Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 20) ppt

Doctors from a variety of specialties use local anaesthetics and the pharmacology of these drugs is discussed in Obstetric analgesia and anaesthesia Anaesthesia in patients already takin

Anaesthesia and neuromuscular

block

SYNOPSIS

The administration of general anaesthetics and

neuromuscular blocking drugs is generally

confined to trained specialists Nevertheless,

nonspecialists are involved in perioperative

care and will benefit from an understanding of

how these drugs act Doctors from a variety of

specialties use local anaesthetics and the

pharmacology of these drugs is discussed in

Obstetric analgesia and anaesthesia

Anaesthesia in patients already taking drugs

Anaesthesia in the diseased, the elderly and

children; sedation in intensive therapy units

General anaesthesia

Until the mid-19th century such surgery as was

possible had to be undertaken at tremendous speed

Surgeons did their best for terrified patients by

using alcohol, opium, hyoscine,1 or cannabis With

the introduction of general anaesthesia, surgeons

could operate for the first time with careful eration The problem of inducing quick, safe andeasily reversible unconsciousness for any desiredlength of time in man only began to be solved inthe 1840s when the long-known substances nitrousoxide, ether, and chloroform were introduced inrapid succession

delib-The details surrounding the first use of surgicalanaesthesia were submerged in bitter disputes onpriority following an attempt to take out a patentfor ether The key events around this time were:

• 1842 — W E Clarke of Rochester, New York,administered for a dental extraction However,this event was not made widely known at thetime

• 1844 — Horace Wells, a dentist in Hartford,Connecticut, introduced nitrous oxide toproduce anaesthesia during dental extraction

• 1846 — On October 16 William Morton, a Bostondentist, successfully demonstrated the

anaesthetic properties of ether

• 1846 — On December 21 Robert Listonperformed the first surgical operation in Englandunder ether anaesthesia.2

1 A Japanese pioneer of about 1800 wished to test the anaesthetic efficacy of a herbal mixture including solanaceous plants (hyoscine-type alkaloids) His elderly mother volunteered as subject since she was anyway expected to die soon But the pioneer administered it to his wife for, 'as all three agreed, he could find another wife, but could never get another mother' (Journal of the American Medical Association 1966 197:10).

18A N A E S T H E S I A AND N E U R O M U S C U L A R B L O C K

• 1847 — James Y Simpson, professor of

midwifery at the University of Edinburgh,

introduced chloroform for the relief of labour

pain

The next important developments in anaesthesia

were in the 20th century when the appearance of

new drugs both as primary general anaesthetics

and as adjuvants (muscle relaxants), new apparatus,

and clinical expertise in rendering prolonged

anaes-thesia safe, enabled surgeons to increase their range

No longer was the duration and type of surgery

determined by patients' capacity to endure pain

STAGES OF GENERAL ANAESTHESIA

Surgical anaesthesia is classically divided into four

stages: analgesia, delirium, surgical anaesthesia

(subdivided into four planes), and medullary

paralysis (overdose) This gradual procession of

stages was described when ether was given to

un-premedicated patients, a slow unpleasant process

Ether is obsolete and the speed of induction with

modern inhalational agents or intravenous

anaes-thesia drugs makes a detailed description of these

separate stages superfluous

Balanced surgical anaesthesia (hypnosis with

analgesia and muscular relaxation) with a single

drug requires high doses that will cause adverse

effects such as slow and unpleasant recovery, and

depression of cardiovascular and respiratory

func-tion In modern practice, different drugs are used to

attain each objective so that adverse effects are

minimised

DRUGS USED

The perioperative period may be divided into three

phases and in each of these a variety of factors will

determine the choice of drugs given:

2 Frederick Churchill, a butler from Harley Street, had his leg

amputated at University College Hospital, London After

removing the leg in 28 seconds, a skill necessary to

compensate for the previous lack of anaesthetics, Robert

Listen turned to the watching students, and said "this

Yankee dodge, gentlemen, beats mesmerism hollow" That

night he anaesthetised his house surgeon in the presence of

two ladies Merrington W R1976 University College

Hospital and its Medical School: A History Heinemann,

London.

