Show Summary Details
Page of

Intravenous Anesthetics 

Intravenous Anesthetics
Intravenous Anesthetics

Alina Bodas

, Vera Borzova

, and Ricardo Riveros

Page of

PRINTED FROM OXFORD MEDICINE ONLINE ( © Oxford University Press, 2020. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 13 August 2020


Mechanism of Action

Etomidate is a short-acting intravenous anesthetic introduced for clinical use in 1972.1 Etomidate interacts with a stereoselectivity on gamma amino-butyric acid type A (GABAa). Etomidate is composed by two isomers: the R(+), which is responsible for the anesthetic effect, and the S(-) with minimal effect inducing transmission on GABAa receptor2 (Figure 13.1). The effect of etomidate on GABA receptors contrasts with the absence of effect on other ion channels.

Pharmacokinetics and Pharmacodynamics

Plasma protein binding of etomidate is high (75%), but less than propofol (98%) and barbiturates (85%). Because of its high solubility in fat, etomidate has a large central and peripheral volume of distribution, 4.5 L/kg and 74.9 L/kg respectively. After an induction dose of etomidate (0.2–0.6 mg/kg), plasma concentration follows a pharmacokinetic profile of the three-compartment model. Etomidate has a rapid onset and short duration of activity. The redistribution of etomidate out of the central nervous system (CNS) into peripheral tissues (mainly muscle) is responsible for the short duration of action (4–8 min) after an induction dose.

Metabolism and Excretion

Etomidate is metabolized in the liver by hepatic esterases to inactive metabolites including carboxylic acid and an ethanol-leaving group. Elimination is mostly renal (78%) and to a lesser extent biliary (22%) for the carboxylate metabolite. Etomidate plasma clearance is 15–20 mL/min/kg with a terminal metabolic half-life of 2–5 hours. Because etomidate has a context-sensitive half-life shorter than propofol (Figure 13.2), the use of etomidate infusion for sedation and anesthesia was advocated during the first decade of clinical availability.3,4 However, the demonstration of secondary effects (adrenal toxicity) precludes the use of etomidate for infusion.

Figure 13.2 Context-sensitive half-life of the intravenous anesthetics.

Figure 13.2 Context-sensitive half-life of the intravenous anesthetics.

Effect on Circulation

Of the intravenous anesthetics, etomidate provides the least cardiovascular depression, including minimal changes in blood pressure and heart rate. Therefore, etomidate is commonly used for induction of general anesthesia in patients with poor cardiac function such as those with ischemic heart or valvular disease.5 On the other hand, etomidate does not inhibit sympathetic tone during laryngoscopy, and opioids frequently are given to blunt these responses.

Etomidate offers a favorable profile as an induction agent in the setting of intravascular volume depletion. In a pig model of moderate hemorrhage, the pharmacokinetic and pharmacodynamic of etomidate were minimally affected.6 Therefore etomidate has been used as a hypnotic agent for rapid sequence induction in the setting of hemorrhagic shock.

Effect on Respiration

Compared with barbiturates and propofol, etomidate produces less apnea, rarely induces allergic reactions, and induces no histamine release. Etomidate does not inhibit sympathetic response to direct laryngoscopy.

Effect on Other Organs

Etomidate is capable of causing reduced cerebral metabolic rate and reduced cerebral blood flow and intracranial pressure while maintaining cerebral perfusion pressure.5 Electroencephalographic changes associated with use of etomidate are similar to those observed with barbiturates.7Different effects associated with using etomidate are seen on evoked potentials. On auditory evoked potentials, etomidate decreases amplitude and increases latency8; Somatosensory evoked potential amplitudes are increased,9 while motor evoked potential amplitudes are decreased; the latter effect is minimal when compared with propofol and barbiturates.10 Etomidate produces minimal hepatic metabolic inhibition of cytochrome P450 without having an effect on the metabolism of other anesthetic or analgesic drugs.11

Side Effects and Toxicity

After a single dose for induction of anesthesia, etomidate can cause pain on injection and myoclonic movements. The type of solvent used for etomidate preparation is responsible for pain on injection as follows: aqueous solutions > propylene glycol > medium chain length or cyclodextrines. Myoclonic movements are not associated with electroencephalographic changes and can be attenuated using premedication opioids such as benzodiazepines or dexmedetomidine or by splitting the induction dose.12

Postoperative nausea and vomiting (PONV) has been considered as an adverse effect of etomidate. Early studies reported similar incidences of PONV compared with barbiturates.13,14 Comparing etomidate in lipid emulsion with propofol for induction of anesthesia, the incidence of nausea is similar between both medications, while the incidence of vomiting is higher with etomidate.15,16

Adrenal cortical inhibition is a well-recognized adverse effect of etomidate. Etomidate’s effect on the adrenal axis is through blockade of 11β‎‎-hydroxylase, an important enzyme in the synthesis of cortisol. Adrenal suppression lasts 6–8 hours after a single induction dose and more than 24 hours after infusion of etomidate.

