benzodiazepines results in benzodiazepine site downregulation, with decreased binding affinity and function, explaining, at least in part, the development of tolerance. Chronic administration also leads to physical and psychological dependence, although these drugs are less addictive than opioids and barbiturates. Abrupt withdrawal may lead to a clinical syndrome similar to that seen in acute alcohol withdrawal; consequently, doses of benzodiazepines should be reduced gradually after chronic administration.

Sedation occurs as a dose-dependent depression of cerebral activity with mild sedation at low receptor occupancy progressing to a state similar to general anaesthesia when most receptor sites are occupied (Table 7.2). Benzodiazepines have a high therapeutic index (ratio of effective to lethal dose) because, in overdose, the differences in receptor density result in greater sensitivity to cortical than to medullary depression. However, upper airway obstruction and loss of protective reflexes occur before profound sedation ensues, and are a major hazard following inadvertent oversedation or self-poisoning.

TABLE 7.2

Relationship Between the Effects Seen with Benzodiazepines and Receptor Occupancy

Amnesia is a common sequel to intravenous administration of benzodiazepines and is useful for patients undergoing unpleasant or repeated procedures. Amnesia is anterograde, affecting the acquisition of new information; retrograde amnesia has not been demonstrated following administration of benzodiazepines.

Antiepileptic activity is the result of prevention of the subcortical spread of seizure activity. Intravenous lorazepam and diazepam may be used to terminate seizures and clonazepam is used as an adjunct in chronic antiepileptic therapy. Benzodiazepines increase the threshold to seizure activity in local anaesthetic toxicity but may also mask the early signs.

Benzodiazepines have enjoyed wide use as a treatment for insomnia and are effective particularly for acute insomnia. However, chronic use is not recommended because of problems with tolerance and dependence, leading to difficulty in withdrawal of treatment. The use of benzodiazepines as hypnotics has now been partly superseded by more modern non-benzodiazepine hypnotics such as zopiclone, which also acts at the benzodiazepine site, and dependence can still occur.

Benzodiazepines decrease cerebral metabolic oxygen requirement and cerebral blood flow in a dose-dependent fashion, and the cerebrovascular response to carbon dioxide is preserved; consequently, they are suitable for use in selected patients with intracranial pathology. However, it should be noted that benzodiazepines do not prevent the increase in intracranial pressure associated with laryngoscopy and tracheal intubation. In addition, depression of ventilation caused by benzodiazepines in the spontaneously breathing patient results in an increase in arterial PaCO₂, which is undesirable if intracranial compliance is reduced.

Unwanted CNS side-effects include drowsiness and impaired psychomotor performance. Even when residual sedative effects are minimal, there may be impaired cognitive function and motor coordination, which should be taken into consideration when assessing fitness for discharge in ambulatory surgery.

Muscle Relaxation

Benzodiazepines produce a mild reduction in muscle tone, which may be advantageous, e.g. during mechanical ventilation in the ICU, when reducing articular dislocations or during endoscopy. However, muscle relaxation is partly responsible for the airway obstruction which may occur during intravenous sedation. The muscle relaxation is not related to any effect at the neuromuscular junction, but results from suppression of the internuncial neurones of the spinal cord and depression of polysynaptic transmission in the brain.

Respiratory Effects

Benzodiazepines produce dose-related central depression of ventilation. The ventilatory response to carbon dioxide is impaired and hypoxic ventilatory responses are markedly depressed. It follows that patients with hypoventilation syndromes and type 2 respiratory failure are particularly sensitive to the respiratory depressant effects of benzodiazepines. Ventilatory depression is exacerbated by airway obstruction and is more common in the elderly. Synergism occurs when both opioids and benzodiazepines are administered. If both types of drug are to be given intravenously, the opioid should be given first and its effect assessed. A reduction of up to 75% in the dose requirement of the benzodiazepine should be anticipated. It should be standard practice to provide supplemental oxygen and to monitor oxygen saturation continuously by pulse oximetry during intravenous sedation.