Before surgery, an assessment is made of:

• the patient's physical and psychologicalcondition

• any intercurrent illness

• the relevance of any existing drug therapy.All of these may influence the choice of anaestheticdrugs

During surgery, drugs will be required to provide:

• unconsciousness

• analgesia

• muscular relaxation when necessary

• control of blood pressure, heart rate, andrespiration

After surgery, drugs will play a part in:

• reversal of neuromuscular block

• relief of pain, and nausea and vomiting

• other aspects of postoperative care, includingintensive care

Patients are often already taking drugs affectingthe central nervous and cardiovascular systems andthere is considerable potential for interaction withanaesthetic drugs

The techniques for giving anaesthetic drugs andthe control of ventilation and oxygenation are ofgreat importance, but are outside the scope of thisbook

Before surgery (premedication)

The principal aims are to provide:

Anxiolysis and amnesia A patient who is going tohave a surgical operation is naturally apprehensiveand this anxiety is reduced by reassurance and aclear explanation of what to expect Very anxiouspatients will secrete a lot of adrenaline (epineph-rine) from the suprarenal medulla and this maymake them more liable to cardiac arrhythmiaswith some anaesthetics In the past, sedative pre-medication was given to virtually all patients under-going surgery This practice has changed dramaticallybecause of the increasing proportion of operationsundertaken as 'day cases' and the recognition thatsedative premedication prolongs recovery Sedativepremedication is now reserved for those who are

particularly anxious or those undergoing major

surgery

Benzodiazepines, such as temazepam (10-30mg

for an adult), provide anxiolysis and amnesia for

the immediate presurgical period

Analgesia is indicated if the patient is in pain

preoperatively or it can be given pre-emptively to

prevent postoperative pain Severe preoperative

pain is treated with a parenteral opioid such as

morphine Nonsteroidal anti-inflammatory drugs

and paracetamol are commonly given orally

pre-operatively to prevent postoperative pain after minor

surgery For moderate or major surgery, these drugs

are supplemented with an opioid towards the end

of the procedure

Drying of bronchial and salivary secretions using

antimuscarinic drugs to inhibit the parasympathetic

autonomic system is rarely undertaken these days

The exceptions include those patients who are

expected to require an awake fibreoptic intubation

or those undergoing bronchoscopy Glycopyrronium

is the antimuscarinic of choice for this purpose and

atropine and hyoscine are alternatives

Timing Premedication is given about an hour

before surgery

Gastric contents Pulmonary aspiration of gastric

contents can cause severe pneumonitis Patients at

risk of aspiration are those with full stomachs, e.g.,

bowel obstruction, recently consumed food and

drink, third trimester of pregnancy, and those with

incompetent gastro-oesophageal sphincters, e.g

hiatus hernia A single dose of an antacid, e.g sodium

citrate, may be given before a general anaesthetic to

neutralise gastric acid in high-risk patients

Alter-natively or additionally, a histamine H2-receptor

blocker, e.g ranitidine, or proton-pump inhibitor,

e.g omeprazole, will reduce gastric secretion volume

as well as acidity Metoclopramide usefully hastens

gastric emptying, increases the tone of the lower

oesophageal sphincter and is an antiemetic

During surgery

The aim is to induce unconsciousness, analgesia

and muscular relaxation Total muscular relaxation

G E N E R A L A N A E S T H E S I A

(paralysis) is required for some surgical procedures,e.g., intra-abdominal surgery, but most surgery can

be undertaken without neuromuscular blockade

A typical general anaesthetic consists of:

• Induction:

1 Usually intravenous: pre-oxygenation followed

by a small dose of an opioid, e.g., fentanyl oralfentanil to provide analgesia and sedation,followed by propofol or, less commonly,thiopental or etomidate to induce anaesthesia.Airway patency is maintained with an oralairway and face-mask, a laryngeal mask air-way (LMA), or a tracheal tube Insertion of atracheal tube usually requires paralysis with aneuromuscular blocker and is undertaken ifthere is a risk of pulmonary aspiration fromregurgitated gastric contents or from blood

2 Inhalational induction, usually with flurane, is undertaken taken less commonly It

sevo-is used in children, particularly if intravenousaccess is difficult, and in patients at risk fromupper airway obstruction

• Maintenance:

1 Most commonly with nitrous oxide and

oxy-gen, or oxygen and air, plus a volatile agent,e.g., isoflurane or sevoflurane Additional doses

of a neuromuscular blocker or opioid are given

as required

2 A continuous intravenous infusion of propofolcan be used to maintain anaesthesia This

technique of total intravenous anaesthesia is

becoming more popular because the quality ofrecovery may be better than after inhalationalanaesthesia

