Intravenous (IV) anesthetics are commonly used for the induction and maintenance of general anesthesia and for sedation. The rapid onset and offset of these drugs are due to their physical translocation into and out of the brain. After a bolus IV injection, lipid-soluble drugs such as propofol, thiopental (not available in the United States), and etomidate rapidly distribute into the vessel-rich group of highly perfused tissues (e.g., brain, heart, liver, and kidneys), causing an extremely rapid onset of effect. Plasma concentrations decrease as the drug is taken up by the less well-perfused tissues (e.g., muscle and fat), and the drug rapidly leaves the brain. This redistribution from the brain is responsible for the termination of effects, but the clearance of the active drug must still occur, typically by hepatic metabolism and renal elimination. Elimination half-life is defined as the time required for the plasma concentration of a drug to decrease by 50% during the elimination phase of clearance. Context-sensitive half-time (CSHT) is defined as the time required for a 50% decrease in the central compartment drug concentration after a steady-state infusion of specified duration (duration is the “context”).

A. Propofol (2, 6-diisopropylphenol) is used for the induction or maintenance of general anesthesia and for procedural sedation. It is prepared as a 1% isotonic oil-in-water emulsion, which contains egg lecithin, glycerol, and soybean oil. Bacterial growth is inhibited by ethylenediaminetetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA), sulfite, or benzyl alcohol depending on the manufacturer.

1. Mode of action. Facilitates inhibitory neurotransmission by enhancing the function of γ-aminobutyric acid type A (GABA_A) receptors in the central nervous system (CNS). The modulation of glycine receptors, N-methyl-d-aspartate (NMDA) receptors, cannabinoid receptors, and voltage-gated ion channels may also contribute to propofol’s actions.

a. Hepatic and extrahepatic metabolism to inactive metabolites which are renally excreted.

b. CSHT remains short (15 minutes after a 2-hour infusion), making propofol infusions useful for the maintenance of anesthesia.

1. Induction doses rapidly produce unconsciousness (30 to 45 seconds), followed by a rapid termination of effect due to redistribution. Emergence is rapid and often accompanied by mood elevation. Low doses produce sedation and amnesia.

2. Weak analgesic effects at hypnotic concentrations.

3. Decreases intracranial pressure (ICP) and also cerebral perfusion pressure (CPP) due to markedly decreased mean arterial pressure (MAP). Cerebral autoregulation as well as vasoconstriction in response to hyperventilation are unaffected.

4. Propofol is an anticonvulsant and raises the seizure threshold more than that with methohexital.

5. Frontal alpha oscillations (8 to 12 Hz), delta oscillations (1 to 4 Hz), and slow oscillations (<1 Hz) appear on the electroencephalogram (EEG). Higher doses cause burst suppression and isoelectric EEG.

6. Depresses somatosensory-evoked potentials (SSEPs) and motor-evoked potentials (MEPs), but little effect on brainstem auditory-evoked potentials (BAEPs).

7. Postoperative nausea and vomiting (PONV) occurs less frequently after a propofol-based anesthetic compared with other techniques, and subhypnotic doses have antiemetic effects.

1. Dose-dependent decreases in preload, afterload, and contractility lead to decreases in blood pressure (BP) and cardiac output. Hypotension may be marked in hypovolemic, elderly, or hemody-namically compromised patients.

2. Heart rate (HR) is minimally affected, and baroreceptor reflex is blunted.

1. Dose-dependent decreases in respiratory rate (RR) and tidal volume (TV).

2. Ventilatory responses to hypoxia and hypercarbia are diminished.

4. Dosage and administration. Table 12.1.

a. Titrate with reduced incremental doses in hypovolemic, elderly, or hemodynamically compromised patients or if administered with other anesthetics.

b. Relatively larger induction and maintenance doses are required in infants and small children.

c. Propofol emulsion supports bacterial growth despite the addition of antimicrobials; prepare drug under sterile conditions, label with date and time, and discard unused, opened propofol after 6 hours to prevent inadvertent bacterial contamination.