Indications and Contraindications

Currently the use of etomidate is approved as an anesthetic induction agent and for anesthetic maintenance in short surgical procedures. Given the risk for adrenal toxicity, etomidate is not indicated for use for prolonged infusion. A controversy exists about the use of a single dose of etomidate in critically ill patients. Effects of a single dose of etomidate in patients with septic shock include adrenal suppression, an increase in 28-day mortality, and nonbenefit of steroid replacement therapy.17 However, other studies have failed to demonstrate such effect on mortality.18,19,20 Therefore further larger studies to define the role of a single induction dose of etomidate on clinical outcomes in critically ill patients are needed.


Mechanism of Action

Propofol is the most common parenteral anesthetic used in the United States. Propofol is a lipid formulation composed as 1% emulsion in 10% soybean oil, 2.25% glycerol, and 1.2% egg phosphatide. In order to inhibit bacterial growth, disodium EDTA (0.05 mg/mL) or sodium metabisulfite (0.25 mg/mL) is added. However, it is recommended to discard any unused propofol after 4 hours of removal of its sterile packaging. Because the lipid emulsion of propofol is associated with hyperlipidemia and pain on injection, a new aqueous solution, fospropofol, offers an alternative as an induction agent without the adverse effects. Fospropofol, which is a prodrug of propofol, is hydrolyzed by the endothelium to propofol, phosphate, and formaldehyde, which is converted to formic acid then transformed to CO2 and water by tetrahydrofolate dehydrogenase.21

Propofol inhibits the response to noxious stimuli, which is mediated by its action on GABAA receptors by specific activity on B3 subunits, whereas the sedative effects are mediated by the B2 subunit in the same receptor. The agonistic action of propofol on GABAA receptors increases the activity of glycine-gated chloride channels resulting in a hyperpolarization of neurons secondary to an increase in chloride conduction, which is responsible for the inhibitory neurotransmission in the spinal cord and brain stem.

Pharmacokinetics and Pharmacodynamics

Propofol is highly bound to plasma proteins (98%), including albumin and red blood cells. After an induction dose of 1.5 to 2.5 mg/kg, the pharmacokinetics of propofol follows a three-compartment model, with central compartment and the slow and fast distribution compartments of 9.3 L, 44.2 L, and 266 L, respectively. The elimination half-life B is 1.8 hours. The clearance of propofol is faster than barbiturates, facilitating shorter recovery and discharge after a surgical procedure.22 After infusion, propofol has a context-sensitive half-life shorter than 25 minutes for an infusion lasting up to 3 hours, and 40 minutes for infusions lasting up to 8 hours. Propofol used for infusion for more than 3 days increases the risk of hypertriglyceridemia, and monitoring of triglyceride in plasma is recommended.23

The pharmacokinetic profile of propofol changes with patient’s age. Neonates have a reduced clearance, having risk for delayed emergence after anesthesia or sedation with propofol. The induction and maintenance doses of propofol are higher in children due to a higher volume of distribution and clearance of the medication. In geriatric patients, the elimination of propofol is slower and clearance decreases in patients older than 60 years of age. Since the volume of the central compartment in patients older than 65 years is reduced, an increase in the rate of propofol infusion can represent a significant rise in plasma concentration. Therefore, the induction and maintenance doses of propofol administered to geriatric patients need to be reduced between 30% and 75%.24

The induction dose of propofol in obese patients should be adjusted to the ideal body mass. Propofol does not exhibit an accumulation pattern in obese patients. It is recommended to adjust the maintenance doses based on the maintenance lean body mass, because higher concentrations during emergence and hemodynamic instability can be observed when the dose is calculated based on total body weight.

Metabolism and Excretion

Propofol is metabolized in the liver. The initial step is an oxidation to 1,4-di-isopropylquinol, followed by coupling with glucuronic acid and production of glucuronides; all of these metabolites are renally excreted. Extrahepatic metabolism of propofol has been described in organs such as the kidneys, small intestine, brain, and lungs.25 Since propofol has a high hepatic extraction ratio, there is a relationship between its elimination, cardiac output, and hepatic blood flow.26

Since propofol is highly bound to protein and has a high extraction ratio in pathological states such hypoalbuminemia or anemia, a higher free fraction is not compensated by higher clearance or elimination; therefore, intensified effects of propofol are expected in patients with these disease processes.

