Page of

E 

E
Chapter:
E
Source:
Drugs in Anaesthesia and Intensive Care (5 ed.)
Author(s):

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0005

Edrophonium

Uses

Edrophonium is used:

  1. 1. for the reversal of non-depolarizing neuromuscular blockade

  2. 2. in the diagnosis of suspected phase II block

  3. 3. in the diagnosis of myasthenia gravis (the ‘Tensilon® test’) and

  4. 4. in the differentiation of myasthenic and cholinergic crisis in myasthenic patients.

Chemical

A synthetic quaternary ammonium compound.

Presentation

As a clear, colourless solution for injection containing 10 mg/ml of edrophonium chloride.

Main action

Cholinergic.

Mode of action

Edrophonium is a synthetic reversible inhibitor of acetylcholinesterase; it competes with acetylcholine for the anionic site of the enzyme and reversibly binds to it. At least, part of the effect of the drug appears to be exerted pre-junctionally.

Route of administration/doses

The drug is usually administered intravenously; it has a more rapid onset (its peak effect occurring at 0.8–2 minutes) and shorter duration of effect (10 minutes) than does neostigmine. The ‘Tensilon® test’ for the diagnosis of myasthenia gravis consists of the slow administration of 2 mg of edrophonium, followed by a further 8 mg if clinical deterioration does not occur. When used in the differentiation of a myasthenic and cholinergic crisis, a dose of 2 mg of edrophonium is used—weakness will increase if the crisis is cholinergic (and improve if myasthenic) in nature. An anticholinergic agent (e.g. atropine) must be immediately available when these tests are performed. The dose for reversal of competitive neuromuscular blockade is 0.5–0.7 mg/kg by slow intravenous injection, preceded by an appropriate dose of an anticholinergic agent to counter the peripheral muscarinic side effects of the drug.

Effects

CVS

The drug may cause bradycardia, leading to a fall in the cardiac output; it decreases the effective refractory period of cardiac muscle and increases the conduction time.

RS

Edrophonium increases bronchial secretion and may cause broncho- constriction.

CNS

Agitation and dreaming may occur; the drug has a predictable miotic effect. Weakness leading to fasciculation and paralysis may occur when edrophonium is administered to normal subjects.

AS

The drug increases salivation, lower oesophageal and gastric tone, gastric acid output, and lower gastrointestinal tract motility. Nausea and vomiting may occur.

GU

Edrophonium increases ureteric peristalsis and may lead to involuntary micturition.

Metabolic/other

Sweating and lacrimation are increased by the drug.

Toxicity/side effects

The side effects are manifestations of its pharmacological actions, as described above. Cardiac arrest has been reported after the use of edrophonium.

Kinetics

Data are incomplete.

Distribution

The VD is 0.9–1.3 l/kg.

Metabolism

The metabolic fate of edrophonium is uncertain; it is not hydrolysed by anticholinesterases.

Excretion

Details of the excretory pathways of the drug are unknown. The clearance is 6.9–12.3 ml/min/kg, and the elimination half-life is 110 minutes.

Special points

The potency of edrophonium is 12–16 times less than that of neostigmine; the muscarinic effects of the drug are correspondingly easier to counteract than those of neostigmine. Edrophonium is less predictable than neostigmine when used to reverse profound competitive neuromuscular blockade.

Enflurane

Uses

Enflurane is used for the induction and maintenance of general anaesthesia.

Chemical

A halogenated methylethyl ether which is a geometric isomer of isoflurane.

Presentation

As a clear, colourless liquid (that should be protected from light) with a characteristic sweet smell. The commercial preparation contains no stabilizers or preservatives; it is non-flammable in normal anaesthetic concentrations. The molecular weight of enflurane is 184.5, the boiling point 56.5°C, and the saturated vapour pressure 23.3 kPa at 20°C. The MAC of enflurane is 1.68 (0.57 in 70% N2O), the oil/water solubility coefficient 120, and the blood/gas solubility coefficient 1.91. The drug is readily soluble in rubber; it does not attack metals.

Main action

General anaesthesia (reversible loss of both awareness and recall of noxious stimuli).

Mode of action

The mechanism of general anaesthesia remains to be fully elucidated. General anaesthetics appear to disrupt synaptic transmission (especially in the area of the ventrobasal thalamus). This mechanism may include potentiation of the GABAA and glycine receptors and antagonism at NMDA receptors. Their mode of action at the molecular level appears to involve expansion of hydrophobic regions in the neuronal membrane, either within the lipid phase or within hydrophobic sites in cell membrane proteins.

