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.
What is ketamine stored as?
As acidic solution of pH 3.5-5.5
What EEG activity does ketamine produce?
Dissociative anaesthesia with predominant theta and delta activity
What effects on cerebral circulation does ketamine have?
Cerebral O2 consumption, blood flow and intracranial pressure are all increased by ketamine.
How protein bound is ketamine?
25-50%
Does ketamine have direct myocardial depressant effects?
Ketamine increases sympathetic tone and circulating levels of adrenaline and noradrenaline. This produces the cardiovascular effects seen clinically of tachycardia, increased cardiac output, increased / maintained blood pressure and elevated CVP.
However, ketamine also produces a mild direct myocardial depressant effect that is masked, less so for the S+ isomer.
How is etomidate prepared?
With 35% propylene glycol
What % of people feel pain on injection of etomidate?
25%
Is N+V a SE of etomidate?
Yes
What is the induction dose of etomidate?
The IV induction dose is 0.2-0.3 mg/kg
Which is the most likely IV induction agent to cause excitatory movements with epileptiform activity on EEG?
Etomidate is the most likely IV induction agent to cause myoclonic movements and epileptiform activity on EEG - in around 20% of cases.
What is etomidate?
Etomidate is an imidazole derivative and an ester.
What happens if you give a patient with porphyria etomidate?
Porphyric crisis
How highly protein bound is etomidate?
75%
How does etomidate affect aldosterone and cortisol synthesis?
Etomidate has been shown to inhibit 11-beta and 17-alpha hydroxylase function and impair aldosterone and cortisol synthesis for up to 24 hours after administration. Steroidogenesis occur in the adrenal cortex.
What does etomidate have the same volume of distribution as?
Ketamine, both 3L/kg
What is thiopentone prepared as?
Hygroscopic yellow powder in 6% sodium carbonate
What % solution does thiopentone produce when reconstituted with water?
2.5%
What % of thiopentone is unionized in blood?
60%
What is thiopentone metabolized to?
Pentobarbitone (active metabolite)
What is thiopentone predominantly when it’s in solution?
It is predominantly in its enol form when in solution. The enol form is soluble. Thiopentone is tautomeric and alkaline conditions promote the switch from keto to enol.
Where is the sulphur group on thiopentone?
On 2nd carbon
What effects does thiopentone have on the RS?
It can cause laryngospasm and bronchospasm
Why does thiopentone cause reduced urine output?
It stimulates ADH release
Is thiopentone an enzyme inhibitor or inducer?
Inducer
Is thiopentone more active in acidic or alkalotic conditions?
Acidotic conditions.
Acidosis + hypoalbuminaemia increases the amount of free unionized drug. So a lower dose should be used in critically ill patients.