Effect on Circulation

Propofol induces a dose-dependent decrease in arterial blood pressure after induction of anesthesia. This effect can be explained by a decrease in peripheral vascular resistance and myocardial contractility.27 Propofol should be used with caution in patients with hypovolemia, cardiac failure, and hypertension, because they are prone to develop greater decreases in arterial blood pressure after an induction dose. After induction of propofol no significant changes are seen in heart rate.

Effect on Respiration

Propofol produces a respiratory depression with decrease in tidal volume, increase in respiratory frequency, and reduction in the inspiratory time followed by apnea that can last at least 30 seconds. The effect of propofol on tidal volume is more significant than the decrease on respiratory rate. Compared with tiopenthal, an induction dose of propofol causes slightly more pronounced respiratory depression.28

A propofol maintenance infusion dose (50–120 mcg/kg/min) decreases the ventilatory response to CO2 and to hypoxia. Propofol does not induce bronchospasm and may be used as induction agent in patients with asthma or chronic obstructive pulmonary disease. Propofol decreases vagal (muscarinic receptors) and metacholine-induced bronchoconstriction. The use of metabisulfite as a preservative ablates the bronchodilator effect of propofol.29

Effect on Other Organs

Propofol decreases cerebral blood flow, cerebral metabolic rate, and intracranial pressure. Propofol can produce dose-dependent EEG burst suppression. Despite the beneficial neurological effects, no outcome studies of propofol as a neuroprotective agent have been performed. After an induction dose, propofol can induce transient choreiform movements and opisthotonus. These movements are not associated with seizure activity, are transient, and infrequently occur. Propofol does not trigger malignant hyperthermia and may be a good choice for patients at risk to develop this condition. At subhypnotic doses such as a 10–20 mg bolus followed by 10 mcg/kg/min, propofol has antiemetic activity. Propofol does not affect renal, hepatic, or hematologic functions.

Side Effects and Toxicity

A propofol induction dose can cause pain on injection and in some cases thrombophlebitis in the vein used to infuse propofol. The incidence of pain on injection is similar to that with etomidate. Strategies to decrease the incidence of pain on injection include avoiding small veins, avoiding use of those on the dorsum of the hand, and adding lidocaine to the propofol solution. Other side effects previously discussed include myoclonic movements that are transient, apnea after induction dose that can last more than 30 seconds, and decrease of systemic blood pressure associated with low vascular resistance and decreased myocardial contractility.

Propofol is considered a safe anesthetic in general; however, propofol infusion syndrome (PRIS) is a serious and lethal adverse effect associated with high doses (>4 mg/kg for single dose or >67 mcg/kg/min for infusion) for a prolonged period (48 hours) of propofol. Propofol infusion syndrome is clinically characterized by severe metabolic acidosis, hyperkalemia, rhabdomyolysis, lipemia, hepatomegaly, renal failure, and myopathy. The pathophysiology of PRIS remains unclear. Factors that have been implicated as potential causes include a failure in the mitochondrial respiratory chain as well as genetic factors related with inborn error in the fatty acid oxidation.

Indications and Contraindications

Propofol is the most common parenteral intravenous anesthetic used in clinical practice. Indications for the administration of propofol include induction and maintenance of anesthesia, and sedation for procedures in or outside of the operating room. Based on the physiological patient condition, an induction dose can be between 1.0 and 2.5 mg/kg. After an induction with propofol, a maintenance dose is recommended between 100 and 200 mcg/kg/min. Adjustments are made based on physiological patient status, surgical needs, and use of other intravenous anesthetics. The use of propofol and an opioid for total intravenous anesthesia has demonstrated reduction in the incidence of postoperative nausea and vomiting.30

Propofol provides a reliable level of sedation that is easy to titrate and a rapid recovery after infusion. Therefore, propofol is suitable for use in sedation in the intensive care unit (ICU) and during short surgical procedures and as a supplement for patients receiving regional anesthesia.

Propofol should be used with caution in patients with limited cardiac reserve such those with cardiac failure, those undergoing cardiac surgery, and those with hypovolemia or hypertension, as they are prone to develop greater decreases in arterial blood pressure after an induction dose.

Anaphylactoid reactions with the current propofol formulation are uncommon, and have been reported in patients with multiple other allergies. Therefore, in patients with history of multiple allergies, propofol should be used with caution. Patients with known allergies to egg and soy products may have an allergic response to propofol; as such, cautious use should be considered in these patients.31


Mechanism of Action

Benzodiazepines bind to specific benzodiazepine receptors. This binding modulates and increases the efficiency of the inhibitory GABA neurotransmitter system through the coupling of the GABA receptor with the chloride ion channel. This results in the hyperpolarization of the postsynaptic cell membrane and renders postsynaptic neurons resistant to the effects of the excitatory neurotransmitters. Clinically it produces anxiolysis, sedation, and hypnosis.

Pharmacokinetics and Pharmacodynamics

The three benzodiazepine receptor agonists available in clinical practice are short-acting midazolam (Versed), intermediate-acting diazepam (Valium), and long-acting lorazepam (Ativan). All three are highly lipophilic and produce a rapid CNS response. The high lipophilicity also leads to the large volume of distribution of benzodiazepines. Redistribution from the highly perfused central compartment to the less perfused peripheral compartment is responsible for the termination of the clinical effect of the benzodiazepines after the initial doses.

Metabolism and Excretion

All benzodiazepines are metabolized in the liver by oxidation and glucuronide conjugation. Water-soluble glucuronide conjugates are excreted by the kidney. Unlike lorazepam, which has no active metabolites, diazepam produces two active metabolites that can prolong its drug effect. Prolonged infusion of midazolam can result in accumulation of active metabolites especially in the presence of renal impairment.

Effect on Circulation

Benzodiazepines decrease systemic vascular resistance and lead to a small reduction in the arterial blood pressure. Their ability to preserve homeostatic reflex mechanisms results in overall stable hemodymanics even in the presence of ischemic and valvular heart disease. Midazolam can increase cardiac output and decrease filling pressure in patients with elevated left ventricular pressures. When given in combination with opioids, benzodiazepines can decrease systemic blood pressure via the synergistic reduction in sympathetic tone.

Effect on Respiration

Benzodiazepines produce dose-dependent respiratory depression, modestly attenuate upper airway reactivity, and depress the swallowing reflex. All of the benzodiazepines can cause apnea if used in sufficient doses. Apnea is more likely in the presence of opioids. Benzodiazepines and opioids produce synergistic (supra-additive) respiratory depression.

Effect on Other Organs

All benzodiazepines reduce the cerebral metabolic oxygen consumption and cerebral blood flow. The ratio of cerebral blood flow to cerebral metabolic oxygen consumption remains relatively normal. Importantly, cerebral vasomotor response to carbon dioxide is preserved during midazolam administration. Midazolam has little effect on intracranial pressure. All benzodiazepines increase the seizure threshold, including a seizure caused by local anesthestics, and all can be used to treat status epilepticus. Lorazepam is the most efficacious of all the benzodiazepines in treating status epilepticus.

Side Effects and Toxicity

The most significant side effect of midazolam is respiratory depression, which can be reversed with flumazenil. Flumazenil is a competitive benzodiazepine receptor antagonist. Flumazenil is cleared rapidly and may require repeated boluses or a continuous infusion to prevent resedation. Reversal of the sedation and respiratory depression with flumazenil does not produce adverse cardiovascular effects even in the presence of ischemic heart disease. It can, however, precipitate withdrawal in individuals physically dependent on benzodiazepines. Lorazepam and diazepam can cause venous irritation and thrombophlebitis.

Indications and Contraindications

Midazolam, lorazepam, and diazepam have amnestic, sedative, anxiolytic, hypnotic, anticonvulsant, and centrally mediated muscle-relaxing properties. Clinically, benzodiazepines are used to provide anxiolysis and anterograde amnesia prior to surgery and during moderate and deep sedation. Midazolam is the most frequently used drug due to the rapid onset and short duration of action. Long-term administration of benzodiazepines leads to a decrease of efficacy (tolerance) most likely related to the down-regulation of the benzodiazepine–GABA receptor complexes.

Midazolam appears to have a role in prevention of postoperative nausea and vomiting. In several studies intravenous midazolam was shown to reduce postoperative nausea and vomiting similar to intravenous ondansetron and dexamethasone.

Small intravenous doses of midazolam can be administered safely to the mother during a cesarean section without significant unwanted effects on the newborn baby, though the risk of anterograde amnesia remains for the mother.


Mechanism of Action

Ketamine is a unique intravenous anesthestic with significant analgesic effect. It is structurally related to phencyclidine (PCP). Ketamine antagonizes the effect of glutamate on the N-methyl-D-aspartate (NMDA) receptor, thus inhibiting the excitatory response and producing a dissociative state of hypnosis and analgesia. It also binds to nicotinic, muscarinic, and opioid receptors. Ketamine has two stereoisomers, S(+) and R(-), with S(+) being more potent. Ketamine is water soluble and exists in an aqueous solution.

Metabolism and Excretion

Ketamine is metabolized by hepatic microsomal cytochrome P450 enzymes to form active metabolites norketamine and hydroxynorketamine that are excreted by the kidney. The elimination half-life of ketamine is 2–3 hours. Ketamine can be given intravenously, intramuscularly, intranasally, orally, and rectally. Bioavailability of oral ketamine is 20%–30% due to first-pass metabolism.

Effect on Respiration

Ketamine produces minimal respiratory depression when used alone. Ketamine preserves autonomic reflexes better than other intravenous agents. Despite that, aspiration can occur in the presence of full stomach and airway reflexes should not be assumed to be protective. Ketamine is a potent bronchodilator and can be used for intravenous induction in the presence of bronchospasm. Ketamine is known to increase salivation and lacrimation and can lead to laryngospasm, especially in the lightly anesthetized child.

Effect on Circulation

Ketamine has a significant effect on the cardiovascular system and produces an elevation in blood pressure, heart rate, and cardiac output that can lead to an increase in myocardial oxygen consumption. Coronary blood flow might be limited in the presence of a stenotic coronary lesion, and myocardial ischemia can ensue. Ketamine-induced tachycardia and systemic hypertension can be attenuated by prior administration of a benzodiazepine. Despite the central cardiovascular stimulation, ketamine can cause myocardial depression in the seriously ill patient with depleted catecholamine reserves. Ketamine is well tolerated in children with congenital heart diseases. It does not change either the direction or magnitude of the shunt, and it helps to maintain systemic oxygenation. Caution should be used in patients with pulmonary hypertension, because ketamine causes more pronounced elevation in pulmonary than systemic vascular resistance. This effect is less pronounced in children, and ketamine has been used safely in pediatric pulmonary hypertension.

Effect on Other Organs

The dissociative anesthesia caused by ketamine is characterized by profound analgesia, variable amnesia in a patient who might appear conscious with open eyes, and relatively well preserved reflexes. Ketamine dilates pupils, causes horizontal and vertical nystagmus, and increases salivation and lacrimation.

Ketamine increases cerebral metabolic rate, cerebral blood flow, and intracranial pressure. Hyperventilation would attenuate this increase. Ketamine also elevates intraocular pressure through elevation of the systemic blood pressure and increase in intracranial pressure.

Side Effects and Toxicity

Ketamine anesthesia can produce hallucinations, vivid dreaming, and illusions that can cause fear, confusion, and euphoria. These adverse effects can be attenuated by the use of benzodiazepine premedication. Ketamine was shown to accentuate neonatal brain cell apoptosis in animal models. There is not enough evidence to support the restriction of the use of ketamine in human neonates at the present time.

Indications and Contraindications

Ketamine is useful for patients with reactive airway disease; patients with septic shock; healthy trauma victims; patients with hypovolemia, cardiomyopathy, cardiac tamponade, and restrictive pericarditis; and patients with congenital heart disease with right-to-left shunt. Intramuscular injection of ketamine can be used in the emergency situation in the absence of intravascular access and in combative and uncooperative patients without intravenous lines. Subanesthetic doses of ketamine can provide postoperative analgesia and have opioid-sparing effects. Ketamine is a good choice for procedural sedation for painful procedures, especially in children.

In patients with elevated intracranial and intraocular pressure, pulmonary hypertension, ischemic heart disease, vascular aneurysms, and psychiatric disorders, ketamine should be used cautiously if at all. Nonetheless, there is emerging evidence that ketamine does not cause elevation of intracranial pressure in traumatic brain injury, though further studies are warranted.



Barbiturates were the earliest nonopioid intravenous anesthetics that were used in clinical practice. Although synthesized in the 1860s, it was not until 1920 that IV barbiturates became available for widespread use. Thiopental was introduced into clinical practice in the mid-1930s and became the most commonly used IV barbiturate in anesthetic practice. The principal barbiturate in clinical use today is phenobarbital for the treatment of intractable status epilepticus. Even though barbiturates are infrequently used in modern anesthetic practice (as of 2011, thiopental is no longer manufactured), understanding their metabolism and pharmacology offers further insight into the understanding of anesthetic medications.


