How does propofol (a sedative-hypnotic agent) work?

How Propofol Works

Propofol produces sedation and anesthesia by potentiating GABA-A receptors, which reduces the rate of GABA-receptor dissociation, leading to prolonged chloride influx into neurons and subsequent hyperpolarization of neuronal cell membranes. 1

Mechanism of Action

Propofol (2,6-diisopropylphenol) is a hypnotic agent that works through positive modulation of the inhibitory neurotransmitter GABA via ligand-gated GABA-A receptors. 2 This interaction extends the duration of contact between GABA and its receptor site, promoting an extended chloride influx into the neuron and leading to hyperpolarization of the neuronal cell membrane. 1

Additional Neurochemical Effects

Beyond GABA potentiation, propofol exerts multiple effects on the central nervous system:

• Propofol inhibits NMDA receptors and modulates calcium influx through slow calcium ion channels. 3
• The drug inhibits GABAergic neurons in the lateral hypothalamus, which plays a critical role in controlling wakefulness and contributes to its hypnotic state. 4
• Propofol acts as a global central nervous system depressant with anticonvulsant properties. 3

Pharmacokinetic Profile

Onset and Duration

Propofol has a rapid onset of action equivalent to one arm-brain circulation time (30-45 seconds), with blood-brain equilibration occurring within 1-3 minutes. 1, 2 The duration of effect after a single bolus dose is 4-8 minutes. 1

Metabolism and Elimination

• Propofol is highly lipid-soluble, allowing rapid passage through the blood-brain barrier. 5
• The drug is rapidly metabolized in the liver by conjugation to glucuronide and sulfate, producing water-soluble compounds that are excreted by the kidneys. 1
• Recovery is rapid even after prolonged use due to fast redistribution into peripheral tissues and metabolic clearance. 6
• Pharmacokinetic parameters are altered by weight, sex, age, and concomitant disease, but cirrhosis or renal failure does not significantly affect its profile. 1

Clinical Properties

Sedative-Hypnotic Effects

Propofol is classified as a pure sedative with minimal to no analgesic effect. 1 At subhypnotic doses, propofol produces sedation and amnesia, though its amnestic effects at light sedation levels are less reliable than benzodiazepines. 5

Important Clinical Caveat

Because propofol lacks analgesic properties, it must be combined with short-acting opioids for painful procedures. 5 For painless diagnostic studies such as MRI or CT scans, propofol is generally used alone. 1

Cardiovascular and Respiratory Effects

Hemodynamic Changes

Propofol causes dose-dependent cardiovascular depression, including decreases in cardiac output, systemic vascular resistance, and arterial blood pressure (sometimes >30% decrease). 1, 2 These effects are more pronounced than with other intravenous induction agents. 2

• Hypotension is the most common complication, particularly in volume-depleted patients. 3
• Negative cardiac inotropy can occur but responds rapidly to dose reduction or interruption of drug infusion. 1
• If ventilation is assisted or controlled with positive pressure, there is an increased incidence and degree of cardiac output depression. 2

Respiratory Depression

Propofol causes dose-dependent respiratory depression and is frequently associated with apnea in both adults and pediatric patients. 2

• In adults receiving 2-2.5 mg/kg, apnea lasted <30 seconds in 7%, 30-60 seconds in 24%, and >60 seconds in 12% of patients. 2
• During maintenance, propofol decreases spontaneous minute ventilation with increased carbon dioxide tension, especially when combined with opioids or sedatives. 2

Formulation and Contraindications

The current formulation contains 1% propofol, 10% soybean oil, 2.25% glycerol, and 1.2% purified egg phosphatide. 1

• Propofol should be avoided in persons with allergies to egg, soy, or sulfite. 1
• Propofol is NOT contraindicated in patients with sulfonamide allergy. 1
• Pain on injection occurs in up to 30% of patients receiving an intravenous bolus. 1

Drug Interactions

Co-administration of other central nervous system medications such as opioids and barbiturates potentiate the sedative effect of propofol. 1, 5 This synergistic effect allows for lower doses of propofol when combined with these agents, potentially reducing cardiovascular and respiratory side effects.

Additional Beneficial Properties

Beyond its primary sedative-hypnotic effects, propofol demonstrates several advantageous properties:

• Propofol is a potent antioxidant with anti-inflammatory properties. 3
• The drug acts as a bronchodilator. 3
• Propofol decreases cerebral oxygen consumption and reduces intracranial pressure. 3
• Propofol has antiemetic, antiepileptic, and antipruritic effects. 7