Intravenous Anesthetics: Propofol

PROPOFOL

Mechanisms of Action

Propofol induction of general anesthesia may involve facilitation of inhibitory neurotransmission mediated by GABA _A receptor binding. Propofol allo-sterically increases binding affinity of GABA for the GABA_A receptor. This receptor, as previously noted, is coupled to a chloride channel, and activation of the receptor leads to hyperpolarization of the nerve membrane. Propofol (like most general anesthetics) binds multiple ion channels and receptors. Propofol actions are not reversed by the specific benzodiaz-epine antagonist flumazenil.

Structure–Activity Relationships

Propofol consists of a phenol ring substituted with two isopropyl groups (see Figure 9–4). Propofol is not water soluble, but a 1% aqueous solution (10 mg/mL) is available for intravenous administration as an oil-in-water emulsion containing soybean oil, glycerol, and egg lecithin. A history of egg allergy does not necessarily contraindicate the use of pro-pofol because most egg allergies involve a reaction to egg white (egg albumin), whereas egg lecithin is extracted from egg yolk. This formulation will often cause pain during injection that can be decreased by prior injection of lidocaine or less effectively by mixing lidocaine with propofol prior to injection (2 mL of 1% lidocaine in 18 mL propofol). Propofol formulations can support the growth of bacteria, so sterile technique must be observed in preparation and handling. Propofol should be administered within 6 h of opening theampule. Sepsis and death have been linked to con-taminated propofol preparations. Current formula-tions of propofol contain 0.005% disodium edetate or 0.025% sodium metabisulfite to help retard the rate of growth of microorganisms; however, these additives do not render the product “antimicrobi-ally preserved” under United States Pharmacopeia standards.

Pharmacokinetics

A. Absorption

Propofol is available only for intravenous adminis-tration for the induction of general anesthesia and for moderate to deep sedation (see Table 9–3).

B. Distribution

Propofol has a rapid onset of action. Awakening from a single bolus dose is also rapid due to a very short initial distribution half-life (2–8 min). Most investigators believe that recovery from propofol is more rapid and is accompanied by less “hangover” than recovery from methohexital, thiopental, ket-amine, or etomidate. This makes it a good agent for outpatient anesthesia. A smaller induction dose is recommended in elderly patients because of their smaller V_d. Age is also a key factor determining required propofol infusion rates for TIVA. In coun-tries other than the United States, a device called the Diprifusor is often used to provide target (con-centration) controlled infusion of propofol. The user must enter the patient’s age and weight and the desired target concentration. The device uses these data, a microcomputer, and standard phar-macokinetic parameters to continuously adjust the infusion rate.

C. Biotransformation

The clearance of propofol exceeds hepatic blood flow, implying the existence of extrahepatic metabo-lism. This exceptionally high clearance rate probably contributes to relatively rapid recovery after con-tinuous infusions. Conjugation in the liver results in inactive metabolites that are eliminated by renal clearance. The pharmacokinetics of propofol do not appear to be affected by obesity, cirrhosis, or kidney failure. Use of propofol infusion for long-term seda-tion of children who are critically ill or young adultneurosurgical patients has been associated with spo-radic cases of lipemia, metabolic acidosis, and death, the so-termed propofol infusion syndrome.

D. Excretion

Although metabolites of propofol are primarily excreted in the urine, chronic kidney failure does not affect clearance of the parent drug.

Effects on Organ Systems

A. Cardiovascular

The major cardiovascular effect of propofol is a decrease in arterial blood pressure due to a drop in systemic vascular resistance (inhibition of sympathetic vasoconstrictor activity), preload, and cardiac con-tractility. Hypotension following induction is usually reversed by the stimulation accompanying laryngos-copy and intubation. Factors associated with propo-fol-induced hypotension include large doses, rapid injection, and old age. Propofol markedly impairs the normal arterial baroreflex response to hypotension. Rarely, a marked drop in preload may lead to a vagally mediated reflex bradycardia. Changes in heart rate and cardiac output are usually transient and insignificant in healthy patients but may be severe in patients at the extremes of age, those receiving β-adrenergic blockers, or those with impaired ventricular function. Although myocardial oxygen consumption and coronary blood flow usually decrease comparably, coronary sinus lac-tate production increases in some patients, indicating some mismatch between myocardial oxygen supply and demand.

B. Respiratory

Propofol is a profound respiratory depressant that usually causes apnea following an induction dose. Even when used for conscious sedation in sub-anesthetic doses, propofol inhibits hypoxic venti-latory drive and depresses the normal response to hypercarbia. As a result, only properly educated and qualified personnel should administer propofol for sedation. Propofol-induced depression of upper airway reflexes exceeds that of thiopental, allowing intubation, endoscopy, or laryngeal mask placement in the absence of neuromuscular blockade. Although propofol can cause histamine release, induction with propofol is accompanied by a lower incidence of wheezing in asthmatic and nonasthmatic patients compared with barbiturates or etomidate.

C. Cerebral

Propofol decreases cerebral blood flow and intracra-nial pressure. In patients with elevated intracranial pressure, propofol can cause a critical reduction in CPP (<50 mm Hg) unless steps are taken to support mean arterial blood pressure. Propofol and thiopen-tal probably provide a similar degree of cerebral pro-tection during experimental focal ischemia. Unique to propofol are its antipruritic properties. Its anti-emetic effects (requiring a blood propofol concen-tration of 200 ng/mL) provide yet another reason for it to be a preferred drug for outpatient anesthesia. Induction is occasionally accompanied by excitatory phenomena such as muscle twitching, spontaneous movement, opisthotonus, or hiccupping. Although these reactions may occasionally mimic tonic–clonic seizures, propofol has anticonvulsant properties and has been used successfully to terminate status epi-lepticus. Propofol may be safely administered to epileptic patients. Propofol decreases intraocular pressure. Tolerance does not develop after long-term propofol infusions. Propofol is an uncommon agent of physical dependence or addiction; however, both anesthesia personnel and medically untrained indi-viduals have died while using propofol inappropri-ately to induce sleep in nonsurgical settings.

Drug Interactions

Fentanyl and alfentanil concentrations may be increased with concomitant administration of pro-pofol. Many clinicians administer a small amount of midazolam (eg, 30 mcg/kg) prior to induction with propofol; midazolam can reduce the required pro-pofol dose by more than 10%.