Intravenous Anaesthetic Agents
General anaesthesia may be produced by many drugs which depress the CNS, including sedatives, tranquillizers and hypnotic agents. However, for some drugs, the doses required to produce surgical anaesthesia are so large that cardiovascular and respiratory depression commonly occur, and recovery is delayed for hours or even days. Only a few drugs are suitable for use routinely to produce anaesthesia after intravenous (i.v.) injection.
Intravenous anaesthetic agents are used commonly to induce anaesthesia, as induction is usually smoother and more rapid than that associated with most of the inhalational agents. Intravenous anaesthetics may also be used for maintenance, either alone or in combination with nitrous oxide; they may be administered as repeated bolus doses or by continuous i.v. infusion. Other uses include sedation during regional anaesthesia, sedation in the intensive care unit (ICU) and treatment of status epilepticus.
Rapid recovery – early recovery of consciousness is usually produced by rapid redistribution of the drug from the brain into other well-perfused tissues, particularly muscle. The plasma concentration of the drug decreases, and the drug diffuses out of the brain along a concentration gradient. The quality of the later recovery period is related more to the rate of metabolism of the drug; drugs with slow metabolism are associated with a more prolonged ‘hangover’ effect and accumulate if used in repeated doses or by infusion for maintenance of anaesthesia
None of the agents available at present meets all these requirements. Features of the commonly used i.v. anaesthetic agents are compared in Table 3.1, and a classification of i.v. anaesthetic drugs is shown in Table 3.2.
Rapidly Acting (Primary Induction) Agents
Thiobarbiturates – thiopental, thiamylal
Imidazole compounds – etomidate
Sterically hindered alkyl phenols – propofol
Steroids – eltanolone, althesin, minaxolone (none currently available)
Eugenols – propanidid (not currently available)
Slower-Acting (Basal Narcotic) Agents
Benzodiazepines – diazepam, flunitrazepam, midazolam
Large-dose opioids – fentanyl, alfentanil, sufentanil, remifentanil
Neuroleptic combination – opioid + neuroleptic
In common with inhalational agents, all intravenous anaesthetics, with the exception of ketamine, potentiate GABAA receptors to inhibit CNS neurotransmission. Benzodiazepines act at a different binding site on the GABAA receptor, the α/γ subunit interface, to increase chloride conductance. Propofol and barbiturates also potentiate the inhibitory effects of glycine at glycine receptors in the brain and, to a lesser extent, the spinal cord. In addition to effects on GABAA and glycine receptors, propofol has inhibitory actions on sodium channels and 5HT3 receptors. The latter may explain its antiemetic effects.
Ketamine, in common with nitrous oxide and xenon, has its predominant effect at NMDA receptors. These CNS receptors usually bind glutamate and are excitatory. Binding by ketamine to the NMDA receptor in a non-competitive manner reduces transmission. Ketamine appears to have no effect at GABA or glycine receptors.
After i.v. administration of a drug, there is an immediate rapid increase in plasma concentration followed by a slower decline. Anaesthesia is produced by diffusion of drug from arterial blood across the blood–brain barrier into the brain. The rate of transfer into the brain, and therefore the anaesthetic effect, is regulated by the following factors:
Protein binding. Only unbound drug is free to cross the blood–brain barrier. Protein binding may be reduced by low plasma protein concentrations or displacement by other drugs, resulting in higher concentrations of free drug and an exaggerated anaesthetic effect. Protein binding is also affected by changes in blood pH. Hyperventilation decreases protein binding and increases the anaesthetic effect.
Blood flow to the brain. Reduced cerebral blood flow (CBF), e.g. carotid artery stenosis, results in reduced delivery of drug to the brain. However, if CBF is reduced because of low cardiac output, initial blood concentrations are higher than normal after i.v. administration, and the anaesthetic effect may be delayed but enhanced.
Extracellular pH and pKa of the drug. Only the un-ionized fraction of the drug penetrates the lipid blood–brain barrier; thus, the potency of the drug depends on the degree of ionization at the pH of extracellular fluid and the pKa of the drug.
Speed of injection. Rapid i.v. administration results in high initial concentrations of drug. This increases the speed of induction, but also the extent of cardiovascular and respiratory side-effects.
The anaesthetic effect of all i.v. anaesthetic drugs in current use is terminated predominantly by distribution to other tissues. Figure 3.1 shows this distribution for thiopental. The percentage of the injected dose in each of four body compartments as time elapses is shown after i.v. injection. A large proportion of the drug is distributed initially into well-perfused organs (termed the vessel-rich group, or viscera – predominantly brain, liver and kidneys). Distribution into muscle (lean) is slower because of its low lipid content, but it is quantitatively important because of its relatively good blood supply and large mass. Despite their high lipid solubility, i.v. anaesthetic drugs distribute slowly to adipose tissue (fat) because of its poor blood supply. Fat contributes little to the initial redistribution or termination of action of i.v. anaesthetic agents, but fat depots contain a large proportion of the injected dose of thiopental at 90 min, and 65–75% of the total remaining in the body at 24 h. There is also a small amount of redistribution to areas with a very poor blood supply, e.g. bone. Table 3.3 indicates some of the properties of the body compartments in respect of the distribution of i.v. anaesthetic agents.