Cardiovascular Effects

Benzodiazepines produce modest haemodynamic effects, with good preservation of homeostatic reflex mechanisms and a much wider margin of safety than intravenous anaesthetic agents. A decrease in systemic vascular resistance results in a small decrease in arterial pressure. Significant hypotension may occur in the hypovolaemic patient.

Pharmacokinetics

Benzodiazepines are relatively small lipid-soluble molecules, which are readily absorbed orally and which pass rapidly into the CNS. Midazolam undergoes significant first-pass hepatic metabolism with only around 50% of an oral dose reaching the systemic circulation. Volume of distribution is large, as would be expected from such a highly lipid soluble compound. All benzodiazepines are extensively protein bound (> 96%).

After intravenous bolus administration, termination of action occurs largely by redistribution and hepatic metabolism. Compared with drugs such as propofol, benzodiazepines have a slower effect site equilibration time. This suggests that time should be allowed to assess the full clinical effect before administering a further intravenous incremental dose. Elimination takes place by hepatic metabolism followed by renal excretion of the metabolites. There are two main pathways of metabolism involving either microsomal oxidation or conjugation with glucuronide. The significance of this is that oxidation is much more likely to be affected by age, hepatic disease, drug interactions and other factors which alter the concentration of cytochrome P450. Some of the benzodiazepines, including diazepam, have active metabolites which greatly prolong their clinical effects. Renal dysfunction results in the accumulation of these metabolites, and this is an important factor in delayed recovery from prolonged sedation in the ICU. Benzodiazepines do not induce hepatic enzyme metabolism pathways.

Diazepam

Diazepam was the first benzodiazepine available for parenteral use. It is insoluble in water and was formulated initially in propylene glycol, which is very irritant to veins and which is associated with a high incidence of thrombophlebitis. A lipid emulsion (Diazemuls) was developed later. Both formulations are presented in 2-mL ampoules containing 5 mg mL^–1. Diazepam is also available orally as tablets or a syrup with a bioavailability of 100% and as a rectal solution and suppositories. The elimination half-life is 20–70 h, but active metabolites are produced, including desmethyldiazepam (half-life 36–200 h) and nordiazepam (half-life > 100 h). Clearance is reduced in the presence of hepatic dysfunction. Although diazepam can be given by the intramuscular route, absorption is unpredictable, and the injection is very painful.

Dosage

Premedication: 10–20 mg orally 1–1.5 h preoperatively.

Sedation: 5–10 mg i.v. slowly; incremental boluses of 1–2 mg.

Status epilepticus: 2 mg, repeated every minute until seizure ends; maximum dose 20 mg.

Intensive care: not suitable for infusion; i.v. bolus dose 5–10 mg may be used 4–hourly. However, the long half-life of the active metabolites makes diazepam undesirable for sedation in critical care patients.

Temazepam

This benzodiazepine is only available orally but is used widely as a premedicant because of its anxiolytic properties. Oral absorption is complete but it may take up to 2 h to reach peak plasma concentrations. Metabolism takes place in the liver by conjugation with glucuronide and there are no significant active metabolites. Elimination half-life is shorter than diazepam (8–15 h) and onset of action more rapid (45–60 min). Tolerance and dependence are less likely to occur with chronic use of temazepam and it has been prescribed widely as a hypnotic.

Dosage

Premedication: 10–30 mg orally 60-120 min preoperatively.

Lorazepam

This drug is available for parenteral, oral and intramuscular administration but is not used routinely as an intravenous sedative because it is limited by a slow onset of action. The intramuscular route should be used only when no other route is available. Intravenous lorazepam is currently the drug of choice in the management of status epilepticus, because it has a longer duration of antiepileptic action than diazepam (see below). It can also be used in the management of severe acute panic attacks. Metabolism is by glucuronidation, with an elimination half-life of 12–15 h. Amnesia is a marked feature of this drug.

Premediciation: 1–4 mg orally 1–2 h preoperatively.

Panic attacks: 25–30 μg kg^–1 i.v. or i.m. (maximum 4 mg).

