NCLEX: Anesthetics

General anesthesia is a reversible state of central nervous system (CNS) depression, causing loss of response to and perception of stimuli. For patients undergoing surgical or medical procedures, anesthesia provides five important benefits:

  • Sedation and reduced anxiety
  • Lack of awareness and amnesia
  • Skeletal muscle relaxation
  • Suppression of undesirable reflexes
  • Analgesia

Because no single agent provides all desirable properties, several categories of drugs are combined to produce optimal anesthesia. Preanesthetics help calm patients, relieve pain, and prevent side effects of subsequently administered anesthetics or the procedure itself. Neuromuscular blockers facilitate tracheal intubation and surgery. Potent general anesthetics are delivered via inhalation and/or intravenous (IV) injection. Except for nitrous oxide, inhaled anesthetics are volatile, halogenated hydrocarbons. IV anesthetics consist of several chemically unrelated drug types commonly used to rapidly induce anesthesia.





Focus topic: Anesthetics

Drugs are chosen to provide safe and efficient anesthesia based on the type of procedure and patient characteristics such as organ function, medical conditions, and concurrent medications.

A. Status of organ systems

  • Cardiovascular system: Anesthetic agents suppress cardiovascular function to varying degrees. This is an important consideration in patients with coronary artery disease, heart failure, dysrhythmias, valvular disease, and other cardiovascular disorders. Hypotension may develop during anesthesia, resulting in reduced perfusion pressure and ischemic injury to tissues. Treatment with vasoactive agents may be necessary. Some anesthetics, such as halothane, sensitize the heart to arrhythmogenic effects of sympathomimetic agents.
  • Respiratory system: Respiratory function must be considered for all anesthetics. Asthma and ventilation or perfusion abnormalities complicate control of inhalation anesthetics. Inhaled agents depress respiration but also act as bronchodilators. IV anesthetics and opioids suppress respiration. These effects may influence the ability to provide adequate ventilation and oxygenation during and after surgery.
  • Liver and kidney: The liver and kidneys influence long-term distribution and clearance of drugs and are also target organs for toxic effects. Release of fluoride, bromide, and other metabolites of halogenated hydrocarbons can affect these organs, especially if they accumulate with frequently repeated administration of anesthetics.
  • Nervous system: The presence of neurologic disorders (for example, epilepsy, myasthenia gravis, neuromuscular disease, compromised cerebral circulation) influences the selection of anesthetic.
  • Pregnancy: Special precautions should be observed when anesthetics and adjunctive agents are administered during pregnancy. Effects on fetal organogenesis are a major concern in early pregnancy. Transient use of nitrous oxide may cause aplastic anemia in the fetus. Oral clefts have occurred in fetuses when mothers received benzodiazepines in early pregnancy. Benzodiazepines should not be used during labor because of resultant temporary hypotonia and altered thermoregulation in the newborn.

B. Concomitant use of drugs

  • Multiple adjunct agents: Commonly, patients receive one or more of these preanesthetic medications: H2 blockers (famotidine, ranitidine) to reduce gastric acidity; benzodiazepines (midazolam, diazepam) to allay anxiety and facilitate amnesia; nonopioids (acetaminophen, celecoxib) or opioids (fentanyl) for analgesia; antihistamines (diphenhydramine) to prevent allergic reactions; antiemetics (ondansetron) to prevent nausea; and/or anticholinergics (glycopyrrolate) to prevent bradycardia and secretion of fluids into the respiratory tract. Premedications facilitate  smooth induction of anesthesia and lower required anesthetic doses. However, they can also enhance undesirable anesthetic effects (hypoventilation) and, when coadministered, may produce negative effects not observed when given individually.
  • Concomitant use of other drugs: Patients may take medications for underlying diseases or abuse drugs that alter response to anesthetics. For example, alcoholics have elevated levels of liver enzymes that metabolize anesthetics, and drug abusers may be tolerant to opioids.




Focus topic: Anesthetics

General anesthesia has three stages: induction, maintenance, and recovery. Induction is the time from administration of a potent anesthetic to development of effective anesthesia. Maintenance provides sustained anesthesia. Recovery is the time from discontinuation of anesthetic until consciousness and protective reflexes return. Induction of anesthesia depends on how fast effective concentrations of anesthetic reach the brain. Recovery is essentially the reverse of induction and depends on how fast the anesthetic diffuses from the brain. Depth of anesthesia is the degree to which the CNS is depressed.

A. Induction

General anesthesia in adults is normally induced with an IV agent like propofol, producing unconsciousness in 30 to 40 seconds. Additional inhalation and/or IV drugs may be given to produce the desired depth of anesthesia. [Note: This often includes an IV neuromuscular blocker such as rocuronium, vecuronium, or succinylcholine to facilitate tracheal intubation and muscle relaxation.] For children without IV access, nonpungent agents, such as sevoflurane, are inhaled to induce general anesthesia.

B. Maintenance of anesthesia

After administering the anesthetic, vital signs and response to stimuli are monitored continuously to balance the amount of drug inhaled and/or infused with the depth of anesthesia. Maintenance is commonly provided with volatile anesthetics, which offer good control over the depth of anesthesia. Opioids such as fentanyl are used for analgesia along with inhalation agents, because the latter are not good analgesics. IV infusions of various drugs may be used during the maintenance phase.

C. Recovery

Postoperatively, the anesthetic admixture is withdrawn, and the patient is monitored for return of consciousness. For most anesthetic agents, recovery is the reverse of induction. Redistribution from the site of action (rather than metabolism of the drug) underlies recovery. If neuromuscular blockers have not been fully metabolized, reversal agents may be used. The patient is monitored to assure full recovery, with normal physiologic functions (spontaneous respiration, acceptable blood pressure and heart rate, intact reflexes, and no delayed reactions such as respiratory depression).

D. Depth of anesthesia

The depth of anesthesia has four sequential stages characterized by increasing CNS depression as the anesthetic accumulates in the brain. [Note: These stages were defined for the original anesthetic ether, which produces a slow onset of anesthesia. With modern anesthetics, the stages merge because of the rapid onset of stage III.]

  • Stage I—Analgesia: Loss of pain sensation results from interference with sensory transmission in the spinothalamic tract. The patient progresses from conscious and conversational to drowsy. Amnesia and reduced awareness of pain occur as stage II is approached.
  • Stage II—Excitement: The patient displays delirium and possibly combative behavior. A rise and irregularity in blood pressure and respiration occur, as well as a risk of laryngospasm. To shorten or eliminate this stage, rapid-acting IV agents are given before inhalation anesthesia is administered.
  • Stage III—Surgical anesthesia: There is gradual loss of muscle tone and reflexes as the CNS is further depressed. Regular respiration and relaxation of skeletal muscles with eventual loss of spontaneous movement occur. This is the ideal stage for surgery. Careful monitoring is needed to prevent undesired progression to stage IV.
  • Stage IV—Medullary paralysis: Severe depression of the respiratory and vasomotor centers occurs. Ventilation and/or circulation must be supported to prevent death.




Focus topic: Anesthetics

Inhaled gases are used primarily for maintenance of anesthesia after administration of an IV agent. Depth of anesthesia can be rapidly altered by changing the inhaled concentration. Inhalational agents have very steep dose–response curves and very narrow therapeutic indices,
so the difference in concentrations causing surgical anesthesia and severe cardiac and respiratory depression is small. No antagonists exist. To minimize waste, potent inhaled agents are delivered in a recirculation system containing absorbents that remove carbon dioxide and allow rebreathing of the agent.




A. Common features of inhalation anesthetics

Modern inhalation anesthetics are nonflammable, nonexplosive agents, including nitrous oxide and volatile, halogenated hydrocarbons. These agents decrease cerebrovascular resistance, resulting in increased brain perfusion. They cause bronchodilation but also decrease both spontaneous ventilation and hypoxic pulmonary vasoconstriction (increased pulmonary vascular resistance in poorly aerated regions of the lungs, redirecting blood flow to more oxygenated regions). Movement of these agents from the lungs to various body compartments depends upon their solubility in blood and tissues, as well as on blood flow. These factors play a role in induction and recovery.

B. Potency

Potency is defined quantitatively as the minimum alveolar concentration (MAC), the end-tidal concentration of inhaled anesthetic needed to eliminate movement in 50% of patients stimulated by a standardized incision. MAC is the median effective dose (ED50) of the anesthetic, expressed as the percentage of gas in a mixture required to achieve that effect. Numerically, MAC is small for potent anesthetics such as sevoflurane and large for less potent agents such as nitrous oxide. The inverse of MAC is, thus, an index of potency. MAC values are used to compare pharmacologic effects of different anesthetics (high MAC equals low potency. Nitrous oxide alone cannot produce complete anesthesia, because an admixture with sufficient oxygen cannot approach its MAC value. The more lipid soluble an anesthetic, the lower the concentration needed to produce anesthesia and, thus, the higher the potency.Factors that can increase MAC (make the patient less sensitive) include hyperthermia, drugs that increase CNS catecholamines, and chronic ethanol abuse. Factors that can decrease MAC (make the patient more sensitive) include increased age, hypothermia, pregnancy, sepsis, acute intoxication, concurrent IV anesthetics, and α2-adrenergic receptor agonists (for example, clonidine, dexmedetomidine).




C. Uptake and distribution of inhalation anesthetics

The principal objective of inhalation anesthesia is a constant and optimal brain partial pressure (Pbr) of inhaled anesthetic (partial pressure equilibrium between alveoli [Palv] and brain [Pbr]). Thus, the alveoli are the “windows to the brain” for inhaled anesthetics. The partial pressure of an anesthetic gas at the origin of the respiratory pathway is the driving force moving the anesthetic into the alveolar space and, thence, into the blood (Pa), which delivers the drug to the brain and other body compartments. Because gases move from one body compartment to another according to partial pressure gradients, steady state is achieved when the partial pressure in each of these compartments is equivalent to that in the inspired mixture. [Note: At equilibrium, Palv = Pa = Pbr.] The time course for attaining this steady state is determined by the following factors:

1. Alveolar wash-in: This refers to replacement of normal lung gases with the inspired anesthetic mixture. The time required for this process is directly proportional to the functional residual capacity of the lung (volume of gas remaining in the lungs at the end of a normal expiration) and inversely proportional to ventilatory rate. It is independent of the physical properties of the gas. As the partial pressure builds within the lung, anesthetic transfer from the lung begins.

2. Anesthetic uptake (removal to peripheral tissues other than the brain): Uptake is the product of gas solubility in the blood, cardiac output (CO), and the gradient between alveolar and blood anesthetic partial pressures.

  • Solubility in blood: This is determined by a physical property of the anesthetic called the blood/gas partition coefficient (the ratio of the concentration of anesthetic in the blood phase to the concentration of anesthetic in the gas phase when the anesthetic is in equilibrium between the two phases. For inhaled anesthetics, think of the blood as a pharmacologically inactive reservoir. Drugs with low versus high solubility in blood differ in their speed of induction of anesthesia. When an anesthetic gas with low blood solubility such as nitrous oxide diffuses from the alveoli into the circulation, little anesthetic dissolves in the blood. Therefore, equilibrium between inhaled anesthetic and arterial blood occurs rapidly, and relatively few additional molecules of anesthetic are required to raise arterial anesthetic partial pressure. Agents with low solubility in blood, thus, quickly saturate the blood. In contrast, anesthetic gases with high blood solubility, such as halothane, dissolve more completely in the blood, and greater amounts of anesthetic and longer periods of time are required to raise blood partial pressure. This results in increased times of induction and recovery and slower changes in depth of anesthesia in response to changes in the concentration. The solubility in blood is ranked as follows: halothane > isoflurane > sevoflurane > nitrous oxide > desflurane.
  • Cardiac output: CO affects removal of anesthetic to peripheral tissues, which are not the site of action. For inhaled anesthetics, higher CO removes anesthetic from the alveoli faster (due to increased blood flow through the lungs) and thus slows the rate of rise in alveolar concentration of gas. It therefore takes longer for the gas to reach equilibrium between the alveoli and the site of action in the brain. For inhaled anesthetics, higher CO equals slower induction. Again, for inhaled anesthetics, think of the blood as a pharmacologically inactive reservoir. Low CO (shock) speeds the rate of rise of the alveolar concentration of gas, since there is less removal to peripheral tissues. [Note: See section on Intravenous Anesthetics for effects of CO on IV anesthetics.]
  • Alveolar-to-venous partial pressure gradient of anesthetic: This is the driving force of anesthetic delivery. For all practical purposes, pulmonary end-capillary anesthetic partial pressure may be considered equal to alveolar anesthetic partial pressure if the patient does not have severe lung diffusion disease. The arterial circulation distributes the anesthetic to various tissues, and the pressure gradient drives free anesthetic gas into tissues. As venous circulation returns blood depleted of anesthetic to the lung, more gas moves into the blood from the lung according to the partial pressure difference. The greater the difference in anesthetic concentration between alveolar (arterial) and venous blood, the higher the uptake and the slower the induction. Over time, the partial pressure in venous blood closely approximates that in the inspired mixture, and no further net anesthetic uptake from the lung occurs.



3. Effect of different tissue types on anesthetic uptake: The time required for a particular tissue to achieve steady state with the partial pressure of an anesthetic gas in the inspired mixture is inversely proportional to the blood flow to that tissue (greater flow results in a more rapidly achieved steady state). It is also directly proportional to the capacity of that tissue to store anesthetic (a larger capacity results in a longer time required to achieve steady state). Capacity, in turn, is directly proportional to the tissue’s volume and the tissue/ blood solubility coefficient of the anesthetic. Four major tissue compartments determine the time course of anesthetic uptake:

  • Brain, heart, liver, kidney, and endocrine glands: These highly perfused tissues rapidly attain steady state with the partial pressure of anesthetic in the blood.
  • Skeletal muscles: These are poorly perfused during anesthesia and have a large volume, which prolongs the time required to achieve steady state.
  • Fat: Fat is also poorly perfused. However, potent volatile anesthetics are very lipid soluble, so fat has a large capacity to store them. Slow delivery to a high-capacity compartment prolongs the time required to achieve steady state in fat tissue.
  • Bone, ligaments, and cartilage: These are poorly perfused and have a relatively low capacity to store anesthetic. Therefore, these tissues have minimal impact on the time course of anesthetic distribution in the body.

4. Washout: When an inhalation anesthetic is discontinued, the body becomes the “source” that drives the anesthetic back into the alveolar space. The same factors that influence attainment of steady state with an inspired anesthetic determine the time course of its clearance from the body. Thus, nitrous oxide exits the body faster than halothane.




D. Mechanism of action

No specific receptor has been identified as the locus of general anesthetic action. The fact that chemically unrelated compounds produce anesthesia argues against the existence of a single receptor. It appears that a variety of molecular mechanisms may contribute to the activity of general anesthetics. At clinically effective concentrations, general anesthetics increase the sensitivity of the γ-aminobutyric acid (GABAA) receptors to the inhibitory neurotransmitter GABA. This increases chloride ion influx and hyperpolarization of neurons. Postsynaptic neuronal excitability and, thus, CNS activity are diminished. Unlike other anesthetics, nitrous oxide and ketamine do not have actions on GABAA receptors. Their effects are likely mediated via inhibition of the N-methyl-d-aspartate (NMDA) receptors. [Note: The NMDA receptor is a glutamate receptor. Glutamate is the body’s main excitatory neurotransmitter.] Other receptors are also affected by volatile anesthetics. For example, the activity of the inhibitory glycine receptors in the spinal motor neurons is increased. In addition, inhalation anesthetics block excitatory postsynaptic currents of nicotinic receptors. The mechanism by which anesthetics perform these modulatory roles is not fully understood.




E. Halothane

Halothane is the prototype to which newer inhalation anesthetics are compared. When halothane [HAL-oh-thane] was introduced, its rapid induction and quick recovery made it an anesthetic of choice. Due to adverse effects and the availability of other anesthetics with fewer complications, halothane has been replaced in most countries.

  • Therapeutic uses: Halothane is a potent anesthetic but a relatively weak analgesic. Thus, it is usually coadministered with nitrous oxide, opioids, or local anesthetics. It is a potent bronchodilator. Halothane relaxes both skeletal and uterine muscles and can be used in obstetrics when uterine relaxation is indicated. Halothane is not hepatotoxic in children (unlike its potential effect on adults). Combined with its pleasant odor, it is suitable in pediatrics for inhalation induction, although sevoflurane is now the agent of choice.
  • Pharmacokinetics: Halothane is oxidatively metabolized in the body to tissue-toxic hydrocarbons (for example, trifluoroethanol) and bromide ion. These substances may be responsible for toxic reactions that some adults (especially females) develop after halothane anesthesia. This begins as a fever, followed by anorexia, nausea, and vomiting, and possibly signs of hepatitis. Although the incidence is low (approximately 1 in 10,000), half of affected patients may die of hepatic necrosis. To avoid this condition, halothane is not administered at intervals of less than 2 to 3 weeks. All halogenated inhalation anesthetics have been associated with hepatitis, but at a much lower incidence than with halothane.
  • Adverse effects:

a. Cardiac effects: Halogenated hydrocarbons are vagomimetic and may cause atropine-sensitive bradycardia. In addition, halothane has the undesirable property of causing cardiac arrhythmias. [Note: Halothane can sensitize the heart to effects of catecholamines such as norepinephrine.] Halogenated anesthetics produce concentration-dependent hypotension. This is best treated with a direct-acting vasoconstrictor, such as phenylephrine.

b. Malignant hyperthermia: In a very small percentage of susceptible patients, exposure to halogenated hydrocarbon anesthetics or the neuromuscular blocker succinylcholine may induce malignant hyperthermia (MH), a rare life-threatening condition. MH causes a drastic and uncontrolled increase in skeletal muscle oxidative metabolism, overwhelming the body’s capacity to supply oxygen, remove carbon dioxide, and regulate temperature, eventually leading to circulatory collapse and death if not treated immediately. Strong evidence indicates that MH is due to an excitation–contraction coupling defect. Burn victims and individuals with muscular dystrophy, myopathy, myotonia, and osteogenesis imperfecta are susceptible to MH. Susceptibility to MH is often inherited as an autosomal dominant disorder. Should a patient exhibit symptoms of MH, dantrolene is given as the anesthetic mixture is withdrawn, and measures are taken to rapidly cool the patient. Dantrolene [DAN-tro-lean] blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells, reducing heat production and relaxing muscle tone. It should be available whenever triggering agents are administered. In addition, the patient must be monitored and supported for respiratory, circulatory, and renal problems. Use of dantrolene and avoidance of triggering agents such as halogenated anesthetics in susceptible individuals have markedly reduced mortality from MH.

F. Isoflurane

This agent undergoes little metabolism and is, therefore, not toxic to the liver or kidney. Isoflurane [eye-so-FLOOR-ane] does not induce cardiac arrhythmias or sensitize the heart to catecholamines. However, like other halogenated gases, it produces dose-dependent hypotension. It has a pungent odor and stimulates respiratory reflexes (for example, breath holding, salivation, coughing, laryngospasm) and is therefore not used for inhalation induction. With higher blood solubility than desflurane and sevoflurane, isoflurane is typically used only when cost is a factor.

G. Desflurane

Desflurane [DES-floor-ane] provides very rapid onset and recovery due to low blood solubility. This makes it a popular anesthetic for outpatient procedures. However, it has a low volatility, requiring administration via a special heated vaporizer. Like isoflurane, it decreases vascular resistance and perfuses all major tissues very well. Because it stimulates respiratory reflexes, desflurane is not used for inhalation induction. It is relatively expensive and thus rarely used for maintenance during extended anesthesia. Its degradation is minimal and tissue toxicity is rare.

H. Sevoflurane

Sevoflurane [see-voe-FLOOR-ane] has low pungency, allowing rapid induction without irritating the airways. This makes it suitable for inhalation induction in pediatric patients. It has a rapid onset and recovery due to low blood solubility. Sevoflurane is metabolized by the liver, and compounds formed in the anesthesia circuit may be nephrotoxic if fresh gas flow is too low.

Nitrous oxide

Nitrous oxide [NYE-truss OX-ide] (“laughing gas”) is a nonirritating potent analgesic but a weak general anesthetic. It is frequently used at concentrations of 30 to 50% in combination with oxygen for analgesia, particularly in dentistry. Nitrous oxide alone cannot produce surgical anesthesia, but it is commonly combined with other more potent agents. Nitrous oxide is poorly soluble in blood and other tissues, allowing it to move very rapidly in and out of the body. Within closed body compartments, nitrous oxide can increase the volume (for example, causing a pneumothorax) or pressure (for example, in the sinuses), because it replaces nitrogen in various air spaces faster than the nitrogen leaves. Its speed of movement allows nitrous oxide to retard oxygen uptake during recovery, thereby causing “diffusion hypoxia,” which can be overcome by significant concentrations of inspired oxygen during recovery. Nitrous oxide does not depress respiration and does not produce muscle relaxation. When co-administered with other anesthetics, it has moderate to no effect on the cardiovascular system or on increasing cerebral blood flow, and it is the least hepatotoxic of the inhalation agents. Therefore, it is probably the safest of these anesthetics, provided that sufficient oxygen is administered simultaneously.





Focus topic: Anesthetics

IV anesthetics cause rapid induction often occurring within one “arm–brain circulation time,” or the time it takes to travel from the site of injection (usually the arm) to the brain, where it has its effect. Anesthesia may then be maintained with an inhalation agent. IV anesthetics may be used as sole agents for short procedures or administered as infusions to help maintain anesthesia during longer cases. In lower doses, they may be used for sedation.

A. Induction

After entering the blood, a percentage of drug binds to plasma proteins, and the rest remains unbound or “free.” The degree of protein binding depends upon the physical characteristics of the drug, such as the degree of ionization and lipid solubility. The drug is carried by venous blood to the right side of the heart, through the pulmonary circulation, and via the left heart into the systemic circulation. The majority of CO flows to the brain, liver, and kidney (“vessel-rich organs”). Thus, a high proportion of initial drug bolus is delivered to the cerebral circulation and then passes along a concentration gradient from blood into the brain. The rate of this transfer is dependent on the arterial concentration of the unbound free drug, the lipid solubility of the drug, and the degree of ionization. Unbound, lipid-soluble, nonionized molecules cross into the brain most quickly. Once the drug has penetrated the CNS, it exerts its effects. Like inhalation anesthetics, the exact mode of action of IV anesthetics is unknown.

B. Recovery

Recovery from IV anesthetics is due to redistribution from sites in the CNS. Following initial flooding of the CNS and other vessel-rich tissues with nonionized molecules, the drug diffuses into other tissues with less blood supply. With secondary tissue uptake, predominantly by skeletal muscle, plasma concentration of the drug falls. This allows the drug, to diffuse out of the CNS, down the resulting reverse concentration gradient. This initial redistribution of drug into other tissues leads to the rapid recovery seen after a single IV dose of induction agent. Metabolism and plasma clearance become important only following infusions and repeat doses of a drug. Adipose tissue makes little contribution to the early redistribution of free drug following a bolus, due to its poor blood supply. However, following repeat doses or infusions, equilibration with fat tissue forms a drug reservoir, often leading to delayed recovery.

C. Effect of reduced cardiac output on IV anesthetics

When CO is reduced (for example, in shock, the elderly, cardiac disease), the body compensates by diverting more CO to the cerebral circulation. A greater proportion of the IV anesthetic enters the cerebral circulation under these circumstances. Therefore, the dose of the drug must be reduced. Further, decreased CO causes prolonged circulation time. As global CO is reduced, it takes a longer time for an induction drug to reach the brain and exert its effects. The slow titration of a reduced dose of an IV anesthetic is key to a safe induction in patients with reduced CO.

D. Propofol

Propofol [PRO-puh-fol] is an IV sedative/hypnotic used for induction and/or maintenance of anesthesia. It is widely used and has replaced thiopental as the first choice for induction of general anesthesia and sedation. Because propofol is poorly water soluble, it is supplied as an emulsion containing soybean oil and egg phospholipid, giving it a milk-like appearance.

  • Onset: Induction is smooth and occurs 30 to 40 seconds after administration. Following an IV bolus, there is rapid equilibration between the plasma and the highly perfused tissue of the brain. Plasma levels decline rapidly as a result of redistribution, followed by a more prolonged period of hepatic metabolism and renal clearance. The initial redistribution half-life is 2 to 4 minutes. The pharmacokinetics of propofol are not altered by moderate hepatic or renal failure.
  • Actions: Although propofol depresses the CNS, it is occasionally accompanied by excitatory phenomena, such as muscle twitching, spontaneous movement, yawning, and hiccups. Transient pain at the injection site is common. Propofol decreases blood pressure without depressing the myocardium. It also reduces intracranial pressure, mainly due to systemic vasodilation. It has less of a depressant effect than volatile anesthetics on CNSevoked potentials, making it useful for surgeries in which spinal cord function is monitored. It does not provide analgesia, so supplementation with narcotics is required. Propofol is commonly infused in lower doses to provide sedation. The incidence of postoperative nausea and vomiting is very low, as this agent has some antiemetic effects.

E. Barbiturates

Thiopental [thigh-oh-PEN-tahl] is an ultra–short-acting barbiturate with high lipid solubility. It is a potent anesthetic but a weak analgesic. Barbiturates require supplementary analgesic administration during anesthesia. When given IV, agents such as thiopental and methohexital [meth-oh-HEX-uh-tall] quickly enter the CNS and depress function, often in less than 1 minute. However, diffusion out of the brain can also occur very rapidly because of redistribution to other tissues. These drugs may remain in the body for relatively long periods, because only about 15% of a dose entering the circulation is metabolized by the liver per hour. Thus, metabolism of thiopental is much slower than its redistribution. Thiopental has minor effects on the normal cardiovascular system, but may contribute to severe hypotension in patients with hypovolemia or shock. All barbiturates can cause apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm (of particular concern for asthmatics). These agents have largely been replaced with newer agents that are better tolerated. Thiopental is no longer available in many countries, including the United States.




