F0078-Ch03.qxd 28/08/2006 04:23 PM Page 34 3 Intravenous anaesthetic agents General anaesthesia may be produced by many drugs ● No emetic effects which depress the CNS, including sedatives, tranquil- ● No excitatory phenomena (e.g. coughing, hiccup, lizers and hypnotic agents. However, for some drugs involuntary movement) on induction the doses required to produce surgical anaesthesia are ● No emergence phenomena (e.g. nightmares) so large that cardiovascular and respiratory depres- ● No interaction with neuromuscular blocking drugs sion commonly occur, and recovery is delayed for ● No pain on injection hours or even days. Only a few drugs are suitable for ● No venous sequelae use routinely to produce anaesthesia after intravenous ● Safe if injected inadvertently into an artery (i.v.) injection. ● No toxic effects on other organs Intravenous anaesthetic agents are used commonly ● No release of histamine to induce anaesthesia, as induction is usually ● No hypersensitivity reactions smoother and more rapid than that associated with ● Water-soluble formulation most of the inhalational agents. Intravenous anaes- ● Long shelf-life thetics may also be used for maintenance, either alone ● No stimulation of porphyria. or in combination with nitrous oxide; they may be administered as repeated bolus doses or by continu- None of the agents available at present meets all these ous i.v. infusion. Other uses include sedation during requirements. Features of the commonly used i.v. anaes- regional anaesthesia, sedation in the intensive therapy thetic agents are compared in Table 3.1, and a classifica- unit (ITU) and treatment of status epilepticus. tion of i.v. anaesthetic drugs is shown in Table 3.2. PROPERTIES OF THE IDEAL INTRAVENOUS PHARMACOKINETICS OF INTRAVENOUS ANAESTHETIC AGENT ANAESTHETIC DRUGS ● Rapid onset – this is achieved by an agent which is After i.v. administration of a drug, there is an immedi- mainly unionized at blood pH and which is highly ate rapid increase in plasma concentration followed by soluble in lipid; these properties permit penetration a slower decline. Anaesthesia is produced by diffusion of the blood–brain barrier of drug from arterial blood across the blood–brain bar- ● Rapid recovery – early recovery of consciousness is rier into the brain. The rate of transfer into the brain, usually produced by rapid redistribution of the and therefore the anaesthetic effect, is regulated by the drug from the brain into other well-perfused following factors: tissues, particularly muscle. The plasma Protein binding. Only unbound drug is free to cross concentration of the drug decreases, and the drug the blood–brain barrier. Protein binding may be diffuses out of the brain along a concentration reduced by low plasma protein concentrations or dis- gradient. The quality of the later recovery period is placement by other drugs, resulting in higher concen- related more to the rate of metabolism of the drug; trations of free drug and an exaggerated anaesthetic drugs with slow metabolism are associated with a effect. Protein binding is also affected by changes in more prolonged ‘hangover’ effect and accumulate blood pH. Hyperventilation decreases protein binding if used in repeated doses or by infusion for and increases the anaesthetic effect. maintenance of anaesthesia Blood flow to the brain. Reduced cerebral blood flow ● Analgesia at subanaesthetic concentrations (CBF), e.g. carotid artery stenosis, results in reduced ● Minimal cardiovascular and respiratory depression delivery of drug to the brain. However, if CBF is reduced 34 F0078-Ch03.qxd 28/08/2006 04:23 PM Page 35 INTRAVENOUS ANAESTHETIC AGENTS 3 Table 3.1 Main properties of intravenous anaesthetics Thiopental Methohexital Propofol Ketamine Etomidate Physical properties Water-soluble ++−++a Stable in solution −−+++ Long shelf-life − – +++ Pain on i.v. injection −+++b −++b Non-irritant on s.c. injection − ± ++ Painful on arterial injection ++− No sequelae from intra-arterial injection − ± + Low incidence of venous thrombosis ++++− Effects on body Rapid onset +++++ Recovery due to: Redistribution ++++ Detoxification ++ Cumulation ++ + − − − Induction Excitatory effects − ++ + + +++ Respiratory complications −++−− Cardiovascular Hypotension ++++−+ Analgesic −−−++− Antanalgesic ++−−? Interaction with relaxants −−−−− Postoperative vomiting −−−+++ Emergence delirium −−−++− Safe in porphyria −−++− aAqueous solution not commercially available. bPain may be reduced when emulsion with medium-chain triglycerides is used. because of low cardiac output, initial blood concentra- depends on the degree of ionization at the pH of extra- tions are higher than normal after i.v. administration, cellular fluid and the pKa of the drug. and the anaesthetic effect may be delayed but enhanced. The relative solubilities of the drug in lipid and water. Extracellular pH and pKa of the drug. Only the non- High lipid solubility