When appropriate, peripheral nerve block with alocal anaesthetic, or neural axis block, e.g., spinal orepidural, provides intraoperative analgesia andmuscle relaxation These local anaesthetic techniquesprovide excellent postoperative analgesia

After surgery

The anaesthetist ensures that the effects of muscular blocking agents and opioid-induced res-piratory depression have either worn off or havebeen adequately reversed by an antagonist; thepatient is not left alone until conscious, withprotective reflexes restored, and a stable circulation

neuro-18A N A E S T H E S I A A N D N E U R O M U S C U L A R B L O C K

Relief of pain after surgery can be achieved with a

variety of techniques An epidural infusion of a

mixture of local anaesthetic and opioid provides

excellent pain relief after major surgery such as

laparotomy Parenteral morphine, given

intermit-tently by a nurse or by a patient-controlled system,

will also relieve moderate or severe pain but has the

attendant risk of nausea, vomiting, sedation and

respiratory depression The addition of regular

paracetamol and a NSAID, given orally or rectally,

will provide additional pain relief and reduce the

requirement for morphine NSAIDs are

contra-indicated if there is a history of gastrointestinal

ulceration of if renal blood flow is compromised

Postoperative nausea and vomiting (PONV) is

common after laparotomy and major gynaecological

surgery, e.g., abdominal hysterectomy The use

of propofol, particularly when given to maintain

anaesthesia, has dramatically reduced the incidence

of PONV Antiemetics, such as cyclizine,

metoclo-pramide, and ondansetron, may be helpful

SOME SPECIALTECHNIQUES

Dissociative anaesthesia is a state of profound

analgesia and anterograde amnesia with minimal

hypnosis during which the eyes may remain open

(see ketamine, p 353) It is particularly useful where

modern equipment is lacking or where access to the

patient is limited, e.g at major accidents or on

battlefields

Sedation and amnesia without analgesia are

provided by midazolam i.v or, less commonly

nowadays, diazepam These drugs can be used

alone for procedures causing mild discomfort, e.g

endoscopy, and with a local anaesthetic where more

pain is expected, e.g., removal of impacted wisdom

teeth Benzodiazepines produce anterograde, but

not retrograde, amnesia By definition, the sedated

patient remains responsive and cooperative (For a

general account of benzodiazepines and the

com-petitive antagonist flumazenil, see Ch 19.)

Benzodiazepines can cause respiratory

depres-sion and apnoea especially in the elderly and in

patients with respiratory insufficiency The

com-bination of an opioid and a benzodiazepine is

particularly dangerous Benzodiazepines depresslaryngeal reflexes and place the patient at risk ofinhalation of oral secretions or dental debris

Entonox, a 50:50 mixture of nitrous oxide and

oxygen, is breathed by the patient using a demandvalve It is particularly useful in the prehospitalenvironment and for brief procedures, such assplinting limbs

Pharmacology of anaesthetics

All successful general anaesthetics are given venously or by inhalation because these routesallow closest control over blood concentrations and

intra-so of effect on the brain

MODE OF ACTION

General anaesthetics act on the brain, primarily

on the midbrain reticular activating system Manyanaesthetics are lipid soluble and there is goodcorrelation between this and anaesthetic effective-ness (the Overton-Meyer hypothesis); the morelipid soluble tend to be the more potent anaes-thetics, but such a correlation is not invariable.Some anaesthetic agents are not lipid soluble andmany lipid soluble substances are not anaesthetics.Until recently it was thought that the principal site

of action of general anaesthetics was the neuronallipid bilayer membrane The current view is thattheir anaesthetic activity is caused by interactionwith protein receptors It is likely that there areseveral modes of action, but the central mechanism

of action of volatile anaesthetics is thought to befacilitation at the inhibitory y-aminobutyric acid(GABAA) and glycine receptors Agonists at thesereceptors open chloride ion channels and the influx

of chloride ions into the neuron results in polarisation This prevents propagation of nerveimpulses and renders the patient unconscious Somegeneral anaesthetics increase the time that thechloride channels are open while others increasethe frequency of chloride channel opening