Routes of administration/doses

Enflurane is administered by inhalation, conventionally via a calibrated vaporizer. The concentration used for the inhalational induction of anaesthesia is 1–10% and for maintenance 0.6–3%.

Effects

CVS

Enflurane is a negative inotrope; it also causes a decrease in the systemic vascular resistance, and these two effects produce a decrease in the mean arterial pressure. Unlike halothane, enflurane produces a slight reflex tachycardia. The drug decreases coronary vascular resistance; it also reduces the rate of phase IV depolarization, increases the threshold potential, and prolongs the effective refractory period. Enflurane is not markedly arrhythmogenic but does sensitize the myocardium to the effects of circulating catecholamines.

RS

Enflurane is a powerful respiratory depressant, markedly decreasing the tidal volume, although the respiratory rate may increase during the administration of the drug. A slight increase in the PaCO2 may result in spontaneously breathing subjects; the drug also decreases the ventilatory response to hypoxia and hypercapnia. Enflurane is non-irritant to the respiratory tract; it causes bronchodilatation and no increase in secretions. The drug inhibits pulmonary macrophage activity and mucociliary transport.

CNS

The principal effect of enflurane is general anaesthesia; the drug has little analgesic effect. The drug increases the cerebral blood flow, leading to an increase in the intracranial pressure; it also decreases cerebral oxygen consumption. The drug may induce tonic/clonic muscle activity and may also produce epileptiform EEG traces, especially in the presence of hypocapnia. A marked decrease in skeletal muscle tone results from the use of enflurane, mediated by an effect on the post-junctional membrane.

AS

Enflurane decreases the splanchnic blood flow as a result of the hypotension it produces.

GU

Enflurane decreases the renal blood flow and glomerular filtration rate; a small volume of concentrated urine results. The drug reduces the tone of the pregnant uterus.

Metabolic/other

Enflurane decreases plasma noradrenaline concentration and may increase blood sugar concentration. The drug causes a fall in the body temperature, predominantly by cutaneous vasodilation. Enflurane depresses white cell function for 24 hours post-operatively but has no effect on platelet function.

Toxicity/side effects

Enflurane is a recognized trigger agent for the development of malignant hyperthermia. The drug may also cause the appearance of myocardial dysrhythmias, particularly in the presence of hypoxia, hypercapnia, or excessive catecholamine concentrations. Shivering (‘the shakes’) may occur post-operatively. There have been isolated reports of hepatotoxicity associated with the repeated use of enflurane; there is also the theoretical risk of fluoride ion toxicity occurring with the use of the drug, particularly in patients with renal failure.

Kinetics

Absorption

The major factors affecting the uptake of volatile anaesthetic agents are solubility, cardiac output, and the concentration gradient between the alveoli and venous blood. Enflurane is less soluble in blood than is halothane; the alveolar concentration therefore reaches inspired concentration relatively rapidly, resulting in a rapid induction of anaesthesia. An increase in the cardiac output increases the rate of alveolar uptake and slows the induction of anaesthesia. The concentration gradient between alveoli and venous blood approaches zero at equilibrium; a large concentration gradient favours the onset of anaesthesia.

Distribution

The drug is initially distributed to organs with a high blood flow (brain, heart, liver, and kidney) and later to less well-perfused organs (muscles, fat, and bone).

Metabolism

2.4% of an administered dose is slowly metabolized in the liver via cytochrome P450 2El, principally by oxidation and dehalogenation; plasma fluoride ion concentrations may reach ten times those observed after the use of halothane or isoflurane.

Excretion

More than 80% is exhaled unchanged; 2.4% of an administered dose is excreted in the urine as non-volatile fluorinated compounds. The remainder is excreted via the skin, sweat, and faeces.

Special points

Enflurane markedly potentiates the action of co-administered non-depolarizing relaxants.

The dose of co-administered adrenaline should not exceed 10 ml of a 1:100 000 solution in a 10-minute period to guard against the development of ventricular dysrhythmias.

Enflurane is not recommended for use in epileptic patients.

Drug structure

For the drug structure, please see Fig. 2.


Fig. 2 Drug structure of enflurane.

Fig. 2 Drug structure of enflurane.

Enoximone

Uses

Enoximone is used:

  1. 1. in the treatment of acute-on-chronic heart failure

  2. 2. during and after the withdrawal of cardiopulmonary bypass, and

  3. 3. in the treatment of low-output states prior to cardiac transplantation.

Chemical

An imidazolone derivative.

Presentation

As a clear, yellow solution containing 5 mg/ml of enoximone.

Main action

Positive inotropism and vasodilation.

