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Premedication
PREMEDICATION
Premedication
Some drugs to be considered perioperatively
Aidan Marsh
Cardiovascular drugs • β-adrenoreceptor antagonists – to continue • Angiotensin-converting enzyme inhibitors – withhold on day of surgery • Angiotensin II receptor antagonists – withhold on day of surgery • Calcium-channel antagonists – to continue • Diuretics – withhold on day of surgery • Antiarrhythmics – to continue • Nitrates – to continue • Aspirin – consider omitting 7 days before surgery, otherwise continue • Anticoagulants – may require conversion to heparin infusion while omitting warfarin. At-risk patients may require thromboembolic prophylaxis • Antibiotics – as endocarditis prophylaxis
Andrew K McIndoe
Premedication, or pre-anaesthetic medication, involves the administration of drugs before the induction of anaesthesia. The aims of premedication are: • anxiolysis, amnesia and sedation • anti-emesis • analgesia (systemic and topical) • antacid • antisialogogue. Original anaesthetic agents were slow in onset and delivered by open systems. Opioids (e.g. papavaretum) were often prescribed to aid smooth induction of anaesthesia along with hyoscine as an anti-emetic, anticholinergic and sedative (Omnopon and scopolamine premedication). Ether and cyclopropane stimulate salivary secretions, which may precipitate coughing and laryngospasm, thus an anticholinergic premedication was often prescribed. The routine use of premedication is in decline because: • induction agents with a more rapid onset have been developed • it is thought that sedative premedication before day-case surgery delays recovery • the time between preoperative assessment and anaesthesia has been reduced following the increase in day-case surgery. The anaesthetist should review the patient’s usual medications to determine which should be continued or omitted before anaesthesia. Following the preoperative assessment (see Anaesthesia and Intensive Care 4:10: 319) other drugs and conditions may require attention in the perioperative period (Figure 1).
Respiratory drugs • Bronchodilators – continue, consider nebulization • Cigarettes – omit for as long as possible Neuromuscular drugs • Anticonvulsants – to continue, may require parenteral or rectal route • Anti-Parkinsonian drugs – to continue, may require nasal tube postoperatively • Anticholinesterases – to continue, may require neostigmine i.v. postoperatively • Tricyclic antidepressants – to continue with precautions • Monoamine oxidase inhibitors – to continue with precautions • Lithium – controversial, consider stopping 1 day before minor surgery, 2–3 days before major surgery Renal • Haemodialysis – given 24 hours before surgery, then 1–2 days after
Anxiolysis, sedation and amnesia Surgical patients have a high incidence of anxiety which is unpleasant for the patient and can have undesirable consequences for the anaesthetist, such as the activation of the sympathetic nervous system. The preoperative visit can allay much of the patient’s anxiety, but an anxiolytic remains the most commonly prescribed premedication. Sedation is not synonymous with anxiolysis and some drugs (e.g. opioids) possess sedative, but few anxiolytic,
Metabolic • Diabetes mellitus – may require conversion to insulin sliding scale; omit long-acting oral hypoglycaemic agents and metformin • Steroids – may require supplementation perioperatively 1
properties. Sedation before anaesthesia is not usually required, but may be needed for some patients (e.g. children and those with learning disabilities). Amnesia may be beneficial for a particularly frightened patient but is often undesirable. The pharmacology of anxiolytics and hypnotics is discussed in greater detail on page 252.
