Department of Anaesthesia

University of Cape Town

Intravenous Anaesthetic Agents

An intravenous (IV) induction agent will induce loss of consciousness when injected at the start of a
general anaesthetic. These drugs also allow rapid recovery from unconsciousness as they are rapidly
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 plus an 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 (stage of excitement)
3. More pleasant for the patient
4. Pollution free

Disadvantages
1. Venepuncture required
2. Overdose easy
3. No removal of drug via the lungs (as with inhalational agents). Once it’s in, it’s in; there is no
going back (cf. the inhalational agents that can be switched off to reverse the effect).
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 γ-aminobutyric acid (GABA) neuronal transmission, thereby interfering with transmembrane
electrical activity. 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 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. Sub-anaesthetic concentrations may persist in the brain
for some time, and may impair function of higher centres required for driving or operating machinery.
This also increases 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 IV infusion.
 Intravenous induction agents

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 / nitrous oxide 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 a propofol infusion in adults has been published.
Initial bolus of 1 mg kg-1, followed by an
Infusion of 10 mg kg-1 hr-1 for 10 min, then
8 mg kg-1 hr-1 for 10 min 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 (Cp) of 3 μg ml-1 and is used in adult
TIVA where it is known as the “10 - 8 - 6” regimen.
Extrapolation to children is inaccurate, due to their larger volume of distribution (Vd) of the drug;
and generally require higher doses, in the range of “15 - 13 - 11” mg kg-1 hr-1 or even higher, to
target the same Cp of 3 μg 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 (μg ml-1 or рg ml-1) in the plasma or an “effect
site”, i.e. where the drug takes effect, which is the patient’s 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
Propofol’s 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 (essentially Intralipid 10 %). This fat
emulsion may act as a culture medium, and 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).
It is also available as a 2 % solution (20 mg ml-1) for infusions.
It is highly lipophilic, enhancing its ability to cross the blood-brain barrier.
There is often 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.

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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 N20 and / or opioids.
Plasma concentration (Cp) for TCI: Induction 4 - 8 μg ml-1 and maintenance 3 - 6 μg ml-1.
Sedation: 1,5 - 3 mg kg-1 hr-1 and Cp 0,1 - 2,5 μg 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. It is 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 %.
The clinical impression is that propofol depresses laryngeal reflexes; thus an oropharyngeal airway
is tolerated in light anaesthesia and laryngospasm is uncommon. It does not release histamine.
GIT: Anti-emetic properties, even at sub-anaesthetic doses. A 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 are 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 the
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 a 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 (CMRO2) and intracranial pressure.

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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.
However, it is not a known trigger for bronchospasm in asthmatics.
Renal-, Hepatic-, Gastrointestinal- system: Depressed function but not of clinical significance.
Local effects: Extremely irritant to the tissues.
Venous thrombosis is more common with a 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 onset of anaesthesia. Late signs
are ulcers, blisters, oedema of the arm, and gangrene.
Treatment of an 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 (not available in South Africa)
or c) Phenoxybenzamine 0,5 mg (not available in South Africa)
4. Brachial plexus or stellate ganglion block: Sympathetic block for vasodilatation
5. Treat thrombosis with anticoagulation (heparin bolus of 5 000 iu)
6. Analgesia

Contraindications:
Absolute: Porphyria
Know allergy (anaphylaxis occurs with 1 in 20 000 thiopentone administrations)
Relative: Cardiovascular system disorders as mentioned
Asthma (this is disputed, as thiopentone rarely induces 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 occurs in 25 - 50 % of patients – This can be reduced by
fast injection, use of a large vein or by the addition of 10 - 20 mg of lignocaine. It is now also available
in a soybean fat emulsion (cf. propofol) and may lessen this incidence.

Pharmacokinetics
Recovery is rapid ± 6 - 8 min. Repeated doses are not cumulative, but it is not used as an 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 VT and RR but less than other agents.
Does not cause release of histamine (suitable for asthmatics).

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GIT: High incidence of nausea and vomiting postoperatively. Jokingly referred to as “vomidate” in the
anaesthetic community. An anti-emetic 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 in ICU were associated with an 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 a long shelf life. Non-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 premedicant. 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 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 central
catecholamine release; however, it is a direct myocardial depressant that 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 – 2nd 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

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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 have 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 (= 5 mg) or 3 ml ampoule with 5 mg ml-1 (= 15 mg). 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: 7,5 - 15 mg orally in adults
0,5 mg kg-1 (max. 7,5 mg) in children }
30 - 60 min 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 make 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.

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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 mother’s 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 - 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 patient’s consciousness,
respiration and cardiovascular response. Then adjust your dose accordingly.
2. Doses (per kg) are generally higher for children, whilst generally lower for neonates and the
elderly.
3. Rapidity of onset depends on nature of drug, speed of injection, central Vd and cardiac output.
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.