With the exception of phenobarbital, barbiturates are hepatically metabolized. The metabolites are inactive and excreted in the urine. Barbiturates are known to induce the action of hepatic enzymes. For this reason they are to be avoided in patients with acute intermittent porphyria. Barbiturates can stimulate the hepatic enzyme (aminolevulinic acid synthetase) responsible for producing porphyrins that are intermediaries in heme synthesis.

Phenobarbital is renally cleared. Alkalinizing the urine enhances its excretion.


Rapid redistribution explains the termination of action of a single dose of barbiturate. When a continuous infusion of barbiturate is used, the recovery time increases, as termination of action becomes dependent on uptake into adipose tissue (a slower process, as blood flow to adipose tissue is proportionally lower) and hepatic metabolism.


First-order kinetics (a constant fraction of the drug is cleared from the body per unit time) are observed in standard induction doses (3–5 mg/kg). At higher doses, as receptors are saturated, zero-order kinetics (a constant amount of the drug is cleared per unit of time) are observed (see the Pharmacology chapter for more details). Thiopental can readily accumulate in tissue because it is a lipophilic drug that has a relatively high volume of distribution and a low rate of hepatic clearance. Obese patients are thus at greater risk for prolonged clearance of thiopental.

Mechanism of Action

Barbiturates enhance the activity of the inhibitory neurotransmitter GABA. By binding to the GABAa receptor, barbiturates enhance the action of GABA, causing increased influx of chloride and hyperpolarization of the cell membrane. This increases the excitability threshold of the postsynaptic neuron. Furthermore, barbiturates inhibit the synaptic transmission of excitatory neurotransmitters such as glutamate and acetylcholine.


Barbiturates act to depress consciousness and produce some degree of amnesia. They are not known to have analgesic properties; in fact, at low blood concentrations, they can decrease the pain threshold.

Onset of Action

There are four key factors that determine the speed with which a drug enters the CNS: the lipid solubility, ionization (pKa), level of protein binding, and plasma drug concentration. Thiopental, for instance, is very lipid soluble and has a pKa of 7.6, meaning that at close to physiologic pH about half the drug is in its nonionized and therefore lipophilic form, able to cross readily into the CNS. The implications of this pKa are such that when the patient is acidotic, more of the drug is in the nonionized form, so less drug is needed to induce the desired clinical effect. The converse is also true, so that in an alkalotic patient more drug may be needed. Protein binding also affects the onset of action, as only free unbound drug can cross the blood-brain barrier. Barbiturates are highly bound to albumin, and pH and disease states that affect the amount of protein in the body affect barbiturate protein binding. While hepatic or liver disease may decrease total body protein, this usually bears little clinical significance. Finally the plasma concentration of the drug determines how quickly it crosses the blood-brain barrier based on its concentration gradient. Plasma concentration is determined by the dose of the drug and the speed with which it is given.

Termination of Action

The most important factor governing termination of action is plasma disappearance of the drug. As drug is cleared from the plasma more drug that is in the CSF can travel down its concentration gradient out of the CSF and to the liver to be metabolized. Lipid solubility, the degree of ionization, and CSF concentration gradients all play an important role. Two main mechanisms account for the decrease of barbiturates in the plasma: (1) redistribution to peripheral tissue (muscle then fat) and (2) metabolism and clearance by the liver.

Effect on Cerebral Metabolic Rate

Barbiturates decrease the CMRO2, causing progressive slowing of the EEG and decreased ATP consumption. At an isoelectric EEG no further decrease in CMRO2 is noted. Cerebral blood flow and, therefore, intracranial pressure are also reduced by barbiturates.

Side Effects and Contraindications


Barbiturates depress the cardiovascular system by causing peripheral vasodilation, leading to venous pooling. They also have negative inotropic effects (decreased calcium influx into cells), decreased ventricular filling from venous pooling of blood, and decreased sympathetic output from the autonomic nervous system. Caution must be given if using a barbiturate in hypovolemic patients, as a significant decrease in cardiac output and hemodynamic instability may occur.


Barbiturates cause central respiratory depression and transient apnea after administration. Recovery of respiratory function after a one-time dose is fairly quick, with respiratory parameters returning to normal about 15 minutes after a single induction dose of thiopental.

Contraindications to barbiturate use include the following:

  1. 1. Respiratory compromise

  2. 2. Hemodynamic instability

  3. 3. Status asthmaticus

  4. 4. Acute intermittent porphyria


Dexmedetomidine is a highly selective alpha-2 agonist that has shown to have a broad set of uses. Alpha-2 adrenergic receptor agonists have several effects: sedation, anxiolysis, hypnosis, analgesia, and sympatholysis.


