IV agents and sedatives Flashcards
How does propofol produce vasodilatation?
By nitric oxide production.
It causes hypotension (reduction in SVR + CO) without tachycardia.
Bradycardia is common, esp with opiate co-administration.
How unionized is propofol at physiological pH?
pKa of propofol is 11, therefore at pH 7.4 is almost entirely unionized
Where is the hydroxyl group situated in propofol?
1st carbon.
Phase 1 metabolism into a quinol derivative involves hydroxylation of the 4th carbon.
What phases of metabolism does propofol undergo?
Phase 1 and 2.
Glucuronidation is the predominant metabolic pathway, hydroxylation by cytochrome P450 to a quinol derivative prior to conjugation is also an important pathway.
The relative importance of each pathway varies amongst patients.
What is the paediatric dose of propofol for IV paediatric induction?
Approx double that of adults.
How does propofol cause a reduction in cardiac output?
Reduces HR, myocardial contractility and sympathetic tone.
How is propofol cleared?
Hepatic metabolism but extra-hepatic metabolism is significant suggested by the fact that clearance is higher than hepatic blood flow.
Sites for extra-hepatic metabolism: kidneys (1/3) and lungs (to 2,6-diisopropyl- 1,4-quinol)
How is the anti emetic effect of propofol mediated by?
Dopamine receptor antagonism
What can happen in children with a prolonged infusion of propofol?
Propofol infusion syndrome
- hypertriglyceridaemia
- organ fatty infiltration
- severe bradycardias
- metabolic acidosis
- increased mortality
What is the VoD of propofol, ketamine, etomidate and thiopentone?
Propofol 4 L/kg
Ketamine 3 L/kg
Etomidate 3 L/kg
Thiopentone 2.5 L/kg
Which of the IV induction agents has the highest clearance rate?
Propofol (30-60 ml/kg/min)
What are the clearance rates of the IV induction agents?
Propofol 30-60 ml/kg/min
Etomidate 10-20 ml/kg/min
Ketamine 17 ml/kg/min
Thiopentone 3.5 ml/kg/min
Which has a higher percentage of protein binding, thiopentone or methohexitone?
Thiopentone 80%
Methohexitone 60%
What is the pKa of thiopentone?
7.6
How protein bound is midazolam?
98%
What % of midazolam is unionized at physiological pH?
Midazolam is a tautomeric molecule consisting of benzene and diazepine rings.
In a pH > 4 the diazepine ring closes producing a lipid soluble unionized molecule.
With a pKa of 6.5 around 89% of molecules are unionized at physiological pH.
What is midazolam metabolised to?
The phase 1 metabolite 1-alpha-hydroxy-midazolam is active. This may then be conjugated (glucuronidation) prior to excretion.
Which enzyme system is midazolam metabolised by?
CP450 3A3/4.
The action of midazolam may be prolonged by co-administration of alfentanil.
What dose of midazolam can you give to children as a pre-medication?
Oral dose of up to 1mg/kg 30 mins prior to induction.
Monitoring is required if doses >0.5 mg/kg are used.
What receptors does ketamine act on?
It is a non-competitive antagonist of NMDA
Which isomer is more potent in the racemic mixture of ketamine?
S+ is 2-3 times more potent than the R- isomer. It may also produce less intense emergence phenomena.
What dose can you give of ketamine as an oral premedication?
2-5 mg/kg
It has 20% bioavailability. Dose of up to 10mg/kg have been used in extreme cases.
Using ketamine, who is less likely to get emergence phenomena?
Young/elderly
What is the metabolism of ketamine?
Undergoes cytochrome P450 demethylation to norketamine which is active, this then undergoes glucuronidation to an inactive metabolite which is excreted.