ASSESSMENT OF ANAESTHETIC

AGENTS

Comparison of the efficacy of inhalational agents is

made by measuring the minimum alveolar

concen-tration (MAC) in oxygen required to prevent

move-ment in response to a standard surgical skin incision

in 50% of subjects The MAC of the volatile agent is

reduced by the co-administration of nitrous oxide

Inhalation anaesthetics

PREFERRED ANAESTHETICS

The preferred inhalation agents are those that are

minimally irritant and nonflammable, and comprise

nitrous oxide and the fluorinated hydrocarbons,

e.g., isoflurane

PHARMACOKINETICS (VOLATILE

LIQUIDS, GASES)

The level of anaesthesia is correlated with the

tension (partial pressure) of anaesthetic drug in the

brain tissue and this is dependent on the

develop-ment of a series of tension gradients from the high

partial pressure delivered to the alveoli and

decreasing through the blood to the brain and other

tissues These gradients are dependent on the

blood/gas and tissue/gas solubility coefficients, as

well as on alveolar ventilation and organ blood

flow

An anaesthetic that has high solubility in blood,

i.e., a high blood/gas partition coefficient, will

provide a slow induction and adjustment of the

depth of anaesthesia This is because the blood acts

as a reservoir (store) for the drug so that it does not

enter the brain easily until the blood reservoir has

been filled A rapid induction can be obtained by

increasing the concentration of drug inhaled initially

and by hyperventilating the patient

Agents that have low solubility in blood, i.e., a

low blood/gas partition coefficient (nitrous oxide,

sevoflurane), provide a rapid induction of

anaes-thesia because the blood reservoir is small and

agent is available to pass into the brain sooner

I N H A L A T I O N A G E N T S

During induction of anaesthesia the blood istaking up anaesthetic agent selectively and rapidlyand the resulting loss of volume in the alveoli leads

to a flow of agent into the lungs that is independent

of respiratory activity When the anaesthetic isdiscontinued the reverse occurs and it moves fromthe blood into the alveoli In the case of nitrousoxide, this can account for as much as 10% of theexpired volume and so can significantly lower thealveolar oxygen concentration Thus mild hypoxiaoccurs and lasts for as long as 10 minutes Thoughharmless to most, it may be a factor in cardiac arrest

in patients with reduced pulmonary and cardiacreserve, especially when administration of the gashas been at high concentration and prolonged,when the outflow is especially copious Oxygenshould therefore be given to such patients duringthe last few minutes of anaesthesia and the early

postanaesthetic period This phenomenon, diffusion hypoxia, occurs with all gaseous anaesthetics, but is

most prominent with gases that are relativelyinsoluble in blood, for they will diffuse out mostrapidly when the drug is no longer inhaled, i.e just

as induction is faster, so is elimination Nitrousoxide is especially powerful in this respect because

it is used at concentrations of up to 70% Highlyblood-soluble agents will diffuse out more slowly,

so that recovery will be slower just as induction

is slower, and with them diffusion hypoxia isinsignificant

NITROUS OXIDE

Nitrous oxide (1844) is a gas with a slightly sweetishsmell It is neither flammable nor explosive Itproduces light anaesthesia without demonstrablydepressing the respiratory or vasomotor centreprovided that normal oxygen tension is maintained

Advantages Nitrous oxide reduces the

require-ment for other more potent and intrinsically moretoxic anaesthetic agents It has a strong analgesicaction; inhalation of 50% nitrous oxide in oxygen(Entonox) may have similar effects to standard doses

of morphine Induction is rapid and not unpleasantalthough transient excitement may occur, as withall agents Recovery time rarely exceeds 4 min evenafter prolonged administration

18A N A E S T H E S I A AND N E U R O M U S C U L A R B L O C K

Disadvantages Nitrous oxide is expensive to buy

and to transport It must be used in conjuction with

more potent anaesthetics to produce full surgical

anaesthesia

Uses Nitrous oxide is used to maintain surgical

anaesthesia in combination with other anaesthetic

agents, e.g., isoflurane or propofol, and, if required,

muscle relaxants Entonox provides analgesia for

obstetric practice, for emergency management of

injuries, and during postoperative physiotherapy

Dosage and administration For the maintenance

of anaesthesia, nitrous oxide must always be mixed

with at least 30% oxygen For analgesia, a

concen-tration of 50% nitrous oxide with 50% oxygen

usually suffices

Contraindications Any closed, distendable

air-filled space expands during administration of

nitrous oxide, which moves into it from the blood It

is therefore contraindicated in patients with:

demon-strable collections of air in the pleural, pericardial

or peritoneal spaces; intestinal obstruction; arterial

air embolism; decompression sickness; severe

chronic obstructive airway disease; emphysema

Nitrous oxide will cause pressure changes in closed,

noncompliant spaces such as the middle ear, nasal

sinuses, and the eye

Precautions Continued administration of oxygen

may be necessary during recovery, especially in

elderly patients (see diffusion hypoxia, above)

Adverse effects The incidence of nausea and

vomiting increases with the duration of

anaes-thesia Nitrous oxide interferes with the synthesis of

methionine, deoxythymidine and DNA Exposure

of to nitrous oxide for more than 4 hours can cause

megaloblastic changes in the bone marrow Because

prolonged and repeated exposure of staff as well as

of patients may be associated with bone-marrow

de-pression and teratogenic risk, scavenging systems

are used to minimise ambient concentrations in

operating theatres

Drug interactions Addition of 50% nitrous oxide/

oxygen mixture to another inhalational anaesthetic

reduces the required dosage (minimum alveolarconcentration, MAC) of the latter by about 50%

Storage Nitrous oxide is supplied under pressure

in cylinders, which must be maintained below25°C Cylinders containing premixed oxygen 50%and nitrous oxide 50% (Entonox) are available foranalgesia The constituents separate out at -7°C, inwhich case adequate mixing must be assured beforeuse

HALOGENATED ANAESTHETICS

Halothane was the first halogenated agent to beused widely, but in the developed world it has beenlargely superseded by isoflurane and sevoflurane

We provide a detailed description of isoflurane, and

of the others in so far as they differ The MAC ofsome volatile agents is:

a pungent odour and can cause bronchial irritation,which makes inhalational induction unpleasant.Isoflurane is minimally metabolised (0.2%), andnone of the breakdown products has been related toanaesthetic toxicity

Respiratory effects Isoflurane causes respiratory

depression: the respiratory rate increases, tidal ume decreases, and the minute volume is reduced.The ventilatory response to carbon dioxide isdiminished Although it irritates the upper airway

vol-it is a bronchodilator

Cardiovascular effects Anaesthetic concentrations

of isoflurane, i.e 1-1.5 MAC, cause only a slightimpairment of myocardial contractility and strokevolume and cardiac output is usually maintained

by a reflex increase in heart rate Isoflurane causes

peripheral vasodilatation and reduces blood

press-ure It does not affect atrioventricular conduction

and does not sensitise the heart to catecholamines

Low concentrations of isoflurane (< 1 MAC) do not

increase cerebral blood flow or intracranial

press-ure, and cerebral autoregulation is maintained

Isoflurane is a potent coronary vasodilator and in

the presence of a coronary artery stenosis it may

cause redistribution of blood away from an area of

inadequate perfusion to one of normal perfusion

This phenomenon of 'coronary steal' may cause

regional myocardial ischaemia

Other effects Isoflurane relaxes voluntary muscles

and potentiates the effects of nondepolarising

muscle relaxants Isoflurane depresses cortical EEG

activity and does not induce abnormal electrical

activity or convulsions

Sevoflurane is a chemical analogue of isoflurane.

It is less chemically stable than the other volatile

anaesthetics in current use About 3% is metabolised

in the body and it is degraded by contact with

carbon dioxide absorbents, such as soda lime The

reaction with soda lime causes the formation of a

vinyl ether (Compound A), which may be

nephro-toxic Sevoflurane is less soluble than isoflurane

and is very pleasant to breathe, which makes it an

excellent choice for inhalational induction of

anaes-thesia, particularly in children The respiratory and

cardiovascular effects of Sevoflurane are very similar

to isoflurane

Enflurane is a structural isomer of isoflurane It is

more soluble than isoflurane It causes more

respiratory depression than the other volatile

anaesthetics and hypercapnia is almost inevitable

in patients breathing spontaneously It causes more

cardiovascular depression than isoflurane and is

occasionally associated with cardiac arrythmias

Two percent of enflurane is metabolised and

prolonged administration or use in enzyme-induced

patients generates sufficient free inorganic fluoride

from the drug molecule to cause polyuric renal

failure There have been a few cases of jaundice and

heptatoxicity associated with enflurane but the

incidence of about one in 1-2 million anaesthetics is

lower than with halothane

I N H A L A T I O N A G E N T S

Desflurane has the lowest blood/gas partition

co-efficient of any inhaled anaesthetic agent and thusgives particularly rapid onset and offset of effect