a. Venous irritation. May cause pain during IV administration, which can be reduced by administration in a large vein or by adding
lidocaine to the solution (e.g., 20 mg of lidocaine to 200 mg of propofol). The most effective method to reduce pain is to give lidocaine (0.5 mg/kg, IV) 1 to 2 minutes before propofol injection with a tourniquet proximal to the IV site.

b. Lipid disorders. Propofol is a lipid emulsion and should be used cautiously in patients with disorders of lipid metabolism (e.g., hyperlipidemia and pancreatitis).

c. Myoclonus and hiccups can occur after induction doses, although less frequently than with methohexital or etomidate.

d. Propofol infusion syndrome is a rare and often fatal disorder that occurs in critically ill patients (usually children) subjected to prolonged, high-dose propofol infusions. Typical features include rhabdomyolysis, metabolic acidosis, cardiac failure, and renal failure.

B. Barbiturates such as thiopental and methohexital rapidly produce unconsciousness (30 to 45 seconds) after IV administration, followed by rapid termination of effects due to redistribution. Barbiturate preparations for IV administration are highly alkaline (pH >10) and are usually prepared as dilute solutions (1.0% to 2.5%).

1. Mode of action. Similar to propofol, barbiturates facilitate inhibitory neurotransmission by enhancing GABA_A receptor function. They also inhibit excitatory neurotransmission via glutamate and nicotinic acetylcholine receptors.

a. Hepatic metabolism. Methohexital has a much higher clearance than thiopental. Thiopental is metabolized to pentobarbital, an active metabolite with a longer half-life.

b. Multiple doses or prolonged infusions may produce prolonged sedation or unconsciousness due to the reduced rate of redistribution, the return of the drug to the central compartment, and slow hepatic metabolism. The CSHT of thiopental is long, even after short infusions.

1. Dose-dependent CNS depression ranging from sedation to unconsciousness. Much higher doses are required to suppress responses to painful stimuli.

2. Dose-dependent cerebral vasoconstriction and decrease in cerebral metabolic rate (CMRO₂) cause reductions in ICP and cerebral blood flow (CBF). Cerebral autoregulation remains unaffected.

3. At high doses, thiopental will produce an isoelectric EEG. In contrast, methohexital can elicit seizure activity.

4. Minimal effects on SSEPs or MEPs, but dose-dependent depression of BAEPs.

1. Cause venodilation and depress myocardial contractility, leading to dose-dependent decreases in BP and cardiac output, especially in patients who are preload dependent. Decrease in BP is less pronounced than with propofol.

2. Baroreceptor reflexes remain largely intact; therefore, HR may increase in response to hypotension.

1. Dose-dependent decreases in RR and TV. Ventilatory responses to hypoxia and hypercarbia are markedly depressed. Apnea may result for 30 to 90 seconds after an induction dose.

2. Laryngeal reflexes remain more intact compared with propofol; therefore, the incidence of cough and laryngospasm is higher.

4. Dosage and administration. See Table 12.1.

a. Reduce doses in hypovolemic, elderly, or hemodynamically compromised patients.

b. May precipitate when mixed with drugs in lower pH solution (e.g., succinylcholine) and cause the precipitation of other drugs (e.g., vecuronium). Therefore, it is prudent to use a free-running IV and avoid simultaneous injection with other drugs.

a. Allergy. True allergies are unusual. Thiopental occasionally causes anaphylactoid reactions (i.e., hives, flushing, and hypotension) due to histamine release.

1. Absolutely contraindicated in patients with acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria.

2. Barbiturates induce porphyrin synthetic enzymes such as δ-aminolevulinic acid synthetase; patients with porphyria may accumulate toxic heme precursors and suffer an acute attack.

1. May cause pain at the site of administration due to venous irritation.

2. Thiopental can cause severe pain and tissue necrosis if injected extravascularly or intra-arterially. If intra-arterial administration occurs, phentolamine (α-blocker), heparin, vasodilators, and regional sympathetic blockade may be helpful in treatment.

d. Myoclonus and hiccups are often seen during induction with methohexital.

