Pharmacy Blog – Dr Vibore

The concurrent use of neuromuscular blockers and lithium is normally safe and uneventful,but four patients taking lithium experienced prolonged blockade and respiratory difficulties afterreceiving standard doses of pancuronium and/or suxamethonium(succinylcholine).

A manic depressive woman taking lithium carbonate with a lithium level of 1.2 mmol/L,underwent surgery and was given thiopental, 310mg of suxamethonium (succinylcholine) over a period of 2 hours, and 500 micrograms of pancuronium. Prolonged neuromuscular blockade with apnoea occurred (See reference number 1).

Three other patients taking lithium experienced enhanced neuromuscular blockade when given pancuronium alone,(See reference number 2) with suxamethonium,(See reference number 3) or both.(See reference number 4) The authors of one of these reports(See reference number 4)say that “. . .We have seen potentiation of neuromuscular blockade produced by succinylcholine in several patients taking lithium carbonate. . . ” but give no further details. In contrast,a retrospective analysis of data from 17 patients taking lithium carbonate, who received suxamethonium during a total of 78 ECT treatments, failed to reveal any instances of unusually prolonged recovery.(See reference number 5) Interactions between lithium and pancuronium(See reference number 1) or suxamethonium(See reference number 6,7) have been demonstrated in dogs,and an interaction between lithium and tubocurarine has been demonstrated in cats,(See reference number 8) but no clear interaction has been demonstrated with any other neuromuscular blocker.(See reference number 7,9)A case of lithium toxicity has been described in a woman taking lithium who was given suxamethonium,but it is doubtful if it arose because of an interaction.(See reference number 10)

Uncertain. One suggestion is that, when interaction occurs, it may be due to changes in electrolyte balance caused by lithium, which results in changes in release of acetylcholine at neuromuscular junction (See reference number 8,11).

Information is limited. There are only four definite reports of this interaction in man,and good evidence that no adverse interaction normally occurs. Concurrent use need not be avoided but it would be prudent to be on alert for this interaction in any patient taking lithium who is given any neuromuscular blocker.

Hill GE,Wong KC, Hodges MR. Potentiation of succinylcholine neuromuscular blockade bylithium carbonate. Anesthesiology (1976) 44, 439–42.

Borden H,Clarke MT, Katz H. The use of pancuronium bromide in patients receiving lithiumcarbonate. Can Anaesth Soc J (1974) 21, 79–82.

Rabolini V,Gatti G. Potenziamento del blocco neuro-muscolare di tipo depolarizzante da salidi litio (relazione su un caso). Anest Rianim (1988) 29, 157–9.

Rosner TM,Rosenberg M. Anesthetic problems in patients taking lithium. J Oral Surg (1981) 39, 282–5.

Martin BA,Kramer PM. Clinical significance of the interaction between lithium and a neuromuscular blocker. Am J Psychiatry (1982) 139, 1326–8.

Reimherr FW,Hodges MR, Hill GE, Wong KC. Prolongation of muscle relaxant effects bylithium carbonate. Am J Psychiatry (1977) 134, 205–6.

Hill GE,Wong KC, Hodges MR. Lithium carbonate and neuromuscular blocking agents. Anesthesiology (1977) 46, 122–6.

Basuray BN,Harris CA. Potentiation of d-tubocurarine (d-Tc) neuromuscular blockade incats by lithium chloride. Eur J Pharmacol (1977) 45, 79–82.

Waud BE,Farrell L, Waud DR. Lithium and neuromuscular transmission. Anesth Analg (1982) 61, 399–402.

Jephcott G,Kerry RJ. Lithium: an anaesthetic risk. Br J Anaesth (1974) 46, 389–90.

Dehpour AR,Samadian T, Roushanzamir F. Interaction of aminoglycoside antibiotics andlithium at the neuromuscular junctions. Drugs Exp Clin Res (1992) 18, 383–7.

Rifampicin increases metabolism of ropivacaine, but thisprobably has little clinical relevance to its use as a local anaesthetic. Smoking appears to have only a minor effect on ropivacainepharmacokinetics. Tobacco smoking may enhance cocaine-associated myocardial ischaemia.

Clinical evidence,mechanism, importance and management

In a study involving 42 smokers (36 with proven coronary artery disease) mean product of heart rate and systolic arterial pressure increased by 11 % after intranasal cocaine 2 mg/kg, by 12 % after one cigarette and by 45 % after both cocaine use and one cigarette. Compared with baseline measurements, diameters of non-diseased coronary arterial segments decreased on average by 7 % after cocaine use, 7 % after smoking and 6 % after cocaine and smoking. However, diameters of diseased segments decreased by 9%, 5 % and 19%, respectively (See reference number 1). Cigarette smoking increases myocardial oxygen demand and induces coronary-artery vasoconstriction through an alpha-adrenergic mechanism similar to cocaine and therefore tobacco smoking may enhance cocaine-associated myocardial ischaemia (See reference number 1,2).

A study in 10 healthy non-smokers and 8 healthy smokers given ropivacaine 600 micrograms/kg by intravenous infusion over 30 minutes found that smoking increased urinary excretion of metabolite 3-hydroxyropivacaine and decreased urinary excretion of 2′,6′-pipecoloxylidide by 62%, but did not significantly affect ropivacaine AUC. However, pretreatment with rifampicin 600mg daily for 5 days increased clearance (by 93 % and 46%) and decreased AUC by 52 % and 38 % and half-life of ropivacaine in both non-smokers and smokers, respectively.(See reference number 3) Ropivacaine undergoes oxidative hepatic metabolism mainly by cytochrome P450 isoenzymes CYP1A2 and CYP3A4. Cigarette smoking may increase CYP1A2-mediated metabolism of ropivacaine, and elimination of ropivacaine may be considerably accelerated by rifampicin, which is a potent cytochrome P450 enzyme inducer. However, in clinical use local anaesthetic is given near nerves to be desensitised and induction of isoenzymes is not likely to affect local anaesthetic before it enters systemic blood circulation.(See reference number 3) This interaction is therefore of little clinical relevance.

Rifampicin may also increase metabolism of lidocaine to a minor extent, see Lidocaine + Rifampicin (Rifampin) interaction, and smoking may reduce oral bioavailability of lidocaine, .

Moliterno DJ,Willard JE, Lange RA, Negus BH, Boehrer JD, Glamann DB, Landau C, RossenJD, Winniford MD, Hillis LD. Coronary-artery vasoconstriction induced by cocaine, cigarettesmoking, or both. N Engl J Med (1994) 330, 454–9.

Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med (1995) 333,1267–72.

Jokinen MJ,Olkkola KT, Ahonen J, Neuvonen PJ. Effect of rifampin and tobacco smoking onthe pharmacokinetics of ropivacaine. Clin Pharmacol Ther (2001) 70, 344–50.

Clinical evidence,mechanism, importance and management

A generalised tonic-clonic seizure occurred in a 42-year-old woman immediately after she was anaesthetised with 120mg of intravenous methohexital for last in a series of six electroconvulsive therapies. She had been receiving paroxetine 40mg daily throughout series

Two women in their mid-twenties,who had been taking fluoxetine 20mg daily for 4 to 6 months, had pronounced involuntary upper limb movements lasting 20 to 30 seconds immediately after anaesthetic induction with 180mg of propofol (2 to 2.5 mg/kg). The movements ceased spontaneously and rest of anaesthesia and surgery were uneventful. Neither had any history of epilepsy or movement disorders. It is not clear whether this was an interaction between propofol and fluoxetine or just a rare (but previously reported) reaction to propofol (See reference number 2).

Folkerts H. Spontaneous seizure after concurrent use of methohexital anesthesia for electroconvulsive therapy and paroxetine: a case report. J Nerv Ment Dis (1995) 183,115–16.

Armstrong TSH,Martin PD. Propofol, fluoxetine and spontaneous movement. Anaesthesia (1997) 52, 809–10.

The mean procaine half-life in 6 healthy subjects was increased by66% (from 1.46 to 2.43 minutes) 2 hrs after they were givenacetazolamide 250mg orally. This appears to be because hydrolysis of procaine is inhibited by acetazolamide.(See reference number 1) As evidence of this interaction is limited to one report, its general significance is unclear.

1. Calvo R,Carlos R, Erill S. Effects of disease and acetazolamide on procaine hydrolysis by redblood cell enzymes. Clin Pharmacol Ther (1980) 27, 179–83.

