Intravenous Anaesthetic Agents
Properties of the Ideal Intravenous Anaesthetic Agent
Rapid onset – this is achieved by an agent which is mainly un-ionized at blood pH and which is highly soluble in lipid; these properties permit penetration of the blood–brain barrier
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
Analgesia at subanaesthetic concentrations
Minimal cardiovascular and respiratory depression
No excitatory phenomena (e.g. coughing, hiccup, involuntary movement) on induction
No emergence phenomena (e.g. nightmares)
No interaction with neuromuscular blocking drugs
Safe if injected inadvertently into an artery
No toxic effects on other organs
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.
TABLE 3.1
Main Properties of Intravenous Anaesthetics
aAqueous solution not commercially available.
bPain may be reduced when emulsion with medium-chain triglycerides is used.
TABLE 3.2
Classification of Intravenous Anaesthetics
Rapidly Acting (Primary Induction) Agents
Barbiturates:
Methohexital
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
Ketamine
Benzodiazepines – diazepam, flunitrazepam, midazolam
Large-dose opioids – fentanyl, alfentanil, sufentanil, remifentanil
Neuroleptic combination – opioid + neuroleptic
Pharmacokinetics of Intravenous Anaesthetic Drugs
Distribution to Other Tissues
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.
BARBITURATES
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:
substitution of a sulphur atom for oxygen at position 2
substitution of a methyl group at position 1; this also confers potential convulsive activity and increases the incidence of excitatory phenomena.
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
Physical Properties and Presentation
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.
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.
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.
Adverse Effects
Laryngeal spasm. The causes have been discussed above.
Bronchospasm. This is unusual, but may be precipitated in asthmatic patients.
Thrombophlebitis. This is uncommon (Table 3.5) when the 2.5% solution is used.