Aidan Marsh is Specialist Registrar in Anaesthesia at the Bristol Royal Infirmary. He graduated from Bristol University, trained in general medicine in Southampton, and trained in anaesthesia in the Bristol region. Andrew K McIndoe is Consultant Anaesthetist and Senior Clinical Lecturer in the Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary. He is also the Director of Research and Education at the Bristol Medical Simulation Centre where he has developed a specific interest in human factors and crisis management.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 5:8
Benzodiazepines are the most commonly used anxiolytics. γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS. Benzodiazepines are agonists at GABAA receptors, increasing the opening frequency of their chloride channels,
250
© 2004 The Medicine Publishing Company Ltd
PREMEDICATION
increasing chloride conductance and hyperpolarizing the neuronal membrane. Temazepam is available as a tablet or elixir, 2 mg/ml. Its short duration of action (about 90 minutes) does not significantly delay recovery from anaesthesia. The usual adult dose is 10–30 mg, 1 hour before the operation. Midazolam m is water-soluble at pH 3.5, but becomes lipid-soluble at physiological pH. It is presented as a colourless solution with 2 or 5 mg/ml. The dose is 0.5 mg/kg orally (the main disadvantage is its bitter taste), but 0. 2 mg/kg may also be given intranasally or sublingually. The intramuscular dose is 0.07–0.1 mg/kg. Lorazepam, 0.05 mg/kg, maximum 4 mg, 1–2 hours before surgery may also be used. This can provide marked amnesia. Diazepam, 5–10 mg, 2 hours before the procedure may also be used. It has a long half-life and active metabolites.
hyoscine are tertiary amines and able to cross the blood–brain barrier, however glycopyrrolate is a quaternary amine and has no anti-emetic effect as it cannot cross the blood–brain barrier. Atropine is not used to treat PONV owing to its cardiovascular effects. Hyoscine, 0.3-0.6 mg i.m., is used as a premedicant and also sedates as well as having other peripheral antimuscarinic effects. Antihistamines: cyclizine, 1 mg/kg p.o., i.v. or i.m., maximum 50 mg, is a histamine H1-antagonist, which also has antimuscarinic activity. 5-HT3 receptor antagonists: 5-HT release in the small intestine activates vagal afferents via 5-HT3 receptors that stimulate the vomiting centre, again via 5-HT3 receptors. Thus 5-HT3 receptor antagonists act peripherally and at the chemoreceptor trigger zone to prevent nausea and vomiting. These agents are expensive and cheaper agents appear to be as effective in preventing PONV, however, 5-HT3 receptor antagonists have a better side-effect profile than many of the other agents. Ondansetron is given as 16 mg p.o. 1 hour before anaesthesia, or 8 mg 1 hour before anaesthesia and 8 mg at 8 and 16 hours. It may also be given as 4 mg i.v. at induction. In children, the dose is 100 µg/kg i.v., maximum 4 mg. Side-effects include headache, constipation, flushing and alteration in liver enzymes. Granisetron, 1 mg, is given before induction of anaesthesia (40 µg/kg in children). Tropisetron, 2 mg, is given before induction.
Other anxiolytics and sedatives: zopiclone, 3.75–7.5 mg, has also been used. In children, alimemazine, 2 mg/kg, has been used. It is a phenothiazine, acting mainly via histamine H1-receptor anatagonism but with some anticholinergic and antidopaminergic activity. Anti-emetics The incidence of postoperative nausea and vomiting (PONV) has decreased with current anaesthetic agents, but it still occurs in about 25% of patients. It is one of the most unpleasant postoperative experiences for the patient. Vomiting can cause dehydration, wound breakdown, worsen pain control, reduce oral intake and delay discharge in the day-case setting. It is particularly undesirable in neurosurgery, and ophthalmic and ENT surgery. The risk factors for PONV are given in Anaesthesia and Intensive Care Medicine 4:10: 335. The vomiting centre in the medulla coordinates vomiting. It receives input from many afferents, including the vestibular apparatus, mainly via muscarinic acetylcholine receptors but also via histamine H1-receptors. It also receives input from the chemoreceptor trigger zone in the area postrema of the floor of the fourth ventricle. This is rich in receptors for dopamine and 5-hydroxytryptamine (5-HT3). The prevention of PONV is aimed at reducing afferent supply to the vomiting centre through specific receptor blockade. It may be necessary to use a combination of agents to block the different inputs as part of balanced anti-emesis. Studies show improved outcomes with combination therapy compared with monotherapy.
