CHAPTER 19 Perioperative Medications

M. Bernie Miller

Introduction

The aim of general anesthesia is to ensure patient safety, reduce patient suffering, and allow optimal conditions for the surgeon to perform the operation. The patient properties that facilitate this are unconsciousness, amnesia, analgesia, and often paralysis. No single agent reliably produces all these properties safely. Often, an operating room pharmacy will prepare a standardized tray (Fig. 19.1) containing medications from each class (induction agent, neuromuscular blocker, antiemetics, etc.). Medications are the cornerstone of an anesthetic, and as an anesthesia technician, you will need a thorough understanding of the wide variety of medications used by the anesthesia provider. This may seem overwhelming, but in fact, many have already been discussed in this text along with the organ systems they affect:

Guimaraes2e-ch019-image001 — FIGURE 19.1. Sample anesthesia tray, replenished for each case, with drugs from each common class of noncontrolled medication.

Cardiovascular drugs in Chapter 6

Respiratory medications in Chapter 9

Drugs affecting the central nervous system in Chapter 11

Local anesthetics in Chapters 12 and 16

Drugs affecting the sympathetic and parasympathetic nervous systems in Chapter 13

Neuromuscular blockers and their reversal in Chapter 14, and

General anesthetic medications in Chapter 17.

In addition, principles of pharmacology have been discussed in Chapter 3. This chapter will provide more comprehensive coverage of the fundamental intravenous medications used to induce anesthesia: the sedative-hypnotics, the opioids, and the neuromuscular blockers. Adjunct pain medications will be discussed, as well as antinausea medications. Proper medication handling will be discussed later in the book, in Chapter 34.

Sedative Hypnotics

Propofol

Propofol (Fig. 19.2) is one of the most recognized medications anesthesia providers use due to its high frequency of utilization and characteristic milky white appearance. The active drug is not soluble in water, and is thus formulated in a lipid emulsion, which can cause pain on injection. Propofol is used in a single bolus dose to induce anesthesia, as well as in an infusion for maintenance of anesthesia. Its rapid onset and offset make it particularly useful in the operating room setting. The mechanism of propofol is not entirely understood. Like many other sedative-hypnotic drugs, it likely involves stimulation of the so-called GABA receptor. GABA is an important “inhibitory” neurotransmitter, decreasing activity throughout the brain. Important effects of propofol in the body include a decrease in blood pressure primarily due to decrease systemic vascular resistance, as well as respiratory depression and apnea. Propofol can also cause decreased cardiac output at higher doses.

Guimaraes2e-ch019-image002 — FIGURE 19.2. Propofol, a sedative-hypnotic and anesthesia induction agent.

Etomidate

Etomidate (Fig. 19.3) is another agent commonly used to induce general anesthesia. It works by binding the GABA receptor directly as well as increasing the affinity of the receptor for the GABA molecule itself. The onset of action is approximately 1-2 minutes, and offset is accordingly rapid. Etomidate is perhaps best known for its minimal cardiovascular effects. It is particularly useful in the induction of unstable patients who cannot tolerate a reduction in blood pressure. Respiratory depression is minimal unless given at high doses or combined with other agents. One limitation of etomidate is adrenal suppression caused by the inhibition of the 11β-hydroxylase enzyme. This effect is most pronounced when etomidate is given as a continuous infusion. Ironically, critically ill patients who benefit most from etomidate’s minimal effect on blood pressure are most sensitive to this adverse effect. Therefore, risks and benefits must be carefully weighed on an individual patient basis. Etomidate is also strongly associated with nausea and vomiting.

Guimaraes2e-ch019-image003 — FIGURE 19.3. Etomidate, another sedative-hypnotic anesthesia induction agent. (Photo printed with permission from AuroMedics Pharma LLC.)

Benzodiazepines

This class of medications reduces anxiety and induces a sense of calm and well-being by stimulating the GABA_A receptor in the central nervous system (CNS). Benzodiazepines also cause amnesia, one of the principal components of an anesthetic. Midazolam is used most commonly by anesthesiologists, and is often administered intravenously just before heading to the operating room. It can also be given orally to pediatric patients prior to IV placement and induction of general anesthesia. Benzodiazepines are also very effective antiseizure medications and are the first line of treatment for an active seizure. Other drugs in this class include lorazepam (Ativan) and diazepam (Valium).

