Department of Anaesthesia

University of Cape Town

Lecture 5
Intravenous Anaesthetic Agents

An intravenous (IV) induction agent will induce unconsciousness when injected at the start of a
general anaesthetic. These drugs also allow rapid recovery from unconsciousness as they are
redistributed. Some can be given intermittently or by infusion for the maintenance of anaesthesia.

General pharmacology

Classification
Intravenous anaesthetics may be classified into 2 groups: Those which produce rapid loss of
consciousness in one arm

-

brain circulation time,

30 seconds; and those with a slower onset.
Rapidly-acting agents ("true" induction agents)
1. Propofol
2. Thiopentone
3. Etomidate
4. Ketamine

Slower-acting agents

1. Benzodiazepines: Diazepam, Midazolam ) Not "true"
2. Neurolept anaesthetics: Neuroleptics (Droperidol or Haloperidol + opioid) ) IV induction
3. Large-dose opioids: Fentanyl, Sufentanil, Remifentanil, Alfentanil, Morphine ) agents

Advantages of intravenous induction
1. Rapid onset of action
2. Smooth induction with rapid transfer through stage II
3. More pleasant for the patient
4. Pollution free

Disadvantages
1. Venepuncture required
2. Overdose easy
3. No removal of drug via lungs (vs. inhalational agent)
Recovery requires redistribution, metabolism and excretion.
4. Sudden loss of normal protective mechanisms and often apnoea

Mechanisms of action
Although not fully understood, current evidence suggests that most of the anaesthetic induction drugs
modulate GABA-ergic neuronal transmission, thereby interfering with transmembrane electrical
activity. -Aminobutyric acid (GABA) is the most common inhibitory neurotransmitter.
Ketamine is an opioid receptor agonist and antagonises the n-methyl d-aspartate (NMDA) receptor.

Pharmacokinetics
The termination of the action of the IV induction agents is due to redistribution of drug from the brain
to other less well-perfused tissues, i.e. the drug is mobilised from the tissues where it is initially
deposited because of their rich blood supply, to tissues of poorer blood supply. The reason the
patient awakens after a number of minutes is due to this redistribution of drug from the brain. Rapid
awakening is not due to metabolism or excretion of the drug. However, sub-anaesthetic
concentrations may persist in the brain for some time. These low concentrations impair higher centre
function required for driving or operating machinery. This also results in increased sensitivity to
sedatives, analgesics and alcohol. Patients must be cautioned about partaking in these activities or
taking any legally binding decisions for at least 24 hours after even the shortest general anaesthetic.

Metabolism and excretion
These lipid-soluble drugs are metabolised in the liver to inactive water-soluble metabolites; then
excreted in the urine. The importance of metabolism and excretion terminating the drug effect
increases with high plasma concentrations; due to multiple doses or continuous I.V. infusion.
Intravenous induction agents
5 - 2
TIVA and TCI
TIVA stands for Total Intravenous Anaesthesia, and refers to an anaesthetic technique in which no
inhalational agents are used during induction or maintenance of general anaesthesia. The patient
would still require a mixture of Air

/

N
2
O and oxygen to be delivered via the breathing circuit of the
anaesthetic machine. Propofol is most commonly used for TIVA. Ketamine is used on occasion. In
order to reliably administer the intravenous agent at a steady, set rate and avoid either over-dosage or
awareness under anaesthesia, a syringe pump is commonly used. Syringe pumps are manufactured
to be accurate at very low flow rates. Most contain a library of frequently used drugs and their usual
concentrations. Continuous monitoring of the syringe pump and the dedicated intravenous line to
which it is attached is vital to prevent unwanted patient awakening and awareness.
A simple regimen for Propofol infusion in adults has been published. The regimen consists of an initial
bolus of 1 mg kg
-1
, followed by an infusion of 10 mg kg
-1
hr
-1
for 10 minutes, then 8 mg kg
-1
hr
-1
for 10
minutes and then 6 mg kg
-1
hr
-1
thereafter. The flow rate in ml hr
-1
for each phase is manually entered
on the syringe driver by the anaesthetist. This regimen targets a plasma concentration (C
p
) of 3 g ml
-
1
and is used in adult TIVA where it is known as the 10-8-6 rule. Extrapolation to children is
unsuitable due to their larger volume of distribution (V
d
); they generally require higher doses in the
range of 15-13-11 mg kg
-1
hr
-1
or even higher, to target the same C
p
of 3 g ml
-1
.