Other agents Dexamethasone, 4–8 mg p.o. or i.v., has been used to prevent PONV. Its mechanism of action is unclear. Neurokinin (NK1) receptors are located in the nucleus tractus solitarius and in the area postrema. They may represent a useful new class of anti-emetic. Nabilonee (a cannabinoid) has been used for chemotherapyinduced nausea and vomiting and may have a role in PONV. Lorazepam – anxiety can stimulate the vomiting centre, and lorazepam has been used to treat chemotherapy-induced vomiting. Analgesia Opioid premedication is not usually necessary, unless there is acute preoperative pain, because opioids with a rapid onset of action have been developed (e.g. fentanyl, alfentanil, remifentanil). Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclo-oxygenase (COX), preventing the production of prostaglandins and thromboxanes from arachidonic acid. COX has at least two iso-enzymes, COX-1 and COX-2. COX-1 is important in the production of prostaglandins that control renal blood flow and produce the protective gastric mucosal barrier; COX-2 is induced when tissues are exposed to inflammatory stimuli. Inhibition of COX-1 enzymes is responsible for the adverse effects of NSAIDs, such as gastric irritation, renal impairment and precipitation of asthma, while inhibition of COX-2 is responsible for the anti-inflammatory and analgesic effects. Specific COX-2 inhibitors have been developed with the aim of reducing some of the adverse effects associated with COX-1 inhibition. Their role is uncertain as they appear only to reduce gastrointestinal side-effects. The Committee on Safety of Medicines (CSM) advises that all NSAIDs are
Antidopaminergic agents antagonize dopamine receptors in the chemoreceptor trigger zone. The most important side-effects are extrapyramidal reactions such as acute dystonias and akathisia, particularly in children and young adults. Phenothiazines such as prochlorperazine, 5–20 mg p.o. or 12.5 mg i.m., also have some anti-adrenergic, anticholinergic and antihistamine effects. Droperidol, a butyrophenone used as an anti-emetic, is no longer available. Metoclopramide, 10 mg p.o., i.v. or i.m., is used as a prokinetic as well as an anti-emetic, though some studies show that it is no more effective than placebo as an anti-emetic. Anticholinergics have little activity at nicotinic receptors and are selective antagonists at muscarinic receptors. Atropine and
ANAESTHESIA AND INTENSIVE CARE MEDICINE 5:8
251
© 2004 The Medicine Publishing Company Ltd
PREMEDICATION
contraindicated in patients with active peptic ulceration, and that non-selective NSAIDs are contraindicated in patients with a history of peptic ulceration. It also states that ibuprofen is in the group of NSAIDs with the lowest risk of serious upper gastrointestinal side-effects, while diclofenac and others are associated with an intermediate risk. Nonspecific COX inhibitors include diclofenac, 50-100 mg p.o. or p.r., and ibuprofen, 400 mg p.o. Specific COX-2 inhibitors include parecoxib, 40 mg i.m. or i.v., and rofecoxib, 25–50 mg p.o. Pre-emptive analgesia refers to the suppression of dorsal horn neuronal activity involved in pain transmission before the painful stimulus, thus reducing total analgesic requirements. Although its clinical relevance is disputed, premedication with analgesics may be justified by the prediction of postoperative pain and the need to administer effective analgesia in the immediate postoperative period. Topical anaesthetic creams can be applied to the skin before intravenous cannulation and are particularly useful in children. Eutectic mixture of local anaesthetics (Emla) cream contains 2.5% lidocaine and 2.5% prilocaine and should be applied for 60–90 minutes under an occlusive dressing to ensure analgesia. Tetracaine gel 4% works within 30–45 minutes and is effective for 4–6 hours.