Status epilepticus: 4 mg i.v., repeated after 10 min.

Midazolam

Midazolam is available for intravenous, intramuscular, oral, rectal and buccal administration. The drug becomes highly lipid-soluble and penetrates the brain rapidly with the onset of sedation in less than 90 s and peak effect at 2–5 min. Oral bioavailability is 40–50%. Unlike diazepam, intramuscular absorption is rapid. Midazolam undergoes hepatic oxidative metabolism and has an elimination half-life of 2 h. The major metabolite, hydroxymidazolam, has a half-life of around 1 h, and although it is biologically active, it is clinically important only after prolonged infusion in patients with renal impairment. Midazolam is 1.5–2 times more potent than diazepam and has much more favourable pharmacokinetics for use as a short-term intravenous sedative.

Premedication: 0.5 mg kg^− 1 orally (maximum 30 mg) or 70–100 μg kg^− 1 i.m. 30–60 min preoperatively.

Sedation: 25–50 μg kg^− 1 i.v., then incremental boluses of 0.5–1 mg to a maximum of 7.5 mg. Reduce dose by at least 50% in the elderly.

ICU sedation: loading dose of 30–300 μg kg^− 1 i.v., then infusion of 30–200 μg kg^− 1 h^− 1.

Flumazenil

Flumazenil is a very high-affinity competitive antagonist for all other ligands at the benzodiazepine binding site. It rapidly reverses all the CNS effects of benzodiazepines and also the other potentially dangerous adverse physiological effects, including respiratory and cardiovascular depression, and airway obstruction. It is used to reverse excessive sedation following benzodiazepine administration, either by iatrogenic overdose, following prolonged periods of sedation in ICU or by deliberate ingestion to cause self-harm. Flumazenil has only very slight intrinsic activity at high doses and is very well tolerated, with minimal adverse effects. It has no effect on benzodiazepine metabolism. Flumazenil is rapidly cleared from plasma and metabolized by the liver. It has a very short elimination half-life of less than 1 h. Its duration of action depends on the dose administered and the identity and dose of the agonist. It ranges from 20 min to 2 h and the potential exists for resedation if the agonist has a long half-life, necessitating a period of close observation. Repeated administration may be necessary.

The usual clinically effective dose is 300–600 μg i.v. given as 100–200 μg boluses and repeated at 1-min intervals to a maximum of 1 mg. When used in ICU, a total dose of up to 2 mg may be necessary. Flumazenil may also be given as an infusion (100–400 μg h^− 1).

Epileptic patients: there is a risk of seizures, especially if a benzodiazepine has been prescribed as antiepileptic therapy.

Benzodiazepine dependence: withdrawal symptoms may be precipitated.

Anxiety reactions: these may occur after rapid reversal of heavy sedation.

Patients with severe head injury: flumazenil may precipitate a sudden increase in intracranial pressure.

NEUROLEPTICS

This group of sedative drugs includes the phenothiazines and the butyrophenones, which are structurally similar drugs. These drugs are used primarily as antipsychotics in psychiatry. Both classes of drug have a high therapeutic index and a flat dose-response curve which result in a good safety profile with a low incidence of respiratory depression even when taken in overdose. Neurolepsis describes a characteristic drug-induced change in behaviour. There is an altered state of awareness, with suppression of spontaneous movement and a placid compliant affect. Loss of consciousness does not occur, and spinal and central reflexes remain intact. The combination of a neuroleptic drug with an opioid, usually fentanyl, is termed neuroleptanalgesia. This was a popular means of providing sedation before the advent of intravenous benzodiazepines. There is no amnesia and the patient may subsequently report unpleasant mental agitation despite a calm demeanour. The opioid obtunds the unpleasant mental experience but may result in respiratory depression. The addition of nitrous oxide may be used to produce neuroleptanaesthesia, in which consciousness is lost.

