|a. List the ideal properties of an intravenous induction agent.
- A drug or combination of drugs which will induce anaesthesia safely and reversibly when injected in sufficient doses and which could also be used intermittently or by infusion for maintenance of anaesthesia.
Barbiturates, imidazoles, phenols, steroids, eugenols
Phencyclidines, benzodiazepines, opioids, neurolept combinations
b. Describe the structure-activity relationship of the barbiturates.
- Simple preparation
- Compatible with other agents and IV fluids
- Painless on administration
- High potency and efficacy
- Predictable action within one circulation time
- Minimal cardiovascular effects or other toxicity
- Depression of airway reflexes for intubation
- Rapid and predictable offset of effect
- Rapid metabolism for minimal hangover
Barbituric acid is formed by the condensation of urea and malonic acid:
It is insoluble in water and has no activity in vivo. Barbiturates have two structural isomers which are in equilibrium, keto and enol forms:
The barbiturates have substitutions of functional groups of barbituric acid:
X is oxygen (oxybarbiturates) or sulfur (thiobarbiturates). The thiobarbiturates such as thiopentone are generally more lipid-soluble and so have a more rapid onset of action. R3 is usually hydrogen, but in the case of methohexitone a methyl group is substituted which increases convulsive effect and shortens elimination half-life. The R1 and R2 groups can be short alkyl or aryl chains in the hypnotic barbiturates or longer (more than 5 carbon) chains in the anticonvulsants. Branched chains give greater hypnotic than anticonvulsant effect. Phenobarbitone has phenol and ethyl groups at R1 and R2 and is an anticonvulsant.
c. Describe the pharmacology of propofol, thiopentone and methohexitone and the factors which influence their effects.
Presented as the Na+ salt of the enol form
0.5 g in 20 ml ampoule with N2, Na2CO3 30 mg to pH 11
Prepared with water or saline to 25 mg/ml solution
pH 11-12 precipitates in neutral or acid solution
Stable (<7% loss of potency) for 5 days at 25°C or 45 days at 5°C
- pKa 7.6
- 85% protein bound
- Vdss 1-2 l/kg
- t1/2a fast 8 min, slow 60 min, t1/2ß 11 h
- Clearance 3 ml/min/kg
- Rapid redistribution from VRG into muscle (30 min peak) and fat
- Slow hepatic metabolism, easily saturated in infusion
- Pentobarbitone is one metabolite
- Potentiates GABAA transmission, prolongs channel opening
- May depress excitatory transmission by inhibiting Ca2+ transport
- Acts at reticular formation, hypothalamus and limbus
- Brief stimulatory phase before sleep
- Anticonvulsant at hypnotic doses
- Decrease in CMRO2, CBF, vasoconstrictor (may cause inverse steal)
- Not analgesic
- Effects depend on dose and rate of administration and filling
- Venodilator: decrease in LVEDV
- Myocardial depressant at high doses: decrease in SV, CO, MAP
- But increase in myocardial O2 demand in anaesthetic doses
- Not an arterial vasodilator: baroreceptor reflex increase in SVR
- Central depressant
- Decreased rate, increased VT followed by apnoea
- Decrease in CO2 sensitivity
- Decrease in upper airway reflexes when deep
- Minimal decrease in function
- Crosses placenta readily, no effect on tone
- Thrombophlebitis, pain, thrombosis
- Intraarterial injection causes vasospasm due to endogenous vasoconstrictor release
- Treat with local anaesthetic, vasodilator, heparin, regional
Above plus anaphylaxis (1/14000), anaphylactoid
Induction of general anaesthesia around 4 mg/kg
Cerebral protection (5 mg/kg + 5 mg/kg/h)
- No IV access, no airway support equipment
- Respiratory obstruction (croup, epiglottitis)
- Cardiac disease
- Septicaemia, acidosis
- Adrenocortical insufficiency
500 mg in 50 ml glass ampoule
White/yellow powder, sodium salt
Stabilized with anhydrous sodium carbonate
Mostly aL and aD isomers. ß isomers increase involuntary movement.
Prepared with water or saline
70% protein bound
t1/2a fast 6 min, slow 60 min, t1/2ß 2-4 h
clearance 11 ml/min/kg
- Excitatory phenomena
- More irritant to vessels
- Dose 1-1.5 mg/kg
10 mg/ml in 20, 50 and 100 ml ampoules
White aqueous isotonic emulsion
Solubilized with 2.25% glycerol, 10% soybean oil, 1.2% purified egg
Previously solubilized in Cremaphor EL --> anaphylaxis
pH 6.0 to 8.5
Weak organic acid, pKa 11
98% protein bound
Vdss 10 l/kg
Metabolism by conjugation in liver
Three compartment model
t1/2a 2 min, t1/2ß 45 min, t1/2d 4 h
Similar to thiopentone
GABAA transmission effect may be its mechanism of action
- Excitatory effect, but anticonvulsant
- ? analgesic
- Little psychomotor effect after awakening
PNS: potentiates effect of NMJ blockers
Respiratory: greater incidence of apnoea
CVS: Decreased SVR, SV, MAP
Induction 2-2.5 mg/kg (less in elderly or hypovolaemic)
maintenance 0.1-0.2 mg/kg/min
||Psychomotor effects |
||Minor surgery |
500 mg/10 ml, 100 mg/ml 10 ml, 2 ml vials
Benzethonium chloride preservative
(+) isomer 3-5 times more potent
Vd 3 l/kg
Hepatic metabolism hydroxylation or N-demethylation, conjugation
Norketamine has 20% potency
Clearance 18 ml/kg/min
t1/2a 10 min, t1/2ß 3 h
Inhibits thalamic transmission to cortex
Increased CBF, ICP, IOP
Hallucinations on emergence
Increased sympathetic tone (central and decreased NA uptake)
Increased HR, MAP, PVR
Direct cardiac depressant
Retention of airway reflexes in low dose
Increased secretions, bronchodilation
Muscle: Increased tone, movements, inhibits PlChE
||1-2 mg/kg IV (4-6 mg/kg IM)|
||150 ng/ml |
||1000 ng/ml |
- Alphaxolone and alphadolone (3a-hydroxy steroids)
- Not available
alphaxolone 9 mg/ml, alphadolone 3 mg/ml in Cremaphor EL
Rapid induction of anaesthesia in one circulation time
Alphaxolone is twice as potent as alphadolone
High therapeutic index (30.6)
Excitatory movements common
Cardiodepressant --> hypotension
50 mg/ml in Cremaphor EL
Rapidly metabolized by pseudocholinesterase
Competes with suxamethonium
Excitatory movements common
Marked hyperventilation in induction
d. Describe the formulation of thiopentone, methohexitone, propofol, diazepam and midazolam.
1 ml of 5 mg/ml glass ampoule
Solubilized in soybean oil
2 ml of 5 mg/ml brown glass ampoule
Clear yellow solution
Dissolved in 40% propylene glycol, 10% ethyl alcohol, 5% Na benzoate
- 5 ml of 1 mg/ml or 1, 3 or 10 ml of 5 mg/ml glass ampoules
- Clear aqueous solution
- Buffered to pH 3.3
- Precipitates in strongly alkaline solutions
e. Compare the pharmacokinetic and pharmacodynamic differences between thiopentone, methohexitone, midazolam, diazepam, ketamine, etomidate and the steroid anaesthetics.
Thiopentone and methohexitone are barbiturate induction agents used intravenously. Their brief duration of action results from rapid distribution from the vessel-rich group into skeletal muscle and then fat. Methohexitone is slightly less dependent on redistribution for its duration of action as its rate of hepatic metabolism and renal clearance is significantly higher.
Both are highly protein-bound, lipid soluble and metabolized by hepatic oxidation (and desulfuration in the case of thiopentone) to inactive and less lipid-soluble metabolites which are renally cleared. Elimination half-life is shortened in children and patients with induced liver enzymes.