As it undergoes negligible metabolism (0.03%), anyrelease of free inorganic fluoride is minimised; thischaracteristic favours its use for prolonged anaes-thesia Desflurane is extremely volatile and cannot

be administered with conventional vaporisers Ithas a very pungent odour and causes airwayirritation to an extent that limits its rate of induction

of anaesthesia

Halothane has the highest blood/gas partition

coefficient of the volatile anaesthetic agents andrecovery from halothane anaesthesia is compara-tively slow It is pleasant to breathe and is secondchoice to Sevoflurane for inhalational induction

of anaesthesia Halothane reduces cardiac outputmore than any of the other volatile anaesthetics Itsensitises the heart to the arrhythmic effects ofcatecholamines and hypercapnia; arrhythmias arecommon, in particular atrioventricular dissociation,nodal rhythm and ventricular extrasystoles Halo-thane can trigger malignant hyperthermia in thosewho are genetically predisposed (see p 363).About 20% of halothane is metabolised and itinduces hepatic enzymes, including those of anaes-thetists and operating theatre staff Hepatic damageoccurs in a small proportion of exposed patients.Typically fever develops 2 or 3 days after anaes-thesia accompanied by anorexia, nausea and vomit-ing In more severe cases this is followed by transientjaundice or, very rarely, fatal hepatic necrosis Severehepatitis is a complication of repeatedly administeredhalothane anaesthesia and has an incidence of1:50000 It follows immune sensitisation to anoxidative metabolite of halothane in susceptibleindividuals This serious complication, along with theother disadvantages of halothane and the popularity

of sevoflurane for inhalational induction, has almosteliminated its use in the developed world Itremains in common use other parts of the worldbecause it is comparatively inexpensive

OXYGEN IN ANAESTHESIA

Supplemental oxygen is always used with tional agents to prevent hypoxia, even when air isused as the carrier gas The concentration of oxygen

inhala-18AN A E S T H E S I A AND N E U R O M U S C U L A R B L O C K

in inspired anaesthetic gases is usually at least 30%,

but oxygen should not be used for prolonged

periods at a greater concentration than is necessary

to prevent hypoxaemia After prolonged

adminis-tration, concentrations greater than 80% have a

toxic effect on the lungs, which presents initially as

a mild substernal irritation progressing to

pul-monary congestion, exudation and atelectasis Use

of unnecessarily high concentrations of oxygen in

incubators causes retrolental fibroplasia and

per-manent blindness in premature infants

Oxygen is supplied under pressure in cylinders,

when it remains in the gaseous state In most

hospitals a vacuum insulated evaporator is used to

store oxygen in liquid form This provides for huge

volumes of gaseous oxygen and will supply all the

piped oxygen outlets in the hospital

ATMOSPHERIC POLLUTION OF

OPERATING THEATRES

Pollution by inhalation anaesthetics has been

suspected of being harmful to theatre personnel

Epidemiological studies have raised questions

relating to excess of fetal malformations and

mis-carriages, hepatitis and cancer in operating theatre

personnel Sensible use of preventive measures

renders the risks negligible, e.g use of circle systems

that allow low fresh gas flows, scavenging systems,

and improved ventilation of theatres The increasing

use of total intravenous anaesthesia (TIVA) and

regional anaesthesia will also reduce pollution

Intravenous anaesthetics

Intravenous anaesthetics should be given only by

those fully trained in their use and who are

experi-enced with a full range of techniques of managing

the airway, including tracheal intubation

PHARMACOKINETICS

Intravenous anaesthetics allow an extremely rapid

induction because the blood concentration can be

raised rapidly, establishing a steep concentration

gradient and expediting diffusion into the brain

The rate of transfer depends on the lipid solubilityand arterial concentration of the unbound, non-ionised fraction of the drug After a single, inductiondose of an intravenous anaesthetic recovery occursquite rapidly as the drug is redistributed aroundthe body and the plasma concentration reduces.Recovery from a single dose of intravenous anaes-thetic is not related to its rate of metabolic break-down With the exception of propofol, repeateddoses or infusions of intravenous anaesthetics willresult in considerable accumulation and prolongedrecovery Attempts to use thiopental as the soleanaesthetic in war casualties led to its being described

as an ideal form of euthanasia.3 It is common practice

to induce anaesthesia intravenously and then to use

a volatile anaesthetic for maintenance Whenadministration of a volatile anaesthetic is stopped,

it is eliminated quickly through the lungs and thepatient regains consciousness The recovery frompropofol is rapid, even after repeat doses or aninfusion This advantage, and others, has resulted inpropofol displacing thiopental as the most popularintravenous anaesthetic

