Propofol Flashcards
Describe the pharmaceutical presentation of propofol
1% emulsion of fat droplets in water –> milky white
The vial contains 6 things:
1% propofol
1.2 % Egg phospholipid
2.25% Glycerol
10% Soybean oil
EDTA
NaHCO3
Why is propofol a lipid emulsion
It is not water soluble and requires a vehicle to carry it into the patient
Why is Glycerol added into the propofol vial
To adjust tonicity
Why is NaHCO3 added to the propofol vial. What is the pKa of the emulsion and what is the implication of this.
To adjust pH –> 6.5 - 8.0
pKa = 11
It is a weak acid and as acids ionize at physological pH above their pKa, at physiological pH (7.4 which is below pKa of 11) –> most of the drug is unionized and able to cross BBB
Why is EDTA added to propofol vial
Antimicrobial
Why can patients with egg allergies get propofol
The 1.2% Egg phospholipid is a yolk component rather than an egg white component –> The usual egg allergy is to egg white albumin.
What is fospropofol. What are its advantages and disadvantages
It is a prodrug of propofol which is more water soluble leading to reduced pain on injection.
Summarise the relevant pharmacokinetics of propofol
Adminstration
- IV only –> 100% bioavailability
Distribution
- Onset: 1 arm brain circulation (10 - 20 s)
- Bolus Vd = 4.1 L/kg
- Protein bind = 98%
- Bolus t1/2 = 2 minutes
- Steady State t 1/2 = 5 - 12 hours
Metabolism
- Liver: glucoronide and sulphate conjugation
- ?? Extrahepatic metabolism too (cirrhotic patients metabolize normal quantities of propofol)
- inactive metabolites:
- CYP450: 60% into quinol –> a glucoronide and sulfate. 40% straight into a glucoronide
- Unaffected by renal and hepatic disease
Excretion
- Clearance: 30 - 60 ml/kg/min (10 x faster than thiopentone)
- Clearance decreased in neonates and elderly
- Terminal elimination half life: 5 - 12 hours
- 0.3 % excreted unchanged
What is the context sensitive half time for propofol at 3 hours and also at 8 hours
3 hours = context sensitive half time is 10 mins
8 hours = context sensitive half time of 30 minutes
Define volume of distribution
Volume of distribution is the apparent volume into which a specific dose of a drug distributes to give the measured drug concentration in plasma. It is calculated by dividing the dose administered by the plasma concentration and is measured in L/Kg.
Compare the volumes of distribution and plasma protein binding of the IV induction agents
Propofol Thiopentone Ketamine Etomidate
Vd 4.0 2.5 3.0 3.0
Protein 98% 80% 25% 75%
Define clearance
The volume of blood cleared of a drug per unit time
What is the mechanism of action of propofol
Propofol potentiates GABA A receptors which are Chloride channels. More chloride channels open allowing increased Cl- into the cell. This causes hyperpolarization of the resting membrane potential and reduced threshold breach and AP generation in CNS neurons.
List the effects of propofol
CNS
- Anaesthesia / sedation
- Choreiform movements ± opisthotonus
- Anti-epileptic
- Reduced CBF + reduced CMRO2
CVS
Sympathetic Nervous System Inhibition (indirect effects)
1. Reduced preload (venodilatation)
2. Reduced afterload (vasodilatation)
3. Minimal direct effect on contractility
4. Net effect on cardiac output in a patient not in compensated shock is minimal.
RSP
- Decreased tidal volume
- Increased RR
- Abolished response to hypoxia and hypercapnoea
- Bronchodilatation
- Depressed laryngeal reflex
GIT
- Antiemetic (D2 antagonism)
- Antihistamine
MSK
1. Muscle relaxation (higher doses)
Renal
1. Green urine (and hair) –> from phenols
List the contra-indications to propofol
- Extreme Haemodynamic fragility
- Allergy to one of the ampuole contents
- Ridiculously high serum triglycerides
- Very high intracranial pressure
When does the Propofol Infusion Syndrome (PRIS) occur
4 mg/kg/hr for 48 hours
70 kg male
28 ml/hour of propofol for 48 hours
What are the clinical features of Propofol Infusion Syndrome (PRIS)
HEART
- Acute bradycardia –> asystole
- Cardiogenic shock / Heart Failure
ACIDOSIS
3. HAGMA
FAT
- Hyperlipidaemia
- Fatty Liver
MUSCLE and KIDNEY
6. Rhabdomyolysis
Describe the mechanism of the propofol infusion syndrome
Prolonged high doses of propofol –> inhibition of co-enzyme Q and cytochrome C in the ETC. i.e electrons cannot be transported between protein complexes on the mitochondrial membrane –> breakdown of oxidative phosphorylation –> reduced ATP synthesis –> anaerobic respiration –> hyperlactataemia HAGMA
Also: Impaired fatty acid metabolism: FFAs are not converted to acteyl-CoA –> thus no ATP via lipolysis + FFA accumulation in blood stream –> contributes toward acidosis
What is the treatment of PRIS
- Supportive
- STOP propofol
- Charcoal haemoperfusion can reduce FFAs
What are the early ECG changes in PRIS
Sudden onset RBBB with STE in V1 to V3
What are the properties of an ideal intravenous anaesthetic agent
PHARMACEUTICAL/PHYSICAL
Soluble in water Chemically Stable: - no reconstitution required - no additives/preservatives required - prolonged shelf life at room temperature - Stable in presence of air and light Not support of bacterial growth Chemically inert - Non-reactive: rubber/metal/glass/plastic
PHARMACOKINETICS
Administration/Availability
- multiple routes
Distribution
- Rapid onset
- No accumulation with infusion
- Rapid and predictable offset
- Safe in Renal or Liver impairment
PHARMACODYNAMICs
Pain on injection - NO Intra-arterial/extravasation - SAFE Anaesthesia within one arm brain circulation time Analgaesic Antiemetic Antiepileptic Muscle relaxation No emergence No change in CBF or ICP Minimal CVS or RSP depression No histamine release or bronchospasm Safe in Obs and paeds Not teratogenic
Why is propofol the ideal agent for TIVA
- Short acting
- Short half life
Reduced risk of accumulation and recovery - Smooth and rapid induction
- high metabolic clearance and elimination
What is the context sensitive half life at 2 hours, 6 hours and 9 hours for a propofol infusion
2 hours infusion - 20 minutes
6 hours - 30 minutes
9 hours - 50 minutes
Why is propofol TIVA particularly suited to neuroanaesthesia
Smooth and rapid induction
Predictable pharmacokinetics and recovery
Reduced risk of accumulation
Does not impair cerebral autoregulation
Does not increase CBF/CMRO2/ICP