enhances transfer into the brain. ionized fraction of the drug penetrates the lipid Speed of injection. Rapid i.v. administration results blood–brain barrier; thus, the potency of the drug in high initial concentrations of drug. This increases 35 F0078-Ch03.qxd 28/08/2006 04:23 PM Page 36 INTRAVENOUS ANAESTHETIC AGENTS 100 Table 3.2 Classification of intravenous anaesthetics 80 P o Le Rapidly acting (primary induction) agents o a l n Barbiturates: Methohexital 60 Thiobarbiturates – thiopental, thiamylal % of dose 40 Imidazole compounds – etomidate ra e c is at Sterically hindered alkyl phenols – propofol V F 20 Steroids – eltanolone, althesin, minaxolone (none currently available) 0 1 2 4 8 16 32 128 0.5 Eugenols – propanidid (not currently available) 0.06 0.25 0.125 Slower-acting (basal narcotic) agents min Fig. 3.1 Ketamine Distribution of thiopental after intravenous bolus administration. Benzodiazepines – diazepam, flunitrazepam, midazolam Large-dose opioids – fentanyl, alfentanil, sufentanil, remaining in the body at 24 h. There is also a small remifentanil amount of redistribution to areas with a very poor blood supply, e.g. bone. Table 3.3 indicates some of the Neuroleptic combination – opioid + neuroleptic 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 the speed of induction, but also the extent of cardio- blood decreases as distribution occurs into viscera, vascular and respiratory side-effects. and particularly muscle. Drug diffuses from the brain In general, any factor which increases the blood into blood along the changing concentration gradient, concentration of free drug, e.g. reduced protein bind- and recovery of consciousness occurs. Metabolism of ing or low cardiac output, also increases the intensity most i.v. anaesthetic drugs occurs predominantly in of side-effects. the liver. If metabolism is rapid (indicated by a short Distribution to other tissues Table 3.3 Factors influencing the distribution The anaesthetic effect of all i.v. anaesthetic drugs in of thiopental in the body current use is terminated predominantly by distribu- tion to other tissues. Figure 3.1 shows this distribution Viscera Muscle Fat Others for thiopental. The percentage of the injected dose in each of four body compartments as time elapses is Relative blood flow Rich Good Poor Very shown after i.v. injection. A large proportion of the poor drug is distributed initially into well-perfused organs Blood flow (L min−1) 4.5 1.1 0.32 0.08 (termed the vessel-rich group, or viscera – predomi- nantly brain, liver and kidneys). Distribution into Tissue volume (L; A) 6 33 15 13 muscle (lean) is slower because of its low lipid content, but it is quantitatively important because of its rela- Tissue/blood 1.5 1.5 11.0 1.5 tively good blood supply and large mass. Despite their partition coefficient (B) high lipid solubility, i.v. anaesthetic drugs distribute slowly to adipose tissue (fat) because of its poor blood Potential capacity 9 50 160 20 supply. Fat contributes little to the initial redistribution (L; A × B) or termination of action of i.v. anaesthetic agents, but fat depots contain a large proportion of the injected Time constant (capacity/flow; min) 2 45 500 250 dose of thiopental at 90 min, and 65–75% of the total 36 F0078-Ch03.qxd 28/08/2006 04:23 PM Page 37 BARBITURATES 3 elimination half-life), it may contribute to some extent O H 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 R´ C N excreted unchanged in the urine; the amount depends 6 1 on the degree of ionization and the pH of urine. C 5 2 C O BARBITURATES R 4 3 C N Amobarbital and pentobarbital were used i.v. to induce anaesthesia in the late 1920s, but their actions were unpredictable and recovery was prolonged. R Manipulation of the barbituric acid ring (Fig. 3.2) O enabled a short duration of action to be achieved by: Fig. 3.2 Structure of barbiturate ring. ● substitution of a sulphur atom for oxygen at position 2 out the world. Its pharmacology is therefore described ● substitution of a methyl group at position 1; this fully in this chapter. Many of its effects are shared by also confers potential convulsive activity and other i.v. anaesthetic agents and consequently the increases the incidence of excitatory phenomena. pharmacology of these drugs is described more briefly. 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 THIOPENTAL SODIUM at position 5 produces compounds with convulsant Chemical structure properties; direct substitution with a phenyl group confers anticonvulsant activity. Sodium 5-ethyl-5-(1-methylbutyl)-2-thiobarbiturate. The anaesthetically active barbiturates are classi- fied chemically into four groups (Table 3.4). The Physical properties and presentation methylated oxybarbiturate hexobarbital was moder- ately successful as an i.v. anaesthetic agent, but was Thiopental sodium, the sulphur analogue of pentobar- superseded by the development in 1932 of thiopental.