Limited evidence suggests that failure rate of spinal anaesthesia with bupivacaine may be markedly increased in patients whoare receiving antirheumatic drugs and/or who drink alcohol

Clinical evidence,mechanism, importance and management

The observation that regional anaesthetic failures seemed to be particularly high among patients undergoing orthopaedic surgery who were suffering from rheumatic joint diseases,prompted further study of a possible interaction. It was found that failure rate of low-dose spinal anaesthesia with 0.5 % bupivacaine (average volume of 2 mL) increased from 5 % in control group (no alcohol or long-term treatment) to 32 % to 42 % in those who had been taking antirheumatic drugs (indometacin or unspecified) for at least 6 months or who drank at least 80 g of ethanol daily, or both. The percentage of those patients who had a reduced response (i.e. an extended latency period and/or a reduced duration of action) also increased from 3 % up to 39 to 42%.(See reference number 1) The reasons are not understood. This appears to be only report of such an effect.

1. Sprotte G,Weis KH. Drug interaction with local anaesthetics. Br J Anaesth (1982) 54, 242P– 243P.

Phenylephrine eye drops given to patients undergoing general anaesthesia caused marked cyanosis and bradycardia in a baby,andhypertension in a woman.

Clinical evidence,mechanism, importance and management

A 3-week-old baby anaesthetised with halothane and nitrous oxide/oxygen became cyanosed shortly after 2 drops of 10 % phenylephrine solution were put into one eye. The heart rate decreased from 160 to 60 bpm,S-T segment and T wave changes were seen, and blood pressure measurements were unobtainable. The baby recovered uneventfully when anaesthesia was stopped and oxygen given. It was suggested that phenylephrine caused severe peripheral vasoconstriction, cardiac failure and reflex bradycardia (See reference number 1). A 54-year-old woman anaesthetised with isoflurane developed hypertension (a rise from 125/70 to 200/90 mmHg) shortly after having two drops of 10 % phenylephrine put into one eye. The hypertension responded to nasal glyceryl trinitrate (nitroglycerin) and increasing concentrations of isoflurane (See reference number 1). The authors of this report consider that general anaesthesia may have contributed to systemic absorption of phenylephrine. They suggest that phenylephrine should be given 30 to 60 minutes prior to anaesthesia,and not during anaesthesia. However, if it is necessary, use lowest concentrations of phenylephrine (2.5%). They also point out that following are effective mydriatics: single drop combinations of 0.5 % cyclopentolate and 2.5 % phenylephrine or 0.5 % tropicamide and 2.5 % phenylephrine.

Phenylephrine is a sympathomimetic,and as such may carry some risk of potentiating arrhythmias if it is used with inhalational anaesthetics such as halothane –see Anaesthetics, general + Inotropes and Vasopressors interaction,

. However,it is considered that it is much less likely than adrenaline (epinephrine) to have this effect, since it has primarily alpha-agonist activity (See reference number 2).

Van der Spek AFL,Hantler CB. Phenylephrine eyedrops and anesthesia. Anesthesiology (1986) 64, 812–14.

Smith NT,Miller RD, Corbascio AN, eds. Sympathomimetic drugs, in Drug Interactions inAnesthesia. Philadelphia: Lea and Febiger; 1981 P. 55–82.

The respiratory depressant effects of ketamine and morphinemay be additive. The dose requirements of desflurane,etomidate,propofol and thiopental may be lower after opioid use. Opisthotonos or grand mal seizures have rarely been associated with theuse of propofol with alfentanil and/or fentanyl. The effects of inhalational anaesthetics may be enhanced by opioid analgesics.

Clinical evidence,mechanism, importance and management

Opioid analgesics have been reported to reduce MAC values of inhalational anaesthetics. For example, fentanyl has been shown to lower MAC value of desflurane, probably in a dose-dependent manner, and this has been subject of a review (See reference number 1). The manufacturer notes that lower doses of desflurane are required in patients receiving opioids (See reference number 2). Remifentanil at a target-controlled plasma level of 1 nanogram/mL was found to decrease MAC of sevoflurane with nitrous oxide by 60%, and remifentanil 3 nanograms/mL produced a further 30 % decrease in MAC of sevoflurane (See reference number 3). Another study found that remifentanil (dose-dependently) decreased level of sevoflurane required to maintain anaesthesia (See reference number 4). However, 100 microgram/kg doses of morphine given during anaesthesia did not alter awakening concentration of sevoflurane (See reference number 5).

The manufacturer of etomidate recommends that dose of etomidate should be reduced in patients who have already received opioids (See reference number 6)

Ketamine is a respiratory depressant like morphine,but less potent, and its effects can be additive with morphine (See reference number 7). The manufacturer notes that prolonged recovery time may occur if opioids are used with ketamine (See reference number 8).