Mode of action

Enoximone acts by inhibiting type III phosphodiesterase, the enzyme responsible for the degradation of cAMP. The drug thus has a synergistic effect with those catecholamines, which directly activates adenylate cyclase and leads to an increase in the intracellular concentration of cAMP.

Route of administration/doses

Enoximone is administered intravenously, diluted in a ratio of 1:1 with either water or saline, either by a slow bolus injection of 0.5–1 mg/kg to a maximum dose of 3 mg/kg every 3–6 hours or by infusion at the rate of 90 micrograms/kg/min over 10–30 minutes and thereafter at the rate of 5–20 micrograms/kg/min. The drug acts within 10–30 minutes after intravenous administration; the mean duration of effect is 4–6 hours.

Effects

CVS

Enoximone has a positive inotropic action and leads to an increase in the cardiac output; the left ventricular stroke work index and cardiac index increase by 40–55% in patients with heart failure. Similarly, right atrial pressure, pulmonary capillary wedge pressure, PVR, and systemic vascular resistance all decrease by 30%. The drug has little effect on myocardial oxygen consumption; myocardial efficiency and coronary blood flow increase in animal models. Enoximone usually has little effect on the blood pressure or heart rate; dysrhythmias occur uncommonly.

Metabolic/other

The drug has little effect on plasma renin activity or catecholamine concentrations. A decrease in the platelet count has been observed in a small percentage of patients receiving the drug.

Toxicity/side effects

Dysrhythmias, hypotension, and CNS and gastrointestinal disturbances occur uncommonly with the use of enoximone.

Kinetics

Absorption

Enoximone is readily absorbed but undergoes extensive first-pass metabolism to an active sulfoxide form.

Distribution

The drug is 70% protein-bound in the plasma; the VD is 2.1–8 l/kg.

Metabolism

Enoximone is primarily metabolized in the liver to an active sulfoxide form.

Excretion

The drug appears predominantly in the form of sulfoxide in the urine; trace amounts are excreted unchanged. The clearance is 3.7–13 ml/min/kg, and the elimination half-life is 6.2 hours. A decreased dose should be used in the presence of renal or hepatic impairment.

Enoximone appears to be partially removed by haemodialysis.

Ephedrine

Uses

Ephedrine is used in the treatment of:

  1. 1. hypotension occurring in general, spinal, or epidural anaesthesia

  2. 2. nocturnal enuresis

  3. 3. narcolepsy

  4. 4. diabetic autonomic neuropathy

  5. 5. hiccups and

  6. 6. as a nasal decongestant.

Chemical

A naturally occurring sympathomimetic amine.

Presentation

As 15/30/60 mg tablets, an elixir containing 3 mg/ml, as 0.5/1% nasal drops, as a constituent of proprietary cold cures, and as a clear, colourless solution for injection containing 30 mg/ml of ephedrine hydrochloride. It has four isomers, with only the L-isomer being active.

Main action

Sympathomimetic.

Mode of action

Ephedrine acts both indirectly (by causing release of noradrenaline from sympathetic nerve terminals) and directly by stimulation of alpha- and beta-adrenoceptors.

Route of administration/doses

The adult dose by the oral route is 30 mg 8-hourly; as a nasal decongestant, 1–2 drops may be administered every 4 hours. The parenteral preparation should be diluted before use in 0.9% sodium chloride. The recommended intravenous dose in adults is 3–7.5 mg (maximum 9 mg), administered slowly, repeated every 3–4 minutes to a maximum of 30 mg, titrated to response. When administered orally, the drug acts within 60 minutes and has a duration of action of 3–5 hours. When administered intravenously, the onset of the cardiovascular effects of the drug is rapid; the duration of action is up to 1 hour.

Effects

CVS

The effects of ephedrine are similar to those of adrenaline but are more prolonged, as the drug is not metabolized by monoamine oxidase or catechol-O-methyl transferase. Ephedrine has positive inotropic and chronotropic actions, producing an increase in the cardiac output, myocardial work, and myocardial oxygen consumption. Myocardial irritability is increased by the drug. Ephedrine increases the coronary blood flow, systolic and diastolic blood pressures, and pulmonary artery pressure. An increase in the circulating volume may follow the use of the drug due to post- capillary vasoconstriction.

RS

Ephedrine is a respiratory stimulant and causes marked broncho- dilatation.

CNS

Ephedrine has a stimulatory effect similar to amphetamine; the cerebral blood flow increases after the administration of the drug. Mydriasis occurs, but light reflexes remain unaffected. The drug has local anaesthetic properties.