Anxiolytics and hypnotics Barbara J Pleuvry
Until recently the pharmacology of drugs used to treat anxiety (anxiolytics) and insomnia (hypnotics) were identical because the same drugs were used for both purposes. While the anxiolytic action of hypnotics was probably an advantage, the hypnotic action of anxiolytics was a major drawback. Daytime drowsiness severely limited their usefulness in treating long-term anxiety states. More recently, greater understanding of GABAA receptor subtypes has made it possible to separate the hypnotic and anxiolytic action of drugs modulating GABAA neurotransmission. In addition, drugs that lack marked hypnotic activity, acting on tryptaminergic receptors, have been introduced. These drugs (e.g. buspirone) have obvious advantages in psychiatry but they generally take several days or even weeks to produce their effects and are of limited use in anaesthesia.
Antacids Pulmonary aspiration of gastric contents occurs in 1/900 emergency operations and 1/3900 elective operations, with an overall mortality of 1/70,000 anaesthetics. Work on animals suggests that the morbidity is related to the volume and pH of the aspirated material, with a critical pH of 2.5 and volume of 0.4 ml/kg required to produce the syndrome. Premedicants to reduce gastric volume and increase gastric pH may be given to those with conditions that may affect gastric emptying or fluid volume, such as patients who are obese, pregnant, diabetic, have a hiatus hernia, have gastro-oesophageal reflux, are fed with an enteral tube, and those in whom airway management may be difficult. However, they are not routinely recommended in fit patients with no apparent risk of aspiration undergoing elective surgery. H2-receptor antagonists such as ranitidine, 150 mg p.o., or 50 mg i.v., increase gastric pH and reduce gastric volume. They should be given at least 1 hour before surgery, and for best effect, on the night before. Proton-pump inhibitors such as omeprazole, 20–40 mg p.o. or 40 mg i.v., may also be used. A non-particulate antacid such as sodium citrate increases gastric pH; 30 ml of a 0.3 M solution is effective for up to 45 minutes. Metoclopramide, 10 mg p.o., i.m. or i.v., is used as a prokinetic agent to reduce gastric volume.
γ-aminobutyric acid (GABA) The traditional hypnotics and anxiolytic drugs, such as barbiturates and benzodiazepines, enhance GABA transmission via the GABAA receptor. GABA is the main inhibitory neurotransmitter in the brain and it is known to interact with three receptor types, GABAA and GABA AC, which are ligand-gated ion channels, and GABAB, which is a G-protein-coupled receptor (Figure 1). The GABA AC receptor is a simple form of the GABAA receptor in that all five subunits are of the same type, in this case the ρ subunit. The characteristics of these three receptors are listed in Figure 2. The GABAA receptor is probably the most complicated. Five subunits are arranged in a rosette and the central area, where they meet, forms a channel through which chloride ions can pass. In normal circumstances, opening of the chloride channel causes the negative chloride ions to flow into the cell, causing hyperpolarization and thus inhibition of cellular activity. Many types of subunit can make up the GABA receptor, but the GABAA receptor uses α, β, γ and δ subunits, though the first three are the most common. The α and β subunits provide the binding site for the GABA molecule while α and γ subunits are necessary for benzodiazepine binding. Thus, benzodiazepines bind to a separate site from GABA and this ‘benzodiazepine receptor’ is just one of at least 11 modulatory sites on the GABAA ion channel. The barbiturates, neurosteroids and many general anaesthetic agents bind to other modulatory sites. (The neurosteroids are related to the steroid hormones but do not act on the conventional intracellular steroid receptors. Their
Antisialogogues Glycopyrrolate, 200 µg i.m. or i.v., may be prescribed to reduce airway secretions before awake fibre-optic intubation.
FURTHER READING Kroll W, Gassmayr S E. Pre-operative anxiety, stress and pre-medication. Baillière’s Clin Anaesthesiol 1998; 12: 485–95. Watcha F. Nausea and vomiting: choice of drugs and treatment. Curr Opin Anesthesiol 1996; 9: 300–5.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 5:8
Barbara J Pleuvry y is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK. She is a pharmacist by first degree but has been involved in teaching pharmacology to postgraduates and undergraduates for over 30 years. Her research interests include pain, analgesia and anticonvulsant drugs.
252
© 2004 The Medicine Publishing Company Ltd
Premedication
Some drugs to be considered perioperatively
Aidan Marsh
Cardiovascular drugs • β-adrenoreceptor antagonists – to continue • Angiotensin-converting enzyme inhibitors – withhold on day of surgery • Angiotensin II receptor antagonists – withhold on day of surgery • Calcium-channel antagonists – to continue • Diuretics – withhold on day of surgery • Antiarrhythmics – to continue • Nitrates – to continue • Aspirin – consider omitting 7 days before surgery, otherwise continue • Anticoagulants – may require conversion to heparin infusion while omitting warfarin. At-risk patients may require thromboembolic prophylaxis • Antibiotics – as endocarditis prophylaxis
Andrew K McIndoe
Premedication, or pre-anaesthetic medication, involves the administration of drugs before the induction of anaesthesia. The aims of premedication are: • anxiolysis, amnesia and sedation • anti-emesis • analgesia (systemic and topical) • antacid • antisialogogue. Original anaesthetic agents were slow in onset and delivered by open systems. Opioids (e.g. papavaretum) were often prescribed to aid smooth induction of anaesthesia along with hyoscine as an anti-emetic, anticholinergic and sedative (Omnopon and scopolamine premedication). Ether and cyclopropane stimulate salivary secretions, which may precipitate coughing and laryngospasm, thus an anticholinergic premedication was often prescribed. The routine use of premedication is in decline because: • induction agents with a more rapid onset have been developed • it is thought that sedative premedication before day-case surgery delays recovery • the time between preoperative assessment and anaesthesia has been reduced following the increase in day-case surgery. The anaesthetist should review the patient’s usual medications to determine which should be continued or omitted before anaesthesia. Following the preoperative assessment (see Anaesthesia and Intensive Care 4:10: 319) other drugs and conditions may require attention in the perioperative period (Figure 1).
Respiratory drugs • Bronchodilators – continue, consider nebulization • Cigarettes – omit for as long as possible Neuromuscular drugs • Anticonvulsants – to continue, may require parenteral or rectal route • Anti-Parkinsonian drugs – to continue, may require nasal tube postoperatively • Anticholinesterases – to continue, may require neostigmine i.v. postoperatively • Tricyclic antidepressants – to continue with precautions • Monoamine oxidase inhibitors – to continue with precautions • Lithium – controversial, consider stopping 1 day before minor surgery, 2–3 days before major surgery Renal • Haemodialysis – given 24 hours before surgery, then 1–2 days after
Anxiolysis, sedation and amnesia Surgical patients have a high incidence of anxiety which is unpleasant for the patient and can have undesirable consequences for the anaesthetist, such as the activation of the sympathetic nervous system. The preoperative visit can allay much of the patient’s anxiety, but an anxiolytic remains the most commonly prescribed premedication. Sedation is not synonymous with anxiolysis and some drugs (e.g. opioids) possess sedative, but few anxiolytic,
Metabolic • Diabetes mellitus – may require conversion to insulin sliding scale; omit long-acting oral hypoglycaemic agents and metformin • Steroids – may require supplementation perioperatively 1
properties. Sedation before anaesthesia is not usually required, but may be needed for some patients (e.g. children and those with learning disabilities). Amnesia may be beneficial for a particularly frightened patient but is often undesirable. The pharmacology of anxiolytics and hypnotics is discussed in greater detail on page 252.
