propofol

Propofol

Overview

Alkylphenol derivative
Most commonly used IV anesthetic
Formulated as an emulsion - 1% propofol wt/vol, 10% soybean oil, 2.25% glycerol, 1.2% purified egg phosphatide (lecithin), 0.005% disodium edetate as an inhibitor of bacterial growth
o Must use aseptic technique when giving Propofol, as bacterial growth rapidly accelerates six hours after inoculation
o ASA recommends using Propofol within 12 hours if given directly from the vial (i.e. sedation in ICU patients)
Great for hypnosis and sedation, but PROPOFOL LACKS ANALGESIA
o Analgesic medication may be co-administered with propofol
Used for induction and maintenance of anesthesia, and conscious sedation
Major Side Effects
o Pain on injection
o Hypotension
o Respiratory Depression
IN THE WORKS: fospropofol - phosphorylated prodrug of propofol, which has a slightly longer time to peak effect, but more prolonged action

Pharmacokinetics

Propofol's pharmacokinetic profile is best described using a two or three compartment model
Important Pharmacokinetic Variables
o Vd_ss = 2-10 L/kg
o Clearance = 20-30 mL/kg/min
o Alpha Elimination Half-life =2-4 min
o Beta Elimination Half-life = 4-7 hours
o 98% protein bound
Metabolism - Propofol is rapidly metabolized by liver
o Conjugation with glucuronide and sulfate = water soluble, inactive metabolites that undergo renal excretion
o ALSO, extrahepatic metabolism occurs
§ Kidneys = 30% total body clearance (excretion plus metabolism)
§ Lungs= 30% uptake and first-pass elimination after bolus.
o Fospropofol undergoes hydrolysis by endothelial cell surface alkaline phosphatases to yield propofol
What happens with a single bolus injection of propofol?
o Propofol enters the CNS rapidly due to its high lipid solubility, resulting in a rapid onset (<1min, with peak effect at 90-100 sec)
o However, plasma propofol levels decrease rapidly due to redistribution.
§ Redistribution from highly perfused, pharmacologically active tissues (CNS) to well-perfused, pharmacologically inactive tissues (lean body mass) occurs very quickly due to its high lipid solubility. Patients may awaken in 5-10 minutes (dose-dependent) after administration of a bolus of propofol.
§ After the redistribution of propofol, the pharmacologically inactive compartments behave as a reservoir that slowly returns propofol back to the central compartment. However, this reservoir effect is negated by propofol's rapid elimination from the central compartment (by liver, kidneys and lungs), and therefore accounting for its short context-sensitive half-time over a wide range of infusion times (<40 min. for infusions up to 8 hours long)
Special Considerations
o Peds - In children <3 yo, dosing requirements increased due to increased clearance and central compartment volume
o Hepatic disease - elimination half-life slightly prolonged
o Fospropofol- decline of plasma concentrations is slower for fospropofol
§ apparent clearance, volume of distribution, and peak propofol concentrations much higher with fospropofol
§ Fospropofol has similar time to loss of response to verbal command as propofol, but has a longer recovery profile

Pharmacodynamics

CNS
o Propofol binds to the ß subunit of GABA_A receptors in the hippocampus, which potentiates Cl^-current and hyperpolarizes the neurons, and leads to the inhibition of acetylcholine release in the hippocampus and prefrontal cortex ® hypnosis/sedation, and amnesia
o Also widespread inhibition of NMDA receptors through modulation of sodium channels
o Direct depressant effect on nerves in the spinal cord
o Propofol decreases ICP in patients with either normal or increased ICP (30-50%) BUT the decrease ICP is associated with a decrease in cerebral perfusion pressure (CPP), so use caution!
o Intraocular pressure decreases by 30-40% with propofol
o Interesting side effects:
§ Antiemesis at subhypnotic doses (10mg bolus)® decrease in serotonin in the area postrema
§ Euphoria ® increases dopamine concentrations in the nucleus accumbens
Respiratory System
o PROFOUND RESPIRATORY DEPRESSANT
§ Reduces hypercarbic ventilatory response
§ Attenuates hypoxic ventilatory response by direct action on carotid body chemoreceptors
o apnea occurs after an induction dose of propofol and results in an acute increase in PaCO₂and a decrease in pH
§ incidence increases with addition of an opiate
Cardiovascular System
o Propofol decreases sympathetic outflow from the brain, causing a decrease in systemic vascular resistance by 15-25% (SVR)
o most prominent effect of propofol is a decrease in arterial BP during induction (25-40% reduction) mainly through SVR decreases
o during maintenance with propofol arterial systolic BP remains decreased by 20-30% (although the decrease is less significant than at induction, since the decrease in SVR is dose-dependent)
o Decrease in BP is associated with a decrease in cardiac output (CO) of about 15%; likely due to the decreased sympathetic outflow, rather than a direct myocardial depressant effect
o propofol may reset or inhibit the baroreflex of the heart (thus limiting the tachycardic response to hypotension) which explains why HR does not change
o propofol attenuates the HR response to atropine, which can cause profound bradycardia
o myocardial blood flow and myocardial oxygen consumption are both decreased with propofol, however the myocardial oxygen supply-to-demand ratio is preserved (doesn't result in increased ischemia)
o BEWARE ® HR may increase, decrease, or remain unchanged with maintenance using propofol
Miscellaneous
o Does not enhance neuromuscular blockade
o Does not trigger malignant hyperthermia
o At subhypnotic doses:
§ good antiemetic
§ relieves cholestatic pruritis
§ relieves pruritis due to spinal opiates
o Inhibits phagocytosis and killing of Staph aureus and E. coli (mainly due to inhibition of chemotaxis)
§ INTRALIPID IS AN EXCELLENT CULTURE MEDIUM - must use aseptic technique when administering propofol
o has been associated with hypertriglyceridemia leading to pancreatitis, especially with longer infusions and the elderly

Uses

Induction and Maintenance of Anesthesia
o induction dose ® 1-2.5 mg/kg (best determined by age, lean body mass, and central blood volume)
§ older than 60 years and/or diminished cardiovascular reserve, use 1 -1.5 mg/kg due to the risk of hypotension
§ children may need 2-3 mg/kg! (increased clearance and central compartment volume)
o maintenance dose ® 50-150 mg/kg/min (combined with N₂O or opiate)
§ Maintenance requirements decreased with volatile anesthetics and opiates
Sedation
o Sedation dose: 30-60 mg/kg/min (about ½ the maintenance dose)
o Regardless of the duration of infusion, propofol can be titrated to a desired level of sedation and terminated with a rapid recovery due to its short context-sensitive half-time
o At first glance, propofol seems perfect for long-term sedation, BUT need to consider the following:
§ hemodynamic effects
§ need for analgesia, PROPOFOL LACKS ANALGESIA
§ tolerance to propofol
§ hypertriglyceridemia (causing pancreatitis)
§ propofol infusion syndrome
o Perks = rapid on, rapid off = more rapid extubation

Side effects/Contraindications

Induction
o hypotension (most common side effect)
o pain on injection (less than or equal to etomidate, greater than thiopental), which is reduced by:
§ using lidocaine in the propofol solution
§ using a large vein
§ avoiding veins in the dorsum of the hand
o myoclonus - etomidate, methohexital > propofol > thiopental
o apnea, especially with coadministered opiate
o rarely thrombophlebitis
Maintenance
o Propofol infusion syndrome ® first described in children, but also seen in critically ill adults and is associated with an infusion of propofol > 60 mg/kg/min for > 48 hours
§ Clinical features:
acute, refractory bradycardia leading to asystole
metabolic acidosis
rhabdomyolysis
hyperlipidemia
enlarged/fatty liver
§ Possible causes ® mitochondrial toxicity, mitochondrial defects, poor tissue O₂, or carbohydrate deficiency
§ Risk factors ® poor oxygen delivery to tissues, sepsis, serious cerebral injury, and high propofol dosage

Anesthesiology Rotation & Elective