TCI is another method of delivering a TIVA. It stands for Target Controlled Infusion, in which a
microprocessor-controlled syringe pump automatically and variably controls the rate of infusion of a
drug to attain the anaesthetist-defined target level in g ml
-1
in the plasma or an effect site i.e.
where the drug takes effect, which is the patients CNS. The anaesthetist enters variables which may
include age, gender, weight and height of the patient. TCI systems are programmed with
pharmacokinetic models that mathematically describe the processes of drug distribution and
elimination. The two main models used for Propofol were described by Marsh and Schnider.
This technique greatly simplifies maintenance of a steady blood or brain level, in spite of the fact that it
can only provide an estimate of the actual drug concentration.

Individual agents and their pharmacology

1) Propofol
Propofols chemical structure is 2,6 di-isopropylphenol. Now the most commonly used IV induction
agent in the world as the original patent has expired and cheap generics are available.

Physical properties
Insoluble in water. Current preparation 1 % w

/

v (10 mg ml
-1
) aqueous emulsion containing 10 %
soybean oil, 1,2 % egg phosphatide and 2,25 % glycerol. This is a fat emulsion (essentially Intralipid
10 %) and can act as a culture medium. An ampoule should be used within 6 hours of opening.
Ampoule sizes: 20 ml, 50 ml, 100 ml (each containing 10 mg ml
-1
of Propofol). Available as a 2 %
solution (20 mg ml
-1
) for infusions. It is highly lipophilic, enhancing its ability to cross the blood-brain
barrier. Pain on injection, with an incidence of 30

40 %.
Patients with egg allergy do not usually react to Propofol.

Pharmacokinetics
Unique pharmacokinetic properties make Propofol suitable for:
1. Induction of anaesthesia
2. Maintenance of anaesthesia
3. Sedation - ICU sedation, regional anaesthesia, cardioversion.
Propofol's clearance exceeds hepatic blood flow; it is also highly fat-soluble and sequesters in fat
following long infusions. These properties result in a rapid decrease in Propofol concentration
following continuous infusions, regardless of infusion duration. The nett effect is that Propofol can be
infused for long periods of time, while still resulting in rapid emergence on termination of the infusion.

Intravenous induction agents
5 - 3
Pharmacodynamics
Induction: 1,5

2,5 mg kg
-1
in adults. With slower rates of injection, induction can be performed with
doses as low as 1

1,5 mg kg
-1
; this is particularly important in the elderly.
2,5

3 mg kg
-1
in infants and young children.
Maintenance: TIVA - 6

12 mg kg
-1
hr
-1
. Reduce in combination with N
2
0 and

/

or opioids.
Plasma concentration (C
p
) for TCI: Induction 4

8 g ml
-1
and maintenance 3

6 g ml
-1
.
Sedation: 1,5

3 mg kg
-1
hr
-1
and C
p
0,1

2,5 g ml
-1
.

Organ effects
CNS: Rapid loss of consciousness and rapid recovery (

4

6 min) following induction. Sedation and
drowsiness at low doses. Impairment of psychomotor function is minimal with complete recovery in
about 3 hours. Less hangover effect than with barbiturates, benzodiazepines or inhalational
agents. Low incidence of excitatory phenomena. Does not produce antanalgesia (Def: Lowering of
a previous elevation in pain threshold) as with Thiopentone, but there is no clinically useful analgesia.
Antipruritic.
CVS: Dose-related cardiovascular depression is generally considered to be worse than those of an
equivalent dose of Thiopentone. Compensatory tachycardia is less, which with the decreased
systemic vascular resistance, accounts for its greater hypotensive effect.
Respiratory system: Dose-dependent respiratory depression. High incidence of apnoea,

100 %.
Clinical impression that Propofol depresses laryngeal reflexes; an oropharyngeal airway is
tolerated in light anaesthesia and laryngospasm is uncommon. Does not release histamine.
GIT: Antiemetic properties, even at sub-anaesthetic doses. Very useful effect!
Metabolic: Propofol Infusion Syndrome (PRIS) is a rare syndrome of lipaemia, metabolic acidosis,
cardiomyopathy and cardiac failure, skeletal myopathy and death. Doses exceeding 5 mg kg
-1
hr
-1

for >

48 hours implicated in this. Children appear to be at a greater risk.
Other: Unpleasant burning sensation on injection. New formulation (Lipuro) reduces burning.
Adding Lignocaine (2 %) 1

2 ml; using a new IV line, and larger size cannula may also reduce
incidence.

Recommendations
Induction agent of choice for porphyria.
Good agent for asthmatics.
Very suited to day-case anaesthesia.
Use with caution in the elderly.
Best avoided in heart failure, hypovolaemia, fixed cardiac output.

2) Sodium Thiopentone (STP)
Thiopentone (introduced 1934) remains the gold-standard induction agent, but has largely been
replaced by Propofol worldwide.

Physical properties
Yellow, amorphous powder which can be dissolved in water or normal saline. It is a barbiturate. The
aqueous solution is strongly alkaline (pH = 10,5) and must not be mixed with low pH solutions such as
glucose containing fluids, because this results in precipitation of free barbituric acid. It also
precipitates when mxed with muscle relaxants; they have a higher pH as they are weak bases.
Preferred strength 2,5 % (Mix 500 mg amp with 20 ml = 25 mg ml
-1
) do not use a higher
concentration due to local irritant effects. Solution is stable for 24

48 hours.

Pharmacodynamics
Induction: 3

5 mg kg
-1
in adults; children need 5

6 mg kg
-1
. Use with caution in the elderly
Not used for maintenance of anaesthesia because of long elimination half-life with accumulation.

Organ effects:
CNS: Smooth loss of consciousness within 30 sec; without spontaneous movement, cough or
hiccough. Recovery

5

10 min. Small doses may cause antanalgesia, i.e. increase sensitivity to
pain. A good anti-convulsant. Possible brain protection implied by decreased cerebral metabolic
rate of Oxygen consumption (CMRO
2
) and intracranial pressure.
Intravenous induction agents
5 - 4
CVS: Decreased cardiac output (10

20 %) due to peripheral vasodilatation, negative inotropic effect
and decrease in central catecholamine release. Baroreceptor reflexes cause a compensatory
tachycardia. However, in healthy patients, standard doses have very little effect on mean arterial
pressure. CVS depression is exaggerated in heart failure, hypovolaemia, fixed cardiac output
(stenotic valve lesions, cardiac tamponade, and constrictive pericarditis). Small doses
administered very slowly are acceptable under these conditions, but there are better alternatives.
Respiratory system: Potent depressant of the respiratory centre - patient will often take a few deep
breaths followed by a transient period of apnoea. Laryngeal reflexes are not depressed until
deeply anaesthetised and early instrumentation may provoke laryngospasm. Histamine release
and active respiratory reflexes are the reasons why alternative drugs should be used in asthmatics.
Renal-, Hepatic-, Gastrointestinal- system: Functions are depressed but rarely of clinical
significance.
Local effects: Extremely irritant to the tissues.
Venous thrombosis is more common after 5 % solution (which should never be used). With extra-
vascular injection, sequelae vary from slight pain to extensive tissue sloughing and necrosis.
An intra-arterial injection is a serious complication. The pH of blood (7,4) causes precipitation of
solid crystals of Thiopentone blocking arterioles and capillaries of narrow diameters. This does not
happen in the venous blood because Thiopentone is diluted by collaterals. The irritation causes
intense arterial spasm and thrombosis. Patient feels severe pain down the arm. Early signs are a
white hand with cyanosed fingers, skin discoloration, and slow loss of consciousness. Late signs
are ulcers, blisters, oedema of the arm, and gangrene.
Treatment of Intra-arterial injection:
1. Prevention - use veins not adjacent to known arteries.
2. Use 2,5% solution and give test dose.
3. Treat spasm leave the cannula in the artery and inject one of the following:
a) Papaverine 40

80 mg in 10

20 ml saline
b) Procaine 10

20 ml of 0,5 % solution (n

/

a in South Africa)
or c) Phenoxybenzamine 0,5 mg (n

/

a in South Africa)
4. Brachial plexus or stellate ganglion block to remove vasoconstrictor impulses with
sympathetic blockade.
5. Treat thrombosis with anticoagulation (Heparin bolus of 5 000 units).
6. Analgesia.

Contraindications:
Absolute: Porphyria
Know allergy (Anaphylaxis occurs with 1 in 20 000 Thiopentone administrations)
Relative: Cardiovascular system disorders as mentioned.
Asthma (although Thiopentone rarely iduces bronchospasm)

3) Etomidate
Physical properties
Etomidate is an imidazole derivative. Presented in 10 ml ampoules containing 2 mg ml
-1
of the drug
dissolved in water with 35 % Propylene glycol. pH = 8,1. May be mixed with 10 ml saline or water to
make a 1 mg ml
-1
solution. Pain on injection 25

50 % - this can be reduced by fast injection, use of a
large vein or by the addition of 10

20 mg of Lignocaine.

Pharmacokinetics
Recovery is rapid

6

8 min. Repeated doses are not cumulative, but not used as infusion because
of adrenal cortical depression.

Pharmacodynamics
Induction: 0,2

0,3 mg kg
-1

Organ effects
CNS: Rapid onset. High incidence of involuntary movements and myoclonus - these can be reduced
by opiates and Midazolam. Quality of recovery is good.
CVS: Very stable and is especially suitable for high-risk patients with cardiovascular disease.
May cause marked bradycardia when combined with synthetic opioids and suxamethonium.
Respiratory system: Little respiratory depression - reduces V
T
and RR but less than other agents.
Does not cause release of histamine (suitable for asthmatics).
Intravenous induction agents
5 - 5
GIT: High incidence of nausea and vomiting postoperatively. Jokingly referred to as vomidate in the
anaesthetic community. An antiemetic is recommended.
Endocrine: Inhibits Cortisol and Aldosterone synthesis in the adrenal cortex. One dose suppresses
adrenal function for 5

8 hr, but this is probably of little clinical significance in healthy patients.
Infusions were associated with increased mortality in septic patients.

4) Ketamine
Dissociative anaesthetic derived from Phencyclidine (PCP)

Physical properties
Acidic solution suitable for intravenous, intramuscular and oral administration. Available as a
1 % (10 mg ml
-1
) and 10 % (100 mg ml
-1
) solution. Stable in solution with long shelf life. Not irritant.

Pharmacokinetics
When surgical anaesthesia is terminated, 50

60 % of the drug still remains in the body in the active
form. Main metabolite, norKetamine, has weak hypnotic properties. Both of these probably account
for the protracted emergence.

Pharmacodynamics
Induction: 1

2 mg kg
-1
IV. Onset 30

60 sec. Lasts 5

15 min.
5

10 mg kg
-1
IM. Onset 3

8 min. Lasts 10

30 min.
Maintenance: 0,5 mg kg
-1
IV as incremental boluses or 1

4 mg kg
-1
hr
-1
by infusion.
Analgesia: 0,2

0,4 mg kg
-1
IV or 2

4 mg kg
-1
IM, followed by infusion of 0,2

0,3 mg kg
-1
hr
-1


Organ effects
CNS: Dissociative anaesthetic characterised by complete analgesia and amnesia; however
involuntary movements, nystagmus, hypertonus and even vocalisation are not uncommon.
Excitatory phenomena not really influenced by a premed. The electro-encephalogram (EEG)
shows dissociation between the thalamus + limbic system and the cerebral cortex. IV induction is
also not complete within one arm-brain circulation time, it takes

90 sec.
In contrast to other IV anaesthetics, Ketamine increases intracranial and intraocular pressure.
Major side effects are the psychic reactions occurring during recovery; varying from pleasant
dreamlike states, a floating feeling with vivid imagery, to hallucinations and emergence delirium.
These may be reduced by concurrent administration of benzodiazepines or opioids. Incidence is
said to be lower in children, elderly, males, long procedures, repeated administration. Higher
incidence if patient is stimulated during awakening and it is best to place patients in a quiet
darkened area to recover peacefully. Tolerance can develop to Ketamines effects due to liver
enzyme induction.
Ketamine is a very effective analgesic agent at sub-anaesthetic doses.
CVS: Sympathomimetic effects cause a rise in blood pressure, pulse rate, peripheral resistance and
cardiac output. Dysrhythmias are uncommon. Ketamine causes direct stimulation of the central
catecholamine release; however it is a direct myocardial depressant, which may be unmasked if
the catecholamine stores are depleted, as in severe shock.
Respiratory System: Respiratory depression is minimal. Pharyngeal reflexes are preserved and
airway control is good. Airway does not need to be instrumented, however it will not be protected
from aspiration should the patient have a full stomach. Bronchodilatation due to sympathomimetic
effects; and no histamine release 2
nd
line agent in treatment of status asthmaticus. Salivary and
bronchial secretions are increased, and administration of an anti-sialogogue (drying agent) is
recommended e.g. Glycopyrrolate or Atropine.
GIT: Postoperative nausea and vomiting relatively common.
Uterus: May cause uterine contractions in first trimester of pregnancy.

Indications
Poor risk surgical patients.
Paediatric surgery
Debridement, painful dressings and skin-grafts in patients suffering from burns.
Short procedures -diagnostic or surgical.
Analgesia.
Anaesthesia in sub-optimal conditions e.g. trauma, "field work".
Has been used for the treatment of status asthmaticus.

Intravenous induction agents
5 - 6
Contraindications
CVS disorders - hypertension, ischaemic heart disease, aortic aneurysms, severe heart failure
Raised intracranial pressure, cerebral aneurysms
Open eye injuries, increased intraocular pressure
Psychiatric patients
Epileptics
Thyrotoxicosis
Does not protect the patient from regurgitation or aspiration. Relatively intact reflexes can lead
to cough or laryngospasm, so that Ketamine is unsuitable for oral cavity or airway surgery.
Early pregnancy.
Patients on tricyclic antidepressants - the drug interaction causes hypertension and cardiac
dysrhythmias.

5) Benzodiazepines

This class of drugs all has the same range of actions on the CNS. In anaesthesia practice they are
mainly used as premedication or to produce sedation during regional anaesthesia. They have not
proven sufficiently reliable to gain universal acceptance as induction agents. Discussion here is
limited to the injectable preparations:
Diazepam (Valium

) and Midazolam (Dormicum

)

Physical properties
Diazepam: Insoluble in water. The original preparation contains 5 mg ml
-1
. Also available in tablet
form and suppositories.

Midazolam: Water soluble. Exhibits a pH dependent ring-opening phenomenon. The parenteral
formulation is acidic with the ring open and the drug water soluble. In the body, the pH increases to
7,4, causing the ring to close and making the drug highly lipid soluble. It causes the least veno-
irritation of the benzodiazepines.
Preparations: 5 ml ampoule with 1 mg ml
-1
or 3 ml ampoule with 5 mg ml
-1
. Check the concentration
carefully as the ampoules looks identical. Oral tablets (15 mg) available.

Pharmacokinetics
Diazepam is poorly absorbed when administered intra-muscularly but rapidly absorbed after oral
administration. Diazepam has a long elimination half-life and its metabolite has pharmacological
activity, thus Diazepam has a long duration of action and accumulates with repeated doses.
Midazolam is rapidly absorbed after oral and intra-muscular administration. Metabolites are of little
clinical significance. Midazolam has a high clearance and short elimination half-life, giving the drug a
shorter duration of action. Accumulation is much less likely to occur and therefore Midazolam may be
administered by continuous infusion. However, in elderly or obese patients, clearance and elimination
half-lives may be prolonged, requiring dosage adjustments.

Pharmacodynamics
Premed: Diazepam: 0,1

0,2 mg kg
-1
orally 1

2 hours pre-op
Midazolam: 15 mg orally in adults } 30

60 min
0,5 mg kg
-1
in children } pre-op
Induction: Significant inter-individual variation in dose
Diazepam: 0,1

0,6 mg kg
-1
IV
Midazolam: 0,1

0,3 mg kg
-1
IV
Sedation: Midazolam: 0,1 mg kg
-1
IV Elderly and sick patients require much less.

Organ effects
CNS: Induction is much slower than one arm-brain circulation time

55

143 sec for Midazolam. Not
suited to rapid sequence inductions. Good anterograde amnesia. Low incidence of cough,
hiccough, laryngeal spasm and spontaneous movement. Anticonvulsant. Lower concentration of
inhalation anaesthetic agents needed for maintenance. Often a long period of disorientation in the
elderly.
The prolonged recovery makes the benzodiazepines unsuitable for day-case anaesthesia.
CVS: Stable with a slight fall in blood pressure comparable to that observed during sleep. Small
transient increase in heart rate.
Intravenous induction agents
5 - 7
Respiratory system: Very little respiratory depression. Larger doses cause respiratory depression,
and apnoea has been reported, especially in conjunction with opioid administration.
No histamine release and no bronchoconstriction.
GIT: Low incidence of nausea and vomiting
Uterus: Not suitable for caesarean section due to hypotonia, hypothermia and respiratory depression
in the neonate (and mothers full stomach).

Flumazenil (Anexate

)
A benzodiazepine antagonist, which specifically blocks the central effects by competitive inhibition at
the benzodiazepine receptor.
Indications
1. Termination of general anaesthesia induced and maintained with benzodiazepines.
2. Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures.
3. Reversal of benzodiazepine overdose.
4. Diagnostic measure in unconsciousness of unknown origin.

Pharmacokinetics
IV onset of action is very rapid (within 5 min), but the duration of effect is relatively short, about 1 to
3,5 hours.
Thus the sedative effect of the originally ingested

/

administered benzodiazepine may return,
depending on the half-life and dose ratio of the agonist and antagonist. May elicit withdrawal
symptoms in habitual users.
Dose: 0,2 mg IV. After 60 sec, a second dose of 0,1 mg may be injected and repeated every 60 sec
up to a total dose of 1 mg. Usual dose is 0,3

0,6 mg.

Practical Points in using IV Induction agents
1. Titrate induction agents to effect, except in rapid sequence inductions. To identify particularly
sensitive persons, inject 25 % of the calculated dose and observe the patients consciousness,
respiration and cardiovascular response. Then adjust your dose accordingly.
2. The paediatric dose is generally higher; the geriatric dose generally lower.
3. Rapidity of onset depends on nature of drug, speed of injection, central V
d
and CO.
4. Assuming that equivalent doses of the IV induction agents are given to a patient; time to recovery
from most rapid to slowest: Propofol, Etomidate, Thiopentone, Midazolam, Ketamine and
Diazepam.

Intravenous induction agents
5 - 8
Notes: