Intravenous Sedative–Hypnotics

HISTORY OF DEVELOPMENT

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Sedative–hypnotics are a relatively new class of anesthetics, beginning with the introduction of sodium thiopental in the early 1930s. Since then, several sedative–hypnotics have been introduced (Table 6–1), with more in the drug development pipeline, such as remimazolam, fospropofol, and isomers of etomidate. Goals of these modified drugs include fast metabolism and breakdown as well as creating “soft” drugs with safer profiles. A major goal in developing methoxycarbonyl-etomidate is the removal of adrenocortical suppression by modifying the pyrrole ring in etomidate. Fospropofol is water-soluble as opposed to propofol, which is administered as an oil–water emulsion. In 2008, fospropofol was approved by the US Food and Drug Administration, although many clinical trials are still underway for specific uses of the drug.¹

Table 6–1History of sedative–hypnotics.

Drug	Year of Discovery	Year of First Clinical Use	Details
Sodium thiopental	1930	1934	Popular for many years for the induction of anesthesia. However, the use in the United States as part of a 3-drug cocktail for lethal injection of death row inmates caused the major supplier to stop sales to the United States. This has limited availability of the drug.
Benzodiazepines	1955	1957	Well known for positive drug effects that include sedation, anticonvulsant properties, and muscle relaxation. However, dependence and withdrawal symptoms have limited their use.
Ketamine	1962	1970	After approval was a popular battlefield anesthetic. However, unpleasant awakening/dissociation has limited use. Illicit use led to classification as a Schedule III controlled substance.
Etomidate	1964	1972	Used for sedation in the intensive care unit until studies showed increased mortality rates due to adrenocortical suppression and inhibition of protein synthesis.⁴
Propofol	1973	1983 (current formulation)	Negative side effects of various formulations led to the current lipid emulsion form. Propensity for bacterial growth led to the addition of EDTA or sodium metabisulfite to prevent bacterial growth. The drug is very popular for induction of anesthesia due to quick action and elimination along with a decrease in intracranial pressure, decreased metabolism of oxygen by the brain and anticonvulsant effects.⁵
Dexmedetomidine	1970s	1999	The D-steroisomer of medetomidine was used for years as an α2-receptor agonist in veterinary medicine. The drug was approved by the FDA for use in humans in 1999.

MECHANISM OF ACTION AND DRUG EFFECTS

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Most sedative–hypnotics work via the γ-aminobutyric acid (GABA) receptor complex by enhancing the effect of GABA (Figure 6–1), the major inhibitory neurotransmitter in the central nervous system. GABA receptors are transmembrane, made up of 5 subunits (2 α, 2 β, 1 γ), with a central pore. There are several types of each subunit, leading to a variety of slightly different GABA receptors. Overall, there are 2 types: type A, a chloride channel, and type B, a potassium channel. Type A receptors are very similar to other ligand-linked ion channels (eg, serotonin and nicotinic acetylcholine receptors) and are commonly found on the postsynaptic cleft of a neuron junction. As chloride passes through the GABA receptor channel, neuronal cell wall membranes are hyperpolarized (stabilizing the resting membrane state), producing an inhibitory effect on action potentials. Mild potentiation of GABA type A receptor function leads to anxiolysis, whereas more pronounced potentiation of receptor function leads to sedation and loss of responsiveness. Of note, GABA triggers GABA type A receptors at sites between the α and β subunits.

Other sedatives, such as dexmedetomidine and clonidine produces an analgesic effect by selective α2-adrenoreceptor agonism leading to presynaptic inhibition of norepinephrine release decreasing sympathetic tone (Figure 6–2). Sedation and anxiolysis are likely mediated through α2-adrenoreceptor agonism in an area of the brain called the locus coeruleus.

Figure 6–1

Schematic diagram of postsynaptic cleft transmembrane receptors, the sedative–hypnotics that act on each receptor and the ions each receptor allows to pass through.

Figure 6–2

Schematic diagram of the α-adrenergic synapse and site of action for dexmedetomidine.

Tables 6–2, 6–3, 6–4, 6–5, 6–6, and 6–7 detail the mechanism of action and drug effects of selected sedative–hypnotics used in anesthetic practice. These data are important when formulating a complete drug regimen. For example, propofol has hypnotic but no analgesic effects, unlike ketamine. Benzodiazepines produce anxiolysis and anterograde amnesia, but they are slow to reach peak effect, have prolonged drug effect, and cause dependency and withdrawal. Thus benzodiazepines are more common as an adjunct to another anesthetic.^2,3

Table 6–2Sodium thiopental.

Mechanism of action	Sodium thiopental, a barbiturate, acts on the GABA-A receptor and may inhibit nicotinic acetylcholine receptors in the CNS.⁶
CNS	Sodium thiopental causes significant decreases in CBF, CMRO₂, and ICP. It also causes increased CPP. It has no analgesic effect and can actually lower the pain threshold.
Cardiovascular	Sodium thiopental causes moderate heart rate increase and moderate MAP decrease. Baroreceptor response is necessary for maintaining cardiac output. Absence due to hypovolemia, congestive heart failure, or β-adrenergic blockade can cause a severe drop in cardiac output and blood pressure.
Respiratory	Sodium thiopental causes profound respiratory depression with a small decrease in bronchodilation.
Clinical uses	Sodium thiopental is used as an intravenous induction agent, for treatment of elevated ICP, and for neuroprotection from focal cerebral ischemia. Thiopental is not a complete anesthetic, lacking the ability to produce amnesia, analgesia, and reflex suppression.
Adverse effects	Injection of thiopental into the intra-arterial space can cause extreme pain/tissue damage. It can also cause laryngospasm and generally depresses the respiratory system. It can cause allergic reactions in rare cases.

Table 6–3Benzodiazepines (midazolam, diazepam, lorazepam, clonazepam).

Mechanism of action	Benzodiazepines bind to unique receptor sites on the GABA-A receptor complex between the α and g subunits. This binding increases the efficiency of GABA coupling to the chloride ion channel. Since benzodiazepines only modulate this effect, there is a “ceiling” in CNS depression from these drugs.
CNS	Benzodiazepines reduce brain CMRO₂, prevent/control grand mal seizures, provide anterograde amnesia, serve as mild muscle relaxants at the spinal cord level, and provide anxiolysis.
Cardiovascular	Benzodiazepines produce slight decreases in arterial blood pressure, cardiac output, and peripheral vascular resistance. They may cause a slight increase in heart rate.
Respiratory	Benzodiazepines are respiratory depressants when administered intravenously, although this is generally insignificant via other pathways.
Clinical uses	Benzodiazepines are used for anxiolysis, sedation, induction of anesthesia, and suppression of seizure activity, and they may be used to treat insomnia and epilepsy.⁵ Effects can quickly be reversed with the benzodiazepine antagonist flumazenil.
Adverse effects	Benzodiazepines cause pain during injection, particularly diazepam due to the organic solvent, propylene glycol. Benzodiazepines are also associated with dependence and withdrawal symptoms.

Table 6–4Ketamine.

Mechanism of action	Is an antagonist of the N-methyl-d-aspartate (NMDA) receptor, which functions as an ion channel. Ketamine also interacts with phencyclidine binding sites that inhibit NMDA receptor function, interacts with selected opioid receptors (μ, Δ, and κ), muscarinic receptors, voltage-gated calcium channels, and monoaminergic receptors. It has S and R isomers, both of which are pharmacologically active and can produce anesthesia, dysphoria, analgesia, and dissociation. The S isomer is up to 3 times more analgesic than the R isomer. At high doses, ketamine also behaves as a local anesthetic by blocking sodium channels in a comparable fashion to lidocaine or procaine.
CNS	Increases CMRO₂, CBF, and ICP.
Cardiovascular	Increases arterial blood pressure, heart rate, and cardiac output due to stimulation of the sympathetic nervous system. Ketamine also blocks reuptake of epinephrine. It increases pulmonary artery pressure and myocardial work. These can be useful properties in patients with acute hypovolemic shock.
Respiratory	Causes minimal respiratory depression with significant bronchodilation.
Clinical uses	Induction and maintenance of anesthesia, but unpleasant emergence limits its use. Ketamine is a potent analgesic. Ketamine can be administered via oral, rectal, intravenous, or epidural routes, making it useful in cases of mentally challenged or uncooperative pediatric patients. A popular use is administration in subanalgesic doses in order to limit or reverse opioid tolerance.⁵
Adverse effects	Psychological effects of ketamine are the major limiting-factor of use. Common experiences include vivid dreams, hallucinations, out-of-body experiences, and a general dissociative mental state. Combination with benzodiazepines can limit these symptoms.⁸

Table 6–5Etomidate.

Mechanism of action	Etomidate binds to a subunit of the GABA-A receptor, which increases the receptor’s affinity for GABA. It can produce disinhibitory effects on extrapyramidal motor activity, resulting in a 30%–60% chance of myoclonus.
CNS	Etomidate is a potent cerebral vasoconstrictor. It decreases CBF and ICP. It does not share the neuroprotective properties of propofol and thiopental.
Cardiovascular	Etomidate infusions are characterized by cardiovascular stability. There is a modest to no decrease in systemic blood pressure due to systemic vascular resistance (these can be exaggerated during hypovolemia). There are minimal changes in heart rate and cardiac output.
Respiratory	Etomidate induces mild ventilatory depression, much less than propofol. This depression can be exaggerated in combination with inhaled anesthetics or opioids.
Clinical uses	Intravenous induction of anesthesia. Etomidate is often used in patients who have compromised myocardial contractility.
Adverse effects	More frequent deaths in ICU patients led to the discovery that etomidate suppresses adrenocortical function by inhibiting synthesis of cortisol. A portion of etomidate, specifically its pyrrole ring, inhibits 11-b-hydroxylase, an enzyme known to play a key role in steroid synthesis. Following only a routine induction dose, etomidate can suppress adrenal function up to and beyond 24 hours. This can be dangerous in septic and critically ill patients who require steroids to maintain their immune function and metabolic homeostasis. Consider abandoning etomidate as an induction drug for septic patients or at a minimum, providing supplemental corticosteroid therapy following etomidate administration. Etomidate can cause myoclonic movement. This can be reduced by premedication with benzodiazepines, but at the cost of prolonged emergence. Etomidate can cause pain on injection due to the organic solvent propylene glycol. Premedication with benzodiazepines and opioids can reduce pain on injection. Etomidate is often associated with postoperative nausea and vomiting, usually requiring addition of an antiemetic.

Table 6–6Propofol.

Mechanism of action	Propofol potentiates GABA-A receptor function by slowing channel closing time, blocks sodium channels, and may influence the endogenous cannabinoid system.
CNS	Propofol is a sedative–hypnotic but not an analgesic. It decreases CBF and CMRO₂. It also decreases ICP and IOP, found to be protective during focal ischemia. Propofol also has anticonvulsant effects, although some twitching and movement can occur during induction.
Cardiovascular	Propofol produces a significant decrease in systemic blood pressure and profound vasodilation in both arterial and venous circulation. It inhibits the baroreflex response and can contribute to a small increase in heart rate.
Respiratory	Propofol is responsible for significant respiratory depression, with high probability of apnea with induction doses. It also causes significant reduction in upper airway reflexes.
Clinical uses	Intravenous induction and maintenance of anesthesia, sedation (popular for mechanically ventilated patients), and as an antiemetic.
Adverse effects	Preservative-free propofol use is associated with higher infection rates in ICU patients. The FDA has approved the use of propofol in the United States with addition of either EDTA or sodium metabisulfite. Propofol formulations are also stored under nitrogen atmospheres to prevent growth. Propofol can also cause some pain on injection; this effect can be lessened by preinjection or mixed injection with lidocaine. Studies have also shown that addition of remifentanil can also reduce pain on injection. Propofol infusion syndrome is a very rare but often fatal condition that can occur with propofol infusions over 48 hours in high doses (> 4 mg/kg/h).^5,9,10