Dexmedetomidine is metabolized extensively by the liver and excreted in the urine. More than 90% is protein bound.


The elimination half-life of dexmedetomidine is 2–3 hours. The context-sensitive half-life is from about 4 minutes after a 10-minute infusion to about 250 minutes after an 8-hour infusion.

Effects on the Central Nervous System

Dexmedetomidine produces sedative and hypnotic effects by affecting alpha-2 agonists in the locus ceruleus and spinal cord. Sedation and anxiolysis are mediated primarily via the locus ceruleus, and analgesia is mediated primarily via the spinal cord. Although the effects of dexmedetomidine alone on cerebral blood flow and intracranial pressure are not well characterized, some studies support a decrease in cerebral blood flow in healthy volunteers. Dexmedetomidine is known to decrease the minimum alveolar concentration of inhalational anesthetics, and in higher concentrations it can affect memory and recall.

Respiratory Effects

While dexmedetomidine does reduce minute ventilation, it retains the ventilatory response to increasing CO2 levels. Dexmedetomidine appears to decrease tidal volume without affecting respiratory rate. The combination of dexmedetomidine with an opioid enhances analgesia but does not appear to potentiate further respiratory depression.

Cardiovascular Effects

The overall effects of dexmedetomidine on the cardiovascular system include a decrease in heart rate, decreased systemic vascular resistance, and decreased cardiac output, myocardial contractility, and blood pressure. A bolus dose of dexmedetomidine causes a biphasic response, with an initial increase in blood pressure and decrease in heart rate. This initial increase in blood pressure is likely due to its effects on peripheral alpha-2 receptors.

Dosage and Uses

Dexmedetomidine is not indicated for the induction or maintenance of anesthesia. Rather, it functions as a postoperative sedative and as an adjunct medication to reduce hypnotic and opioid requirements. Generally, it is administered as a bolus dose followed by an infusion. The usual loading dose is 1 mcg/kg over 10 minutes; however, ranges between 0.5 and 2.5 mcg/kg have been described. Infusing over 10 minutes decreases the hypertension seen with a rapid bolus. The typical infusion rate is anywhere from 0.2 to 1 mcg/kg/h. There is a growing body of evidence that another possible role for dexmedetomidine is the attenuation of emergence delirium that is observed in some pediatric patients. Research into the optimal dosage for this indication is ongoing.

Questions and Answers

This chapter has accompanying questions and answers which are available to subscribers as part of the Oxford eLearning platform. To access the questions, follow the link below, or go to


1. Bergen J, Smith D. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med. 1997;15:221–230.Find this resource:

    2. Tomlin S, Jenkins A, Lieb W, Frank N. Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals. Anesthesiology. 1998;88:708–717.Find this resource:

    3. Kay B. Total intravenous anesthesia with etomidate: I. A trial in children. Acta Anaesthesiol Belg. 1977;28:107–113.Find this resource:

    4. Bird T, Edbrooke D, Newby D, Hebron B. Intravenous sedation for the intubated and spontaneously breathing patient in the intensive care unit. Acta Anaesthesiol Scand. 1984;28:640–643.Find this resource:

    5. Batjer H. Cerebral protective effects of etomidate: experimental and clinical aspects. Cerebrovasc Brain Metab Rev. 1993;5:17–32.Find this resource:

    6. Johnson K, Egan T, Layman J, Kern S, White L, McJames S. The influence of hemorrhagic shock on etomidate: a pharmacokinetic and pharmacodynamic analysis. Anesth Analg. 2003;96:1360–1368.Find this resource:

    7. Ghoneim M, Yamada T. Etomidate: a clinical and electroencephalographic comparison with thiopental. Anesth Analg. 1977;56:479–485.Find this resource:

    8. Thornton C, Heneghan C, Navaratnarajah M, Bateman P, Jones J. Effect of etomidate on the auditory evoked response in man. Br J Anaesth. 1985;57:554–561.Find this resource:

    9. Sloan T, Ronai A, Toleikis J, Koht A. Improvement of intraoperative somatosensory evoked potentials by etomidate. Anesth Analg. 1988;67:582–585.Find this resource:

    10. Taniguchi M, Nadstawek J, Langenbach U, Bremer F, Schramm J. Effects of four intravenous anesthetic agents on motor evoked potentials elicited by magnetic transcranial stimulation. Neurosurgery. 1993;33:407–415, discussion 415.Find this resource:

    11. Atiba J, Horai Y, White P, Trevor A, Blaschke T, Sung M. Effect of etomidate on hepatic drug metabolism in humans. Anesthesiology. 1988;68:920–924.Find this resource:

    12. Forman S. Clinical and molecular pharmacology of etomidate. Anesthesiology. 2011;114:695–707.Find this resource:

    13. Giese J, Stanley T. Etomidate: a new intravenous anesthetic induction agent. Pharmacotherapy. 1983;3:251–258.Find this resource:

    14. Zacharias M, Clarke RS, Dundee JW, Johnston S. Evaluation of three preparations of etomidate. Br J Anaesth. 1978;50:925–929.Find this resource:

    15. Mayer M, Doenicke A, Nebauer A, Hepting L. [Propofol and etomidate-Lipuro for induction of general anesthesia: Hemodynamics, vascular compatibility, subjective findings and postoperative nausea]. Anaesthesist. 1996;45:1082–1084.Find this resource:

    16. St Pierre M, Dunkel M, Rutherford A, Hering W. Does etomidate increase postoperative nausea? A double-blind controlled comparison of etomidate in lipid emulsion with propofol for balanced anaesthesia. Eur J Anaesthesiol. 2000;17:634–641.Find this resource:

    17. Sprung C, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124.Find this resource:

    18. Tekwani KL, Watts HF, Rzechula KH, Sweis R, Kulstad E. A prospective observational study of the effect of etomidate on septic patient mortality and length of stay. Acad Emerg Med. 2009;16:11–14.Find this resource:

    19. Ray D, McKeown D. Effect of induction agent on vasopressor and steroid use, and outcome in patients with septic shock. Crit Care. 2007;11:R56.Find this resource:

    20. Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009;374:293–300.Find this resource:

    21. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill Medical; 2011.Find this resource:

      22. Schuttler J, Ihmsen H. Population pharmacokinetics of propofol: a multicenter study. Anesthesiology. 2000;92:727–738.Find this resource:

      23. McKeage K, Perry C. Propofol: a review of its use in intensive care sedation of adults. CNS Drugs. 2003;17:235–272.Find this resource:

      24. Bienert A, Wiczling P, Grzeskowiak E, Cywiński J, Kusza K. Potential pitfalls of propofol target controlled infusion delivery related to its pharmacokinetics and pharmacodynamics. Pharmacol Rep. 2012;64:782–795.Find this resource:

      25. Takata K, Kurita T, Morishima Y, Morita K, Uraoka M, Sato S. Do the kidneys contribute to propofol elimination? Br J Anaesth. 2008;101:648–652.Find this resource:

      26. Upton R, Ludbrook G, Grant C, Martinez A. Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration. Anesth Analg. 1999;89:545–552.Find this resource:

      27. Kirkpatrick T, Cockshott I, Douglas E, Nimmo W. Pharmacokinetics of propofol (diprivan) in elderly patients. Br J Anaesth. 1988;60:146–150.Find this resource:

      28. Goodman N, Black A, Carter J. Some ventilatory effects of propofol as sole anaesthetic agent. Br J Anaesth. 1987;59:1497–1503.Find this resource:

      29. Miller R, Fleisher L, Johns R, et al., eds. Miller’s Anesthesia. 6th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005.Find this resource:

        30. Visser K, Hassink E, Bonsel G, Moen J, Kalkman C. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous oxide: postoperative nausea with vomiting and economic analysis. Anesthesiology. 2001;95:616–626.Find this resource:

        31. Murphy A, Campbell E, Baines D, Mehr S. Allergic reactions to propofol in egg-allergic children. Anesth Analg. 2011;113(1):140–144. Epub April 5, 2011.Find this resource:

        Further Reading

        Barash P, Cullen B, Stoelting R, Cahalan M, Stock M. Clinical Anesthesia. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:479–500.Find this resource:

          Cote C, Lerman J, Anderson B . Pharmacokinetics and pharmacology of drugs used in children. In: Cote C, Lerman J, Anderson B. A Practice of Anesthesia for Infants and Children. 4th ed. Philadelphia, PA: Elsevier Saunders; 2013:1053.Find this resource:

            Miller R, ed. Miller’s Anesthesia. 6th ed. Philadelphia, PA: Elsevier; 2006:326–334, 355–359.Find this resource:

              Miller R, ed. Miller’s Anesthesia. 7th ed. Philadelphia, PA: Elsevier; 2010:719–768.Find this resource:

                Stoelting R, Hillier S. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.Find this resource:

                  Talke P, Caldwell J, Kirkegaard-Nielsen H, Stafford M. The effects of dexmedetomidine on neuromuscular blockade in human volunteers. Anesth Analg. 1999;88:633–639.Find this resource: