Propofol - Intravenous Anesthetics

PROPOFOL

In most countries, propofol is the most frequently administered drug for induction of anesthesia and has largely replaced barbitu-rates for this indication. 

Because its pharmacokinetic profile allows for continuous infusions, propofol is also used during maintenance of anesthesia and is a common choice for sedation in the setting of monitored anesthesia care. Increasingly, propofol is also used for sedation in the ICU as well as conscious sedation and short-duration general anesthesia in locations outside the operating room (eg, interventional radiology suites, emergency department; see Topic: Sedation & Monitored Anesthesia Care, earlier).

Propofol (2,6-diisopropylphenol) is an alkyl phenol with hyp-notic properties that is chemically distinct from other groups of intravenous anesthetics (Figure 25–6). Because of its poor solubil-ity in water, it is formulated as an emulsion containing 10% soy-bean oil, 2.25% glycerol, and 1.2% lecithin, the major component of the egg yolk phosphatide fraction. Hence, susceptible patients may experience allergic reactions. The solution appears milky white and slightly viscous, has a pH of approximately 7, and a propofol concentration of 1% (10 mg/mL). In some countries, a 2% formu-lation is available. Although retardants of bacterial growth are added to the formulations, solutions should be used as soon as pos-sible (no more than 8 hours after opening the vial) and proper sterile technique is essential. The addition of metabisulfite in one of the formulations has raised concern regarding its use in patients with reactive airway disease (eg, asthma) or sulfite allergies.

The presumed mechanism of action of propofol is through potentiation of the chloride current mediated through the GABA_A receptor complex.

Pharmacokinetics

Propofol is rapidly metabolized in the liver; the resulting water-soluble compounds are presumed to be inactive and are excreted through the kidneys. Plasma clearance is high and exceeds hepatic blood flow, indicating the importance of extrahepatic metabolism, which is thought to occur to a significant extent in the lungs and may account for the elimination of up to 30% of a bolus dose of the drug (Table 25–2). The recovery from propofol is more complete,with less “hangover” than that observed with thiopental, likely due to the high plasma clearance. However, as with other intravenous drugs, transfer of propofol from the plasma (central) compart-ment and the associated termination of drug effect after a single bolus dose are mainly the result of redistribution from highly perfused (brain) to less-well-perfused (skeletal muscle) compart-ments (Figure 25–7). As with other intravenous agents, awakening after an induction dose of propofol usually occurs within 8–10 minutes. The kinetics of propofol (and other intravenous anes-thetics) after a single bolus dose or continuous infusion are best described by means of a three-compartment model. Such models have been used as the basis for developing systems of target-controlled infusions.

The context-sensitive half-time of a drug describes the elimination half-time after a continuous infusion as a function of the duration of the infusion and is an important factor in the suitability of a drug for use as maintenance anesthetic. The context-sensitive half-time of propofol is brief, even after a prolonged infusion, and recovery remains relatively prompt (Figure 25–8).

Organ System Effects

A. CNS Effects

Propofol acts as hypnotic but does not have analgesic properties. Although the drug leads to a general suppression of CNS activity, excitatory effects such as twitching or spontaneous movement are occasionally observed during induction of anesthesia. These effects may resemble seizure activity; however, most studies sup-port an anticonvulsant effect of propofol, and the drug may be safely administered to patients with seizure disorders. Propofol decreases cerebral blood flow and the cerebral metabolic rate for oxygen (CMRO₂), which decreases intracranial pressure (ICP) and intraocular pressure; the magnitude of these changes is com-parable to that of thiopental. Although propofol can produce a desired decrease in ICP, the combination of reduced cerebral blood flow and reduced mean arterial pressure due to peripheral vasodilation can critically decrease cerebral perfusion pressure.

When administered in large doses, propofol produces burst suppression in the EEG, an end point that has been used when administering intravenous anesthetics for neuroprotection during neurosurgical procedures. Evidence from animal studies suggests that propofol’s neuroprotective effects during focal ischemia are similar to those of thiopental and isoflurane.

B. Cardiovascular Effects

Compared with other induction drugs, propofol produces the most pronounced decrease in systemic blood pressure; this is a result of profound vasodilation in both arterial and venous circulationsleading to reductions in preload and afterload. This effect on sys-temic blood pressure is more pronounced with increased age, in patients with reduced intravascular fluid volume, and with rapid injection. Because the hypotensive effects are further augmented by the inhibition of the normal baroreflex response, the vasodilation only leads to a small increase in heart rate. Profound bradycardia and asystole after the administration of propofol have been described in healthy adults despite prophylactic anticholinergic drugs.

C. Respiratory Effects

Propofol is a potent respiratory depressant and generally produces apnea after an induction dose. A maintenance infusion reduces minute ventilation through reductions in tidal volume and respi-ratory rate, with the effect on tidal volume being more pro-nounced. In addition, the ventilatory response to hypoxia and hypercapnia is reduced. Propofol causes a greater reduction in upper airway reflexes than thiopental does, which makes it well suited for instrumentation of the airway, such as placement of a laryngeal mask airway.

D. Other Effects

Although propofol, unlike volatile anesthetics, does not augment neuromuscular block, studies have found good intubating condi-tions after propofol induction without the use of neuromuscular blocking agents. Unexpected tachycardia occurring during propo-fol anesthesia should prompt laboratory evaluation for possible metabolic acidosis (propofol infusion syndrome). An interesting and desirable side effect of propofol is its antiemetic activity. Pain on injection is a common complaint and can be reduced by pre-medication with an opioid or coadministration with lidocaine. Dilution of propofol and the use of larger veins for injection can also reduce the incidence and severity of injection pain.

Clinical Uses & Dosage

The most common use of propofol is to facilitate induction of general anesthesia by bolus injection of 1–2.5 mg/kg IV. Increasing age, reduced cardiovascular reserve, or premedication with benzo-diazepines or opioids reduces the required induction dose; children require higher doses (2.5–3.5 mg/kg IV). Generally, titration of the induction dose helps to prevent severe hemodynamic changes. Propofol is often used for maintenance of anesthesia either as part of a balanced anesthesia regimen in combination with volatile anesthetics, nitrous oxide, sedative-hypnotics, and opioids or as part of a total intravenous anesthetic technique, usually in combi-nation with opioids. Therapeutic plasma concentrations for main-tenance of anesthesia normally range between 3 and 8 mcg/mL (typically requiring a continuous infusion rate between 100 and 200 mcg/kg/min) when combined with nitrous oxide or opioids.When used for sedation of mechanically ventilated patients in the ICU or for sedation during procedures, the required plasma concentration is 1–2 mcg/mL, which can be achieved with a con-tinuous infusion at 25–75 mcg/kg/min. Because of its pronounced respiratory depressant effect and narrow therapeutic range, propo-fol should be administered only by individuals trained in airway management. Subanesthetic doses of propofol can be used to treat postopera-tive nausea and vomiting (10–20 mg IV as bolus or 10 mcg/kg/min as an infusion).