Propofol

Propofol (2,6-diisopropylphenol) is available as a1% or 2% emulsion, which contains soya bean oiland purified egg phosphatide Induction of anaes-thesia with 1.5-2.5 mg/kg occurs within 30 secondsand is smooth and pleasant with a low incidence

of excitatory movements It causes pain on injectionbut adding lidocaine 20 mg to an ampoule ofpropofol eliminates this The recovery from propofol

is rapid and the incidence of nausea and vomiting isextremely low, particularly when propofol is used

as the sole anaesthetic Recovery from a continuousinfusion of propofol is relatively rapid On stoppingthe infusion the plasma concentration decreasesrapidly as a result of both redistribution and clear-ance of the drug Special syringe pumps incor-porating pharmacokinetic algorithms allow theanaesthetist to select a target plasma propofol con-centration (e.g 6 micrograms/ml for induction ofanaesthesia) once details of the patient's age andweight have been entered This technique of target-

3 Halford J J 1943 A critique of intravenous anaesthesia in war surgery Anesthesiology 4: 67.

controlled infusion (TCI) provides a convenient

method for giving a continuous infusion of propofol

Central nervous system Propofol causes

dose-dependent cortical depression and is an

anticon-vulsant It depresses laryngeal reflexes more than

barbiturates, which is an advantage when inserting

a laryngeal mask airway

Cardiovascular system Propofol reduces vascular

tone, which lowers systemic vascular resistance and

central venous pressure The heart rate remains

unchanged and the result is a fall in blood pressure

to about 70-80% of the preinduction level and a

small reduction in cardiac output

Respiratory system Unless it is undertaken very

slowly, induction with propofol causes transient

apnoea On resumption of respiration there is a

reduction in tidal volume and increase in rate

Metabolism Propofol is conjugated in the liver by

glucuronidation making it more water soluble; 88%

then appears in the urine and 2% in the faeces

Thiopental (thiopentone)

Thiopental is a very short-acting barbiturate, which

induces anaesthesia smoothly, within one

arm-to-brain circulation time The typical induction dose

is 3-5mg/kg Rapid distribution (initial t1/2 4min)

allows swift recovery after a single dose The

terminal t l / 2 of thiopental is 11 h and repeated doses

or continuous infusion lead to significant

accumu-lation in fat and very prolonged recovery Thiopental

is metabolised in the liver The incidence of nausea

and vomiting after thiopental is slightly higher than

after propofol The pH of thiopental is 11 and

considerable local damage results if it extravasates

Accidental intra-arterial injection will also cause

serious injury distal to the injection site

Central nervous system Thiopental has no

anal-gesic activity and may be antanalanal-gesic It is a potent

anticonvulsant Cerebral metabolic rate of oxygen

consumption (CMRO2) is reduced, which leads

to cerebral vasoconstriction with a concomitant

reduction in cerebral blood flow and intracranial

pressure

I N T R A V E N O U S A G E N T S

Cardiovascular system Thiopental reduces cular tone, causing hypotension and a slight com-pensatory increase in heart rate Antihypertensives

vas-or diuretics may augment the hypotensive effect

Respiratory system Thiopental reduces respiratoryrate and tidal volume

Methohexitone is a barbiturate similar to thiopental

but its terminal t l / 2 is considerably shorter Since theintroduction of propofol, its use is almost entirelyconfined to inducing anaesthesia for electrocontro-vulsive therapy (ECT) Propofol shortens seizureduration and may reduce the efficacy of ECT

Etomidate is a carboxylated imidazole, which isformulated in a mixture of water and propyleneglycol It causes pain on injection and excitatorymuscle movements are common on induction ofanaesthesia It is associated with a 20% incidence ofnausea and vomiting Etomidate causes adreno-cortical suppression by inhibiting 11 (3- and 17 [3-hydroxylase and for this reason is not used forprolonged infusion; single bolus doses cause short-lived, clinically insignificant adrenocortical sup-pression Despite all these disadvantages it remains

in common use, particularly for emergency thesia, because it causes less cardiovascular depres-sion and hypotension than thiopental or propofol

anaes-Ketamine

Ketamine is a phencyclidine (hallucinogen) tive and an antagonist of the NMDA-receptor.4 Inanaesthetic doses it produces a trance-like state

deriva-known as dissociative anaesthesia (sedation, amnesia,

dissociation, analgesia)

Advantages Anaesthesia persists for up to 15 minafter a single intravenous injection and is charac-terised by profound analgesia Ketamine may beused as the sole analgesic agent for diagnostic andminor surgical interventions In contrast to mostother anaesthetic drugs, ketamine usually produces

a tachycardia and increases blood pressure andcardiac output This effect makes it a popular choicefor inducing anaesthesia in shocked patients The

4 N-methyl-D-aspartate.

18 AN A E S T H ESI A AN D N E U R O M U S C U L A R B L O C K

cardiovascular effects of ketamine are accompanied

by an increase in plasma noradrenaline

(norepi-nephrine) concentration Because pharyngeal and

laryngeal reflexes are only slightly impaired, the

airway may be less at risk than with other general

anaesthetic techniques It is a potent bronchodilator

and is sometimes used to treat severe bronchospasm

in those asthmatics requiring mechanical ventilation

(See also Dissociative anaesthesia, p 348.)

Disadvantages Ketamine produces no muscular

relaxation It increases intracranial and intraocular

pressure Hallucinations can occur during recovery

(the emergence reaction), but they are minimised if

ketamine is used solely as an induction agent and

followed by a conventional inhalational anaesthetic

Their incidence is reduced by administration of a

benzodiazepine both as a premedication and after

the procedure

Uses Subanaesthetic doses of ketamine can be

used to provide analgesia for painful procedures of

short duration such as the dressing of burns,

radio-therapeutic procedures, marrow sampling and minor

orthopaedic procedures Ketamine can be used for

induction of anaesthesia prior to administration of

inhalational anaesthetics, or for both induction and

maintenance of anaesthesia for short-lasting

diag-nostic and surgical interventions, including dental

procedures that do not require skeletal muscle

relaxation It is of particular value for children

requiring frequent repeated anaesthetics

Dosage and administration Premedication with

atropine will reduce the salivary secretions produced

by ketamine and a benzodiazepine will reduce the

incidence of hallucinations

Induction Intravenous route: 1-2 mg/kg by slow

intravenous injection over a period of 60 seconds

A dose of 2 mg/kg produces surgical anaesthesia

within 1-2 min, which will last 5-10 min

Intra-muscular route: 5-10 mg/kg by deep intraIntra-muscular

injection This dose produces surgical anaesthesia

within 3-5 min and may be expected to last up to

25 min

Maintenance Following induction, serial doses of

50% of the original intravenous dose or 25% of the

intramuscular dose is given to prevent movement

in response to surgical stimuli Tonic and clonicmovements resembling seizures occur in somepatients These do not indicate a light plane ofanaesthesia or a need for additional doses of theanaesthetic

A dose of 0.5 mg/kg i.m or i.v provides excellentanalgesia and may be supplemented by furtherdoses of 0.25 mg/kg

Recovery Return to consciousness is gradual.Emergence reactions with delirium may occur.Their incidence is reduced by benzodiazepine pre-medication and by avoiding unnecessary disturb-ance of the patient during recovery

Contraindications include: moderate to severehypertension, congestive cardiac failure or a history

of stroke; acute or chronic alcohol intoxication,cerebral trauma, intracerebral mass or haemorrhage

or other causes of raised intracranial pressure; eyeinjury and increased intraocular pressure; psychi-atric disorders such as a schizophrenia and acutepsychoses

Precautions Ketamine should be used under thesupervision of a clinician experienced in trachealintubation, should this become necessary Pulse andblood pressure must be monitored closely Supple-mentary opioid analgesia is often required insurgical procedures causing visceral pain

Use in pregnancy Ketamine is contraindicated inpregnancy before term, since it has oxytocic activity

It is also contraindicated in patients with eclampsia

or pre-eclampsia It may be used for assisted vaginaldelivery by an experienced anaesthetist Ketamine

is better suited for use during caesarean section; itcauses less fetal and neonatal depression than otheranaesthetics

Muscle relaxants

NEUROMUSCULAR BLOCKING DRUGS

A lot of surgery, especially of the abdomen, requires