Morgan & Mikhail Chap 9(Intravenous Anesthetics) Flashcards
Overview
General anesthesia began with inhalation of ether, nitrous oxide, or chloroform, but in current practice, anesthesia and sedation can be induced and maintained with drugs that enter the patient through a wide range of routes. Preoperative or procedural sedation is
usually accomplished by way of oral or intravenous routes. Induction of general anesthesia is typically accomplished by inhalation or intravenous drug administration.
Alternatively, general anesthesia can be induced and maintained with intramuscular injection of ketamine. General anesthesia is typically maintained with a total intravenous anesthesia (TIVA) technique, an inhalation technique, or a combination of the two. This chapter focuses on the injectable agents used to produce narcosis (sleep),
including barbiturates, benzodiazepines, ketamine, etomidate, propofol, and
dexmedetomidine
Barbiturates
At one time, nearly every general anesthetic in adults was induced with a barbiturate.
These agents were also widely used for control of seizures, anxiolysis, and procedural
sedation and as sleep-inducing agents. They are now much less widely used in
anesthesia.
Mechanisms of Action
Barbiturates depress the reticular activating system in the brainstem, which controls
consciousness. Their primary mechanism of action is through binding to the γ-
aminobutyric acid type A (GABAA) receptor. This site is separate from the GABAA
site to which benzodiazepines bind. Barbiturates potentiate the action of GABA in increasing the duration of openings of a chloride-specific ion channel. Barbiturates also
inhibit kainate and AMPA receptors.
Substitution at carbon C5
determines hypnotic potency and anticonvulsant activity. The phenyl group in phenobarbital is anticonvulsive, whereas the methyl group in methohexital is not. Thus methohexital remains useful for providing anesthesia for electroconvulsive therapy
wherein a seizure is the objective
Pharmacokinetics: Barbiturates
A. Absorption
Prior to the introduction of propofol, thiopental, thiamylal, and methohexital were frequently administered intravenously for induction of general anesthesia in adults and children. Rectal methohexital has been used for induction in children.
B. Distribution
The duration of induction doses of thiopental, thiamylal, and methohexital is determined by redistribution, not by metabolism or elimination. Thiopental’s great lipid solubility and high nonionized fraction (60%) account for rapid brain uptake (within 30 s). If the central compartment is contracted (eg, hypovolemic shock), if the serum albumin is low
(eg, severe liver disease or malnutrition), or if the nonionized fraction is increased (eg, acidosis), larger brain and heart concentrations will be achieved for a given dose with
greater reduction of blood pressure. Redistribution lowers plasma and brain
concentration to 10% of peak levels within 20 to 30 min (Figure 9–2). This
pharmacokinetic profile correlates with clinical experience—patients typically lose consciousness within 30 s and awaken within 20 min.
The minimal induction dose of thiopental will depend on body weight and age.
Reduced induction doses are required for older adult patients. In contrast to the rapid initial distribution half-life of a few minutes, elimination of thiopental is prolonged (elimination half-life ranges of 10–12 h). Thiamylal and methohexital have similar distribution patterns, whereas less lipid-soluble barbiturates have much longer distribution half-lives and durations of action after a sleep dose. Repetitive
administration of highly lipid-soluble barbiturates (eg, infusion of thiopental for
“barbiturate coma” and brain protection) saturates the peripheral compartments,
minimizing any effect of redistribution and rendering the duration of action more
dependent on elimination. This is an example of context sensitivity, which is also seen
with other lipid-soluble agents (eg, potent inhaled anesthetics, fentanyl, sufentanil; see Chapter 7).
C. Biotransformation
Barbiturates are principally biotransformed via hepatic oxidation to inactive, watersoluble metabolites. Because of greater hepatic extraction, methohexital is cleared by the liver more rapidly than thiopental. Therefore, full recovery of psychomotor function
is also more rapid following methohexital.
D. Excretion
Except for the less protein-bound and less lipid-soluble agents such as phenobarbital,
renal excretion is limited to water-soluble end products of hepatic biotransformation.
Methohexital is excreted in the feces.
Effects on Organ Systems: Barbiturates
A. Cardiovascular
Intravenous bolus induction
doses of barbiturates cause a decrease in blood pressure and an increase in heart rate.
Depression of the medullary vasomotor center produces vasodilation and peripheral
pooling of blood, mimicking reduced blood volume.
Cardiac output is often maintained by an increased heartrate and increased heart rate and increased myocardial contractility from compensatory baroreceptor reflexes.
Sympathetically induced vasoconstriction of resistance vessels (particularly with
intubation under light planes of general anesthesia) may actually increase peripheral
vascular resistance. However, in situations where the baroreceptor response will be
blunted or absent (eg, hypovolemia, congestive heart failure, β-adrenergic blockade), cardiac output and arterial blood pressure may fall dramatically due to
uncompensated peripheral pooling of blood and direct myocardial depression.
Patients with poorly controlled hypertension are particularly prone to wide swings in
blood pressure during anesthesia induction.
B. Respiratory
Barbiturates depress the medullary ventilatory center, decreasing the ventilatory
response to hypercapnia and hypoxia. Apnea often follows an induction dose. During
awakening, tidal volume and respiratory rate are decreased. Barbiturates incompletely depress airway reflex responses to laryngoscopy and intubation (much less than propofol), and airway instrumentation may lead to bronchospasm (in asthmatic patients) or laryngospasm in lightly anesthetized patients.
C. Cerebral
Barbiturates constrict the cerebral vasculature, causing a decrease in cerebral
blood flow, cerebral blood volume, and intracranial pressure. Intracranial pressure often decreases to a greater extent than arterial blood pressure, so cerebral perfusion pressure (CPP) usually increases. (CPP equals cerebral artery pressure minus the greater of jugular venous pressure or intracranial pressure.) Barbiturates induce a
greater decline in cerebral oxygen consumption (up to 50% of normal) than in cerebral blood flow; therefore, the decline in cerebral blood flow is not detrimental.
Barbiturates do not impair the perception of pain. Small doses occasionally cause a state of excitement and disorientation. Barbiturates do not produce muscle relaxation, and some induce involuntary skeletal muscle contractions (eg, methohexital). Small doses of thiopental (50–100 mg intravenously) rapidly (but
briefly) control most grand mal seizures.
D. Renal
Barbiturates reduce renal blood flow and glomerular filtration rate in proportion to the fall in blood pressure.
E. Hepatic
Hepatic blood flow is decreased. Chronic exposure to barbiturates leads to the
induction of hepatic enzymes and an increased rate of metabolism. On the other hand, the binding of barbiturates to the cytochrome P-450 enzyme system interferes with the
biotransformation of other drugs (eg, tricyclic antidepressants). Barbiturates may precipitate acute intermittent porphyria or variegate porphyria in susceptible individuals.
F. Immunological
Anaphylactic or anaphylactoid allergic reactions are rare. Sulfur-containing
thiobarbiturates evoke mast cell histamine release in vitro, whereas oxybarbiturates do
not.
Drug Interactions
Contrast media, sulfonamides, and other drugs that occupy the same protein-binding
sites may displace thiopental, increasing the amount of free drug available and
potentiating the effects of a given dose. Ethanol, opioids, antihistamines, and other
central nervous system depressants potentiate the sedative effects of barbiturates.
Benzodiazepines
Mechanisms of Action
Benzodiazepines bind the same set of receptors in the central nervous system as
barbiturates but at a different site. Benzodiazepine binding to the GABAA receptor
increases the frequency of openings of the associated chloride ion channel.
Benzodiazepine-receptor binding by an agonist facilitates binding of GABA to its receptor. Flumazenil (an imidazobenzodiazepine) is a specific benzodiazepine–
receptor antagonist that effectively reverses most of the central nervous system effects of benzodiazepines
The imidazole ring of midazolam contributes to its water solubility at low pH. Diazepam and lorazepam are insoluble in water, so parenteral preparations contain propylene glycol, which can produce pain with intravenous or intramuscular injection.
Pharmacokinetcs: Benzodiazepines
A. Absorption
Benzodiazepines are commonly administered orally and intravenously (or, less commonly, intramuscularly) to provide sedation (or, less commonly, to induce general anesthesia)
B. Distribution
Diazepam is relatively lipid soluble and readily penetrates the blood–brain barrier. Although midazolam is water soluble at reduced pH, its imidazole ring closes at physiological pH, increasing its lipid solubility (see Figure 9–3). The moderate lipid solubility of lorazepam accounts for its slower brain uptake and onset of action.
Redistribution is fairly rapid for benzodiazepines and, like barbiturates, is responsible
for awakening
C. Biotransformation
The benzodiazepines rely on the liver for biotransformation into water-soluble glucuronidated end products. The phase I metabolites of diazepam are
pharmacologically active.
D. Excretion
The metabolites of benzodiazepines are excreted chiefly in the urine.
Effects on Organ Systems: Benzodiazepines
Drug Interactions
Cimetidine binds to cytochrome P-450 and reduces the metabolism of diazepam.
Erythromycin inhibits the metabolism of midazolam and causes a two- to threefold
prolongation and intensification of its effects.
As previously mentioned, the combination of opioids and benzodiazepines markedly
reduces arterial blood pressure and peripheral vascular resistance. This synergistic interaction has often been observed in patients undergoing cardiac surgery who received benzodiazepines before or during induction with larger doses of opioids.
Benzodiazepines reduce the minimum alveolar concentration of volatile anesthetics by as much as 30%. Ethanol, barbiturates, and other central nervous system depressants
potentiate the sedative effects of benzodiazepines.
Ketamine
Ketamine has multiple effects throughout the central nervous system, and it is well
recognized to inhibit N-methyl-D-aspartate (NMDA) channels.
Ketamine functionally “dissociates” sensory impulses from the limbic cortex (which is involved with the awareness of sensation). Clinically, this state of dissociative anesthesia may cause the patient to appear conscious (eg, eye opening, swallowing, muscle contracture) but unable to process or respond to sensory input. Ketamine may have additional actions
on endogenous analgesic pathways.
Ketamine has effects on mood, and preparations of this agent and its single
enantiomer esketamine are now widely used to treat severe, treatment-resistant
depression, particularly when patients have suicidal ideation. Small infusion doses of ketamine are also being used to supplement general anesthesia and to reduce the need for opioids both during and after the surgical procedure.
When intravenous access is lacking, ketamine is useful for
intramuscular induction of general anesthesia in children and uncooperative adults.
Ketamine can be combined with other agents (eg, propofol or midazolam) in small bolus doses or infusions for conscious sedation during procedures such as nerve blocks and endoscopy. Even subanesthetic doses of ketamine may cause hallucinations but usually do not do so in clinical practice, where many patients will have received at least a small dose of midazolam (or a related agent) for amnesia and sedation.
Pharmacokinetics: Ketamine
A. Absorption
Ketamine has been administered orally, nasally, rectally, subcutaneously, and
epidurally, but in usual clinical practice, it is given intravenously or intramuscularly
(Table 9–3). Peak plasma levels are usually achieved within 10 to 15 min after
intramuscular injection.
B. Distribution
Ketamine is highly lipid soluble and, along with a ketamine-induced increase in
cerebral blood flow and cardiac output, results in rapid brain uptake and subsequent
redistribution (the distribution half-life is 10–15 min). Awakening is due to
redistribution from the brain to peripheral compartments.
C. Biotransformation
Ketamine is biotransformed in the liver to several metabolites, one of which
(norketamine) retains anesthetic activity. Patients receiving repeated doses of ketamine (eg, for daily changing of dressings on burns) develop tolerance, and this can only be partially explained by induction of hepatic enzymes. Extensive hepatic uptake (hepatic
extraction ratio of 0.9) explains ketamine’s relatively short elimination half-life (2 h).
D. Excretion
End products of ketamine biotransformation are excreted renally.
Uses and Doses Big 4 of Induction
Summary of nonvolatile anesthetic effects on organ systems.
Effects on Organ Systems: Ketamine
In contrast to other anesthetic agents, ketamine increases arterial blood pressure, heart
rate, and cardiac output (Table 9–4), particularly after rapid bolus injections. These
indirect cardiovascular effects are due to central stimulation of the sympathetic nervous
system and inhibition of the reuptake of norepinephrine after release at nerve terminals.
Accompanying these changes are increases in pulmonary artery pressure and myocardial work. For these reasons, ketamine should be administered carefully to patients with coronary artery disease, uncontrolled hypertension, congestive heart failure, or arterial
aneurysms. The direct myocardial depressant effects of large doses of ketamine may be unmasked by sympathetic blockade (eg, spinal cord transection) or exhaustion of catecholamine stores (eg, severe end-stage shock).
B. Respiratory
Ventilatory drive is minimally affected by induction doses of ketamine, though
combinations of ketamine with opioids may produce apnea. Racemic ketamine is a
potent bronchodilator, making it a good induction agent for asthmatic patients; however,
S(+) ketamine produces minimal bronchodilation. Upper airway reflexes remain largely intact, but partial airway obstruction may occur, and patients at significant risk for aspiration pneumonia (“full stomachs”) should be intubated during ketamine general anesthesia (see Case Discussion, Chapter 17). The increased salivation associated with ketamine can be attenuated by premedication with an anticholinergic agent such as
glycopyrrolate.
C. Cerebral
The received dogma about ketamine is that it increases cerebral oxygen consumption,
cerebral blood flow, and intracranial pressure. These effects would seem to preclude its use in patients with space-occupying intracranial lesions such as occur with head trauma; however, recent publications offer convincing evidence that when combined with a benzodiazepine (or another agent acting on the same GABA receptor system) and controlled ventilation (in techniques that exclude nitrous oxide), ketamine is not
associated with increased intracranial pressure.
Drug Interactions
Ketamine interacts synergistically (more than additive) with volatile anesthetics but in
an additive way with propofol, benzodiazepines, and other GABA-receptor–mediated
agents. Nondepolarizing neuromuscular blocking agents are dose-dependently, but minimally, potentiated by ketamine (see Chapter 11). Diazepam or midazolam attenuate ketamine’s cardiac stimulating effects, and diazepam prolongs ketamine’s elimination half-life.
Etomidate
Etomidate depresses the reticular activating system and mimics the inhibitory effects of GABA. Specifically, etomidate—particularly the R(+) isomer—appears to bind to a subunit of the GABAA receptor, increasing the receptor’s affinity for GABA.
The imidazole ring provides water solubility in acidic solutions and lipid solubility at physiological pH. Therefore, etomidate is dissolved in propylene glycol for injection. This solution often causes pain on injection that can be lessened by a prior intravenous injection of lidocaine.
Pharmacokinetics: Etomidate
Effects on Organ Systems: Etomidate
Drug Interactions
Fentanyl increases the plasma level and prolongs the elimination half-life of etomidate.
Opioids decrease the myoclonus characteristic of an etomidate induction.
Propofol
Propofol induction of general anesthesia likely involves the facilitation of inhibitory
neurotransmission mediated by GABAA receptor binding. Propofol allosterically
increases the binding affinity of GABA for the GABAA 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 benzodiazepine 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 preparation (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 propofol 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 the ampule. Sepsis and death have been
linked to contaminated propofol preparations. Current formulations 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 “antimicrobially preserved” under United States Pharmacopeia standards.
Pharmacokinetics: Propofol
Effects on Organ Systems: Propofol
Drug Interactions
Many clinicians administer a small amount of midazolam (eg, 30 mcg/kg) prior to
induction with propofol; midazolam can reduce the required propofol dose by more than 10%. Propofol is often combined with remifentanil, dexmedetomidine, or ketamine for TIVA.
FOSPROPOFOL
Fospropofol is a water-soluble prodrug that is metabolized in vivo to propofol, phosphate, and formaldehyde. It was released in the United States (2008) and other countries based on studies showing that it produces more complete amnesia and better conscious sedation for endoscopy than midazolam plus fentanyl. It has a slower onset and slower recovery than propofol, offering little reason for anesthesiologists to favor it
over propofol. The place (if any) of fospropofol relative to other competing agents has
not yet been established in clinical practice.
Dexmedetomidine
Dexmedetomidine is an α2-adrenergic agonist similar to clonidine that can be used for
anxiolysis, sedation, and analgesia. Strictly speaking, it is not an anesthetic in humans; however, anesthesiologists have used it in combination with other agents to produce anesthesia. It has also been used in combination with local anesthetics to prolong
regional blocks.
Most commonly, dexmedetomidine is used for procedural sedation (eg, during awake craniotomy procedures or fiberoptic intubation), ICU sedation (eg, ventilated patients recovering from cardiac surgery), or as a supplement to general anesthesia to reduce the need for intraoperative opioids or to reduce the likelihood of emergence delirium (most often in children) after an inhalation anesthetic. It has also been used to treat alcohol withdrawal and the side effects of cocaine intoxication.
Pharmacokinetics: Dexmedetomidine
Effects on Organ Systems: Dexmedetomidine