Barbiturates

Barbiturates are another class of sedative hypnotic medications that work at the GABA_A receptor. Like benzodiazepines, they reliably cause amnesia. Thiopental was once widely used for induction of general anesthesia; however, its use has diminished sharply with the availability of propofol. Methohexital is one of the few hypnotic medications that decreases the threshold for seizure activity; therefore, it is commonly used to produce hypnosis for electroconvulsive therapy (ECT).

Dexmedetomidine

Dexmedetomidine is a highly selective blocker of alpha-2 adrenergic receptors. This causes decreased release of epinephrine and norepinephrine, resulting in a decrease in heart rate and blood pressure. Dexmedetomidine blocks these receptors in an area of the brain responsible for arousal; this results in sedation. Dexmedetomidine also blocks these receptors in part of the spinal cord that transmits pain, resulting in analgesia.

A key property of dexmedetomidine is its ability to produce sedation without significant respiratory depression. It is thus popular for awake fiberoptic intubation and for ICU patients weaning from the ventilator. Dexmedetomidine also has an analgesic effect and can be administered as an adjunct to general anesthesia to reduce opioid administration, particularly in patients with morbid obesity and obstructive sleep apnea.

Ketamine

Ketamine is a unique medication that produces many of the effects of an ideal anesthetic agent including analgesia, hypnosis, amnesia, and immobility. Although known outside medical practice as a recreational drug (special K) or for its structural similarity to phencyclidine (PCP), ketamine is widely used and respected in the clinical setting. In fact, new uses for ketamine are constantly being discovered. Ketamine works by blocking the N-methyl-d-aspartate (NMDA) receptor in the CNS. This is one of the major connectors for information in the brain, and ketamine produces dissociation by interrupting communication between areas of the brain that associate sensation with feelings. This experience can be unpredictable in patients: it can produce unpleasant sensations, but can also produce profound amnesia and pain relief. Ketamine is a very reliable pain reliever that does not cause respiratory depression, and can be used for brief painful procedures like changes of burn dressings. Blood pressure and cardiac output are usually maintained, and ketamine can be used for induction of anesthesia in hemorrhagic shock. Ketamine is commonly given IV, but is also available in a higher concentration that can be given intramuscularly in uncooperative patients. Respiratory drive and airway reflexes are preserved, and ketamine is an effective bronchodilator.

Analgesics

Medications that alleviate pain are called analgesics. Anesthetic medications vary in their analgesic properties. Benzodiazepines and propofol are not analgesic. Volatile anesthetics provide some analgesia, but patients will often respond to a painful stimulus in the form of increased heart rate and blood pressure unless an analgesic is administered. Ketamine and dexmedetomidine provide significant analgesia. The most profoundly analgesic systemic medications, however, are the opioids.

Opioids

Opioids are a family of medications that include the naturally occurring opiates (codeine and morphine) as well as synthetically produced ones such as fentanyl, hydromorphone (Dilaudid), and oxycodone. They are the most widely used medications for the treatment of pain and are particularly effective at treating acute pain. Opioid receptors are found throughout the body, primarily in the brain, spinal cord, peripheral neurons, and GI tract.

Opioids with a rapid onset are given commonly in anesthesia. These include fentanyl (Fig. 19.4), alfentanil, sufentanil, and remifentanil. Opioids with a short half-life may be given by infusion. Opioids with a slower onset and longer half-life, such as morphine (Fig. 19.5) and hydromorphone (Fig. 19.6), may be given when a more predictable or longer duration of action is desired, in the recovery unit, or on the postoperative floor.

Guimaraes2e-ch019-image004 — FIGURE 19.4. Fentanyl, a short-acting opioid.

Guimaraes2e-ch019-image005 — FIGURE 19.5. Morphine, a long-acting opioid.

Guimaraes2e-ch019-image006 — FIGURE 19.6. Hydromorphone, another long-acting opioid.

The reliable analgesia achieved by opioids comes with adverse effects. One of the most important is respiratory depression. Opioids decrease the brain’s response to circulating carbon dioxide, the body’s primary respiratory driver. This causes patients to breathe less frequently. Opioids are also a potent stimulant of nausea and vomiting. Opioids decrease sympathetic activity, which can lower blood pressure and heart rate. Muscle rigidity can occur with higher doses of opioids often given at induction of anesthesia. This can severely impair the ability to mask ventilate a patient. Opioids also can cause urinary retention and constipation.

Nonopioid Analgesics

Opioid analgesics have significant adverse effects, not the least of which is that they are addictive. In addition to their sedating effects, they are less effective than other pain relief methods at relieving pain when patients move, and they reduce appetite: the net result is that patients tend not to get up, move around, and eat—all of which delays surgical recovery. Thus, anesthesia and surgical practice is moving away from opioid-based pain relief to the use of multiple, less-toxic interventions together—a concept known as multimodal analgesia. Not only does it produce better analgesia, multimodal analgesia can reduce opioid administration and its secondary adverse effects.

Acetaminophen

Acetaminophen, commonly known under the brand name of Tylenol, is one of the most common analgesic and antipyretic medications in the world. Unlike aspirin and other Nonsteriodal anti-inflammatory drugs (NSAIDs) acetaminophen has virtually no anti-inflammatory properties. The mechanism of action is unknown. Acetaminophen is often given with other nonopioid analgesics that work through different mechanisms. It produces pain relief on its own, but also has “synergy” with other pain medications—in some studies, it cuts the amount of opioid pain medicine patients use in half.

Acetaminophen is most conveniently given orally with a small sip of water before an operation; an intravenous formulation is currently very costly. A rectal suppository is also available, and in common pediatric use. Liver toxicity is a potential adverse effect, thus proper attention to doses is required.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are some of the most common medications administered in the world for the common ailments, aches, and pains that occur in everyday life. There are many drugs from this class on the market, including many that can be obtained over the counter. NSAIDs work by inhibiting enzymes known as COX-1 and COX-2. The effect diminishes production of prostaglandins, and in turn reduces pain, inflammation, and fever if present. The most commonly used medications in this class, including the over-the-counter NSAIDs like ibuprofen, are nonselective and block both enzymes. Ketorolac is commonly used perioperatively and is the most effective drug in this class. More recently, medications selective for COX-2 only have been developed, the most common used perioperatively is celecoxib (Celebrex).

NSAIDs can cause adverse effects in multiple systems so they must be carefully administered, particularly in surgical patients who may be vulnerable to these effects. Nonselective COX inhibitors can cause decreased platelet function, GI ulceration and bleeding, renal dysfunction, inhibition of bone healing, and bronchospasm. Selective COX-2 inhibitors have improved adverse effect profiles.

Neuromuscular Blocking Agents and Reversal Agents

Muscle paralysis is achieved using medications that interfere with transmission of information at the nicotinic acetylcholine (ACh) receptor at the junction where nerves and muscle cells interact. This interaction is covered in detail in Chapter 14, Neuromuscular Anatomy and Physiology. Neuromuscular blocking agents (NMBAs) are generally grouped into two categories depending on whether they “depolarize” the membrane of the affected muscle cell or not. Thus, the groups are appropriately titled depolarizing and nondepolarizing NMBAs.

Succinylcholine (SCh) is the only currently used depolarizing NMBA. It is essentially two acetylcholine molecules bound together. SCh binds the nicotinic ACh receptor causing the muscle to fire. This causes widespread uncoordinated muscle cell contraction called fasciculations, which can be seen 30-60 seconds after an intubating dose of succinylcholine is given. This large-scale firing leads to desensitization of the receptor to further stimulus, resulting in paralysis. SCh provides excellent intubating conditions, as it has the fastest onset and shortest duration of all the available NMBAs.

There are a number of adverse effects to consider when administering SCh. Perhaps the most potentially dangerous is a transient rise in potassium concentration of about 0.5 mEq/L. This rise can be substantially more when the patient has excess immature nicotinic ACh receptors, which can occur in patients with stroke, burns, or spinal cord injuries. Pediatric patients with muscular dystrophies are also at higher risk of hyperkalemia after SCh administration. Muscle aches are common after SCh administration, occasionally even causing more discomfort than the postoperative surgical pain. The SCh-caused muscle contractions also cause transient increases in pressure in multiple body compartments. Increased intraocular pressure makes SCh controversial in open injuries of the eye. SCh also causes increased intracranial pressure, a consideration in emergency neurosurgery.

The nondepolarizing NMBAs can be divided into two groups based on their chemical structure, the aminosteroids and benzylisoquinoliniums. (Just as with the amide and ester local anesthetics, the two classes of drugs can be distinguished by the spelling of their names: aminosteroids are “-curoniums” and benzylisoquinoliniums are “-curiums”). Vecuronium and rocuronium are the most commonly used nondepolarizing NMBAs in the United States. Both have an “intermediate duration,” (i.e., shorter than the older, “long-acting” NMBAs pancuronium and curare but longer than SCh), minimal metabolites, and are hemodynamically stable. Rocuronium also has the advantage of a fast onset, allowing its use (in high doses) for rapid sequence inductions, with good intubating conditions in less than 60 seconds. The benzylisoquinoliniums include curare (d-tubocur rine, yes, originally derived from South American arrow poisons!) atracurium, and cisatracurium. Cisatracurium is the only benzylisoquinolinium in widespread clinical use in the United States; atracurium and curare are limited by histamine release and adverse effects (hypotension, bronchospasm). Cisatracurium is, however, widely used. Like vecuronium and rocuronium, it is of intermediate duration. Unlike both these drugs, it undergoes nonenzymatic degradation and does not rely on the liver or kidney for elimination. This property makes it very useful in patients with failure of these organs.

Neuromuscular Blocking Reversal Agents

Adequate muscle strength is imperative upon emergence from anesthesia, particularly when the patient will be extubated. Acetylcholinesterase (AChAse) inhibitors, such as neostigmine, are used to reverse neuromuscular blockade. AChAse inhibitors increase the concentration of ACh in the neuromuscular junction, outcompeting the remaining nondepolarizing NMBA and restoring tone and strength.

The rise in ACh is not limited to the neuromuscular junction, but is widespread throughout the body. Excessive concentrations of acetylcholine at autonomic sites cause signs of cholinergic toxicity including bradycardia, bronchospasm, and salivation. (See Chapter 13, Autonomic Nervous System.) Luckily, the muscarinic acetylcholine receptor at autonomic sites is structurally and functionally different from the nicotinic receptor found at the neuromuscular junction. The muscarinic receptor can be blocked by administering a muscarinic antagonist such as glycopyrrolate or atropine. This prevents the cholinergic side effects, while allowing the increased concentrations of ACh to work on the nicotinic receptors at the neuromuscular junction. Secondary effects of glycopyrrolate and other muscarinic blockers include tachycardia and reduced secretions.

Sugammadex

Sugammadex is a relatively new reversal agent that works by selectively binding the steroid nucleus of aminosteroid NMBAs and rendering them impotent. It has no affinity for SCh or the benzylisoquinoliniums. Sugammadex has no affinity for other known receptors and thus has no significant adverse effects, making it an ideal reversal agent.

Antinausea Medications

Postoperative nausea and vomiting (PONV) is a common problem after general and even regional anesthesia. PONV can cause significant distress to the patient, extend the stay in the recovery area, and delay discharge in ambulatory settings, and result in unplanned admissions. Research into effective prevention and treatment has reduced, but not eliminated, PONV. Just as with analgesia, a multimodal approach, using interventions on multiple different pathways at the same time, treats but probably does not eliminate nausea completely. Several interventions (including modifications to anesthesia and pain relief techniques) can only be done for prevention; once nausea and vomiting have begun, available tools are more limited.

Scopolamine, (Fig. 19.7), an anticholinergic medication, is effective for nausea and vomiting, but its preferred route is a transdermal patch, and its effect takes 1.5-2 hours to begin. Thus, it is best applied preop. Dexamethasone, (Fig. 19.8), a glucocorticoid steroid, is an effective preventative but, curiously, does not work for treatment of nausea and vomiting once it has begun. Medications that antagonize the serotonin 5-HT3 receptor are a mainstay of PONV prevention and treatment, as they are effective and have few side effects. These include medications such as ondansetron (Fig. 19.9) and granisetron. Dopamine antagonists are also commonly used medications to treat PONV. Droperidol, haloperidol, metoclopramide, promethazine, and prochlorperazine can all be given for PONV prevention and treatment. All share (as do the 5-HT3 blockers) a concern regarding provocation of arrhythmias in susceptible patients; it is controversial how significant this may be at the low doses used for PONV treatment. The FDA placed a “black box warning” on droperidol, the most commonly used and well-researched anesthesia PONV drug, in 2001, cautioning against its use without careful monitoring. Promethazine and prochlorperazine are effective but sedating. Metoclopramide’s efficacy for PONV is not as well established.

Guimaraes2e-ch019-image007 — FIGURE 19.7. Scopolamine, a skin patch applied preop as part of a prevention plan for postoperative nausea and vomiting.

Guimaraes2e-ch019-image008 — FIGURE 19.8. Dexamethasone, a steroid that helps prevent, but does not treat, PONV.

Guimaraes2e-ch019-image009 — FIGURE 19.9. Ondansetron, an antiemetic.

Review Questions

1. Which of the following medications is commonly administered for procedural sedation when ventilation is a concern, due to its ability to produce sedation without significant respiratory depression?

A) Etomidate

B) Propofol

C) Fentanyl

D) Dexmedetomidine

E) Methohexital

Answer: D

Dexmedetomidine is a highly selective alpha2 agonist. A key property of this medication is its ability to produce sedation without significant respiratory depression, making it a popular choice for procedures like awake fiberoptic intubation.

2. Which sedative hypnotic medication is commonly used for the induction of anesthesia in unstable patients due to its ability to maintain blood pressure and cardiac output?

A) Propofol

B) Ketamine

C) Dexmedetomidine

D) Midazolam

E) Fentanyl

Answer: B

The hemodynamic effects of ketamine make it a favorable medication for many unstable patients. Blood pressure and cardiac output are usually maintained. Respiratory drive and airway reflexes are preserved as well. Propofol commonly reduces blood pressure and cardiac output. Dexmedetomidine is a sedative hypnotic but not an induction agent and is not typically given in bolus doses. Midazolam can be given for the induction of anesthesia and can maintain blood pressure and cardiac output, but it is inadequate to do these things as a sole induction agent even in an unstable patient. Fentanyl does not produce amnesia and is not a sedative-hypnotic agent.

3. Which of the following sedative-hypnotic medications decreases the threshold for seizure activity and is therefore commonly used for sedation in electroconvulsive therapy (ECT)?

A) Midazolam

B) Valium

C) Dexmedetomidine

D) Methohexital

E) Thiopental

Answer: D

Methohexital is one of the few sedative-hypnotic medications that decreases the threshold for seizure activity; therefore, it is commonly used to produce hypnosis for ECT.

4. Of the following medications, which prevents, but does not treat, postoperative nausea and vomiting (PONV)?

A) Ondansetron

B) Promethazine

C) Scopolamine

D) Dexamethasone

E) Droperidol

Answer: D

Dexamethasone prevents, but cannot treat, PONV. Scopolamine treats and prevents PONV but because of its transdermal route, it is delayed significantly in onset, making it best for placement in the preop area. However, if a patient is in the PACU with intractable vomiting, placement of a scopolamine patch may well be of assistance, even if the onset is delayed. (The patient will still need effective antiemetic therapy on board 2 hours later, especially for a nauseating drive home.)

Promethazine and droperidol are both dopaminergic antagonists that can be used for prevention or treatment; a primary difference between the two is that droperidol is currently under an FDA “black box warning” advising that it may be high risk for causing arrhythmias. Ondansetron is a 5-HT3 receptor antagonist. This class of medications blocks a subtype of the serotonin receptor, and can be used to prevent or treat PONV.

5. Which of the following is an opioid medication with a long half-life, appropriate for use at the end of a surgical procedure or in the recovery unit for postoperative pain?

A) Sufentanil

B) Remifentanil

C) Morphine

D) Alfentanil