AS

The drug relaxes gastrointestinal smooth muscle and causes splanchnic vasoconstriction.

GU

Ephedrine constricts renal blood vessels and may lead to a decrease in both renal blood flow and glomerular filtration rate. The drug contracts the bladder sphincter and relaxes the detrusor muscle which may precipitate acute retention of urine. Ephedrine decreases the uterine tone. The drug does not cause alpha-1-mediated vasoconstriction of uterine blood vessels.

Metabolic/other

The drug increases the rate of hepatic glycogenolysis and may increase the basal metabolic rate. The drug has been shown to stimulate oxygen uptake and thermogenesis.

Toxicity/side effects

Insomnia, anxiety, tremor, headache, dysrhythmias, nausea and vomiting, and chest pain may complicate the use of the drug. Ephedrine is irritant to mucous membranes. An acute hypertensive crisis may be precipitated when the drug is administered to patients receiving MAOIs, doxapram, beta-blockers, oxytocin, and ergot alkaloids.

Kinetics

Absorption

Ephedrine is rapidly and completely absorbed when administered orally, intramuscularly, or subcutaneously.

Distribution

Ephedrine is rapidly and extensively distributed throughout the body, with accumulation in the liver, lungs, kidneys, spleen, and brain. The VD ranges from 122 to 320 l. Ephedrine crosses the placental barrier and is excreted into breast milk.

Metabolism

The drug is resistant to metabolism by monoamine oxidase and catechol-O-methyl transferase. A small amount of drug is metabolized in the liver by N-demethylation to phenylpropanolamine (norephedrine), the major metabolite, which may produce central stimulant effects. The drug is also deaminated, yielding benzoic acid, hippuric acid, and 1-phenylpropane-1,2-diol.

Excretion

55–99% of an administered dose is excreted unchanged in the urine. The elimination half-life is 6.3 hours (the half-life of norephedrine is 1.5–4 hours). The clearance is 13.6–44.3 l/hour. Urinary excretion is pH-dependent; elimination is enhanced, and the half-life is accordingly shorter in acidic urine. Excretion is reduced to 20–35% in the presence of an alkaline urine. Renal disease is likely to impair the elimination of ephedrine.

Special points

Tachyphylaxis occurs with prolonged use of the drug. Dysrhythmias occur with a greater frequency when ephedrine is used in the presence of halothane.

Clonidine premedication enhances the pressor effects of ephedrine.

Epoprostenol

Uses

Epoprostenol is used:

  1. 1. as an anticoagulant during renal replacement therapy and cardiopulmonary bypass and may be of use in the treatment of

  2. 2. pre-eclampsia

  3. 3. Raynaud’s disease

  4. 4. the haemolytic–uraemic syndrome, and

  5. 5. pulmonary hypertension.

Chemical

A prostanoid (formerly called prostacyclin, PGI2).

Presentation

As vials containing 500 micrograms of freeze-dried epoprostenol sodium, to be diluted before use in a mixture of sodium chloride and glycine.

Main action

Inhibition of platelet aggregation and vasodilation.

Mode of action

Epoprostenol stimulates adenylate cyclase, leading to an increase in the cAMP concentration within platelets; this, in turn, leads to inhibition of platelet phospholipase and COX, and ultimately of platelet aggregation.

Route of administration/doses

The drug may be administered intravenously or into the extracorporeal circulation; an infusion of 5 ng/kg/min should be started 15–30 minutes before dialysis is commenced and continued throughout the procedure. The effects of epoprostenol may persist for 30 minutes after cessation of an infusion.

Effects

CVS

The drug causes relaxation of vascular smooth muscle, leading to a decrease in the systemic vascular resistance, a slight tachycardia, and a decrease in the diastolic blood pressure.

RS

Epoprostenol causes a decrease in the PVR and interferes with the mechanism of hypoxic pulmonary vasoconstriction.

CNS

The drug produces cerebral vasodilation, leading to increased cerebral blood flow.

AS

Epoprostenol inhibits gastric acid secretion.

Metabolic/other

Epoprostenol is the most powerful inhibitor of platelet aggregation known; the bleeding time may double with high doses. It also appears to have a fibrinolytic effect and increases red cell deformability. The drug stimulates renin secretion and may cause an increase in blood sugar concentrations.

Toxicity/side effects

Facial flushing and headache occur commonly after the administration of the drug. Gastrointestinal upsets and chest, abdominal, and jaw pain have also been reported.

Kinetics

Data are incomplete.

Metabolism

Epoprostenol is rapidly removed from the circulation by hydrolysis to 6-oxo-PGF1 alpha in the blood and by metabolism to a bicyclic 15-oxo derivative in the tissues.

Excretion

The plasma half-life is 30 seconds to 3 minutes.

Special points

Epoprostenol extends the life of filters during renal replacement therapy and decreases the incidence of bleeding in these critically ill patients, compared to heparin.

Eptacog alfa

Uses

Eptacog alfa is used for the treatment of bleeding episodes and for the prevention of bleeding in the following patient groups undergoing surgery or an invasive procedure:

  1. 1. patients with congenital haemophilia with inhibitors to coagulation factors VIII or IX

  2. 2. patients with congenital haemophilia who may have an increased anamnestic response to factor VIII or IX administration

  3. 3. patients with acquired haemophilia

  4. 4. patients with congenital factor VII deficiency, and

  5. 5. patients with Glanzmann’s thrombasthenia.

Chemical

Activated coagulation factor VII produced using recombinant DNA technology from baby hamster kidney cells. The drug is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues. It has a molecular weight of 50 000 daltons.

Presentation

As a white, lyophilized powder together with a solvent for solution for injection. The solution formed has a pH of 6. Eptacog alfa (activated) is available in 1/2/5 mg vials equivalent to 50/100/250 kallikrein inhibitory units (KIU) (1 KIU equals to 1000 IU).

Main actions

Activation of coagulation cascade, leading to thrombin production.

Mode of action

Eptacog alfa (activated) binds to tissue factor, leading to activation of factors IX and X, resulting in the production of thrombin. In addition, the drug also causes the activation of factor X on the surface of platelets, independently of tissue factor.

Routes of administration/doses

The drug is administered intravenously as a bolus at a variety of dosages, depending on the indication. Eptacog alfa (activated) should be given as early as possible after the start of a bleeding episode or immediately prior to an invasive procedure. In patients with haemophilia A or B who have inhibitors or acquired haemophilia, the dose is 90 micrograms/kg, repeated at 2–3 hours initially, with further dose intervals of increasing duration of 4/6/8 or 12 hours, depending on the duration of treatment that is required. In patients with factor VII deficiency, the recommended dose is 15–30 micrograms/kg.

Effects

Metabolic/other

The main effect of the drug is its ability to increase the ability of the clotting cascade to produce thrombin.

Toxicity/side effects

In conditions where tissue factor expression may be greater than considered normal, use of the drug may lead to the development of DIC or thrombotic events. Severe atherosclerotic disease, septicaemia, crush injury, or DIC may lead to increased tissue factor expression. Hypersensitivity reactions may occur in individuals who have antibodies that react with trace elements of mouse immunoglobulin G (IgG), bovine IgG, and trace culture proteins.

Kinetics

Limited data are available on the pharmacokinetic properties of the drug. There appears to be a variation in values, depending on disease states.

Distribution

The VD is 130–165 ml/kg.

Metabolism

The metabolism of the drug is unknown, although, in rat models, hepatic metabolism has been implicated.

Excretion

The clearance is 33–37 ml/kg/hour. The terminal elimination half-life is in the range of 3.9–6 hours.

Special points

The drug should not be used in conjunction with prothrombin complex concentrates due to the potential increased risk of thrombotic events.

Inhibitory antibody formation may occur in patients with factor VII deficiency. This may correlate with an in vitro inhibitory effect.

Erythropoietin

Uses

Erythropoietin is used for the treatment of anaemia associated with:

  1. 1. chronic renal failure

  2. 2. cytotoxic chemotherapy

  3. 3. low birthweight prematurity and is also used

  4. 4. to increase the yield of autologous blood preoperatively.

Chemical

A glycoprotein.

Presentation

Two forms (alpha and beta) of the drug are available, which are clinically indistinguishable. Erythropoietin alpha is presented as a solution for injection containing 2000/4000/10 000 units/ml. Erythropoietin beta is presented as a solution for injection containing 500/1000/5000/10 000 units/ml and as a powder for reconstitution prior to injection.

Main action

Enhancement of erythropoiesis.

Mode of action

Erythropoietin specifically stimulates erythropoiesis by acting as a mitosis-stimulating factor and differentiation hormone.

Routes of administration/doses

The drug is preferably administered subcutaneously initially as 50 units/kg three times a week; the dose is adjusted every 4 weeks in 25 units/kg increments. The maintenance dose is usually 25–100 units/kg three times weekly. The intravenous dose is usually 20–30% greater than the subcutaneous dose. For increasing the yield of autologous blood preoperatively, the usual dose is 600 units/kg once or twice weekly for 3 weeks, together with iron supplementation.

Effects

CVS

The drug causes a dose-dependent increase in the blood pressure.

Metabolic/other

The primary effect of erythropoietin is to enhance erythropoiesis. It causes a dose-dependent increase in the platelet count, but not thrombocytosis.

Toxicity/side effects

Hypertension, influenza-like symptoms, and shunt thrombosis have been reported.

Kinetics

Data are incomplete and available only for patients with renal impairment.

Absorption

The bioavailability after subcutaneous administration is 23–42%.

Distribution

The VD is 5 l.

Excretion

The elimination half-life is 8–15 hours.

Special points

Erythropoietin is not removed by haemofiltration or haemodialysis.

Esmolol

Uses

Esmolol is effective in the treatment of:

  1. 1. acute supraventricular dysrhythmias (atrial fibrillation or flutter)

  2. 2. perioperative hypertension, and

  3. 3. hypotensive anaesthesia.

Chemical

An aryloxypropanolamine.

Presentation

As a clear solution for injection containing 10 mg/ml as 10/250 ml of esmolol hydrochloride.

Main action

Negative inotropism and chronotropism.

Mode of action

Esmolol acts by competitive blockade of beta-adrenoceptors; the drug is relatively selective for beta-1 receptors and has little or no intrinsic sympathomimetic activity.

Routes of administration/doses

The drug is administered by intravenous infusion (preferably via a peripheral vein), diluted in any crystalloid, with the exception of sodium bicarbonate, at a rate of 50–150 micrograms/kg/min according to response. Esmolol has a major advantage over other currently available beta-adrenergic antagonists in that its peak effects are observed within 6–10 minutes of administration and are almost completely attenuated 20 minutes after cessation of the infusion. The advantages of this ‘on–off’ control are obvious.

Effects

CVS

Esmolol causes a fall in the blood pressure and a dose-dependent fall in the heart rate; the cardiac output falls by about 20% (i.e. to a similar extent as with propranolol). It slows AV conduction at doses that have no effect on other haemodynamic or ECG variables. The drug will obtund the cardiovascular responses to intubation and sternotomy and protects against infarction in animal models of myocardial ischaemia.

RS

Esmolol appears to have little effect on airways resistance.

Toxicity/side effects

Hypotension, bradycardia, bronchospasm, nausea and vomiting, alteration of taste, and CNS disturbances may occur with use of the drug.

Kinetics

Distribution

Esmolol is 56% protein-bound in the plasma; the VD is 3.43 l/kg. Rapid, but limited, transplacental passage occurs in animal models.

Metabolism

Occurs primarily by hydrolysis by esterases located in red cells to methanol and a (major) primary acid metabolite which has weak beta-adrenergic antagonist activity, but a long elimination half-life of 3.5 hours.

Excretion

70–80% appears in the urine as the major acid metabolite; 1% is excreted unchanged. The clearance is 285 ml/min/kg, and the elimination half-life is 9.2 minutes. The drug should be used with caution in patients with renal impairment; hepatic disease has no effect.

Special points

The drug has no effect on the pharmacokinetics of co-administered morphine or digoxin; it has been shown to increase the recovery time from suxamethonium from 5.6 to 8.3 minutes.

Ether

Uses

Ether is used for the induction and maintenance of general anaesthesia.

Chemical

Diethyl ether.

Presentation

As a clear, colourless liquid (that should be protected from light) with a characteristic sweet smell. Ether is flammable in air at concentrations of 1.83–48% and explosive in oxygen at concentrations of 2–82%. The molecular weight of ether is 74, the boiling point 35°C, and the saturated vapour pressure 56.7 kPa at 20°C. The MAC of ether is 1.92, the oil/water solubility coefficient 3.2, and the blood/gas solubility coefficient 12. Ether is relatively inert but decomposes on exposure to air, heat, and light to produce acetaldehyde and ether peroxide. Ether is no longer commercially available in the United Kingdom (UK).

Main action

General anaesthesia (reversible loss of both awareness and recall of noxious stimuli) and analgesia.

Mode of action

The mechanism of general anaesthesia remains to be fully elucidated. General anaesthetics appear to disrupt synaptic transmission (especially in the area of the ventrobasal thalamus). This mechanism may include potentiation of the GABAA and glycine receptors and antagonism at NMDA receptors. Their mode of action at the molecular level appears to involve the expansion of hydrophobic regions in the neuronal membrane, either within the lipid phase or within hydrophobic sites in cell membranes.

Routes of administration/doses

Ether is administered by inhalation, conventionally via a calibrated vaporizer. The concentration used for the induction and maintenance of anaesthesia is 3–20%.