Pharmacology

Neuroleptics interfere with dopaminergic transmission in the brain by blocking dopamine receptors. At some synapses, dopamine is the stimulatory transmitter and GABA the inhibitory transmitter, so in common with other sedatives, neuroleptics enhance the effects of GABA. Dopamine blockade results in useful antiemetic activity but also carries the inevitable potential for extrapyramidal side-effects. These include tardive dyskinesia (involuntary movements of tongue, face and jaw), Parkinsonian symptoms, akathisia (restlessness) and dystonia (abnormal face and body movements).

All neuroleptic agents have been reported as a cause of the neuroleptic malignant syndrome, a rare but potentially fatal reaction. The syndrome is characterized by hyperthermia, muscle hypertonicity, autonomic instability and fluctuating levels of consciousness. It has some features in common with malignant hyperthermia associated with anaesthesia. Treatment includes supportive measures, dopamine agonists (e.g. bromocriptine) and dantrolene.

Neuroleptic drugs also have actions at cholinergic, α-adrenergic, histaminergic and serotonergic receptors, and these properties influence their side-effects and the degree of sedation produced. The anti-adrenergic effect is responsible for inducing hypotension, which can result in syncope in the elderly. The elderly are also most at risk of hypo- and hyperthermia due to the drugs’ interference with temperature regulation.

Haloperidol

Haloperidol is a butyrophenone with a long duration of action. It has almost no α-adrenoceptor blocking activity and so has a minimal effect on the cardiovascular system. It is a potent antiemetic but has a high incidence of extrapyramidal side-effects. Haloperidol has fewer antimuscarinic side-effects, but also produces less sedation than that seen with chlorpromazine. Haloperidol may be used in the short-term management of the acutely agitated patient after sinister causes of confusion such as hypoxaemia and sepsis have been excluded and is used increasingly in the management of ICU psychosis. The duration of action of haloperidol is in the region of 24–48 h.

Dosage

Sedation: 2–10 mg i.v. or i.m. (max. 18 mg per 24 h).

Anxiolysis: 500 µg orally every 12 h.

Antiemesis: 1.25 mg i.v. is effective in the prevention of postoperative nausea and vomiting.

Chlorpromazine

Chlorpromazine is a phenothiazine which is prescribed commonly as an antipsychotic but no longer used as an adjunct in anaesthesia. It may be used in the same way as haloperidol in the acutely confused or agitated patient. It has pronounced sedative properties and potentiates the actions of anaesthetic drugs. There is also marked antiemetic activity. A mild anticholinergic action moderates the incidence of extrapyramidal effects. α-Adrenoceptor blockade produces vasodilatation and may result in hypotension which is exacerbated by direct cardiac depression and depression of vasomotor reflexes. Central temperature control mechanisms are affected by chlorpromazine, with a reduced shivering response.

Dosage

Sedation for acute agitation: 25–50 mg orally or i.m. The drug must be diluted and given slowly if used intravenously (unlicensed for i.v. use) to avoid thrombophlebitis.

Droperidol

Droperidol is a butyrophenone with potent antidopaminergic activity. It is a powerful antiemetic, acting at the chemoreceptor trigger zone. Large doses may produce dystonic reactions. Droperidol has mild α-adrenoceptor blocking actions, which may cause vasodilatation after intravenous administration, resulting in hypotension. Droperidol was widely used for premedication and in neuroleptanaesthesia but its availability was discontinued in the UK in 2001 due to cases of prolonged QT syndrome. It has recently been reintroduced with a licence for the prevention of postoperative nausea and vomiting. Droperidol has an onset time of 3–10 min after intravenous injection, with a duration of action of 6–12 h. It undergoes hepatic metabolism, but approximately 10% of the drug is excreted unchanged in the urine.

Dosage

Prophylaxis for PONV: 0.625–1.25 mg i.v. 20 min prior to the end of surgery.

Olanzapine

Olanzapine is a second generation antipsychotic (or atypical antipsychotic) drug. Although not considered a classical neuroleptic, it has a similar mechanism of action, with antidopaminergic, antihistaminergic and antimuscarinic actions. Olanzapine rarely produces hypotension and is being used increasingly in the management of ICU psychoses.

Dosage

Sedation: 5–10 mg orally (maximum 20 mg daily).

α₂-ADRENOCEPTOR AGONISTS

α₂-Adrenergic receptors are involved in the regulation of the release of the neurotransmitter noradrenaline (norepinephrine). These receptors were initially classified anatomically as presynaptic, but α₂-adrenoceptors are also found postsynaptically and extrasynaptically. The more correct pharmacological classification is based on the predominantly α₂-selectivity of the antagonist yohimbine. α₂-Adrenoceptors are located peripherally and centrally, with the centrally mediated effects of particular relevance in anaesthesia.

The characteristic central effects of α₂-adrenoceptor agonists are sedation, anxiolysis and hypnosis. The locus coeruleus is a small neuronal nucleus in the upper brainstem which contains the major noradrenergic cell group in the brain. This nucleus is an important modulator of wakefulness. Activation of α₂-adrenoceptors results in inhibition of transmitter release. The locus coeruleus also has connections to the cortex, thalamus and vasomotor centre.

α₂-Adrenoceptor agonists have analgesic properties. Descending fibres from the locus coeruleus decrease nociceptive transmission at the spinal level. In addition, α₂-adrenoceptors occur in primary sensory neurones and the dorsal horn of the spinal cord.

Many ligands at α₂-adrenoceptors are substituted imidazoles. Non-adrenergic imidazole binding sites exist in some tissues, including the brain: the imidazoline receptors. I₁ imidazoline receptors are found in the medulla and are involved in the regulation of arterial pressure. This may explain the hypotension and bradycardia which may accompany administration of α₂-adrenoceptor agonists. Similarly, the I₂ imidazoline receptor may interact with opioid receptors and may contribute to the analgesic effect of α₂-adrenoceptor agonists.

Clonidine

Clonidine is an imidazoline compound and a selective α₂-adrenoceptor agonist with an α₂:α₁ ratio of 200:1. Clonidine has proved effective in the treatment of patients with severe hypertension but it is recognized that abrupt discontinuation of therapy can result in rebound hypertension. Clonidine is lipid-soluble and is absorbed rapidly and almost completely after oral administration, with peak plasma concentrations occurring in 60–90 min. It may be administered transdermally and is also available as a solution for intravenous, intramuscular, epidural and intrathecal use. The elimination half-life is 9–13 h and this is prolonged in renal failure. Fifty percent of an administered dose is excreted unchanged by the kidneys and 50% is metabolized in the liver to inactive metabolites.

Systemic Effects

CNS Effects: Clonidine produces sedation and anxiolysis. It also reduces requirements for both intravenous and volatile anaesthetic agents. There is a ceiling to the reduction of MAC effect, because of the potential for activity at α₁-receptors at high dose. More selective α₂-adrenoceptor agonists reduce MAC to a much greater extent.

Clonidine is a potent analgesic, acting centrally and on the α₂-adrenoceptors of the dorsal horn. It may be administered intravenously, intrathecally or epidurally to produce an analgesic response. Synergism exists with opioids, and the actions of local anaesthetics are also potentiated. Clonidine is used to provide analgesia in the perioperative period and also in chronic pain syndromes.

CVS Effects: The cardiovascular effects of clonidine probably involve both α₂-adrenoceptors and imidazoline receptors. Administration leads to decreases in heart rate and arterial pressure. Clonidine is known to lower the ‘set point’ around which arterial pressure is regulated. The α₂-agonist effects are a reduction in sympathetic tone and an increase in parasympathetic tone. The resulting decreases in heart rate, myocardial contractility and systemic vascular resistance lead to a reduction in myocardial oxygen requirements. This may be advantageous in attenuating stress-induced haemodynamic responses. However, undesirable cardiovascular depression has been the major limiting factor in developing the use of clonidine as a sedative.

Respiratory Effects: Clonidine has minor respiratory effects, causing only a small reduction in minute ventilation.

Premedication: 150–300 μg orally given 1–2 h preoperatively.

Analgesia: used as an adjunct to local anaesthetics in both central and peripheral nerve blocks.

Critical care: 0–2 μg kg^− 1 h^− 1 i.v. as a sedative, especially for agitation in drug-dependent individuals.

Dexmedetomidine

Dexmedetomidine is a selective α₂-adrenoceptor agonist (1600:1, α₂: α₁) with eight times more affinity for α₂-adrenoceptors than clonidine. It has similar sedative, analgesic and anxiolytic properties to clonidine but has a more rapid elimination half-life (2 h). The reduction in α₁-activity also results in a MAC-sparing effect of up to 90%. Like clonidine, it is metabolized in the liver with > 90% excreted in the urine. The side-effect profile is also similar to that of clonidine, with hypotension and bradycardia the most frequent problems. Dexmedetomidine has recently been approved for use in the UK for sedation in the ICU, although it is also being used off-licence for procedural sedation, e.g. awake craniotomy.

ICU sedation: infusion at an average of 0.7 μg kg^− 1 h^− 1 (normal range 0.2–1.4 μg kg^− 1 h^− 1).

Procedural sedation: 1 μg kg^− 1 over 10 min, then infusion at an average of 0.6 μg kg^− 1 h^− 1 (normal range 0.2–1.0 μg kg^− 1 h^− 1).

OTHER DRUGS

Paraldehyde is the cyclic trimer of acetaldehyde molecules and was used widely as a sedative in psychiatry up to the 1960s. Paraldehyde undergoes hepatic metabolism but 10-30% is excreted by the lungs, giving the patient’s breath a characteristic odour. It is now used for sedation in paediatrics (e.g. for MRI scanning). Paraldehyde is contraindicated in gastric disorders.

Dosage

Sedation: 0.3 mL kg^− 1 rectally (maximum 10 mL) 20–30 min pre-procedure. It is usually diluted 1:1 with olive oil. Paraldehyde dissolves plastic, so if given using a plastic syringe, it must be injected immediately. Alternatively, feeding tubes or glass syringes can be used for administration.

Chloral Hydrate

Chloral hydrate is a sedative drug used in the treatment of insomnia and may be used for the sedation of children for brief procedures. Chloral hydrate may be given by mouth or per rectum although it is corrosive to mucous membranes unless well diluted with water. It has an unpleasant taste which can be disguised with sweet juice. Onset is within 15 min and duration can be as long as 2 h. It is metabolized to trichloroethanol, which has a half-life of 8–10 h. Chloral hydrate is contraindicated in gastric disease, and in patients with cardiac, hepatic or renal impairment.

Dosage

Sedation: 50–75 mg kg^− 1 orally (maximum 2 g) 20–30 min pre-procedure

Barbiturates

These drugs are derived from barbituric acid and are now used primarily for induction of anaesthesia and in the treatment of epilepsy. They have largely been superseded as sedative agents by benzodiazepines but some barbiturates are still used for paediatric sedation in specialist centres, e.g. pentobarbital 2 mg kg^− 1 i.v. (short-acting, effective for 1 h) or quinalbarbitone 7.5–10 mg kg^− 1 orally (to a maximum dose of 200 mg) (intermediate-acting, effective for around 2 h).

Melatonin

Melatonin is a hormone secreted by the pineal gland and has a role in controlling circadian rhythms. It is used primarily in the treatment of sleep disorders, but has also been used as a sedative agent in both adults and children (typical oral dose 3–10 mg). The mechanism by which melatonin causes sedation has not been fully elucidated, but it may be due to an enhancement of GABA activity.

FURTHER READING

American Society of Anesthesiologists. Continuum of depth of sedation: definition of general anesthesia and levels of sedation/analgesia, 2009.

Calvey, N., Williams, N., Principles and practice of pharmacology for anaesthetists. fifth ed. Wiley-Blackwell: Oxford, 2008.

Related

Smith and Aitkenheads Textbook of Anaesthesia 6E