Pharmacology - IV Induction Agents

Question 1

What are the properties of the ideal IV anaesthetic agent?

Answer 1

Physicochemical
Cheap & easy to produce
Stable in storage & at room temp
Long shelf-life
Non-flammable, non-explosive
Inert in standard syringes & giving sets
Compatible with all other drugs
Water soluble
Pharmacological
Hypoallergenic & painless on injection - no histamine release, and safe given intra-arterially
Potent, with high lipid solubility (pKA favouring unionised state at physiological pH)
Rapid onset & offset, with either minimal metabolism, or rapid metabolism with minimal accumulation
Minimal cardiorespiratory depression
Anti-emetic & analgaesic effect
Smooth & comfortable emergence, without hangover or excitation
Predictable recovery

Question 2

Discuss propofol as an IV induction agent

Answer 2

Class & uses
Phenol derivative (2,6 di-isopropylphenol)
Used for induction and maintenance of anaesthesia, and for sedation.
Also used for refractory PONV and status epilepticus

Weak acid, pH 7, with pKa 11.

Presentation & dose
Presented as a white emulsion of 1 or 2% propofol. Also contains:
10% soybean oil
1.2% egg phospholipid
2.25% glycerol as a tonicity adjuster
EDTA
Sodium hydroxide
water

The induction dose is around 1-2.5mg/kg, and a plasma concentration of around 5μg/ml is needed for general anaesthesia

Mechanism of action
Positive allosteric modulator at GABAa and glycine receptors
Inhibitor of nicotinic ACh, and serotonin (5HT-3) reeptors

Effects
CVS - reduces SVR, with occasional reflex tachycardia
Dose dependent bradycardia from direct myocardial depression, especially together with opioids
Respiratory - Depression & apnoea, suppression of laryngeal reflexes, and mild bronchodilator
Neurological - Hypnosis, antiepileptic, reduced CMRO₂ and ICP, hiccups
< 10% of patients demonstrate shivering & dystonias - these aren’t seizures, but subcortical excitation/inhibition imbalance
GI/GU - Anti-emetic, may cause green urine
Haematological - Hyperlipidaemia if given at high doses for a long time (may cause PRIS)

Misc - Pain on injection (worse with 2%), so may be mixed with small amount of 1% lidocaine.
Contraindicated for sedation < 16yrs of age

Pharmacokinetics
Absorption - Oral bioavailability < 2%, always given IV.
Distribution - 4L/kg body weight (highly lipophilic and 98% protein bound). pKa 11 (weak organic acid), almost entirely unionised at physiological pH
Metabolism - Hepatic (Extraction ratio of 8.8-0.9, high first pass metabolism if given PO), 40% metabolised by conjugation to glucuronide, 60% to quinol compound
Excretion - Renal, clearance 30-60ml/kg/minute. Elimination half-life of 8 hours.
Distribution half-life after single bolus dose is 2-8 minutes, and context-sensitive half-life at 8 hours is 40 minutes.

Considered safe in those with egg/soy allergies. Egg component is from yolk, rather than the allergenic proteins in the white. Soybean oil has all allergenic proteins removed.

Question 3

Discuss thiopentone as an IV induction agent

Answer 3

Class & uses
Thiobarbiturate sulphur analogue of pentobarbital
Used for induction of anaesthesia, and for deep sedation on ITU
Also used for status epilepticus and reduction of ICP

Weak acid, pH 11, pKa 7.6

Presentation & dose
500mg sodium thiopental powder (yellow), mixed with sodium carbonate & stored under nitrogen (prevents CO₂ dissociating in water and producing H⁺ ions, which reduce the solubility of thiopentone)
pH 10.5 when reconstituted with 20ml of water to a 2.5% solution - keeps thiopentone soluble in enol form, and prevents bacterial growth.

The induction dose is around 4-6mg/kg

Mechanism of action
Positive allosteric modulator at GABAa and glycine receptors, as well as antagonism at nACh receptors

Effects
CVS - reduces SVR, with occasional reflex tachycardia
Dose dependent myocardial depression and reduction in stroke volume
Respiratory - Depression & apnoea, can trigger bronchospasm & laryngospasm
Neurological - Hypnosis, antiepileptic, reduced CMRO₂ and ICP
Renal - Increased ADH production from combination of CNS & CVS effects - reduced UO
Misc - Anaphylaxis 1/20,000, extremely irritant on arterial administration, porphyria trigger

Pharmacokinetics
Absorption - Extensive first pass metabolism, always given IV
Distribution - 70-80% protein bound, pKa 7.6, 60% unionised at pH 7.4 - undergoes keto-enol tautomerisation to facilitate crossing the BBB. Redistributes rapidly - half life of 8 minutes. Vd 2.5L/kg
Metabolism - Hepatic metabolism to active metabolite pentobarbital
Excretion - Renal, elimination half-life of 11 hours, with long context-sensitive half-time, Cl 3ml/kg/min

Thiopentone was a frequent source of drug errors during induction, as once reconstituted, it is very similar in appearance to many antibiotics.

Intra-arterial injection is managed with high-volume saline dilution, 40mg papaverine to dilate the artery, and consideration of sympathetic blockade.

Reduce plasma protein content results in much more of the drug being available to exert a clinical effect, hence why septic patients need much less.

Question 4

Discuss Ketamine as an IV induction agent

Answer 4

Class & uses
Phencyclidine derivative, dissociative induction agent
Also used for status epilepticus, severe asthma, and acute pain

Weak base, pH 3.3-4.5, pKa 7.5

Presentation & dose
Usually racemate of R & S ketamine, although enantiopure esketamine is available. Clear colourless solution of 10, 50, or 100mg/ml. Analgaesia from 0.1-0.3mg/kg, IV induction dose of 1-2mg/kg, and IM induction dose of 4-10mg/kg

Mechanism of action
Antagonist at the N-methyl-D-aspartate (NDMA) receptor, among others - also inhibiting:
HCN (Hyperpolarisation-activated cyclic nucleotide-gated) channel
nACh receptor
L-type calcium channel

Effects
CVS - Sympathomimetic - CO & BP maintained (slight intrinsic cardio-depressant activity, but noradrenaline & adrenaline release counteract this)
Respiratory - Increased O2 requirement, preserved airway reflexes, bronchodilation. No respiratory depression
Neurological - Dissociative GA in 90 seconds, but unpleasant emergence phenomena & delirium. Raised ICP (But often outweighed by the cardiostable benefits of ketamine), increased CMRO₂ and CBF.
Ocular - Increased IO pressure (tensing of extraocular muscles & increased blood flow)
Renal - Increased ADH production from combination of CNS & CVS effects - reduced UO
GI/GU - Emetogenic, stimulates salivation, ketamine bladder associated with long-term use

Pharmacokinetics
Absorption - Not given PO in clinical practice
Distribution - 25% protein bound, distributes rapidly across lipid membranes - Vd 3L/kg
Metabolism - Hepatic metabolism to active metabolite norketamine, which is then metabolised to inactive glucuronides
Excretion - Renal, Cl 17ml/kg/min

Question 5

Discuss Etomidate as an IV induction agent

Answer 5

Class & uses
Imidazole derivative with ester linkage
Weak base, with pH 8.1, and pKa 4.2

Presentation & dose
Aqueous solution of 0.2% (2mg/ml) etomidate, stabilised in 35% propylene glycol.

Induction dose 0.25-0.3mg/kg

Mechanism of action
GABAa agonist

Effects
CVS - Minimal CVS depression
Endocrine - Inhibits 11β-hydroxylase and 17α-hydroxylase enzymes, suppressing adrenal cortisol & aldosterone production with longer duration infusions.
Misc - Pain on injection, shivering and excitatory movements similar to propofol, emetogenic, and can trigger porphyria

Pharmacokinetics
Absorption - Always given IV
Distribution - 75% protein bound, Vd of 3L/kg
Metabolism - Hepatic
Excretion - Renal, with some plasma cholinesterase elimination as well. 10-20ml/kg/min

Endocrine effect found to directly increase mortality when used for ITU sedation