Effects

CVS

Ether is a negative inotrope in vitro; in vivo, sympathetic stimulation and catecholamine release and a vagolytic effect tend to offset this effect. The cardiac output is increased by 20%; the heart rate and systemic vascular resistance also increase, and the blood pressure is well maintained as a result. The drug causes dilatation of coronary arteries. Dysrhythmias are rare, and the drug does not sensitize the myocardium to the effects of circulating catecholamines. Light ether anaesthesia produces peripheral vasoconstriction, whereas deeper anaesthesia results in vasodilation (due to an effect on the vasomotor centre), causing a decrease in both the cardiac output and blood pressure.

RS

Ether is a respiratory stimulant; at light planes of anaesthesia the respiratory rate may exceed 30 breaths per minute; although the tidal volume decreases, the minute volume remains unaltered. The respiratory centre remains responsive to CO2 at light planes, and the PaCO2 remains constant. At deeper planes of anaesthesia, respiratory depression occurs, and intubation becomes possible without the aid of muscle relaxants. Ether vapour is irritant and may cause breath-holding and coughing if the inspired concentration is increased too rapidly. The drug causes bronchodilatation with no increase in bronchial secretions.

CNS

The principal effect of ether is general anaesthesia; the drug also has an analgesic effect. The drug causes cerebral vasodilation, leading to an increased cerebral blood flow and intracranial pressure. Ether decreases the intraocular pressure and causes progressive pupillary dilatation. Clonus may occur at light planes due to increased stretch receptor reflexes. Skeletal muscle tone decreases as anaesthesia deepens, as a result of both depression of spinal reflexes and a direct action on the neuromuscular junction. Depression of the medulla is a late event, occurring at very deep planes of anaesthesia.

AS

The drug increases both salivation and lacrimation. Ether decreases gastrointestinal motility; hepatic function and biliary secretion are also transiently decreased. Splenic contraction may also occur, resulting in an elevated haematocrit and white cell count.

GU

Ether causes renal arterial vasoconstriction and therefore decreases renal blood flow and the glomerular filtration rate; a small volume of concentrated urine results; albuminuria may also occur. The drug reduces the tone of the pregnant uterus.

Metabolic/other

Ether stimulates gluconeogenesis and may cause an increase in the blood sugar concentration. The drug occasionally causes metabolic acidosis in young children and patients unable to tolerate an increased lactate load.

Toxicity/side effects

The predominant disadvantages of ether are its inflammability and the high incidence of PONV (which occurs in 50% of patients who receive the agent). The dramatic increase in salivation produced by the drug necessitates the use of antisialogogue premedication. Convulsions and post-operative shivering may complicate the use of ether.

Kinetics

Absorption

The major factors affecting the uptake of volatile anaesthetic agents are solubility, cardiac output and the concentration gradient between the alveoli and venous blood. Ether is relatively soluble in blood; the alveolar concentration therefore reaches the inspired concentration relatively slowly, resulting in a slow induction of, and recovery from, anaesthesia. The irritant properties of the drug compound the slow induction. An increase in the cardiac output increases the rate of alveolar uptake and slows the induction of anaesthesia. The concentration gradient between alveoli and venous blood approaches zero at equilibrium; a large concentration gradient favours the onset of anaesthesia.

Distribution

The drug is initially distributed to organs with a high blood flow (brain, heart, liver, and kidney) and later to less well-perfused organs (muscles and fat).

Metabolism

2–3% of an administered dose is metabolized in the liver, to yield acetaldehyde, alcohol, acetic acid, and CO2.

Excretion

85–90% is exhaled unchanged; the metabolites are excreted in the urine.

Special points

Ether potentiates the action of co-administered non-depolarizing relaxants. Diathermy should be used with extreme caution (if at all) in the presence of ether. Ether is cheap and has a wide safety margin; it therefore retains a useful role for anaesthesia in difficult circumstances.

Etomidate

Uses

Etomidate is used:

  1. 1. for the intravenous induction of general anaesthesia

  2. 2. in treatment prior to surgery for Cushing’s syndrome.

Chemical

A carboxylated imidazole derivative.

Presentation

As a clear, colourless solution for injection containing 2 mg/ml of etomidate in an aqueous vehicle of 35% propylene glycol and water. Etomidate is a weak base with a pKa of 4.2. The pH of the aqueous solution is 8.1.

Main action

Hypnotic.

Mode of action

Etomidate appears to act upon GABA type A receptors to modulate fast inhibitory synaptic transmission within the CNS. In animal models, the beta-3 subunit of the GABAA receptor appears to have a role in etomidate-induced anaesthesia. It has a chiral centre resulting in enantiomers. The R(+) isomer of etomidate is ten times more potent than its S(−) isomer at potentiating GABAA receptor activity.

Routes of administration/dose

Etomidate is administered intravenously in a dose of 0.3 mg/kg; the drug acts in 10–65 seconds, with a duration of action of 6–10 minutes. In elderly patients, the dose should be reduced to 0.15–0.2 mg/kg. Etomidate is non-cumulative with repeated administration.

Effects

CVS

Etomidate is notable for its relative cardiovascular stability. Recommended doses of the drug may produce a slight decrease in the cardiac output and systemic vascular resistance, resulting in a mild degree of hypotension; tachycardia is produced only by high doses of the drug. Etomidate has little effect on myocardial or cerebral oxygen delivery and consumption. It does not alter sympathetic or baroreceptor reflexes, and therefore the haemodynamic responses may not be obtunded, unless concomitant administration of an opioid is given.

RS

The drug causes a dose-related decrease in the respiratory rate and tidal volume; transient apnoea, coughing, and hiccuping may occur. There are case reports of laryngospasm occurring, following the administration of etomidate.

CNS

Induction of anaesthesia with etomidate may be accompanied by the development of involuntary muscle movements (up to 50%), tremor, and hypertonus. The drug decreases the intracranial and intraocular pressures, the cerebral blood flow (by 20–30%), and the cerebral metabolic rate. Twenty percent of patients demonstrate generalized epileptiform EEG activity, following the administration of etomidate.

AS

2–15% of patients who have received the drug experience nausea and vomiting post-operatively; this is increased to 40% if an opiate is used.

Metabolic/other

Etomidate is a potent inhibitor of steroidogenesis. The drug inhibits adrenal 11-beta-hydroxylase and 17-alpha-hydroxylase, resulting in depression of cortisol and aldosterone synthesis for 24–48 hours. This effect is seen after single doses and infusions. Etomidate has significant antiplatelet activities. Prolongation of the bleeding time may occur, together with inhibition of ADP- and collagen-induced platelet aggregation.

Toxicity/side effects

25–50% of patients who receive etomidate experience pain on injection; the incidence of this is decreased by the addition of lignocaine, the use of larger veins, or an intravenous dose of fentanyl 1–2 minutes prior to the administration of the drug. Venous thrombosis and thrombophlebitis may occur. Myoclonus may occur in unpremedicated patients. Skeletal muscle movements appear to be commoner in patients who experience pain on injection. Most movements are bilateral. Histamine release and allergic phenomena are rare with the use of etomidate. In vitro studies have shown the drug to be an inhibitor of microsomal enzymes. Limited in vivo studies have demonstrated only minimal inhibition of hepatic metabolism.

The use of etomidate infusions for the sedation of critically ill patients is associated with an increased mortality and is contraindicated. There is no conclusive evidence that anaesthetic doses of etomidate have any effect on morbidity or mortality. However, recent data have questioned the safety of using etomidate for single-bolus administration in patients at risk of adrenal insufficiency. The results of a double-blind randomized controlled trial comparing etomidate with midazolam for intubation of patients with sepsis is awaited.

Kinetics

Distribution

Etomidate is 76.5% protein-bound in the plasma; the VD is approximately 4.5 l/kg. The relatively brief duration of action of a bolus of the drug is due to the rapid redistribution to muscle and later to fat.

Metabolism

Occurs rapidly by plasma and hepatic esterases to yield inactive carboxylic metabolites.

Excretion

Between 75% and 87% of an administered dose is excreted in the urine (80% of which comprise the chief metabolite R-(+)-1-(1-phenyethyl)-1H-imidazole-5-carboxylic acid). Two to 3% is excreted unchanged in the urine. The remainder is excreted in the bile. The clearance is 870–1700 ml/min (this is reduced by 31% in the presence of 67% N2O); the elimination half-life is 1–4.7 hours, reflecting the slow distribution of etomidate from the deep peripheral compartment. Data suggest that, in patients with cirrhosis and oesophageal varices, etomidate has a VD and elimination half-life approximately twice those of healthy subjects.

Special points

Etomidate is porphyrinogenic in animal models and in vitro. The drug may cross the placenta during obstetric anaesthesia. The drug should not be mixed with pancuronium.

Etomidate has been formulated as a lipid emulsion which appears to be less irritant on injection. The lipid formulation has also been shown to have a faster onset of action, compared with the standard preparation.

Copyright © 2021. All rights reserved.