A study in 11 healthy subjects found that combination of ketamine and morphine almost abolished windup-like pain (progressive increase in pain intensity on repeated stimulation) in a skin burn injury. This effect was not found with either drug alone. Further, ketamine alone, but not morphine reduced area of secondary hyperalgesia of local burn and increased pain threshold, but combination did not appear to enhance this effect. The reduction of wind-up pain may be due to ketamineinduced prevention of acute tolerance to morphine (See reference number 9).

Another study in healthy subjects using various experimental pain models found that ketamine antagonised respiratory depressant effect of remifentanil. Remifentanil alone produced analgesic effects with all pain tests, but ketamine only enhanced effect of remifentanil on intramuscular electrical stimulation. Acute remifentanil-induced hyperalgesia and tolerance were detected only by pressure pain test and were not suppressed by ketamine. The combined effects of remifentanil and ketamine probably depend on type of pain (See reference number 10).

A 71-year-old man undergoing a minor orthopaedic operation was given a 500-microgram intravenous injection of alfentanil followed by a slow injection of propofol 2.5 mg/kg. Approximately 15 seconds after propofol, patient developed strong bilateral fits and grimaces, which lasted for 10 seconds. Anaesthesia was maintained with nitrous oxide/oxygen and halothane and there were no other intra- or postoperative complications. The patient had no history of convulsions (See reference number 11). Propofol has also been associated with opisthotonos (a spasm where head and heels bend backwards and body arches forwards) in two patients given fentanyl with or without alfentanil.(See reference number 12) There is a further report of opisthotonos during recovery from anaesthesia with alfentanil,propofol and nitrous oxide.(See reference number 13)Seizures have been reported in patients with and without epilepsy receiving propofol. They mainly occur during induction and emergence or are delayed after anaesthesia,suggesting that they may be caused by changes in cerebral levels of propofol,(See reference number 14) and postanaesthetic opisthotonos may be due to a propofol-induced tolerance to inhibitory transmitters (glycine and gamma-aminobutyric acid).(See reference number 13) Any association with opioid remains unknown, although it has been suggested that opioids may aggravate propofol-induced opisthotonos by antagonising actions of glycine.(See reference number 13)

Alfentanil has been found to reduce amount of propofol needed for loss of eyelash reflex and loss of consciousness, as well as increasing blood pressure fall produced by propofol (See reference number 15). Propofol inhibits both alfentanil and sufentanil metabolism causing an increase in plasma concentrations of these opioids,while alfentanil also increases propofol concentrations (reviewed by Vuyk(See reference number 16)and also described in more recent reports(See reference number 17-20)). Pretreatment with fentanyl may also decrease propofol requirements for induction of anaesthesia,(See reference number 16) and increase blood concentrations of propofol (See reference number 21). However,another study was unable to confirm an effect on blood propofol concentrations (See reference number 22). Remifentanil has been reported to reduce dose of propofol needed for anaesthesia and also to reduce recovery time (See reference number 23,24). Further,propofol and remifentanil caused dose-dependent respiratory-depression, which, during combined use, was synergistic (See reference number 25). One study using EEG-controlled dosing of propofol and remifentanil for anaesthesia found their pharmacodynamic effects were no more than additive (See reference number 26). Although remifentanil alone appears to be ineffective at countering response to stimuli, a study in healthy subjects has found that remifentanil can significantly reduce levels of propofol required to ablate response to shouting, shaking or laryngoscopy (synergistic effect), but effects on EEG measures were additive (See reference number 27). In another study in healthy subjects, synergy that occurred for both analgesic and hypnotic endpoints was found to be greatest at lower levels of drugs which for each drug alone would not be producing maximal effects (See reference number 28). Another study found changes in BIS (Bispectral Index) that suggested that remifentanil may have some hypnotic properties or that it can potentiate hypnotic effect of propofol (See reference number 29). It has been suggested that increased hypnotic effects may be due to a dose-dependent decrease in cardiac output by remifentanil, resulting in an increase in arterial and brain propofol with increased anaesthetic effect (See reference number 30). One pharmacokinetic study found that levels of remifentanil may be increased during concurrent propofol infusion,(See reference number 31) while another study found that concurrent propofol reduced volume of distribution and distribution clearance of remifentanil by 41%. It was concluded that although propofol affects remifentanil bolus dose pharmacokinetics,maintenance infusion rates and recovery times would not be significantly affected (See reference number 32).

The manufacturer notes that required induction dose of propofol may be reduced in patients who have received opioids, and that these drugs may increase anaesthetic and sedative effects of propofol, and also cause greater reductions in blood pressure and cardiac output. They also state that rate of propofol administration for maintenance of anaesthesia may be reduced in presence of supplemental analgesics such as opioids (See reference number 33).

Two reviews have discussed use of opioids and propofol in anaesthesia, their pharmacokinetic and pharmacodynamic interactions, and administration and monitoring techniques (See reference number 34,35).

Opioid analgesics would be expected to potentiate respiratory depressant effects of barbiturate anaesthetics. A study has found that dose of thiopental required to induce anaesthesia was reduced by pretreatment with fentanyl (See reference number 36)

Dale O. Drug interactions in anaesthesia: focus on desflurane and sevoflurane. Baillieres Clin Anaesthesiol (1995) 9,105–17.

Suprane (Desflurane). Baxter Healthcare Corporation. US Prescribing information,November 2005.

Albertin A,Casati A, Bergonzi P, Fano G, Torri G. Effects of two target-controlled concentrations (1 and 3 ng/ml) of remifentanil on MACBAR of sevoflurane. Anesthesiology (2004) 100, 255–9.

Coltura MJ-J,Van Belle K, Van Hemelrijck JH. Influence of remifentanil (Ultiva, GlaxoWellcome) and nitrous oxide on sevoflurane (Sevorane, Abbott) requirement during surgery.2001 Annual Meeting of the American Society of Anesthesiologists, New Orleans USA,2002. Abstract A-462.

Katoh T,Suguro Y, Kimura T, Ikeda K. Morphine does not affect the awakening concentration of sevoflurane. Can J Anaesth (1993) 40, 825–8.

Hypnomidate (Etomidate). Janssen-Cilag Ltd. UK Summary of product characteristics,February 2004.

7.

Bourke DL,Malit LA, Smith TC. Respiratory interactions of ketamine and morphine. Anesthesiology (1987) 66, 153–6.

8.

Ketalar (Ketamine hydrochloride). Pfizer Ltd. UK Summary of product characteristics,January 2006.

9.

Schulte H,Sollevi A, Segerdahl M. The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup-like pain in humans. Anesth Analg (2004) 98, 1574–80.

Luginbühl M,Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M.Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg (2003) 96, 726–32.

Wittenstein U,Lyle DJR. Fits after alfentanil and propofol. Anaesthesia (1989) 44, 532–3.

Laycock GJA. Opisthotonos and propofol: a possible association. Anaesthesia (1988) 43,

257.

Ries CR,Scoates PJ, Puil E. Opisthotonos following propofol: a nonepileptic perspective and treatment strategy. Can J Anaesth (1994) 41, 414–19.

Walder B,Tramèr MR, Seeck M. Seizure-like phenomena and propofol. A systematic review.Neurology (2002) 58, 1327–32.

Vuyk J,Griever GER, Engbers FHM, Burm AGL, Bovill JG, Vletter AA. The interaction between propofol and alfentanil during induction of anesthesia. Anesthesiology (1994) 81, A400.

Vuyk J. Pharmacokinetic and pharmacodynamic interactions between opioids and propofol.J Clin Anesth (1997) 9,23S–26S.

Ihmsen H,Albrecht S, Fechner J, Hering W, Schuttler J. The elimination of alfentanil is decreased by propofol. 2000 Annual Meeting of the American Society of Anesthesiologists, SanFrancisco USA, 2002. Abstract 531.

Mertens MJ,Vuyk J, Olofsen E, Bovill JG, Burm AGL. Propofol alters the pharmacokineticsof alfentanil in healthy male volunteers. Anesthesiology (2001) 94, 949–57.

Mertens MJ,Olofsen E, Burm AGL, Bovill JG, Vuyk J. Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics. Anesthesiology (2004) 100, 795–805.

Schwilden H,Fechner J, Albrecht S, Hering W, Ihmsen H, Schüttler J. Testing and modellingthe interaction of alfentanil and propofol on the EEG. Eur J Anaesthesiol (2003) 20, 363–72.

Cockshott ID,Briggs LP, Douglas EJ, White M. Pharmacokinetics of propofol in female patients. Studies using single bolus injections. Br J Anaesth (1987) 59, 1103–10.

Dixon J,Roberts FL, Tackley RM, Lewis GTR, Connell H, Prys-Roberts C. Br J Anaesth (1990) 64, 142–7.

O’Hare R,Reid J, Breslin D, Hayes A, Mirakhur RK. Propofol–remifentanil interaction: influence on recovery. Br J Anaesth (1999) 83, 180P.

Drover DR,Litalien C, Wellis V, Shafer SL, Hammer GB. Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy inchildren. Anesthesiology (2004) 100, 1382–6.

Nieuwenhuijs,DJF, Olofsen E, Romberg RR, Sarton E, Ward D, Engbers F, Vuyk J, MoorenR, Teppema LJ, Dahan A. Response surface modeling of remifentanil-propofol interaction oncardiorespiratory control and bispectral index. Anesthesiology (2003) 98, 312–22.

Fechner J,Hering W, Ihmsen H, Palmaers T, Schüttler J, Albrecht S. Modelling the pharmacodynamic interaction between remifentanil and propofol by EEG-controlled dosing. Eur J Anaesthesiol (2003) 20, 373–9.

Bouillon TW,Bruhn J, Radulescu L, Andresen C, Shafer TJ, Cohane C, Shafer SL. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance oflaryngoscopy, bispectral index and electroencephalographic approximate entropy. Anesthesiology (2004) 100, 1353–72.

Kern SE,Xie G, White JL, Egan TD. Opioid-hypnotic synergy. Anesthesiology (2004) 100, 1373–81.

Koitabashi T,Johansen JW, Sebel PS. Remifentanil dose/electroencephalogram bispectral response during combined propofol/regional anesthesia. Anesth Analg (2002) 94, 1530–3.

Ludbrook GL,Upton RN. Pharmacokinetic drug interaction between propofol and remifentanil? Anesth Analg (2003) 97, 924–5.

Crankshaw DP,Chan C, Leslie K, Bjorksten AR. Remifentanil concentration during target-controlled infusion of propofol. Anaesth Intensive Care (2002) 30, 578–83.

Bouillon T,Bruhn J, Radu-Radulescu L, Bertaccini E, Park S, Shafer S. Non-steady stateanalysis of the pharmacokinetic interaction between propofol and remifentanil. Anesthesiology (2002) 97, 1350–62.

Diprivan (Propofol). AstraZeneca. US Prescribing information,August 2005.

Lichtenbelt B-J,Mertens M, Vuyk J. Strategies to optimise propofol-opioid anaesthesia. Clin Pharmacokinet (2004) 43, 577–93.

Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions. Acta Anaesthesiol Belg (2001) 52,445–51.

Wang LP,Hermann C, Westrin P. Thiopentone requirements in adults after varying pre-induction doses of fentanyl. Anaesthesia (1996) 51, 831–5.

Thiopental Injection. Link Pharmaceuticals Ltd. UK Summary of product characteristics,January 2003.

Clinical evidence,mechanism, importance and management

Two patients taking levothyroxine developed severe hypertension (240/140 and 210/130 mmHg,respectively) and tachycardia (190 and 150 bpm) when they were given ketamine. Both were effectively treated with 1mg of intravenous propranolol (See reference number 1). It was not clear whether this was an interaction or simply a particularly exaggerated response to ketamine,but care is clearly needed if ketamine is given to patients taking thyroid replacement.

1. Kaplan JA,Cooperman LH. Alarming reactions to ketamine in patients taking thyroid medication — treatment with propranolol. Anesthesiology (1971) 35, 229–30.

This section is concerned with interactions where effects of anaesthetics (both general and local) and neuromuscular blocking drugs are affected by presence of other drugs. Where anaesthetics or neuromuscular blocking drugs are responsible for an interaction they are dealt with under heading of drug affected

Many patients undergoing anaesthesia may be taking long-term medication,which may affect their haemodynamic status during anaesthesia. This section is limited to drug interactions and therefore does not cover many precautions relating to patients taking long-term medication and undergoing anaesthesia in general (for example, drugs affecting coagulation).

In general anaesthesia a balanced approach is often used to meet main goals of anaesthetic procedure. These goals are unconsciousness/amnesia,analgesia, muscle relaxation, and maintenance of homoeostasis. Therefore general anaesthesia often involves use of several drugs, including benzodiazepines, opioids, and anticholinesterases, as well as general anaesthetics (sometimes more than one) and neuromuscular blockers. The use of several different types of drugs in anaesthesia means that there is considerable potential for drug interactions to occur in peri-operative period, but this section is limited to effects of drugs on general anaesthetics and neuromuscular blockers. The interactions of drugs affecting these other drugs used in anaesthesia are covered in other sections (anticholinesterases,, benzodiazepines, , and opioids, ).

There may be difficulty in establishing which of drugs being used in a complex regimen are involved in a suspected interaction. It should also be borne in mind that disease processes and procedure for which anaesthesia is used may also be factors to be taken into account when evaluating a possible interaction

Some established interactions are advantageous and are employed clinically. For example, hypnotic and anaesthetic effects of propofol and midazolam’, , are found to be greater than expected additive effects and this synergy allows for lower dosage regimens in practice. Similarly nitrous oxide reduces required dose of inhalational general anaesthetics (see ‘Anaesthetics, general + Anaesthetics, general). Anticholinesterases oppose actions of competitive neuromuscular blockers, and are used to restore muscular activity after surgery (see Neuromuscular blockers + Anticholinesterases interaction).

The general anaesthetics mentioned in this section are listed in table 1 below,. Barbiturates used as anaesthetics (e.g. thiopental) are largely covered here,whereas those used predominantly for their antiepileptic or sedative properties (e.g. phenobarbital or secobarbital) are dealt with in appropriate sections.

The competitive (non-depolarising) neuromuscular blockers and depolarising neuromuscular blockers mentioned in this section are listed in table 2 below’,. The modes of action of two types of neuromuscular blocker are discussed in monograph ‘Neuromuscular blockers + Neuromuscular blockers. It should be noted that mivacurium (a competitive blocker) and suxamethonium (a depolarising blocker) are hydrolysed by cholinesterase,so share some interactions in common that are not relevant to other competitive neuromuscular blockers.

The local anaesthetics mentioned in this section are listed in table 1 below,. The interactions discussed in this section mainly involve interaction of drugs with local anaesthetics used for epidural or spinal anaesthesia. The interactions of lidocaine used as an antiarrhythmic is dealt with in Antiarrhythmics,.

Table 1 Anaesthetics
General anaesthetics
Halogenated inhalational anaesthetics	Miscellaneous inhalational anaesthetics	Barbiturate parenteral anaesthetics	Miscellaneous parenteral anaesthetics
Chloroform	Anaesthetic ether	Methohexital	Alfadolone
Desflurane	Cyclopropane	Thiamylal	Alfaxolone
Enflurane	Nitrous oxide	Thiopental	Etomidate
Halothane	Xenon		Ketamine
Isoflurane			Propofol
Methoxyflurane
Sevoflurane
Trichloroethylene
Local anaesthetics
Amide-type	Ester-type (ester of benzoic acid)	Ester-type (ester of para-aminobenzoic acid)
Articaine	Cocaine	Chloroprocaine
Bupivacaine		Procaine
Etidocaine		Propoxycaine
Levobupivacaine		Tetracaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine

Table 2 Neuromuscular blockers
Competitive (Non-depolarising) blockers – Aminosteroid type	Competitive (Non-depolarising) blockers – Benzylisoquinolinium type	Depolarising blockers
Pancuronium	Alcuronium	Decamethonium
Pipecuronium	Atracurium	Suxamethonium (Succinylcholine)
Rapacuronium	Cisatracurium
Rocuronium	Doxacurium
Vecuronium	Gallamine
	Metocurine
	Mivacurium
	Tubocurarine (d-Tubocurarine)

Table 3 Anaesthetics
General anaesthetics
Halogenated inhalational anaesthetics	Miscellaneous inhalational anaesthetics	Barbiturate parenteral anaesthetics	Miscellaneous parenteral anaesthetics
Chloroform	Anaesthetic ether	Methohexital	Alfadolone
Desflurane	Cyclopropane	Thiamylal	Alfaxolone
Enflurane	Nitrous oxide	Thiopental	Etomidate
Halothane	Xenon		Ketamine
Isoflurane			Propofol
Methoxyflurane
Sevoflurane
Trichloroethylene
Local anaesthetics
Amide-type	Ester-type (ester of benzoic acid)	Ester-type (ester of para-aminobenzoic acid)
Articaine	Cocaine	Chloroprocaine
Bupivacaine		Procaine
Etidocaine		Propoxycaine
Levobupivacaine		Tetracaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine