Analgesics, Tranquilizers, and Sedatives

Analgesics, Tranquilizers, and Sedatives

CHAPTER

Kristina R. Sullivan, William B. Cammarano, Jeanine P. Wiener-Kronish Opioid Analgesics

The coronary care unit (CCU) has evolved drastically over the past several decades from an area primarily limited to the management of the acute coronary insufficiency patient to a full-fledged cardiac intensive care unit (CICU) concerned with a multitude of life-threatening cardiovascular diseases. With this development has also occurred the parallel need for more adequate and flexible analgesia and sedation because many of these critically ill patients undergo invasive procedures, such as balloon angioplasty and placement of intra-aortic balloon pumps, pulmonary artery catheters, and ventricular assist devices. In addition, many require long-term mechanical ventilation. The goal of therapy in the CICU is frequently more complicated than the simple relief of myocardial ischemia or infarction pain and the anxiety that accompanies it. For example, today's CICU practitioner is more likely to encounter an older and frailer patient, and although the elderly may benefit greatly from analgesic or sedative medications, they are also more likely to suffer the side effects of these medications.1 Likewise, CICU practi­tioners  today are likely to encounter patients who require sedation for long-term ­mechanical ventilation. Only a few decades ago, the options for analgesic and sedative therapy in the CICU were essentially limited to the narcotic morphine sulfate and the benzodiazepine chlordiazepoxide. Since that time, many new agents have been developed for the treatment of pain, anxiety, and delirium, and these often possess more desirable pharmacokinetic and pharmacodynamic properties than their predecessors. Although some of the older agents, especially morphine, have retained clinical usefulness because of their unique and beneficial pharmacokinetic and hemodynamic properties, many agents have been replaced by new drugs that have improved efficacy and safety. This chapter describes the analgesic and sedative agents available for use in the critical care setting, with special attention paid to those drugs of greatest usefulness in the CICU. Intramuscular and other injection routes of administration are not discussed here because the absorption, bioavailability, and pharmacokinetic properties of agents not administered by intravenous injection are highly unpredictable in critically ill patients. Agents used specifically for the induction of anesthesia also are not discussed in detail. Readers are referred to more standard anesthesia texts for information regarding these drugs. Within each classification of medication discussed, basic mechanisms of drug function (e.g., receptor physiology, site of action) are reviewed, and the pharmacokinetics and pharmacodynamics of each agent are discussed. Clinical uses of the

41

Antipsychotic Agents

agents, with special attention paid to those indications most germane to the CICU, are addressed. Finally, established agents that have found new clinical applications in the CICU patient are described.

Opioid Analgesics Morphine History and Structure Morphine has been used for analgesia and sedation for many centuries, but it has only been used by the intravenous route for approximately 150 years.4 Morphine is the only naturally occurring opiate agent obtained from the poppy plant, Papaver somniferum, still used with frequency in the critical care setting. Its proper chemical class is the phenanthrene group, which it shares with the agent codeine.5 Morphine occurs in essentially a rigid, pentacyclic type of structure. Site of Action and Receptor Physiology Since the first description of the opiate receptor in 1973, the mechanism for sedation and pain relief has been investigated.6 The initial system included only the μ-receptor; since then, a number of different opiate receptors have been discovered and named, including β-, к-, σ-, and ε-receptors (Table 41-1).7-9 Additional investigations have shown that the μ-receptor system actually includes two subtypes: the μ1-receptor and the μ2-receptor. Although research is ongoing, it appears that the μl-receptor is responsible primarily for analgesia and sedation, whereas the μ2-receptor may be responsible for euphoria and addiction in addition to analgesia.9,10 Both the δ- and к-receptors may be responsible for mediating respiratory depression. The σ-receptor seems to be related to those physiologic responses usually associated with acute withdrawal syndromes, specifically dysphoria, hallucinations, mydriasis, tachycardia, and hypertension.11 Based on these findings, opioid agents have been designed as selective agonists of certain receptors to maximize beneficial physiologic effects while minimizing deleterious ones. The greater μ-specificity of the synthetic opioid fentanyl compared with morphine is an example. Furthermore, agents with partial antagonist properties (e.g., nalbuphine) have been designed to simultaneously act on several opiate receptors, in this case the к- and μ-receptors, to prevent respiratory depression while allowing analgesia. The different opiate receptors are located in diverse anatomic sites throughout the central nervous system so it is apparent

Analgesics, Tranquilizers, and Sedatives Table 41-1.  Characteristics of Opioid Receptors Tissue Bioassay

Agonists

Major Actions

Mu1

Guinea pig ileum

Morphine Meptazinol Phenylpiperidines

Analgesia Bradycardia Sedation

Mu2

Guinea pig ileum

Morphine Phenylpiperidines

Respiratory depression Euphoria Physical dependence

Delta

Mouse vas deferens

d-Ala-d-Leu Enkephalin

Analgesia (weak) Respiratory depression

Kappa

Rabbit vas deferens

Ketocyclazocine Dynorphin Nalbuphine Butorphanol

Analgesia (weak) Respiratory depression Sedation

SKF 10.047 Pentazocine

Dysphoria-delirium, mydriasis Hallucinations Tachycardia Hypertension

β-Endorphin

Stress ­response Acupuncture

Receptor Mu

Sigma

Epsilon

Rat vas deferens

Adapted from Bailey PL, Stanley TH: Narcotic intravenous anesthetics. In Miller RD (ed): Anesthesia, 3rd ed, vol 1. New York, Churchill Livingstone, 1990, p 281.

that anatomy and receptor type dictate the pharmacodynamic effects of opiate agents. Whereas opiate receptors are located in a number of distinct areas in the brain and spinal cord, the highest density of receptors is located in the substantia gelatinosa of both the cerebral cortex and spinal cord, the periaqueductal gray areas, the thalamus, and the hippocampus.12 Of these areas, laminae II through V of the substantia gelatinosa and the periaqueductal gray areas appear to have the highest concentrations of μ-receptors and hence the greatest input with respect to analgesia. As a general rule, the gray matter of the central nervous system contains more opiate receptors than does the white matter.13 Pharmacokinetics, Pharmacodynamics, and Metabolism Morphine has a rapid initial redistribution phase of 1 to 1.5 minutes and an initial elimination half-life (t1/2α) of 10 to 20 minutes. Its terminal elimination half-life (t1/2β) is much longer (between 2 and 4.5 hours).14 Morphine is unique compared with the other commonly used opioid agents in that it has relatively low lipid solubility (Table 41-2). Interestingly, the shape of the morphine elimination curve is nearly identical to that of fentanyl, even though it is well known that the clinical behavior of the two drugs (e.g., onset time, offset time, duration of action) is quite different. This is explained by the following comparison between fentanyl and morphine, which is intended to illustrate how two drugs with similar pharmacokinetic properties can have different pharmacodynamic profiles. Compared with fentanyl, morphine has low lipid solubility (it is approximately 40 times less lipid soluble than fentanyl) and therefore has slow penetration of the blood-brain barrier.5 In contrast, the high lipid solubility of fentanyl allows rapid penetration of the blood-brain barrier, which leads to a peak effect within several minutes. Conversely,

it is this same property (lipid solubility) that allows fentanyl's rapid redistribution away from the brain and hence its short duration of action. Morphine, with its greater water solubility, crosses the blood-brain barrier much more slowly than fentanyl, resulting in a slower time to peak effect (20 to 30 minutes; Fig. 41-1). Similarly, once morphine has entered the brain, its lower lipid solubility prevents rapid redistribution and hence allows a longer clinical duration of action than fentanyl. Even though morphine appears to be pharmacokinetically similar to fentanyl, it typically has a slower onset time and longer duration of action. Morphine is metabolized by both the liver and the kidneys. Although the liver is responsible for the majority of its metabolism, 40% is metabolized by the kidneys.15 The major metabolic byproduct of morphine metabolism is morphine-3-glucuronide, which is known to have intrinsic opiate activity roughly one half that of morphine.16 When using morphine in patients with renal failure, the presence of this compound is important because cases of prolonged sedation do occur.17,18 Cardiovascular and Hemodynamic Effects For many years, morphine has been used in the management of acute myocardial ischemia and infarction pain and for sedation in patients with underlying myocardial disease.19 Morphine has distinct pharmacodynamic and hemodynamic ­properties that make it advantageous in cardiac patients. Perhaps the most important of these is morphine's ability to decrease venous and arterial tone.20,21 It appears that the increase in venous capacitance produced by morphine is relatively greater than the decrease in arterial resistance.22 This effect on venous capacitance is dose-related, and with large doses it is possible to decrease preload to the point of hypotension.23 In certain cardiac patients, a modest decrease in preload, as occurs with a dose of 505

41

Pharmacologic Agents in the CICU Table 41-2.  Physicochemical and Pharmacokinetic Data of Commonly Used Opioid Agonists

pKa

Morphine

Meperidine

Fentanyl

Sufentanil

Alfentanil

8

8.5

8.4

8

6.5

Percent un-ionized at pH 7.4

23

<10

<10

20

90

Octanol/H2O partition coefficient

1.4

39

813

1778

145

Percent bound to plasma protein

20-40

70

84

93

92

t1/2π (min)

1-2.5

1-2

1-2

1-3

t1/2α (min)

10-20

5-15

10-30

15-20

4-17

t1/2β (hr)

2-4

3-5

2-4

2-3

1-2

Vdoc (L/kg)

0.1-0.4

1-2

0.5-1.0

0.2

0.1-0.3

Vdss (L/kg)

3-5

3-5

3-5

2.5-3

0.4-1

Clearance (L/min/kg)

15-30

8-18

10-20

10-15

4-9

Hepatic extraction ratio

0.8-1

0.7-0.9

0.8-1

0.7-0.9

0.3-0.5

Abbreviations: t1/2π, first distribution half-life; t1/2α, second distribution half-life; t1/2β, elimination half-life; Vdcc, volume of distribution at central compartment; Vdss, volume of distribution at steady state. Adapted from Bailey PL, Stanley TH: Narcotic intravenous anesthetics. In Miller RD (ed): Anesthesia, 3rd ed, vol 1. New York, Churchill Livingstone, 1990, p 281.

doses are given (discussed later).5 Finally, the net chronotropic effect of morphine is to slow the heart rate under usual conditions. The exact mechanism by which morphine achieves this action is not certain, but it is thought to involve both a stimulation of the central vagal nucleus and a direct depressive effect on the sinoatrial node.25,26 Morphine has also been observed to secondarily increase heart rate by causing histamine release (discussed later).

2.0

Morphine conc. ( g/mL or g/g)

1.0 0.5

Brain

0.1 0.05

Serum

30

60

120

180

240

Time (minutes) Figure 41-1.  Serum and brain decrement curves in normocarbic dogs show the relationship of morphine concentrations in the brain to morphine concentrations in serum. Serum and brain morphine decrement curves intersect at approximately 1 hour. Vertical bars are standard error (n = 7). (From Nishitateno K, Ngai SH, Finck AD, Berkowitz BA: Pharmacokinetics of morphine: concentrations in the serum and brain of the dog during hyperventilation. Anesthesiology 1979;50:520-523.)

intravenous morphine, is desirable. It appears that in the dosages commonly used in the critical care setting, morphine has no direct effect on the inotropic state of the heart.24 An exception to this is the negative inotropic state caused by histamine release when morphine is administered rapidly or when large 506

Side Effects, Complications, and Toxicity Many of morphine's side effects are dose-related and can be minimized by reducing the size of doses administered to patients. The most important and potentially dangerous side effect of morphine administration is respiratory depression. The opiate agonists all share the ability to depress ventilation; this is primarily accomplished by decreasing the central ventilatory response to CO2.5 Specifically, the ventilatory response curve to an increasing Paco2 is shifted to the right, and the slope is decreased (Fig. 41-2). This means that for a given rise in Paco2, the patient compensates with a less-than-expected minute ventilation rate.5 The typical breathing pattern is one of slow respiratory rate with preserved or even increased tidal volume. This effect is dose-related, and although apnea can occur with high doses, it is usually preceded by a period of progressive hypoventilation and therefore can be identified early and prevented. The central nervous system side effects of morphine include drowsiness, lethargy, and potentially excessive sedation. In addition to the direct central respiratory depression described previously, excessive sedation with morphine can worsen ­respiratory compromise by causing upper airway obstruction and obstructive apnea. Euphoria with morphine use has been noted but is less common than that occurring with some other opioid agents. Dysphoria can also occur. As in respiratory depression, the central depressant effects are dose-related and progressive. The other organ systems most commonly affected by morphine (or any of the opioid agents) are the gastrointestinal (GI)

Analgesics, Tranquilizers, and Sedatives 30 Control Alveolar ventilation (L/min)

25 30 minutes after 15 mg morphine IV

20 15 10

30 minutes after 30 mg morphine IV

5

40

50

60

70

Alveolar PCO2 mmHg Figure 41-2.  Ventilatory responses to CO2. In control subjects, increases in alveolar Pco2 produce increases in alveolar ventilation. After morphine administration, the response to CO2 is shifted to the right, and the slope of the response is decreased.

and genitourinary (GU) systems. Morphine has many GI effects, including nausea, emesis, constipation, generalized slowing of the GI tract, and spasm of the sphincter of Oddi. Morphine has been reported to cause urinary retention by increasing urethral sphincter and detrusor tone.27 Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone is also occasionally seen with the administration of large doses of morphine.28 When morphine is given to patients with renal failure, prolonged narcotic effect from the accumulation of the active metabolite morphine-3-glucuronide can cause excessive sedation or respiratory depression.17 Although true allergic reactions to morphine are quite rare, morphine is known to cause the release of histamine.29 The release of histamine is from mast cells rather than the basophils, and the mechanism, although not thoroughly understood, is nonimmunologic.30 The release of histamine can lead to a warm flushing sensation, intense pruritus, hypotension, and tachycardia. When hypotension related to histamine release occurs, treatment includes discontinuing morphine infusion, ruling out other causes of anaphylactic or anaphylactoid type of reactions, administering intravenous fluids for hypotension, and ­administering histamine type 1 and type 2 blocking agents.5 One study has demonstrated that pretreatment with histamine type 1 and type 2 receptor antagonists in patients who have received morphine and tubocurarine (another agent associated with histamine release) significantly decreases hypotension when compared with similar patients pretreated with a placebo, although skin flushing was not reduced.30 Other side effects, including respiratory depression, sphincter of Oddi spasm, excessive sedation, and pruritus, can be reversed by the administration of the opiate antagonist naloxone. By titrating small doses of naloxone, it is possible to reverse the side effects of morphine without completely reversing the analgesia. It is prudent to avoid giving large doses of naloxone to cardiac patients because complete reversal of opiate effect can result in dangerous increases in sympathetic tone and, rarely, has been reported to cause ­pulmonary edema.31

Clinical Indications The main reason to administer intravenous morphine in the CICU is to produce analgesia and sedation, especially in the setting of acute myocardial ischemia or infarction or acute cardiogenic pulmonary edema. As mentioned previously, the acute venodilatory effects of intravenous morphine, combined with its analgesic and sedative properties, make it useful in cardiac patients. In contrast to fentanyl, morphine, with its long clinical duration and low lipid solubility, is best suited to administration by intermittent boluses rather than continuous infusion. Morphine may best be avoided altogether in the hemodynamically unstable patient because it is more likely to induce hypotension than is fentanyl. Fentanyl History and Structure Fentanyl and meperidine are probably the best known of the synthetic opioid analgesic agents. These agents, along with sufentanil and alfentanil, are members of the phenylpiperidine class of opiate agents. They are named for the phenylpiperidine skeleton in their chemical structure.5 In terms of analgesic properties, fentanyl is approximately 80 times more potent than morphine because of its greater affinity for the μ-opiate ­receptor.15 Fentanyl was introduced in 1959 and has been in clinical use since the early 1960s, when it was first used in a combination preparation with the butyrophenone agent droperidol (Innovar) for the technique of neuroleptanesthesia.32,33 For many years, fentanyl was used almost exclusively in the operating room by anesthesiologists because of safety concerns related to its high potency and rapid onset. In the past few decades, fentanyl has found greater use as an analgesic and sedative in the critical care setting. Pharmacokinetics, Pharmacodynamics, and Metabolism The initial redistribution half-life for fentanyl is short (1 to 2 minutes), the t1/2α is longer (10 to 30 minutes), and the t1/2β is 2 to 4.5 hours.14 Therefore, pharmacokinetically, fentanyl behaves similarly to morphine; this fact is supported by the nearly identical elimination curve shared by the two drugs. Fentanyl is approximately 40 times more lipid-soluble than morphine, leading to significant differences in the pharmacodynamics between these two drugs. Fentanyl's great lipid solubility allows rapid entry of this drug into the brain, causing a peak effect minutes after a bolus administration.5 Peak effect parallels the serum level for this agent.14 As a corollary, fentanyl redistributes away from the brain very quickly, resulting in a short clinical duration of action of only 30 to 60 minutes after a bolus dose. For these reasons, fentanyl administered by constant infusion leads to more consistent analgesia.34 Prolonged narcotic effect may be observed with fentanyl after prolonged infusions or frequent bolus dose administration.35 The reason for this prolongation of half-life with long-term infusion of fentanyl is thought to be that the high lipid solubility of this agent allows absorption of large amounts of drug into poorly perfused fatty tissue. When this occurs, termination of effect no longer depends on redistribution but rather is dependent on the terminal half-life of the drug. In a situation analogous to that seen with prolonged infusions of sodium thiopental, fatty uptake leads to a prolonged t1/2β and a long clinical duration of effect.5,36,37 507

41

Pharmacologic Agents in the CICU

Fentanyl is metabolized primarily by the liver and somewhat by the kidney. Active metabolites of fentanyl are probably of minimal or no clinical significance.15 Cardiovascular and Hemodynamic Effects When used in analgesic doses, fentanyl has developed a reputation for causing minimal hemodynamic effects. It has been demonstrated that fentanyl does not have negative inotropic effects.38,39 Although its occurrence is unusual, fentanyl can cause hypotension. The etiologies of fentanyl-related hypotension are likely fentanyl-induced bradycardia and a decrease in central sympathetic tone. The cause of the bradycardia is thought to be direct stimulation of the central vagal nucleus by fentanyl.40 Furthermore, the magnitude of the bradycardia is believed to be related to both the total dose administered and the rate of infusion.5,40 Fentanyl is also known to cause hypotension indirectly by decreasing central sympathetic outflow.41 This mechanism is supported by the observation that patients with high basal levels of sympathetic tone are more likely to become hypotensive when given fentanyl.5 Patients with relative or absolute hypovolemia are more prone to hypotension after receiving fentanyl. Although fentanyl administration has minimal hemodynamic effects, it is important to note that reports have suggested that the combination of synthetic opioids and benzodiazepines, especially midazolam, can cause significant decreases in blood pressure.42 It is possible that lorazepam combined with fentanyl may cause less hypotension than does the combination of midazolam and fentanyl.43 Side Effects, Complications, and Toxicity The side effect and toxicity profile of fentanyl is similar to that of morphine, with several exceptions. The cardiovascular and hemodynamic effects of fentanyl have been discussed previously. The respiratory, central nervous system, GI, and GU side effects are similar to those previously discussed for morphine. The pharmacodynamic properties of fentanyl result in apnea and oversedation quickly; therefore, this drug should be used only in a monitored situation. Fentanyl does not release histamine from mast cells in humans.44 It has been rarely reported to cause true anaphylactic reactions in humans.5 The respiratory, GI, and GU side effects of fentanyl are responsive to treatment with the narcotic antagonist naloxone. The same cautions described for the use of naloxone with morphine also apply to its use with fentanyl. Clinical Indications There are few studies that formally address the role of fentanyl in the CICU. Although this is also technically true with morphine, that agent, in comparison with fentanyl, has a long history of safety and familiarity in the CICU. Furthermore, the beneficial hemodynamic effects of morphine in the setting of myocardial ischemia or acute cardiogenic pulmonary edema have also strengthened its role as the primary opiate analgesic-sedative for the cardiac patient. Even so, it appears that those properties that make fentanyl a desirable agent in the operating room also make it attractive in the critical care setting. Fentanyl's rapid onset and short duration of action make it a useful analgesic and sedative agent for invasive procedures, with the caveat that it must be administered by experienced personnel in a monitored setting. Pharmacokinetically, fentanyl is more suitable for constant-infusion administration than is morphine, and it can be 508

easily and rapidly titrated to the desired analgesic effect. During long infusions of fentanyl, t1/2β increases as poorly perfused tissues are saturated. Adjustments in infusion rate must be made to compensate for this effect to prevent an undesired prolonged narcotic effect. The resulting bradycardia seen after fentanyl administration is a beneficial effect in some medically managed cardiology patients. Finally, the more neutral hemodynamic profile of fentanyl may make it a better choice for analgesiasedation in the hemodynamically unstable patient. Benzodiazepines History and Structure The benzodiazepines, which are the most commonly used sedative agents in the critical care unit, have been in use for several decades. The first benzodiazepine, chlordiazepoxide, was formulated in 1955, but it was not noted to have sedative properties until 1957 and was not released for clinical use until 1959.45 Chlordiazepoxide was followed in 1959 by the synthesis of diazepam, in 1971 by the formulation of lorazepam, and in 1976 by the synthesis of midazolam.46,47 In addition to its unique pharmacologic properties (discussed later), midazolam is of great interest to intensivists and anesthesiologists in that it is the first benzodiazepine formulated primarily for use in anesthesia and the critical care setting. The benzodiazepines as a group are relatively small, lipid-soluble molecules that act as agonists at the benzodiazepine receptor.46 Site of Action and Receptor Physiology In 1977, 18 years after their clinical introduction, it was discovered that the site of action of the benzodiazepines was at a receptor complex that it shared with another important class of central nervous system depressants, the barbiturates.48 This receptor, named the BNZ receptor, along with the barbiturate receptor, forms part of a larger receptor system known as the γ-aminobutyric acid (GABA) receptor complex.14 The benzodiazepines act agonistically at this receptor. GABA, one of the primary inhibitory neurotransmitters of the human central nervous system, acts as an agonist at the GABA complex, causing a net influx of chloride ion into the cell, which results in hyperpolarization and resistance to excitation.49 It appears that there are two main GABA receptors in the central nervous system: a GABAa complex and a GABAb complex. The benzodiazepines appear to have their main activity at the GABAa complex.14 When a benzodiazepine binds at its BNZ receptor, the conformation of the GABAa complex is altered such that the binding of the neurotransmitter GABA is facilitated.46 Benzodiazepine receptors are found in greatest concentration in the olfactory bulb, cerebral cortex, cerebellum, hippocampus, substantia nigra, and inferior colliculus.46 Pharmacokinetics, Pharmacodynamics, and Metabolism In the United States, the three benzodiazepines most widely available for intravenous administration, and hence most commonly used in the CICU, are diazepam, lorazepam, and midazolam. Although these agents work similarly at the receptor level, they are quite different with respect to their pharmacology and physical properties (Table 41-3). For example, these agents differ in potency. Midazolam is roughly three times more potent than diazepam, whereas lorazepam is five times more potent than diazepam.46 In general, all three compounds are highly lipid soluble, but lorazepam is less so than diazepam or midazolam.50

Analgesics, Tranquilizers, and Sedatives Table 41-3.  Physicochemical Characterization of Three Benzodiazepines Diazepam

Lorazepam

Midazolam

Molecular weight

284.7

321.2

362

pKa

3.3 (20° C)

11.5 (20° C)

6.2 (20° C)

Water soluble

No*

Almost insoluble

Yes*

Lipid soluble

Yes,* highly lipophilic

Yes, ­relatively less ­lipophilic

Yes,* highly lipophilic

*pH dependent: pH >4 = lipid soluble, pH <4 = water soluble. Adapted from Sasajima M: Analgesic effect of morphine-3-glucuronide. Keio Ogaka 1970;47:421.

The initial t1/2α of these agents is similar: 1 to 2 minutes for midazolam and diazepam and about 3 minutes for lorazepam.51,52 The onset of peak clinical activity mirrors these half-lives; the slightly slower onset of lorazepam is related to its lower lipid solubility. The t1/2β is quite different among these three drugs and is related to a number of factors (discussed later). The absolute range in t1/2β is large; midazolam has a relatively short half-life of 2 to 3 hours, lorazepam has an intermediate half-life of 10 to 20 hours, and diazepam has a long half-life of 20 to 50 hours.46 The benzodiazepines are metabolized in the liver where the parent compounds undergo extensive biotransformation. This often results in metabolic products that have significant benzodiazepine activity. Diazepam, the archetypal compound, undergoes biotransformation to a number of products, two of which (oxazepam and desmethyldiazepam) are potent and longacting BNZ receptor agonists.14 This fact helps to explain the long t1/2β and prolonged sedative effect frequently seen with the use of diazepam.53 Lorazepam is also highly metabolized, but it appears that none of its metabolic compounds have significant activity and that these products are rapidly excreted by the kidneys.51 Midazolam is biotransformed to compounds known as hydroxymidazolams, but controversy exists regarding whether these compounds have any intrinsic benzodiazepine activity.54 As mentioned earlier, there have been many case reports of prolonged sedation from long-term use of diazepam, and this has been traditionally thought to be an effect of accumulation of active metabolites.53 There are reports of prolonged sedation with midazolam infusions. Several studies have shown a prolongation of t1/2β and duration of sedation with midazolam administration in elderly patients and in the critically ill.55,56 These studies have shown a prolongation of the elimination half-life of about 2.5 times; this is thought to be caused by several factors, including increased volume of distribution and extensive fatty tissue uptake after prolonged infusion (recall that midazolam is highly lipid-soluble). One study investigating the effect of prolonged midazolam infusions in critically ill patients found that the mean time from administration to awakening in patients with renal failure was approximately 44 hours (control, 13 hours), and the time to awakening in two patients with renal and hepatic failure was greater than 120 hours.57 Although these same principles could also theoretically apply to lorazepam, with its lower lipid-solubility and inactive metabolites, it appears less likely to cause prolonged sedation.14

Diazepam and lorazepam are water-insoluble and therefore require vehicles for intravenous injection. Diazepam injection is prepared with propylene glycol, alcohol, and benzyl alcohol as vehicles, whereas lorazepam is prepared with polyethylene glycol and benzyl alcohol vehicles.46 The specific toxicities of these agents are discussed later. Midazolam for injection is a simpler solution to commercially prepare and administer because of the drug's pH-dependent water solubility. A study of prolonged midazolam infusion in critically ill patients has noted a need for a progressive increase in dose that appears consistent with the development of acute benzodiazepine tolerance.58 A convincing model for acute benzodiazepine tolerance has also been developed in the dog, showing tolerance with very short-term, albeit high-dose, benzodiazepine exposure.59 The clinical significance of this phenomenon, especially with respect to how it may relate to benzodiazepine addiction in critically ill patients, is uncertain. Cardiovascular and Hemodynamic Effects With respect to hemodynamics, the benzodiazepines have a reputation of safety in patients with cardiac disease of various etiologies, especially coronary artery disease.60,61 High doses of these agents have been found to be safe for the induction of anesthesia in aortic stenosis patients.62 When administered alone, the benzodiazepines cause a mild decrease in arterial blood pressure, which is related to a decrease in systemic vascular resistance.46 Other cardiac indices are minimally affected, and it is believed that a maintenance of normal compensatory cardiovascular reflexes is responsible for this relative preservation in blood pressure.46 It is notable that midazolam has a more potent blood pressure-lowering effect than the other intravenous benzodiazepines.63 As was alluded to previously, it is known that when a combination of a benzodiazepine and an opioid agent are administered, there is a synergistic effect in lowering blood pressure.64 This effect appears to be super-additive and has been demonstrated with several different combinations of benzodiazepines and opioids. The effect appears to be related to a reduction in central sympathetic tone.65 With respect to agents commonly used in the CICU, this synergism has been demonstrated for the combinations of midazolam-fentanyl and lorazepam-fentanyl.66,67 Although the majority of these data are taken from the cardiac anesthesia literature and may be related to the high doses of these drugs routinely used in this setting, common sense dictates that care must also be practiced in the CICU when these combinations are used, even when the doses are significantly lower. Side Effects and Toxicity When used with care, the benzodiazepines are safe sedative agents, largely because of their high therapeutic index.14 The cardiovascular and hemodynamic effects of benzodiazepines were discussed previously. The main side effects of the benzodiazepines applicable to critical care populations are excessive sedation and respiratory depression. Excessive sedation is generally a dose-related phenomenon. It is of greatest concern in the scenario of awake sedation in the nonintubated patient, when it may lead to inability to protect or maintain a patent airway. Central respiratory depression occurs with the benzodiazepines, but again, it appears to be a dose-related phenomenon that is relatively infrequent with reasonable dosages. Although the benzodiazepines flatten the ventilatory response curve to 509

41

Pharmacologic Agents in the CICU

hypercarbia, they do not shift the curve to the right as do opioids.46,68 Apnea does occur with benzodiazepines, but it is most commonly seen with the administration of large doses, as in the induction of anesthesia, and is not common with lower sedative doses used in the CICU. Analogous to the blood pressure–lowering effect seen with opioid-benzodiazepine combinations, it is likely that these combinations also have a synergistic central respiratory depressive effect.46 The sedative and respiratory side effects of benzodiazepines can be reversed by the BNZ receptor antagonist flumazenil, which has a very high affinity for the BNZ receptor.69 Flumazenil has proved effective at acutely reversing benzodiazepine toxicity, but it must be used with caution. It has a relatively short elimination half-life compared with the longer-acting benzodiazepines; therefore, its reversal effect may be short-lived in comparison to the sedative effects of these agents, allowing the patient to become resedated after the flumazenil effect has terminated.46 Additionally, seizures and acute withdrawal symptoms have been reported in patients with benzodiazepine tolerance treated with flumazenil.70 The solvents used to provide an intravenous vehicle for the water-insoluble agents diazepam and lorazepam are known to cause phlebitis with peripheral intravenous injection.46 Propylene glycol toxicity has also been reported with high-dose intravenous diazepam administration.71 Recently, it has been found that the prolonged administration of benzodiazepines to critically ill patients, particularly lorazepam, was found to be an independent risk factor for the development of delirium.72 Furthermore, plasma concentrations of benzodiazepines, or other sedatives, did not correlate well with sedation scores, suggesting that the effects of the drug are influenced by other factors, including age.72a These reports should decrease practitioners’ enthusiasm for infusions of benzodiazepines in critically ill elderly patients. Clinical Indications The benzodiazepines have three main uses in the CICU: as anxiolytics, as sedatives for mechanically ventilated patients, and as anticonvulsants.58 Benzodiazepines are also useful for the treatment of acute alcohol withdrawal and may be useful in the treatment of acute cocaine intoxication.14 A secondary but beneficial property of the benzodiazepines in the critical care setting is amnesia, especially when painful invasive procedures or prolonged mechanical ventilation is necessary. Benzodiazepines do not, by themselves, have analgesic properties. Therefore, if painful procedures (e.g., placement of intra-aortic balloon pump or central lines) are anticipated, the benzodiazepines should be used in conjunction with an opioid analgesic. With respect to anxiolysis, the three commonly used benzodiazepines are equally efficacious and differ only with respect to their potency. The same statement also applies to their efficacy when used for sedation during mechanical ventilation. As discussed previously, because of its pharmacokinetic and pharmacodynamic properties, midazolam may be the best choice for long-term sedation in the mechanically ventilated patient if an intravenous infusion is to be used.58 All of the benzodiazepines are effective when used for the acute termination of seizures. It is believed that lorazepam may be the drug of choice in the termination of status epilepticus because its longer half-life allows treatment with another longer-acting anticonvulsant (i.e., phenytoin) to be begun before seizures can recur.72b 510

With respect to amnesia, all three of these agents appear to be efficacious. Lorazepam maintains a reputation for being a more potent amnestic than either diazepam or midazolam, but this is not fully supported by the literature. Lorazepam and midazolam have been compared in a randomized, controlled fashion with respect to anterograde amnesia, and it is clear that lorazepam provides a longer period of amnesia.73 Likewise, diazepam was compared with midazolam in a similar study that demonstrated that at equal doses, midazolam was a more potent amnestic agent74; however, the doses of midazolam and diazepam were equal but not equipotent in this study. Another study demonstrated the amnestic efficacy and safety of lorazepam when used for procedures in the critical care setting.75 It appears that flumazenil is not as effective at reversing the amnestic effects of the benzodiazepines as it is at reversing the other side effects.76 Propofol History and Structure Propofol is a unique hypnotic agent that was first introduced into clinical use in 1977.77 It has an alkylphenol structure that is water-insoluble at room temperature. Because of this waterinsolubility, propofol was first formulated in a Cremophor solution for anesthetic use, but was then changed to a lipid vehicle because of anaphylactic responses to cremophor.46,78 Since its introduction as an anesthetic agent, propofol has enjoyed progressively greater use in clinical areas outside of the operating room. Propofol is a rapid-acting, highly lipid-soluble central nervous system depressant with hypnotic and amnestic properties, but its exact site and mode of action are not fully understood. Pharmacokinetics, Pharmacodynamics, and Metabolism When administered by bolus or infusion, propofol follows a two-compartment pharmacokinetic model with a rapid t1/2α of 2 to 8 minutes and a slower t1/2β of 1 to 3 hours.79 A three-compartment model with a prolonged t1/2β of 4 to 7 hours has been postulated, implying uptake of propofol by poorly perfused fatty tissue.80,81 Although this would seem to imply that a prolonged period of sedation would occur with constant infusions (as is known to occur with fentanyl and midazolam, discussed previously), this does not seem to be the case with propofol. A study using propofol for sedation in mechanically ventilated CICU patients demonstrated a rapid time to extubation and full recovery (1 and 2 hours, respectively) in patients who were receiving infusions of propofol.82 This rather unique ability is thought to be related to extremely high clearance, which is higher than liver blood flow.79 Therefore, although propofol has high hepatic clearance, it appears that other routes of elimination must exist to explain its short clinical duration of action. It is postulated that respiratory elimination may be partially responsible for this phenomenon.83 Cardiovascular and Hemodynamic Effects The majority of the data regarding the cardiovascular and hemodynamic effects of propofol have been generated in the setting of general anesthesia or sedation for surgery. The most prominent effect of propofol on hemodynamics is a decrease in arterial blood pressure, and several studies have found the average decrease in systolic blood pressure with an induction dose of propofol to be in the range of 25 to 40 mm Hg.84,85 During the maintenance phase of anesthesia with propofol infusion

Analgesics, Tranquilizers, and Sedatives

(a situation more similar to propofol sedation in the CICU), systolic blood pressure was maintained at a level 20% to 30% below preinduction levels.84,85 This hypotension appears to be related to both peripheral vasodilation and a negative inotropic effect of the drug.46 Propofol infusions appear to decrease both myocardial blood flow and myocardial oxygen demand.86 These decreases are of roughly equal magnitude.46 Various chronotropic responses have been reported in patients receiving propofol, including an increase, a decrease, and no change in heart rate.86-88 Side Effects, Complications, and Toxicity Propofol is an agent of high potency that was previously used almost exclusively in the operating room by trained personnel (usually anesthesiologists) in a closely monitored setting. In many aspects, propofol behaves similarly to sodium thiopental. Propofol, like sodium thiopental, has a narrow therapeutic range between desired clinical effect and serious toxicity. The most serious of these side effects include arterial hypotension and central apnea; this apnea may be more prolonged than that seen with thiopental.89 Propofol is a potent compound with a narrow therapeutic index and several dose-related effects, which if managed incorrectly, are potentially life-threatening. Propofol use should be limited to experienced personnel in a closely monitored setting. If propofol is used in nonintubated patients, it can lead to apnea or airway obstruction. Additionally, patients anesthetized with propofol have reported intense dreams in the immediate postoperative period.90 Patients emerging from propofol anesthesia have also been observed to commonly display adventurous or merry behavior compared with patients who have been anesthetized with thiopental.91 Dystonic or choreiform movements not associated with abnormal EEG activity are observed in patients anesthetized with propofol.92 An irritating side effect of propofol is pain at the site of infusion. This can be prevented by avoiding infusion into small hand veins.93 Phlebitis is also occasionally seen.46 Another important possible toxicity is seen after infusion of propofol: the propofol infusion syndrome, PRIS, is associated with some or all of the following: metabolic acidosis, refractory heart failure, progressive and refractory bradycardia, fever, lipemia, and increased creatine phosphokinase, myoglobinemia, and/or myoglobinuria.93a The maximum recommended dose from the manufacturer is 4 mg/kg/hr for adults and all reported cases of PRIS apparently received higher doses than this.93b Propofol infusions are no longer used in many pediatric intensive care units because of PRIS,93c and all practitioners have been encouraged to adhere to the maximum limits suggested and to be watchful for signs of PRIS.93b Clinical Indications The two most common indications for propofol in the CICU have been sedation for elective electrical cardioversion and sedation for mechanical ventilation.94 A study comparing propofol, methohexital, and midazolam as sedatives for the elective electrical cardioversion of patients with supraventricular arrhythmias demonstrated that all three agents were efficacious, but that time to awaken was much more rapid in the propofol and methohexital groups.95 It is notable that in this study two patients in the propofol group experienced recall of their cardioversion, whereas no patients in the methohexital or midazolam treatment groups reported awareness. Although hemodynamics

were well maintained in this group of stable patients, it seems prudent to avoid the use of propofol in the setting of cardioversion accompanied by hemodynamic instability because of propofol's known cardiovascular depressive effects. There have been no randomized, controlled studies specifically investigating the safety or efficacy of propofol for sedation in the CICU patient. There are, however, a number of studies addressing its use in the medical-surgical intensive care unit (ICU) patient96-101 and in the postoperative cardiac surgery patient.102-105 The experience from these studies suggests that when propofol is used in sedative doses ranging between 3 and 50 μg/kg/min, there is excellent patient tolerance and minimal side effects. In a study directly comparing propofol and midazolam for short-term sedation of mechanically ventilated patients after coronary artery bypass graft (CABG) surgery, there was no difference in the number of hypotensive episodes during the maintenance phase of the study, although there was a significantly higher number of hypotensive episodes in the propofol group during propofol loading.105 In addition, despite the mild to moderate degree of hypotension that accompanies the use of this agent, ICU patients sedated with propofol appear to have no compromise in oxygen transport.101 Furthermore, in a study by Stephan and colleagues,86 patients treated with propofol were found to have a parallel and equal decrease in myocardial oxygen supply and demand, implying that this agent may be safe in the setting of coronary artery disease. Despite the fact that propofol is not noted to possess analgesic properties, ICU patients sedated with propofol were noted to have a lower supplemental narcotic requirement than patients sedated with midazolam.99,105 Several studies including patients sedated for prolonged periods show a significantly more rapid awakening time and time to extubation with propofol than with midazolam.82,95 In a study by Carrasco and colleagues,82 the time to extubation in ICU patients treated with propofol was 2 hours as opposed to 37 hours in patients sedated with midazolam for more than 7 days. This experience has not been universal, and in two studies comparing propofol with midazolam in postoperative CABG patients, there was no significant difference in time to extubation.102,105 It is notable that in these studies, the duration of sedation was relatively short, perhaps preventing the fatty tissue uptake of midazolam, which seems to result in the pharmacodynamic changes responsible for prolonged sedation with this agent (discussed previously). The absolute mechanism by which patients awaken so rapidly after prolonged propofol infusions is not clear because several studies have shown a dramatic increase in t1/2β when these agents are infused for long periods.98,100 Even so, Bailie and colleagues100 showed an impressive decrease in plasma propofol level of 50% in the first 10 minutes after termination of propofol infusions in critically ill patients sedated for a mean of 86 hours. Propofol infusions for mechanically ventilated patients provide a good option in the area of critical care and sedation. In terms of applicability to the cardiology patient, the published experience is limited. Experience in the medical-surgical and postoperative CABG patient population suggests that this ­therapy is safe and efficacious. As described previously, the literature suggests that propofol's main advantage over standard sedative agents is rapid awakening, but this improvement in time to awakening may only be significant in patients treated with prolonged infusions. In addition, there is a general ­consensus 511

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in the literature that the minute-to-minute control of sedation is improved with propofol compared with standard sedative agents.94 The available literature supports the use of sedative doses of propofol in the CICU for mechanical ventilation only. Dexmedetomidine History and Structure Dexmedetomidine is the active dextro-isomer of medetomidine and is a highly selective α-adrenergic receptor agonist. The α2-adrenergic agonist class of drugs can be divided into three groups: imidazolines, phenylethylamines, and oxalozepines. Clonidine, a more commonly used α2-agonist, and dexmedetomidine are both imidazole compounds. They exhibit a high ratio of specificity for the α2- versus the α1-receptor. Dexmedetomidine has eight times the potency as clonidine at the α2-receptor, and therefore is considered a full agonist at the α2-receptor.106 As an α2-adrenergic agonist, dexmedetomidine exhibits sedative, anxiolytic, and analgesic properties.107 It was granted FDA approval in December of 1999 for use as a short-term sedative (<24 hours) in ICU patients. Site of Action and Receptor Physiology Dexmedetomidine works at α2-receptors both peripherally and centrally. The sedative and anxiolytic effects of the drug are mediated through stimulation of central α2-receptors. Activation of these receptors attenuates central nervous system excitation, especially in the locus coeruleus.108 Stimulation of central α2-receptors also leads to a decrease in sympathetic outflow and augmentation of cardiac vagal activity.109 In addition, α2receptors modulate pain pathways within the spinal cord. Activation of the α2c-receptor subtype produces an analgesic effect by accentuating the action of opioids.3 Finally, α2-receptors are located on blood vessels and sympathetic terminals where they mediate vasoconstriction and inhibit norepinephrine release, respectively.109 Pharmacokinetics, Pharmacodynamics, and Metabolism Dexmedetomidine has an onset of action of approximately 15 minutes with peak concentrations reached within 1 hour following continuous infusion. It exhibits a rapid distribution phase with a t1/2α of approximately 6 minutes and a t1/2β of approximately 2 hours. The drug is highly protein bound and has a large volume of distribution.110 Dexmedetomidine is highly metabolized by the liver. It undergoes glucuronidation and cytochrome P450 mediated metabolism. Therefore, patients with severe hepatic insufficiency may require lower doses of dexmedetomidine.110 The by-products of dexmedetomidine metabolism are excreted by the kidneys.111 Cardiovascular and Hemodynamic Effects The manufacturer's recommended dose of dexmedetomidine is 1 μg/kg loading infusion over 10 minutes, followed by a continuous intravenous infusion of 0.2 to 0.7 μg/kg/hr.108 A bolus of dexmedetomidine (1 μg/kg over 10 minutes) may result in a transient increase in blood pressure and a reflex decrease in heart rate, especially in young patients.112 This response is likely related to direct vasoconstriction of peripheral vessels. Animal studies show that the pressor response to bolus doses of α2agonists is enhanced after autonomic denervation.110 In other words, when sympathetic inhibition from the central effects of α2-agonists are absent, the peripheral effects predominate, and 512

vasoconstriction leading to high blood pressure occurs.109,110 Alternatively, patients may experience profound hypotension and bradycardia with the bolus dose.112a Most intensivists simply start a continuous infusion of dexmedetomidine between 0.2 and 0.7 µg/kg/hr since omitting the bolus dose may avoid undesirable hemodynamic effects without compromising sedation.112b During a continuous infusion of dexmedetomidine (0.2 to 0.7 µg/kg/hr), patients typically experience a slight decrease in blood pressure, heart rate, and cardiac output.109 Sympatholysis from dexmedetomidine is involved in decreasing the heart rate as evident by the fact that patients taking β-blockers do not experience heart rate slowing.109 Side Effects, Complications, and Toxicity Giving a bolus dose of dexmedetomidine before initiation of a continuous infusion may cause hypertension or hypotension and bradycardia as noted above. Patients may experience hypotension and bradycardia during the continuous infusion of dexmedetomidine as well. This hypotension may be more severe in patients who are hypovolemic. Significant bradycardia and sinus arrest may occur in patients with high vagal tone or during rapid intravenous or bolus administration. Dexmedetomidine should be avoided in patients with advanced heart block and ventricular dysfunction because bradycardia and hypotension may be more pronounced.111 Doses of the drug should be reduced in patients with hepatic impairment because the drug is highly metabolized by the liver. As noted above, the metabolites are excreted in the urine, and although the effects of the metabolites have not been studied, cautious dosing with renal failure may be prudent because these metabolites may accumulate. Mild respiratory depression is seen with bolus dosing of dexmedetomidine. This likely occurs as a result of sedation and is not due to any direct respiratory effects of the drug.109 Clinical Indications Dexmedetomidine is FDA approved for use as a sedative in the intensive care unit for less than 24 hours duration. Studies in intensive care patients have shown that compared with propofol, dexmedetomidine produces similar levels of sedation and time to extubation with less opioid requirements.108 One study by Herr and colleagues examined dexmedetomidine versus propofol-based sedation regimens in post–coronary artery bypass graft patients. The results showed that dexmedetomidine provided safe and effective postoperative sedation in this patient population and reduced the need for analgesics, β-blockers, antiemetics, epinephrine, and diuretics.112c Since dexmedetomidine provides sedation without decreasing respiratory drive, it can be used as a sedative during weaning from mechanical ventilation and throughout the extubation period. This can be particularly useful in anxious patients who otherwise might require large doses of propofol or benzodiazepines to tolerate the endotracheal tube during spontaneous breathing trials. In addition, dexmedetomidine may be beneficial in patients who have a high tolerance to opioids. Finally, current studies are evaluating whether dexmedetomidine is associated with less delirium than other types of sedatives. In the cardiac care unit, many patients may have pre-existent bradycardia, cardiac conduction problems, or reduced ventricular ejection fractions. Patients may also be hypotensive or hypovolemic for a variety of reasons. Caution should be used in choosing dexmedetomidine as a sedative in these patient

Analgesics, Tranquilizers, and Sedatives

­ opulations. The risk of the side effects may outweigh the benp efits in some patients.

Antipsychotic Agents The occurrence of delirium in the intensive care unit is associated with adverse outcomes including lengthened ICU and hospital stay and increased 1-year mortality.113,114 Antipsychotic administration is broadly accepted as a treatment for delirium not associated with hypoglycemia, hypoxemia, or other treatable causes. The hope is that severity and duration of symptoms will be decreased.115,116 Two commonly used antipsychotic agents used to treat delirium in the critical care setting include haloperidol and olanzapine. Haloperidol Haloperidol is a member of the butyrophenone class of neuroleptic major tranquilizers. It has a moderately rapid rate of onset, with a t1/2α of 3 to 19 minutes and a t1/2β of 10 to 19 hours.14 It is a more potent neuroleptic compared with the phenothiazines, with less severe side effects. Haloperidol is reputed to have fewer extrapyramidal, anticholinergic, and α-blocking effects than the other commonly used major tranquilizers.118 In addition, respiratory depression is rare with this agent, as is hypotension.14 Initially developed as an oral neuroleptic agent, haloperidol has gained favor as an intravenous agent for the acute treatment of psychosis and delirium in the critically ill medical patient.119 The intravenous route of administration seems to decrease the incidence of extrapyramidal side effects compared with the usual oral route of administration.120 Intermittent bolus administration with rapid bolus escalation is recommended and commonly used to treat acute delirium.14 Standard doses range from 2 to 10 mg administered every 10 to 15 minutes until the desired effect is obtained. If around the clock dosing is desired the patient may be started on a divided intravenous dose based on the loading dose.14 Although haloperidol is an effective agent for the treatment of delirium it is not without serious side effects that may adversely affect CICU patients. A prolonged Q–T interval, torsades de pointes, ventricular arrhythmias, and cardiac arrest have been reported in patients treated with intravenous haloperidol.121,122 Daily electrocardiograms are warranted to follow the Q–T interval in all patients receiving haloperidol for the treatment of acute delirium. In addition to the cardiovascular effects, haloperidol may cause extrapyramidal effects, such as akathisia and oropharyngeal dysfunction.116,123 Neuroleptic malignant syndrome and dystonic reactions may also occur.118,124 In spite of these side effects, haloperidol has been investigated as a safe and efficacious treatment of agitation and delirium associated with the intra-aortic balloon pump.125 Olanzapine Olanzapine is a second-generation antipsychotic agent that belongs to the thiobenzodiazepine class. It is a selective monoaminergic antagonist with a high affinity for multiple receptors including serotonin 5HT2/2C and 5HT6, dopamine D1-4, ­histamine H1, and adrenergic α1-receptors. The mechanism of action of olanzapine is largely unknown.126 It is available in oral and intramuscular forms, but is more commonly given by mouth in the intensive care setting. The oral form of Olanzapine is well absorbed with good bioavailability. It reaches

peak ­concentrations in approximately 6 hours and its t1/2β is approximately 21 to 54 hours. The drug undergoes direct glucuronidation and cytochrome P450 mediated oxidation. Renal dysfunction does not likely impact pharmacokinetics. 126 If a patient is able to take medications by mouth it is a good alternative to haloperidol for the treatment of ICU delirium, and in fact may be better tolerated with fewer side effects. In one study of olanzapine versus haloperidol, the group taking olanzapine had no extrapyramidal side effects. 116 The drug is typically administered orally in doses that range from 5 to 10 mg daily. 126 Side effects of olanzapine include orthostatic hypotension that is likely the result of antagonism of adrenergic α1-receptors. Q–T prolongation has been reported with atypical antipsychotics such as olanzapine, however, the occurrence rate is lower than that seen with haloperidol.127 Some studies indicate that olanzapine should be avoided in patients with dementia-related psychosis as there may be an increased risk of stroke and death compared to placebo.126,128 A recent prospective study, however, reported that neither the use of atypical antipsychotics nor the use of conventional neuroleptics increased mortality among elderly patients with dementia. 129 Nonetheless, olanzapine is not approved for the treatment of patients with dementiarelated psychosis and should be avoided in this patient population.126 Other side effects include hyperglycemia, neuroleptic malignant syndrome, and hyperlipidemia.

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