Intravenous induction agents Flashcards
What can be added to propofol to reduce pain on injection?
Lidocaine: 1 -2 mls 1% IV solution
What is meant by one “arm brain circulation time”?
The time it takes for the drug to travel from the injection site to the brain ± 30 seconds
What physicochemical property allows a drug to get into the brain?
Lipid solubility
What challenge is presented by highly lipid soluble agents?
Preparation - if they are highly lipid soluble they cannot readily be presented as an aqueous solution
How is propofol presented?
1-2% lipid-water emulsion (soya bean oil and purified egg phosphatide)
How is Thiopental presented?
It is a weak acid and can be dissolved in water as long as it is in its ionized form.
pKa of 7.4
Acids ionize at pH above their pKa
So if thiopental is in its ionized form at a pH above its pKa it will be soluble in water.
Stored in NaCO3 powder –> when mixed with 20 mL of water a 2.5% solution of thiopental with a pH of 10.5 is made.
How is Etomidate presented?
It is soluble in water but is stabilized by 35% propylene glycol to give a 0.2% solution
At what plasma concentration of propofol is there risk of awareness? And how long does it take for propofol to decline to this level after a single induction dose?
- 5ug/ml
- 5 minutes
However, propofol is synergistic with volatile agents meaning that there is an overall effect during the ‘cross-over’ phase that will prevent awareness unless volatile is started later than 2 minutes after IV dose of propofol
List the doses of the following IV induction agents: Propofol Thiopentone Etomidate Ketamine
Propofol: 1 - 2.5 mg/kg
Thiopentone 3 - 7
Etomidate 0.3
Ketamine 0.5 - 2
When should the doses of the induction agent be reduced
Specific clinical scenarios: e.g. shock
Adjuvant drugs used (benzodiazepines/opioids)
With the exception of RSI, how are IV induction agents administered?
Slowly and titrated to effect (loss of eyelash reflex).
What is the onset and offset time of propofol
Onset: 30 s
Offset: 3 - 7 minutes
Describe the metabolism of propofol
Conjugated (liver) –> glucuronide
Hydroxylated (liver) –> quinol –> glucuronidated
CVS effects of propofol
Direct myocardial depression Decreased SVR Hypotension Possible bradycardia (i.e. reduction in CO)
RSP effects of propofol
Dose-dependent respiratory depression
Effects of propofol vs thiopentone on the airway reflexes
Propofol obtunds the airway reflexes more than thiopental – allowing earlier placement of LMA
What are the miscellaneous effects of propofol
Pain on injection (reduced with lidocaine)
LESS PONV
Is propofol licensed for children under 3 years
No
Summarise the physicochemical properties of propofol
Phenol derivative
Highly lipid soluble
pKa of 11 ( weak acid so almost entirely unionized at pH of 7.4)
Plasma protein binding: 98%
What is in the ampoule of propofol
Lipid-water emulsion containing 1% propofol (10mg/ml) Emulsifying agent - Purified egg phosphatide - Glycerol - Soya-bean oil
What is the onset and offset of Thiopental
Onset: 30 s
Offset: 5-10 mins
What is the metabolism of thiopental
Liver –> active oxybarbiturate derivative PENTOBARBITAL and two other inactive metbolites
What are the effects of Thiopental on the CVS
Direct myocardial depression –? low BP and decreased CO
What are the effects of thiopental on the RSP
Dose dependent reduction in Ve
What are the problems with the use of thiopental
- Intra-arterial injection – extreme pain and limb threatening
(Urgent Rx –> saline dilution and papaverine 40mg to dilate artery and SNS blockade to improve blood flow locally. - Hypersensitivity 1 in 15 000
What is an absolute contraindication to the use of thiopental
Porphyria
What are the physicochemical properties of thiopental
Thiobarbiturate
Weak acid with pKa 7.6 (60% exists in unionized form)
Highly lipid soluble
Protein binding 80%
What is in the vial of thiopental
Thiopentone sodium salt 500mg
NaCO3
Stored under Nitrogen
When mixed with 20 ml of water it forms a 25mg/ml solution at pH 10.5 - high pH stops the insoluble acid from precipitating out of solution
Acids ionize above their pH (want solution form for administration. Physiological pH lipid soluble form increases
What is the onset and offset time of etomidate?
Onset: 30 s
Offset: 3-7 minutes
How is etomidate metabolized
Its an ester so undergoes ester hydrolysis in plasma and liver
CVS effects of etomidate
Minimal effect on HR
Minimal effect on CO
Minimal effect on SVR
RSP effects of etomidate
Minimal and transient dose-dependent respiratory depression
What are other important effects of etomidate
Pain on injection (reduced by use of preparation with lipid i.e. etomidate-lipuro)
N and V common compared with propofol
Adrenocortical suppression - especially if used by infusion
Hypersensitivity rxns 1:75 000
What are the physicochemical properties of etomidate
Carboxylated imidazole derivative
High lipid solubility and water soluble
pKa 7.4
Protein binding: 70%
Dose of etomidate
0.3 mg/kg
What is in the ampoule of etomidate
Etomidate 2mg/ml
Aqueous solution of etomidate pH of 8.1
Stabilized by propylene glycol 35%
Define pharmacokinetics
The study of how and why plasma concentrations of drugs change with time
Concerning the negative exponential decline of plasma propofol concentration after a single dose, why is the propofol concentration decreasing?
- Some drug is distributing to other tissues (Brain, fat, muscle)
- Some drug is being metabolized and/or excreted from the body
What determines to which tissues the drug is INITIALLY distributed
Blood flow
- Blood vessel rich tissues take up drug more quickly
- Eventually the blood vessel poor tissue (fat) take up the drug as it recirculates
What causes the initial rapid decline in plasma concentration after a single IV dose of an induction agent
distribution to other tissues
How does the metabolism differ between propofol, thiopental and etomidate
Etomidate is an ester and is rapidly broken down by plasma and hepatic esterases
Propofol is more rapidly broken down than thiopental without active metabolites. Thiopental is metabolized more slowly and has an active metabolite pentobarbital.
What impact does the active metabolite of thiopental, pentobarbital, have on the clinical effect and duration of action of pentobarbital
Single IV dose of thiopental for induction leads to a very low and clinically insignificant level of pentobarbitol which does not influence the duration of action of thiopental.
However, the effects of pentobarbital become more important if thiopental is given by continuous infusion
How is pentobarbital structurally different from thiopental
The Sulfur group is substituted for an Oxygen
What are absolute contraindications to thiopental and etomidate
Previous hypersensitivity
Porphyria
Which induction agent is faster thiopental, propofol or etomidate
Thiopental is slightly faster than propofol which is faster than etomidate
Which agent should be avoided in a patient with egg allergy
Propofol (but there is no evidence for this)
Which induction agent should be used in epilepsy
Thiopental -antiepileptic (or propofol)