C. Benzodiazepines include midazolam, lorazepam, and diazepam. They are often used for sedation, amnesia, anxiolysis, or as adjuncts to general anesthesia. Midazolam is prepared in a water-soluble form at pH 3.5, while diazepam and lorazepam are dissolved in propylene glycol and polyethylene glycol, respectively.

1. Mode of action. Enhance inhibitory neurotransmission by increasing the affinity of GABA_A receptors for GABA. Different clinical effects (e.g., amnesia, sedation, and anxiolysis) appear to be mediated by different GABA_A receptor subtypes.

a. After IV administration, the onset of CNS effects occurs in 2 to 3 minutes for midazolam and diazepam (slightly longer for lorazepam). Effects are terminated by redistribution; therefore, durations of a single dose of diazepam and midazolam are similar. The effects of lorazepam are somewhat more prolonged.

b. All three drugs are metabolized in the liver. Elimination half-lives for midazolam, lorazepam, and diazepam are approximately 2, 11, and 20 hours, respectively. The active metabolites of diazepam last longer than the parent drug and accumulate with repeated dosing. Hydroxymidazolam can accumulate and cause sedation in patients with renal failure.

c. Diazepam clearance is reduced in the elderly, but this is less of a problem with midazolam and lorazepam. Obese patients may require higher initial doses of benzodiazepines, but clearance is not markedly different.

1. Amnestic, anticonvulsant, anxiolytic, muscle relaxant, and sedative-hypnotic effects in a dose-dependent manner. Amnesia may last for only 1 hour after a single premedicant dose of midazolam. Sedation may sometimes be prolonged.

2. Do not produce significant analgesia.

3. Dose-dependent reduction of CBF and CMRO₂.

4. Do not produce burst suppression or isoelectric EEG pattern, even at very high doses.

1. Mild systemic vasodilation and decrease in cardiac output. HR is usually unchanged.

2. Hemodynamic changes may be pronounced in hypovolemic or critically ill patients if rapidly administered in a large dose or with an opioid.

1. Mild dose-dependent decreases in RR and TV. Some decrease in hypoxic ventilatory drive.

2. Respiratory depression may be pronounced if administered with an opioid, in patients with pulmonary disease or in debilitated patients.

4. Dosage and administration. See Table 12.1 for midazolam.

a. Incremental IV doses of diazepam (2.5 mg) or lorazepam (0.25 mg) may be used for sedation.

b. Appropriate oral doses are 5 to 10 mg of diazepam or 2 to 4 mg of lorazepam.

a. Drug interactions. Administration of a benzodiazepine to a patient receiving the anticonvulsant valproate may precipitate a psychotic episode.

1. May be associated with a slightly increased risk of cleft lip and palate when administered during the first trimester.

2. Cross the placenta and may lead to CNS depression in the neonate.

c. Superficial thrombophlebitis and injection pain may be produced by the vehicles in diazepam and lorazepam.

6. Flumazenil (imidazobenzodiazepine) is a competitive antagonist at the benzodiazepine binding site of GABA_A receptors in the CNS.

a. Reversal of benzodiazepine-induced sedative effects occurs within 2 minutes; peak effects occur at approximately 10 minutes. Does not completely antagonize the respiratory depressant effects of benzodiazepines.

b. Half-life is shorter than the benzodiazepine agonists, so repeated administration may be necessary.

c. Metabolized to inactive metabolites in the liver.

d. Dose. 0.3 mg IV every 30 to 60 seconds (to a maximum dose of 5 mg).

e. Contraindicated in patients with tricyclic antidepressant (TCA) overdose (thought to be the unmasking of TCA-induced seizure activity) and in those receiving benzodiazepines for the control of seizures or elevated ICP. Use cautiously in patients who have had long-term treatment with benzodiazepines because acute withdrawal may be precipitated.

D. Etomidate is a sedative-hypnotic agent most commonly used for IV induction of general anesthesia. It is supplied in a solution containing 35% of propylene glycol.

1. Mode of action. Facilitates inhibitory neurotransmission by enhancing GABA_A receptor function.

a. After an induction dose, times to loss of consciousness and return of consciousness are similar to that for propofol. Effects of a single bolus dose are terminated by redistribution.