Aidan Marsh is Specialist Registrar in Anaesthesia at the Bristol Royal Infirmary. He graduated from Bristol University, trained in general medicine in Southampton, and trained in anaesthesia in the Bristol region. Andrew K McIndoe is Consultant Anaesthetist and Senior Clinical Lecturer in the Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary. He is also the Director of Research and Education at the Bristol Medical Simulation Centre where he has developed a specific interest in human factors and crisis management.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 5:8
Benzodiazepines are the most commonly used anxiolytics. γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS. Benzodiazepines are agonists at GABAA receptors, increasing the opening frequency of their chloride channels,
250
© 2004 The Medicine Publishing Company Ltd
PREMEDICATION
increasing chloride conductance and hyperpolarizing the neuronal membrane. Temazepam is available as a tablet or elixir, 2 mg/ml. Its short duration of action (about 90 minutes) does not significantly delay recovery from anaesthesia. The usual adult dose is 10–30 mg, 1 hour before the operation. Midazolam m is water-soluble at pH 3.5, but becomes lipid-soluble at physiological pH. It is presented as a colourless solution with 2 or 5 mg/ml. The dose is 0.5 mg/kg orally (the main disadvantage is its bitter taste), but 0. 2 mg/kg may also be given intranasally or sublingually. The intramuscular dose is 0.07–0.1 mg/kg. Lorazepam, 0.05 mg/kg, maximum 4 mg, 1–2 hours before surgery may also be used. This can provide marked amnesia. Diazepam, 5–10 mg, 2 hours before the procedure may also be used. It has a long half-life and active metabolites.
hyoscine are tertiary amines and able to cross the blood–brain barrier, however glycopyrrolate is a quaternary amine and has no anti-emetic effect as it cannot cross the blood–brain barrier. Atropine is not used to treat PONV owing to its cardiovascular effects. Hyoscine, 0.3-0.6 mg i.m., is used as a premedicant and also sedates as well as having other peripheral antimuscarinic effects. Antihistamines: cyclizine, 1 mg/kg p.o., i.v. or i.m., maximum 50 mg, is a histamine H1-antagonist, which also has antimuscarinic activity. 5-HT3 receptor antagonists: 5-HT release in the small intestine activates vagal afferents via 5-HT3 receptors that stimulate the vomiting centre, again via 5-HT3 receptors. Thus 5-HT3 receptor antagonists act peripherally and at the chemoreceptor trigger zone to prevent nausea and vomiting. These agents are expensive and cheaper agents appear to be as effective in preventing PONV, however, 5-HT3 receptor antagonists have a better side-effect profile than many of the other agents. Ondansetron is given as 16 mg p.o. 1 hour before anaesthesia, or 8 mg 1 hour before anaesthesia and 8 mg at 8 and 16 hours. It may also be given as 4 mg i.v. at induction. In children, the dose is 100 µg/kg i.v., maximum 4 mg. Side-effects include headache, constipation, flushing and alteration in liver enzymes. Granisetron, 1 mg, is given before induction of anaesthesia (40 µg/kg in children). Tropisetron, 2 mg, is given before induction.
Other anxiolytics and sedatives: zopiclone, 3.75–7.5 mg, has also been used. In children, alimemazine, 2 mg/kg, has been used. It is a phenothiazine, acting mainly via histamine H1-receptor anatagonism but with some anticholinergic and antidopaminergic activity. Anti-emetics The incidence of postoperative nausea and vomiting (PONV) has decreased with current anaesthetic agents, but it still occurs in about 25% of patients. It is one of the most unpleasant postoperative experiences for the patient. Vomiting can cause dehydration, wound breakdown, worsen pain control, reduce oral intake and delay discharge in the day-case setting. It is particularly undesirable in neurosurgery, and ophthalmic and ENT surgery. The risk factors for PONV are given in Anaesthesia and Intensive Care Medicine 4:10: 335. The vomiting centre in the medulla coordinates vomiting. It receives input from many afferents, including the vestibular apparatus, mainly via muscarinic acetylcholine receptors but also via histamine H1-receptors. It also receives input from the chemoreceptor trigger zone in the area postrema of the floor of the fourth ventricle. This is rich in receptors for dopamine and 5-hydroxytryptamine (5-HT3). The prevention of PONV is aimed at reducing afferent supply to the vomiting centre through specific receptor blockade. It may be necessary to use a combination of agents to block the different inputs as part of balanced anti-emesis. Studies show improved outcomes with combination therapy compared with monotherapy.
Other agents Dexamethasone, 4–8 mg p.o. or i.v., has been used to prevent PONV. Its mechanism of action is unclear. Neurokinin (NK1) receptors are located in the nucleus tractus solitarius and in the area postrema. They may represent a useful new class of anti-emetic. Nabilonee (a cannabinoid) has been used for chemotherapyinduced nausea and vomiting and may have a role in PONV. Lorazepam – anxiety can stimulate the vomiting centre, and lorazepam has been used to treat chemotherapy-induced vomiting. Analgesia Opioid premedication is not usually necessary, unless there is acute preoperative pain, because opioids with a rapid onset of action have been developed (e.g. fentanyl, alfentanil, remifentanil). Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclo-oxygenase (COX), preventing the production of prostaglandins and thromboxanes from arachidonic acid. COX has at least two iso-enzymes, COX-1 and COX-2. COX-1 is important in the production of prostaglandins that control renal blood flow and produce the protective gastric mucosal barrier; COX-2 is induced when tissues are exposed to inflammatory stimuli. Inhibition of COX-1 enzymes is responsible for the adverse effects of NSAIDs, such as gastric irritation, renal impairment and precipitation of asthma, while inhibition of COX-2 is responsible for the anti-inflammatory and analgesic effects. Specific COX-2 inhibitors have been developed with the aim of reducing some of the adverse effects associated with COX-1 inhibition. Their role is uncertain as they appear only to reduce gastrointestinal side-effects. The Committee on Safety of Medicines (CSM) advises that all NSAIDs are
Antidopaminergic agents antagonize dopamine receptors in the chemoreceptor trigger zone. The most important side-effects are extrapyramidal reactions such as acute dystonias and akathisia, particularly in children and young adults. Phenothiazines such as prochlorperazine, 5–20 mg p.o. or 12.5 mg i.m., also have some anti-adrenergic, anticholinergic and antihistamine effects. Droperidol, a butyrophenone used as an anti-emetic, is no longer available. Metoclopramide, 10 mg p.o., i.v. or i.m., is used as a prokinetic as well as an anti-emetic, though some studies show that it is no more effective than placebo as an anti-emetic. Anticholinergics have little activity at nicotinic receptors and are selective antagonists at muscarinic receptors. Atropine and
ANAESTHESIA AND INTENSIVE CARE MEDICINE 5:8
251
© 2004 The Medicine Publishing Company Ltd
PREMEDICATION
contraindicated in patients with active peptic ulceration, and that non-selective NSAIDs are contraindicated in patients with a history of peptic ulceration. It also states that ibuprofen is in the group of NSAIDs with the lowest risk of serious upper gastrointestinal side-effects, while diclofenac and others are associated with an intermediate risk. Nonspecific COX inhibitors include diclofenac, 50-100 mg p.o. or p.r., and ibuprofen, 400 mg p.o. Specific COX-2 inhibitors include parecoxib, 40 mg i.m. or i.v., and rofecoxib, 25–50 mg p.o. Pre-emptive analgesia refers to the suppression of dorsal horn neuronal activity involved in pain transmission before the painful stimulus, thus reducing total analgesic requirements. Although its clinical relevance is disputed, premedication with analgesics may be justified by the prediction of postoperative pain and the need to administer effective analgesia in the immediate postoperative period. Topical anaesthetic creams can be applied to the skin before intravenous cannulation and are particularly useful in children. Eutectic mixture of local anaesthetics (Emla) cream contains 2.5% lidocaine and 2.5% prilocaine and should be applied for 60–90 minutes under an occlusive dressing to ensure analgesia. Tetracaine gel 4% works within 30–45 minutes and is effective for 4–6 hours.
Anxiolytics and hypnotics Barbara J Pleuvry
Until recently the pharmacology of drugs used to treat anxiety (anxiolytics) and insomnia (hypnotics) were identical because the same drugs were used for both purposes. While the anxiolytic action of hypnotics was probably an advantage, the hypnotic action of anxiolytics was a major drawback. Daytime drowsiness severely limited their usefulness in treating long-term anxiety states. More recently, greater understanding of GABAA receptor subtypes has made it possible to separate the hypnotic and anxiolytic action of drugs modulating GABAA neurotransmission. In addition, drugs that lack marked hypnotic activity, acting on tryptaminergic receptors, have been introduced. These drugs (e.g. buspirone) have obvious advantages in psychiatry but they generally take several days or even weeks to produce their effects and are of limited use in anaesthesia.
Antacids Pulmonary aspiration of gastric contents occurs in 1/900 emergency operations and 1/3900 elective operations, with an overall mortality of 1/70,000 anaesthetics. Work on animals suggests that the morbidity is related to the volume and pH of the aspirated material, with a critical pH of 2.5 and volume of 0.4 ml/kg required to produce the syndrome. Premedicants to reduce gastric volume and increase gastric pH may be given to those with conditions that may affect gastric emptying or fluid volume, such as patients who are obese, pregnant, diabetic, have a hiatus hernia, have gastro-oesophageal reflux, are fed with an enteral tube, and those in whom airway management may be difficult. However, they are not routinely recommended in fit patients with no apparent risk of aspiration undergoing elective surgery. H2-receptor antagonists such as ranitidine, 150 mg p.o., or 50 mg i.v., increase gastric pH and reduce gastric volume. They should be given at least 1 hour before surgery, and for best effect, on the night before. Proton-pump inhibitors such as omeprazole, 20–40 mg p.o. or 40 mg i.v., may also be used. A non-particulate antacid such as sodium citrate increases gastric pH; 30 ml of a 0.3 M solution is effective for up to 45 minutes. Metoclopramide, 10 mg p.o., i.m. or i.v., is used as a prokinetic agent to reduce gastric volume.
γ-aminobutyric acid (GABA) The traditional hypnotics and anxiolytic drugs, such as barbiturates and benzodiazepines, enhance GABA transmission via the GABAA receptor. GABA is the main inhibitory neurotransmitter in the brain and it is known to interact with three receptor types, GABAA and GABA AC, which are ligand-gated ion channels, and GABAB, which is a G-protein-coupled receptor (Figure 1). The GABA AC receptor is a simple form of the GABAA receptor in that all five subunits are of the same type, in this case the ρ subunit. The characteristics of these three receptors are listed in Figure 2. The GABAA receptor is probably the most complicated. Five subunits are arranged in a rosette and the central area, where they meet, forms a channel through which chloride ions can pass. In normal circumstances, opening of the chloride channel causes the negative chloride ions to flow into the cell, causing hyperpolarization and thus inhibition of cellular activity. Many types of subunit can make up the GABA receptor, but the GABAA receptor uses α, β, γ and δ subunits, though the first three are the most common. The α and β subunits provide the binding site for the GABA molecule while α and γ subunits are necessary for benzodiazepine binding. Thus, benzodiazepines bind to a separate site from GABA and this ‘benzodiazepine receptor’ is just one of at least 11 modulatory sites on the GABAA ion channel. The barbiturates, neurosteroids and many general anaesthetic agents bind to other modulatory sites. (The neurosteroids are related to the steroid hormones but do not act on the conventional intracellular steroid receptors. Their
Antisialogogues Glycopyrrolate, 200 µg i.m. or i.v., may be prescribed to reduce airway secretions before awake fibre-optic intubation.
FURTHER READING Kroll W, Gassmayr S E. Pre-operative anxiety, stress and pre-medication. Baillière’s Clin Anaesthesiol 1998; 12: 485–95. Watcha F. Nausea and vomiting: choice of drugs and treatment. Curr Opin Anesthesiol 1996; 9: 300–5.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 5:8
Barbara J Pleuvry y is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK. She is a pharmacist by first degree but has been involved in teaching pharmacology to postgraduates and undergraduates for over 30 years. Her research interests include pain, analgesia and anticonvulsant drugs.
252
© 2004 The Medicine Publishing Company Ltd