Barbiturates act by depressing the reticular activating system, possibly by inhibiting the dissociation of GABA from its receptors. Tolerance develops rapidly with continuous use.
Diazepam and midazolam are benzodiazepines which are active orally, transmucosally, intravenously, and in the case of midazolam, epidurally. Midazolam is used as a sedative and coinduction agent. They are both highly lipid soluble and 96–98% protein bound. They have similar volumes of distribution but differ in metabolism.
Diazepam is oxidized in the liver to desmethyldiazepam, oxazepam and temazepam all of which are active.
Desmethyldiazepam has an elimination half-time of 48-96 hours, greatly prolonging the clinical effect of diazepam. The elimination half-time of diazepam increases with age and hepatic impairment to over 100 h in the elderly. The effective duration of action depends on both metabolism and initially on redistribution into fat.
Midazolam spontaneously converts to a water-soluble form at acidic pH due to a reversible ring-opening reaction and possibly due to ionization of the imidazole nitrogen. This allows preparation of a buffered (pH 3.5) water-based solution for intravenous use.
Midazolam is metabolized by hepatic microsomal enzymes to 1–hydroxymidazolam and 4–hydroxymidazolam both of which are excreted renally as glucuronide conjugates.
Benzodiazepines act by binding to a specific receptor site on GABA receptors, facilitating GABAergic transmission. In the CNS, it acts predominantly in the cortex; the concentration of GABA receptors being less in the more primitive parts of the CNS. There are GABA receptors on spinal motor interneurones, which may account for the activity of diazepam in reducing muscle tone.
Ketamine is a phencyclidine derivative used to induce dissociative anaesthesia.
Ketamine is active intravenously, intramuscularly, epidurally and intrathecally. It is not significantly protein-bound. It is extremely lipid soluble and when administered IV is rapidly redistributed into the vessel-rich group including the brain, with slower redistribution to muscle and fat. It is demethylated by cytochrome p450 enzymes to norketamine (active) and hydroxylated and excreted renally as a glucuronide conjugate. Its metabolism is slowed by the administration of halothane or diazepam. Ketamine induces the enzymes responsible for its metabolism so tolerance and dependence are seen.
Ketamine is thought to interact with opioid receptors in the CNS. Its analgesic effects exhibit cross-tolerance with opiates. It inhibits reuptake of catecholamines, causing an indirect sympathomimetic effect. It blocks glutamic acid NMDA transmission in the CNS. Its direct effect on the heart is depressant, intact sympathetic activity is required for its effect in increasing cardiac output. It enhances the activity of non-depolarizing muscle relaxants and inhibits plasma cholinesterase, prolonging the effect of suxamethonium.
Etomidate is an imidazole containing compound which can be used as an induction agent. It is water-soluble at acidic pH and is used intravenously. Its brief duration of action is a result of redistribution as with thiopentone. It is moderately lipid-soluble at physiological pH. It is 76% protein bound.
Etomidate is metabolized by hydrolysis by hepatic microsomal enzymes and plasma esterases. Its metabolism is more rapid than thiopentone. Metabolites are inactive and renally cleared.
Etomidate probably acts to increase GABA transmission. Like methohexitone lowers the seizure threshold and causes myoclonic movements. It acts to inhibit 11-ß-hydroxylase in the adrenal, reducing synthesis of cortisol and inhibiting the normal stress response. It is not used in Australia.
Water soluble hydrocarbon
High dose (50 mg/kg for induction)
Slow onset (3 min)
Bradycardia, emesis and hallucinations
Solubilized in intralipid
Rapid onset, short duration
t1/2a 10 min, t1/2ß 1 h
Vdss 4 l/kg
Clearance 30-60 ml/kg/min
Dose 0.6 mg/kg
May produce “steroid pyrogen fever”
Similar thrombophlebitis to barbiturates
f. Describe the undesirable systemic effects of individual agents.
g. Describe the toxic and adverse reactions to intravenous agents.
Kindly provided by Dr James Mitchell from his pharmacodynamics series