After a single i.v. dose, the concentration of drug in blood decreases as distribution occurs into viscera, and particularly muscle. Drug diffuses from the brain into blood along the changing concentration gradient, and recovery of consciousness occurs. Metabolism of most i.v. anaesthetic drugs occurs predominantly in the liver. If metabolism is rapid (indicated by a short elimination half-life), it may contribute to some extent to the recovery of consciousness. However, because of the large distribution volume of i.v. anaesthetic drugs, total elimination takes many hours, or, in some instances, days. A small proportion of drug may be excreted unchanged in the urine; the amount depends on the degree of ionization and the pH of urine.
Amobarbital and pentobarbital were used i.v. to induce anaesthesia in the late 1920s, but their actions were unpredictable and recovery was prolonged. Manipulation of the barbituric acid ring (Fig. 3.2) enabled a short duration of action to be achieved by:
An increased number of carbon atoms in the side chains at position 5 increases the potency of the agent. The presence of an aromatic nucleus in an alkyl group at position 5 produces compounds with convulsant properties; direct substitution with a phenyl group confers anticonvulsant activity.
The anaesthetically active barbiturates are classified chemically into four groups (Table 3.4). The methylated oxybarbiturate hexobarbital was moderately successful as an i.v. anaesthetic agent, but was superseded by the development in 1932 of thiopental. Although propofol has become very popular in a number of countries, thiopental remains one of the most commonly used i.v. anaesthetic agents throughout the world. Its pharmacology is therefore described fully in this chapter. Many of its effects are shared by other i.v. anaesthetic agents and consequently the pharmacology of these drugs is described more briefly.
Thiopental sodium, the sulphur analogue of pentobarbital, is a yellowish powder with a bitter taste and a faint smell of garlic. It is stored in nitrogen to prevent chemical reaction with atmospheric carbon dioxide, and mixed with 6% anhydrous sodium carbonate to increase its solubility in water. It is available in single-dose ampoules of 500 mg and is dissolved in distilled water to produce 2.5% (25 mg ml–1) solution with a pH of 10.8; this solution is slightly hypotonic. Freshly prepared solution may be kept for 24 h. The oil/water partition coefficient of thiopental is 4.7, and the pKa 7.6.
Central Nervous System: Thiopental produces anaesthesia usually less than 30 s after i.v. injection, although there may be some delay in patients with a low cardiac output. There is progressive depression of the CNS, including spinal cord reflexes. The hypnotic action of thiopental is potent, but its analgesic effect is poor, and surgical anaesthesia is difficult to achieve unless large doses are used; these are associated with cardiorespiratory depression. The cerebral metabolic rate is reduced and there are secondary decreases in CBF, cerebral blood volume and intracranial pressure. Recovery of consciousness occurs at a higher blood concentration if a large dose is given, or if the drug is injected rapidly; this has been attributed to acute tolerance, but may represent only altered redistribution. Consciousness is usually regained in 5–10 min. At subanaesthetic blood concentrations (i.e. at low doses or during recovery), thiopental has an antanalgesic effect and reduces the pain threshold; this may result in restlessness in the postoperative period. Thiopental is a very potent anticonvulsant.
Sympathetic nervous system activity is depressed to a greater extent than parasympathetic; this may occasionally result in bradycardia. However, it is more usual for tachycardia to develop after induction of anaesthesia, partly because of baroreceptor inhibition caused by modest hypotension and partly because of loss of vagal tone which may predominate normally in young healthy adults.
Cardiovascular System: Myocardial contractility is depressed and peripheral vasodilatation occurs, particularly when large doses are administered or if injection is rapid. Arterial pressure decreases, and profound hypotension may occur in the patient with hypovolaemia or cardiac disease. Heart rate may decrease, but there is often a reflex tachycardia (see above).
Respiratory System: Ventilatory drive is decreased by thiopental as a result of reduced sensitivity of the respiratory centre to carbon dioxide. A short period of apnoea is common, frequently preceded by a few deep breaths. Respiratory depression is influenced by premedication and is more pronounced if opioids have been administered; assisted or controlled ventilation may be required. When spontaneous ventilation is resumed, ventilatory rate and tidal volume are usually lower than normal, but they increase in response to surgical stimulation. There is an increase in bronchial muscle tone, although frank bronchospasm is uncommon.
Laryngeal spasm may be precipitated by surgical stimulation or the presence of secretions, blood or foreign bodies (e.g. an oropharyngeal airway or supraglottic airway device) in the region of the pharynx or larynx. Thiopental is less satisfactory than propofol in this respect, and appears to depress the parasympathetic laryngeal reflex arc to a lesser extent than other areas of the CNS.
Skeletal Muscle: Skeletal muscle tone is reduced at high blood concentrations, partly as a result of suppression of spinal cord reflexes. There is no significant direct effect on the neuromuscular junction. When thiopental is used as the sole anaesthetic agent, there is poor muscle relaxation, and movement in response to surgical stimulation is common.
Uterus and Placenta: There is little effect on resting uterine tone, but uterine contractions are suppressed at high doses. Thiopental crosses the placenta readily, although fetal blood concentrations do not reach the same levels as those observed in the mother.
Eye: Intraocular pressure is reduced by approximately 40%. The pupil dilates first, and then constricts; the light reflex remains present until surgical anaesthesia has been attained. The corneal, conjunctival, eyelash and eyelid reflexes are abolished.
Blood concentrations of thiopental increase rapidly after i.v. administration. Between 75 and 85% of the drug is bound to protein, mostly albumin; thus, more free drug is available if plasma protein concentrations are reduced by malnutrition or disease. Protein binding is affected by pH and is decreased by alkalaemia; thus the concentration of free drug is increased during hyperventilation. Some drugs, e.g. phenylbutazone, occupy the same binding sites, and protein binding of thiopental may be reduced in their presence.
Thiopental diffuses readily into the CNS because of its lipid solubility and predominantly un-ionized state (61%) at body pH. Consciousness returns when the brain concentration decreases to a threshold value, dependent on the individual patient, the dose of drug and its rate of administration, but at this time nearly all of the injected dose is still present in the body.
Metabolism of thiopental occurs predominantly in the liver, and the metabolites are excreted by the kidneys; a small proportion is excreted unchanged in the urine. The terminal elimination half-life is approximately 11.5 h. Metabolism is a zero-order process; 10–15% of the remaining drug is metabolized each hour. Thus, up to 30% of the original dose may remain in the body at 24 h. Consequently, a ‘hangover’ effect is common; in addition, further doses of thiopental administered within 1–2 days may result in cumulation. Elimination is impaired in the elderly. In obese patients, dosage should be based on an estimate of lean body mass, as distribution to fat is slow. However, elimination may be delayed in obese patients because of increased retention of the drug by adipose tissue.
Thiopental is administered i.v. as a 2.5% solution; the use of a 5% solution increases the likelihood of serious complications and is not recommended. A small volume, e.g. 1–2 mL in adults, should be administered initially; the patient should be asked if any pain is experienced in case of inadvertent intra-arterial injection (see below) before the remainder of the induction dose is given.
The dose required to produce anaesthesia varies, and the response of each patient must be assessed carefully; cardiovascular depression is exaggerated if excessive doses are given. In healthy adults, an initial dose of 4 mg kg–1 should be administered over 15–20 s; if loss of the eyelash reflex does not occur within 30 s, supplementary doses of 50–100 mg should be given slowly until consciousness is lost. In young children, a dose of 6 mg kg–1 is usually necessary. Elderly patients often require smaller doses (e.g. 2.5–3 mg kg–1) than young adults.
Induction is usually smooth and may be preceded by a taste of garlic. Adverse effects are related to peak blood concentrations, and in patients in whom cardiovascular depression may occur the drug should be administered more slowly; in very frail patients, as little as 50 mg may be sufficient to induce sleep.
No other drug should be mixed with thiopental. Neuromuscular blocking drugs should not be given until it is certain that anaesthesia has been induced. The i.v. cannula should be flushed with saline before vecuronium or atracurium is administered, to obviate precipitation.
Supplementary doses of 25–100 mg may be given to augment nitrous oxide/oxygen anaesthesia during short surgical procedures. However, recovery may be prolonged considerably if large total doses are used (> 10 mg kg–1).
Hypotension. The risk is increased if excessive doses are used, or if thiopental is administered to hypovolaemic, shocked or previously hypertensive patients. Hypotension is minimized by administering the drug slowly. Thiopental should not be administered to patients in the sitting position.
Tissue necrosis. Local necrosis may follow perivenous injection. Median nerve damage may occur after extravasation in the antecubital fossa, and this site is not recommended. If perivenous injection occurs, the needle should be left in place and hyaluronidase injected.
Intra-arterial injection. This is usually the result of inadvertent injection into the brachial artery or an aberrant ulnar artery in the antecubital fossa but has occurred occasionally into aberrant arteries at the wrist. The patient usually complains of intense, burning pain, and drug injection should be stopped immediately. The forearm and hand may become blanched and blisters may appear distally. Intra-arterial thiopental causes profound constriction of the artery accompanied by local release of norepinephrine. In addition, crystals of thiopental form in arterioles. Thrombosis caused by endarteritis, adenosine triphosphate release from damaged red cells and aggregation of platelets result in emboli and may cause ischaemia or gangrene in parts of the forearm, hand or fingers.
The needle should be left in the artery and a vasodilator (e.g. papaverine 20 mg) administered. Stellate ganglion or brachial plexus block may reduce arterial spasm. Heparin should be given i.v. and oral anticoagulants should be prescribed after operation.
Allergic reactions. These range from cutaneous rashes to severe or fatal anaphylactic or anaphylactoid reactions with cardiovascular collapse. Severe reactions are rare (approximately 1 in 14 000–20 000). Hypersensitivity reactions to drugs administered during anaesthesia are discussed on pages 54–55.