F. Benzodiazepines

The benzodiazepines are used in conjunction with anesthetics for sedation. The most commonly used is midazolam [my-DAZ-olam]. Diazepam [dye-AZ-uh-pam] and lorazepam [lore-AZ-uh-pam] are alternatives. All three facilitate amnesia while causing sedation, enhancing the inhibitory effects of various neurotransmitters, particularly GABA. Minimal cardiovascular depressant effects are seen, but all are potential respiratory depressants (especially when administered IV). They are metabolized by the liver with variable  elimination half-lives, and erythromycin may prolong their effects.Benzodiazepines can induce a temporary form of anterograde amnesia in which the patient retains memory of past events, but new information is not transferred into long-term memory. Therefore, important treatment information should be repeated to the patient after the effects of the drug have worn off.

G. Opioids

Because of their analgesic property, opioids are commonly combined with other anesthetics. The choice of opioid is based primarily on the duration of action needed. The most commonly used opioids are fentanyl [FEN-ta-nil] and its congeners, sufentanil [SOO-fen-tanil] and remifentanil [REMI-fen-ta-nil], because they induce analgesia more rapidly than morphine. They may be administered intravenously, epidurally, or intrathecally (into the cerebrospinal fluid). Opioids are not good amnesics, and they can all cause hypotension, respiratory depression, and muscle rigidity, as well as postanesthetic nausea and vomiting. Opioid effects can be antagonized by naloxone.

H. Etomidate

Etomidate [ee-TOM-uh-date] is a hypnotic agent used to induce anesthesia, but it lacks analgesic activity. Its water solubility is poor, so it is formulated in a propylene glycol solution. Induction is rapid, and the drug is short-acting. Among its benefits are little to no effect on the heart and circulation. Etomidate is usually only used for patients with coronary artery disease or cardiovascular dysfunction. Its adverse effects include decreased plasma cortisol and aldosterone levels, which can persist up to 8 hours. Etomidate should not be infused for an extended time, because prolonged suppression of these hormones is hazardous. Injection site reaction and involuntary skeletal muscle movements are not uncommon. The latter are managed by administration of benzodiazepines and opioids.

I. Ketamine

Ketamine [KET-uh-meen], a short-acting, nonbarbiturate anesthetic, induces a dissociated state in which the patient is unconscious (but may appear to be awake) and does not feel pain. This dissociative anesthesia provides sedation, amnesia, and immobility. Ketamine stimulates central sympathetic outflow, causing stimulation of the heart with increased blood pressure and CO. It is also a potent bronchodilator. Therefore, it is beneficial in patients with hypovolemic or cardiogenic shock and in asthmatics. Conversely, it is contraindicated in hypertensive or stroke patients. The drug is lipophilic and enters the brain very quickly. Like the barbiturates, it redistributes to other organs and tissues. Ketamine is used mainly in children and elderly adults for short procedures. It is not widely used, because it increases cerebral blood flow and may induce hallucinations, particularly in young adults. Ketamine may be used illicitly, since it causes a dream-like state and hallucinations similar to phencyclidine (PCP).

J. Dexmedetomidine

Dexmedetomidine [dex-med-eh-TOM-uh-deen] is a sedative used in intensive care settings and surgery. It is relatively unique in its ability to provide sedation without respiratory depression. Like clonidine, it is an α2 receptor agonist in certain parts of the brain. Dexmedetomidine has sedative, analgesic, sympatholytic, and anxiolytic effects that blunt many cardiovascular responses. It reduces volatile anesthetic, sedative, and analgesic requirements without causing significant respiratory depression.


Focus topic: Anesthetics

Neuromuscular blockers are used to abolish reflexes to facilitate tracheal intubation and provide muscle relaxation as needed for surgery. Their mechanism of action is blockade of nicotinic acetylcholine receptors in the neuromuscular junction.





Focus topic: Anesthetics

Local anesthetics block nerve conduction of sensory impulses and, in higher concentrations, motor impulses from the periphery to the CNS. Na+ ion channels are blocked to prevent the transient increase in permeability of the nerve membrane to Na+ that is required for an action potential. When propagation of action potentials is prevented, sensation cannot be transmitted from the source of stimulation to the brain. Delivery techniques include topical administration, infiltration, peripheral nerve blocks, and neuraxial (spinal, epidural, or caudal) blocks. Small, unmyelinated nerve fibers for pain, temperature, and autonomic activity are most sensitive. Structurally, local anesthetics all include a lipophilic group joined by an amide or ester linkage to a carbon chain, which, in turn, is joined to a hydrophilic group. The most widely used local anesthetics are bupivacaine [byoo-PIV-uh-cane], lidocaine [LYE-doecane], mepivacaine [muh-PIV-uh-cane], procaine [PRO-cane], ropivacaine [roe-PIV-uh-cane], and tetracaine [TET-truh-cane]. Bupivacaine is noted for cardiotoxicity if inadvertently injected IV. Bupivacaine liposome injectable suspension may provide postsurgical analgesia lasting 24 hours or longer after injection into the surgical site. [Note: Non-bupivacaine local anesthetics may cause an immediate release of bupivacaine from the liposomal suspension if administered together locally.] Mepivacaine should not be used in obstetric anesthesia due to its increased toxicity to the neonate.






A. Metabolism

Biotransformation of amides occurs primarily in the liver. Prilocaine [PRY-low-cane], a dental anesthetic, is also metabolized in the plasma and kidney, and one of its metabolites may lead to methemoglobinemia. Esters are biotransformed by plasma cholinesterase (pseudocholinesterase). Patients with pseudocholinesterase deficiency may metabolize ester local anesthetics more slowly. At normal doses, this has little clinical effect. Reduced hepatic function predisposes patients to toxic effects, but should not significantly increase the duration of action of local anesthetics.

B. Onset and duration of action

The onset and duration of action of local anesthetics are influenced by several factors including tissue pH, nerve morphology, concentration, pKa, and lipid solubility of the drug. Of these, the pH of the tissue and pKa are most important. At physiologic pH, these compounds are charged. The ionized form interacts with the protein receptor of the Na+ channel to inhibit its function and achieve local anesthesia. The pH may drop in infected sites, causing onset to be delayed or even prevented. Within limits, higher concentration and greater lipid solubility improve onset somewhat. Duration of action depends on the length of time the drug can stay near the nerve to block sodium channels.

C. Actions

Local anesthetics cause vasodilation, leading to rapid diffusion away from the site of action and shorter duration when these drugs are administered alone. By adding the vasoconstrictor epinephrine, the rate of local anesthetic absorption and diffusion is decreased. This minimizes systemic toxicity and increases the duration of action. Hepatic function does not affect the duration of action of local anesthesia, which is determined by redistribution and not biotransformation. Some local anesthetics have other therapeutic uses (for example, lidocaine is an IV antiarrhythmic).

D. Allergic reactions

Patient reports of allergic reactions to local anesthetics are fairly common, but often times reported “allergies” are actually side effects from epinephrine added to the local anesthetic. Psychogenic reactions to injections may be misdiagnosed as allergic reactions and may also mimic them with signs such as urticaria, edema, and bronchospasm. True allergy to an amide local anesthetic is exceedingly rare, whereas the ester procaine is somewhat more allergenic. Allergy to one ester rules out use of another ester, because the allergenic component is the metabolite para-aminobenzoic acid, produced by all esters. In contrast, allergy to one amide does not rule out the use of another amide. A patient may be allergic to other compounds in the local anesthetic, such as preservatives in multidose vials.

E. Administration to children and the elderly

Before administering local anesthetic to a child, the maximum dose based on weight should be calculated to prevent accidental overdose. There are no significant differences in response to local anesthetics between younger and older adults. It is prudent to stay well below maximum recommended doses in elderly patients who often have some compromise in liver function. Because some degree of cardiovascular compromise may be expected in elderly patients, reducing the dose of epinephrine may be prudent. Local anesthetics are safe for patients who are susceptible to MH.

F. Systemic local anesthetic toxicity

Toxic blood levels of the drug may be due to repeated injections or could result from a single inadvertent IV injection. Aspiration before every injection is imperative. The signs, symptoms, and timing of local anesthetic systemic toxicity are unpredictable. One must consider the diagnosis in any patient with altered mental status or cardiovascular instability following injection of local anesthetic. CNS symptoms (either excitation or depression) may be apparent but may also be subtle, nonspecific, or absent. Treatment for systemic local anesthetic toxicity includes airway management, support of breathing and circulation, seizure suppression and, if needed, cardiopulmonary resuscitation. Administering a 20% lipid emulsion infusion (lipid rescue therapy) is a valuable asset.






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