Aspiration is the inhalation of gastric or oropharyngeal contents into the lungs. Aspiration during general anesthesia occurs in approximately 1 in 8,500 adults and 1 in 4,400 children younger than 16 years of age.1 An earlier study of more than 56,000 patients younger than age 18 years identified an incidence of aspiration of approximately 1 in 2,600 anesthetics. The incidence was 1 in 4,500 patients undergoing elective procedures, but 1 in 400 undergoing emergency procedures. The authors commented that respiratory morbidity was rare and that there was no mortality associated with aspiration of gastric contents in this cohort.2 Previous studies in adults have noted that, in addition to emergency procedures (many in patients with bowel obstruction), patients with an American Society of Anesthesiologists physical classification of 3 or greater had an increased risk of aspiration, associated pulmonary complications, and death. This study noted that approximately one-third of cases of aspiration occurred during laryngoscopy and intubation, one-third occurred during extubation, and the other one-third presumably during the procedure.3
Factors associated with pulmonary complications of aspiration include the volume and acidity of the aspirated gastric contents. Drugs then that increase the pH of gastric contents (antacids) and that decrease the volume of gastric contents (prokinetic drugs) have a role in decreasing the severity of the sequelae of aspirating gastric contents. Enforcement of the American Society of Anesthesiologists Task Force Fasting Recommendations can also reduce the risk of pulmonary aspiration.4
Oral Antacids
Antacids are drugs that neutralize (remove hydrogen ions) from gastric contents or decrease the secretion of hydrogen chloride into the stomach. Oral antacids have been used for centuries. In current practice, the oral antacids used most often are salts of aluminum, calcium, and magnesium; the hydrogen ions in stomach acid react with the base, forming a stable compound. As hydrogen ions are consumed, the pH of the stomach contents increases. The best known example would be sodium bicarbonate, NaHCO3, which in the stomach would combine with HCl to produce NaCl, H2O, and CO2.
Increasing gastric pH relieves the symptoms of gastritis, but if the pH of the stomach is too high, digestion of food is inhibited as an acidic pH is necessary for the breakdown of many foods. In addition, increases in gastric fluid pH to >5 result in inactivation of pepsin and produce bile-chelating effects. Neutralization of gastric fluid pH increases gastric motility via the action of gastrin (aluminum hydroxide is an exception) and increases lower esophageal sphincter tone by a mechanism that is independent of gastrin.
NaHCO3 results in a prompt and rapid antacid action, so much so that the pH is raised to the point that the stomach’s pH is neutral, which can lead to acid rebound. Patients with hypertension or heart disease may not tolerate the increased sodium load associated with chronic use of this antacid.
Magnesium hydroxide (milk of magnesia) also produces prompt neutralization of gastric acid but is not associated with significant acid rebound. In contrast to aluminum hydroxide, a prominent laxative effect (osmotic diarrhea) is characteristic of magnesium hydroxide. Systemic absorption of magnesium may be sufficient to cause neurologic, neuromuscular, and cardiovascular impairment in patients with renal dysfunction. Renal dysfunction can also lead to the development of metabolic alkalosis in some patients.5
Calcium carbonate can also produce metabolic alkalosis with chronic therapy. The plasma concentration of calcium is increased transiently. Symptomatic hypercalcemia may occur in patients with renal disease. The administration of calcium carbonate–containing antacids may result in hypophosphatemia. Even small amounts of calcium carbonate–containing antacids evoke hypersecretion of hydrogen ions (acid rebound).6 The chalky taste of calcium carbonate is an additional disadvantage. The release of CO2 in the stomach may cause eructation and flatulence. Constipation is minimized by including magnesium oxide with calcium carbonate. Acute appendicitis has been reported due to impacted calcium carbonate fecaliths.
Aluminum hydroxide is actually a mixture of aluminum hydroxide, aluminum oxide, and some fixed CO2 as carbonate. Systemic absorption of aluminum is minimal, but in patients with renal disease, the plasma and tissue concentrations of aluminum may become excessive.7 Encephalopathy in patients undergoing hemodialysis has been attributed to intoxication with aluminum especially in patients who ingest solutions containing citrate.8 Aluminum compounds, in contrast to other antacids, cause slowing of gastric emptying and marked constipation. These effects, in addition to an unpleasant taste, contribute to poor patient acceptance.
Occasional failure of particulate antacids to increase gastric fluid pH may reflect inadequate mixing with stomach contents or an unusually large volume of gastric fluid such that the standard dose of antacid is inadequate to neutralize gastric hydrogen ions. Layering is also common with particulate antacids.9 Pneumonitis associated with functional and histologic changes in the lungs may reflect a foreign body reaction to inhaled particulate antacid particles.
Nonparticulate (clear) antacids such as sodium citrate are less likely to cause a foreign body reaction if aspirated, and their mixing with gastric fluid is more complete than is that of particulate antacids.9,10Furthermore, the onset of effect is more rapid with sodium citrate than with particulate antacids that require a longer time for adequate mixing with gastric fluid. Sodium citrate, 15 to 30 mL of a 0.3-mol per liter solution administered 15 to 30 minutes before the induction of anesthesia, is effective in reliably increasing gastric fluid pH in pregnant and nonpregnant patients.11
Complications of Antacid Therapy
The increase in urine and gastric volume pH resulting from antacid use has been associated with adverse events. Chronic alkalinization of gastric fluid has been associated with bacterial overgrowth in the duodenum and small intestine.12 Alkalinization of the urine may predispose to urinary tract infections; if it is chronic, urolithiasis is possible. Increased urine pH may persist >24 hours after administration of an antacid, leading to changes in the renal elimination of drugs.
Acid rebound is a side effect that is unique to calcium-containing antacids. This response is characterized by a marked increase in gastric acid secretion that takes place several hours after neutralization of gastric acid. It is unclear if acid rebound persists with chronic calcium carbonate treatment.
The milk-alkali syndrome is characterized by hypercalcemia, increased blood urea nitrogen and plasma creatinine concentrations, and systemic alkalosis, as reflected by an above-normal plasma pH. The plasma calcium phosphate concentration is usually increased. There may be a marked decrease in renal function with calcification of the renal parenchyma. This syndrome is most commonly associated with ingestion of large amounts of calcium carbonate along with >1 L of milk every day.
Phosphorus depletion can occur in patients who ingest large doses of aluminum salts because they bind phosphate ions in the gastrointestinal tract, thus preventing their absorption. This effect may actually be beneficial in patients with renal disease because it can decrease the plasma phosphate concentration, but, unfortunately, patients with chronic renal failure are at risk of developing toxicity from the aluminum. Individuals with hypophosphatemia may experience anorexia, skeletal muscle weakness, and malaise. Osteomalacia, osteoporosis, and fractures may occur. If it is necessary to administer aluminum-containing antacids on a chronic basis to patients with osteomalacia or osteoporosis, phosphate supplements should be considered.
Drug Interactions
Gastric alkalinazation increases gastric emptying, resulting in a faster delivery of drugs into the small intestine. This may facilitate absorption of drugs that are poorly absorbed or it may shorten the time available for absorption, depending on where in the gastrointestinal tract absorbtion occurs. There are many drugs whose absorption is enhanced by antacids.13 The rate of absorption of salicylates, indomethacin, and naproxen is increased when gastric fluid pH is increased. Aluminum hydroxide accelerates absorption and increases bioavailability of diazepam by an unknown mechanism. Conversely, bioavailability of certain drugs may be decreased because of their capacity to form complexes with antacids. For example, antacids decrease bioavailability of orally administered cimetidine by approximately 15%.14 Antacids containing aluminum, and to a lesser extent, calcium or magnesium, interfere with the absorption of tetracyclines and possibly digoxin from the gastrointestinal tract. It is possible based on physicochemical properties to predict the effect of changes in pH on absorption.
Histamine-Receptor Antagonists
Histamine induces contraction of smooth muscles in the airways, increases the secretion of acid in the stomach, and stimulates the release of neurotransmitters in the central nervous system (CNS) through three receptor subtypes, H1, H2, H3. Recently a fourth histamine receptor, designated as an H4 receptor was cloned,15 which has lead to the development of several drugs that inhibit its action.16–18
Depending on what responses to histamine are inhibited, drugs are classified as H1-, H2-, H3-, and H4-receptor antagonists. Histamine receptor antagonists bind to receptors on effector cell membranes, to the exclusion of agonist molecules, without themselves activating the receptor. For histamine-receptor antagonists, this is a competitive and reversible interaction. It is important to recognize that histamine-receptor antagonists do not inhibit release of histamine but, rather, attach to receptors and prevent responses mediated by histamine.
H3- and H4-receptor modulators do not currently play a role in anesthetic practice and as such are not described in detail. Activation of H3 receptors inhibits the synthesis and release of histamine from neurons in the CNS; as such, they act as presynaptic autoreceptors. The H4 receptor is expressed on mast cells, dendritic cells, basophils, and T lymphocytes. Activation of the H4 receptor induces chemotaxis of immune cells.17
H1-Receptor Antagonists
H1-receptor antagonists are characterized as first-generation and second-generation receptor antagonists (Fig. 35-1).19,20 First-generation drugs tend to produce sedation, whereas second-generation drugs are relatively nonsedating (Table 35-1). H1-receptor antagonists are highly selective for H1 receptors, having little effect on H2, H3, or H4 receptors. First-generation H1-receptor antagonists may also activate muscarinic, cholinergic, 5-hydroxytryptamine (serotonin), or α-adrenergic receptors, whereas few of the second-generation antagonists have any of these properties. The selectivity of the second-generation antagonists for H1 receptors decreases CNS toxicity. An increased understanding of the molecular pharmacologic features of these drugs has resulted in their reclassification as inverse agonists rather than as H1-receptor antagonists.19 H1-receptor antagonists act as inverse agonists that combine with and stabilize the inactive form of the H1 receptor, shifting the equilibrium toward the inactive state.
Pharmacokinetics
H1-receptor antagonists are well absorbed after oral administration, often reaching peak plasma concentrations within 2 hours (see Table 35-1).19,20 Many are highly protein bound, with ranges from 78% to 99%. Most of the new H1-receptor antagonists do not accumulate in tissue to any extent. Interestingly, there is little tachyphyllaxis seen with their use.21 Most H1-receptor antagonists are metabolized by the hepatic microsomal mixed-function oxidase system. Plasma concentrations are relatively low after a single oral dose, which indicates first-pass hepatic extraction. Values for the elimination half-lives of these drugs are variable. For example, the elimination half-life of chlorpheniramine is >24 hours and that of acrivastine is about 2 hours (see Table 35-1).19,20 Acrivastine is excreted mostly unchanged in urine, as is cetirizine, the active carboxylic metabolite of hydroxyzine.
Clinical Uses
H1-receptor antagonists are among the most widely used of all medications.19 H1-receptor antagonists prevent and relieve the symptoms of allergic rhinoconjunctivitis (sneezing, nasal and ocular itching, rhinorrhea, tearing, and conjunctival erythema), but they are less effective for the nasal congestion characteristic of a delayed allergic reaction. In contrast to their role in the treatment of allergic rhinitis, H1-receptor antagonists provide little benefit in the treatment of upper respiratory tract infections and are of no benefit in the management of otitis media. Depending on the H1-receptor antagonist selected and its dose, pretreatment may provide some protection against bronchospasm induced by various stimuli (histamine, exercise, cold dry air). Earlier concerns about drying of secretions in patients with asthma have not been substantiated. In patients with chronic urticaria, H1-receptor antagonists relieve pruritus and decrease the number, size, and duration of urticarial lesions. In some patients with refractory urticaria, concurrent treatment with an H2-receptor antagonist (cimetidine, ranitidine) may enhance relief of pruritus. In addition to a direct effect on H2 receptors, which account for 10% to 15% of all histamine receptors in the vasculature, this effect may be due in part to the ability of some H2-receptor antagonists to inhibit the metabolism of H1-receptor antagonists by the hepatic cytochrome P450 system, leading to an increased plasma and tissue concentration of H1-receptor antagonists. The second-generation H1-receptor antagonists (cetirizine, fexofenadine, loratadine, desloratadine, azelastine) are supplanting first-generation drugs (diphenhydramine, chlorpheniramine, cyproheptadine) in the treatment of allergic rhinoconjunctivitis and chronic urticarial. Their greater cost can be justified because of a more favorable risk-benefit ratio (e.g., they have fewer CNS side effects). For example, the first-generation H1-receptor antagonists have sedating effects that result in delayed reaction times.
Diphenhydramine is prescribed as a sedative, an antipruritic, and as an antiemetic. When administered alone, it modestly stimulates ventilation by augmenting the interaction of hypoxic and hypercarbic ventilatory drives. When diphenhydramine is administered in combination with systemic or neuraxial opioids to control nausea and pruritus, there is the conceptual risk of depression of ventilation. However, diphenhydramine counteracts to some extent the opioid-induced decreases in the slope of the ventilatory response to CO2 and does not exacerbate the opioid-induced depression of the hypoxic ventilatory response during moderate hypercarbia.22
The rich distribution of histamine receptors in the myocardium and coronary vasculature predisposes the heart to cardioregulatory changes during massive histamine release that characterizes type 1 immune-mediated hypersensitivity (anaphylactic) reactions. Use of antihistamines in the acute treatment of anaphylactic reactions is directed at blocking further histamine-mediated vasodilation and resulting homodynamic instability, as well as decreasing respiratory and other systemic complications. As such, the administration of H1-receptor antagonists plus the administration of epinephrine is indicated in the treatment of acute anaphylaxis. H1-receptor antagonists are also useful in the ancillary treatment of pruritus, urticaria, and angioedema. These drugs may also be administered prophylactically for anaphylactoid reactions to radiocontrast dyes. Second-generation H1-receptor antagonists such as terfenadine, fexofenadine, and astemizole have low water solubility, and, unlike first-generation drugs, are not available for parenteral use. The addition of H2-receptor antagonists to H1-receptor antagonists in the treatment of anaphylaxis speeds the resolution of symptoms. Concerns of possible attenuation of H2-mediated increases in inotropy and chronotropy, thereby limiting potential cardioexcitatory compensatory mechanisms, does not seem to be significant clinically.23
Dimenhydrinate is an H1-receptor antagonist that is the theoclate salt of diphenhydramine. Dimenhydrinate has been used to treat motion sickness as well as postoperative nausea and vomiting. It is speculated that the efficacy of dimenhydrinate in motion sickness and inner ear diseases may be due to inhibition of the integrative functioning of the vestibular nuclei by decreasing vestibular and visual input. Manipulation of the extraocular muscles as in strabismus surgery may trigger an “oculoemetic” reflex similar to the well-described oculocardiac reflex. If the afferent arc of this reflex is also dependent on the integrity of the vestibular nuclei apparatus, then dimenhydrinate may attenuate or block this reflex and decrease the incidence of postoperative nausea and vomiting. Administration of dimenhydrinate, 20 mg intravenously (IV), to adults decreases vomiting after outpatient surgery.24 In children, dimenhydrinate, 0.5 mg/kg IV, significantly decreases the incidence of vomiting after strabismus surgery and is not associated with prolonged sedation.25 Compared with serotonin antagonists, dimenhydrinate is an inexpensive antiemetic.
Side Effects
First-generation H1 antagonists often have adverse effects on the CNS, including somnolence, diminished alertness, slowed reaction time, and impairment of cognitive function. Because there is some cross-reactivity with muscarinic receptors, anticholinergic effects such as dry mouth, blurred vision, urinary retention, and impotence may be seen. Tachycardia is common, and prolongation of the QTc interval on the electrocardiogram (ECG), heart block, and cardiac arrhythmias have occurred. First-generation H1-receptor antagonists are still prescribed because they are effective and inexpensive. Administration of these drugs at bedtime is sometimes recommended because drug-related somnolence is of no concern during the night. Indeed, H1-receptor antagonists may be sold as nonprescription sleeping aids.
Second-generation H1 antagonists are unlikely to produce CNS side effects such as somnolence unless the recommended doses are exceeded. Enhancement of the effects of diazepam or alcohol is unlikely by second-generation drugs. Fexofenadine, a metabolite of terfenadine, does not prolong the QTc interval on the ECG, even in large doses. Patients with hepatic dysfunction, cardiac disorders associated with prolongation of the QTc interval, or metabolic disorders such as hypokalemia or hypomagnesemia may be especially prone to adverse cardiovascular effects of H1-receptor antagonists. Most second-generation H1-receptor antagonists are not removed by hemodialysis.
Antihistamine intoxication is similar to anticholinergic poisoning and may be associated with seizures and cardiac conduction abnormalities resembling tricyclic antidepressant overdose. Older nonsedating antihistamine drugs (terfenadine, astemizole) were associated with prolongation of the QTc interval and atypical (torsades de pointes) ventricular tachycardia both after overdose and after coadministration with macrolide antibiotics, or other drugs that interfere with their elimination. These drugs were removed from the market in 1999.
H2-Receptor Antagonists
Cimetidine, ranitidine, famotidine, and nizatidine are H2-receptor antagonists that produce selective and reversible inhibition of H2 receptor–mediated secretion of hydrogen ions by parietal cells in the stomach (Figs. 35-2 and 35-3).26 The relationship between gastric hypersecretion of fluid containing high concentrations of hydrogen ions and peptic ulcer disease emphasizes the potential value of a drug that selectively blocks this response. Despite the presence of H2 receptors throughout the body, inhibition of histamine binding to the receptors on gastric parietal cells is the major beneficial effect of H2-receptor antagonists.
Mechanism of Action
The histamine receptors on the basolateral membranes of acid-secreting gastric parietal cells are of the H2 type and thus are not blocked by conventional H1 antagonists. The occupation of H2 receptors by histamine released from mast cells and possibly other cells activates adenylate cyclase, increasing the intracellular concentrations of cyclic adenosine monophosphate (cAMP). The increased concentrations of cAMP activates the proton pump of gastric parietal cells (an enzyme designated as hydrogen-potassium-ATPase) to secrete hydrogen ions against a large concentration gradient in exchange for potassium ions.26 H2-receptor antagonists competitively and selectively inhibit the binding of histamine to H2 receptors, thereby decreasing the intracellular concentrations of cAMP and the subsequent secretion of hydrogen ions by the parietal cells.
The relative potencies of the four H2-receptor antagonists for inhibition of secretion of gastric hydrogen ions varies from 20- to 50-fold, with cimetidine as the least potent and famotidine the most potent (Table 35-2).26 The duration of inhibition ranges from approximately 6 hours for cimetidine to 10 hours for ranitidine, famotidine, and nizatidine. None of the four H2-receptor antagonists have produced any consistent effects on lower esophageal sphincter function or the rate of gastric emptying. Discontinuation of chronic H2-receptor antagonist therapy is followed by rebound hypersecretion of gastric acid.
Pharmacokinetics
The absorption of cimetidine, ranitidine, and famotidine is rapid after oral administration. Because of extensive first-pass hepatic metabolism, however, the bioavailability of these drugs is approximately 50% (see Table 35-2).26Nizatidine does not undergo significant hepatic first-pass metabolism, and its bioavailability after oral administration approaches 100%. The average time to peak plasma concentrations of the four H2-receptor antagonists ranges from 1 to 3 hours after oral administration. Because the volume of distribution for all four drugs exceeds the body’s total body water content, some binding (13% to 35%) to proteins must occur (see Table 35-2).26
Cimetidine is widely distributed in most organs but not fat. Approximately 70% of the total body content of cimetidine is found in skeletal muscles. The volume of distribution is not altered by renal disease but is increased by severe hepatic disease and can be altered by changes in systemic blood pressure and cardiac output. All four drugs are present in breast milk and can cross the placenta and blood–brain barrier. The presence of cimetidine in cerebrospinal fluid is increased in patients with severe hepatic disease. The dose of cimetidine may need to be decreased to avoid mental confusion in patients with severe liver disease. The volume of distribution of cimetidine is also decreased about 40% in elderly patients, presumably reflecting the decrease in skeletal muscle mass associated with aging.
Although there is considerable variation in the clearance and elimination half-lives of H2-receptor antagonists, their plasma elimination half-lives range from 1.5 to 4 hours (see Table 35-2).26 The elimination of all four drugs occurs by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Hepatic metabolism is the principal mechanism for clearance from the plasma of oral doses of cimetidine, ranitidine, and famotidine, and renal excretion is the principal pathway for clearance from the plasma of an oral dose of nizatidine. The liver may metabolize 25% to 40% of an IV dose of nizatidine. Only nizatidine appears to have an active metabolite (N-2-monodesmethyl-nizatidine), possessing about 60% of the activity of the parent drug. Hepatic metabolism of cimetidine occurs primarily by conversion of its side-chain to a thioether or sulfoxide, and these inactive products appear in the urine as 5-hydroxymethyl and/or sulfoxide metabolites. The renal clearance of all four H2-receptor antagonists is typically two to three times greater than creatinine clearance, reflecting extensive renal tubular secretion. Renal failure increases the elimination half-life of all four drugs, with the greatest effect on nizatidine and famotidine. Decreases in the doses of all four drugs are recommended for patients with renal dysfunction. Doses of H2-receptor antagonists may also need to be decreased in patients with acute burns. Only 10% to 20% of total body cimetidine or ranitidine is cleared by hemodialysis.
Hepatic dysfunction does not seem to significantly alter the pharmacokinetics of H2-receptor antagonists. Increasing age must be considered when determining the dose of H2-receptor antagonists. For example, cimetidine clearance decreases 75% in patients between the ages of 20 years and 70 years.26 There is also a 40% decrease in the volume of distribution of cimetidine in elderly patients. The elimination half-life of ranitidine and famotidine may be increased up to twofold in elderly patients.
Clinical Uses
H2-receptor antagonists are most commonly administered for the treatment of duodenal ulcer disease associated with hypersecretion of gastric hydrogen ions. In the preoperative period, H2-receptor antagonists have been administered as chemoprophylaxis to increase the pH of gastric fluid before induction of anesthesia. However, the American Society of Anesthesiologists’ practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration state that the routine preoperative use of medications that block gastric acid secretion to decrease the risks of pulmonary aspiration in patients who have no apparent increased risk for pulmonary aspiration is not recommended.4 When indicated though, H2-receptor antagonists have been advocated as useful drugs in the preoperative period to decrease the risk of acid pneumonitis if inhalation of acidic gastric fluid were to occur in the perioperative period. One approach is to administer cimetidine, 300 mg orally (3 to 4 mg/kg), 1.5 to 2.0 hours before the induction of anesthesia, with or without a similar dose the preceding evening. Famotidine given the evening before and the morning of surgery or on the morning of surgery is equally effective in decreasing gastric fluid pH in outpatients and inpatients; there is no difference between famotidine doses of 20 mg or 40 mg.
The H2-receptor antagonists also decrease gastric fluid volume.27 Unfortunately, H2-receptor antagonists, in contrast to antacids, have no influence on the pH of the gastric fluid that is already present in the stomach. Cimetidine crosses the placenta but does not adversely affect the fetus when administered before cesarean section. The other H2-receptor antagonists have a profile to similar to that of cimetidine with respect to placental transfer.28
Preoperative preparation of patients with allergic histories or patients undergoing procedures associated with an increased likelihood of allergic reactions (radiographic contrast dye administration) may include prophylactic oral administration of an H1-receptor antagonist (diphenhydramine, 0.5 to 1.0 mg/kg) and an H2-receptor antagonist (cimetidine, 4 mg/kg) every 6 hours in the 12 to 24 hours preceding the possible triggering event. A corticosteroid administered at least 24 hours earlier is commonly added to this regimen. Dramatic reversals of life-threatening allergic reactions after the IV administration of cimetidine may reflect the cumulative effect of prior epinephrine administration in the presence of a prolonged circulation time.29,30 In fact, such treatment could exacerbate bronchospasm due to sudden unmasking of unopposed histamine effects of H1 receptors on bronchial smooth muscle. The risk of further hypotension is also a consideration with IV administration of cimetidine. Furthermore, H2-receptor activity could have desirable effects during allergic reactions, including increased myocardial contractility and coronary artery vasodilation.
Drug-induced histamine release that may follow the rapid IV administration of certain drugs (morphine, atracurium, mivacurium, protamine) is not prevented by pretreatment with an H1-receptor antagonist in combination with an H2-receptor antagonist.31 The magnitude of the systemic blood pressure decrease that occurs in response to drug-induced histamine release is less, confirming that prior occupation of histamine receptors with a specific antagonist drug attenuates the cardiovascular effects of subsequently released histamine.32 Pretreatment with an H1-receptor antagonist (diphenhydramine) or H2-receptor antagonist (cimetidine) alone is not effective in preventing the cardiovascular effects of histamine that are released in response to drug administration, emphasizing the role of both H1 and H2 receptors in these responses. In fact, drug-induced histamine release may be exaggerated in patients pretreated with only H2-receptor antagonists.
Side Effects
The frequency of severe side effects is low with all four H2-receptor antagonists (Table 35-3). The risk for experiencing adverse side effects during treatment with an H2-receptor antagonist is increased by the presence of multiple medical illnesses, hepatic or renal dysfunction, and advanced age. The most common adverse side effects are diarrhea, headache, fatigue, and skeletal muscle pain. Side effects that occur with a prevalence of <1% include mental confusion, dizziness, somnolence, gynecomastia, galactorrhea, thrombocytopenia, increased plasma levels of liver enzymes, drug fever, bradycardia, tachycardia, and cardiac arrhythmias. Cardiac reactions are most likely related to blockade of cardiac H2 receptors. Mental confusion in patients being treated with cimetidine may be more likely in the presence of hepatic or renal dysfunction. Changes in mental status usually occur in the elderly and tend to be associated with high doses of cimetidine administered IV, often to patients in an intensive care unit. Most patients have an improvement in mental status 24 to 48 hours after discontinuing cimetidine. Ranitidine and famotidine also cross the blood–brain barrier and have been reported to produce mental confusion.33 Mental confusion has rarely been observed in ambulatory patients being treated chronically with H2-receptor antagonists.
Cimetidine and, to a lesser extent, ranitidine increase the plasma concentrations of prolactin, which may result in galactorrhea in females and gynecomastia in males. Famotidine and nizatidine do not appear to increase plasma prolactin levels. Cimetidine, but not the other H2-receptor antagonists, inhibits the binding of dihydrotestosterone to androgen receptors. Indeed, impotence and loss of libido may occur in males receiving chronic high-dose treatment with cimetidine.
The adverse effects of H2-receptor antagonists on hepatic function are typically reflected by reversible increases in the plasma level of aminotransaminase enzymes, mostly in patients receiving large IV doses of H2-receptor antagonists. H2-receptor antagonists probably do not markedly alter hepatic blood flow.
Cardiac arrhythmias (sinus bradycardia, sinus arrest, sinus arrest with idioventricular escape rhythm, complete atrioventricular heart block) have been described after either oral or IV administration of H2-receptor antagonists.34Most of the described arrhythmias have occurred after chronic administration. Rare descriptions of prolonged QT interval and fatal cardiac arrest with famotidine have been reported.35Cardiac effects of H2-receptor stimulation are similar to β1 stimulation mediated by cAMP. This would explain why blockade of H2-receptors might evoke bradycardia. Furthermore, blockade of H2 receptors could increase H1-receptor effects, including negative dromotropic effects. Bradycardia and hypotension are generally associated with rapid IV administration of these drugs, most often to critically ill or elderly patients.36 The mechanism for hypotension appears to be peripheral vasodilation. A prudent approach is to administer these drugs over 15 to 30 minutes when IV administration is needed.
Prolonged H2-receptor blockade and associated gastric achlorhydria may weaken the gastric barrier to bacteria and predispose to systemic infections.37,38 Likewise, pulmonary infections from inhaled secretions may be more likely if the acid-killing effect on bacteria in the stomach is altered. Nevertheless, if acid suppression increases the risk of pneumonia, that risk is small and usually amenable to therapy.38 Sustained increases of gastric fluid pH may lead to an overgrowth of other organisms such as Candida albicans. This may account for the occasional case of Candida peritonitis observed after peptic ulcer perforation in patients treated with cimetidine. Prolonged increases of gastric fluid pH also result in the production of nitroso compounds because of an increase in nitrate-reducing bacteria.39 Nitroso derivatives are potent mutagens in vitro, but there is no evidence that this occurs in vivo in association with chronic cimetidine therapy.
Cimetidine, but not ranitidine or famotidine, has been shown to augment cell-mediated immunity through its blockade of H2 receptors on T lymphocytes.26
Drug Interactions
Numerous drug interactions have been described between H2-receptor antagonists, most commonly cimetidine, and other drugs (Table 35-4).26 Drug interactions generally occur when a new drug is either started or discontinued. In this regard, measurement of plasma drug concentrations or laboratory measurements of an effect (prothrombin time) may be useful.
The principal type of drug interaction reported with cimetidine is impairment of the hepatic metabolism of another drug because of the binding of cimetidine to the heme portion of the cytochrome P450 oxidase system. Cimetidine retards metabolism of drugs such as propranolol and diazepam that normally undergo high hepatic extraction.40,41 Slowed metabolism and prolonged elimination half-life with associated exaggerated pharmacologic effects of propranolol and diazepam have been documented with only 24 hours of treatment with cimetidine (Figs. 35-4 and 35-5).41,42 In contrast, benzodiazepines, such as oxazepam and lorazepam that are eliminated almost entirely by glucuronidation are not altered by cimetidine-induced effects on P450 enzyme activity. Cimetidine may slow metabolism of lidocaine and thus increase the possibility of systemic toxicity.43 In contrast, plasma concentrations of bupivacaine after epidural anesthesia for cesarean section are not influenced by a single dose of cimetidine administered before induction of anesthesia (Fig. 35-6).44,45 Indeed, plasma cholinesterase activity is not altered by cimetidine.46 Ranitidine, although more potent than cimetidine, binds less avidly to the cytochrome P450 enzyme system and has less potential than cimetidine to alter the oxidative metabolism of other drugs. Famotidine and nizatidine do not bind notably to the cytochrome P450 enzyme system and thus have very limited potential for inhibiting the metabolism of other drugs.
H2-receptor antagonists compete with cationic compounds for renal tubular secretion. Because of the competition of cimetidine and ranitidine with creatinine for renal tubular secretion, serum creatinine levels are increased about 15%. Cimetidine and ranitidine, but not famotidine, impair renal tubular secretion of procainamide and theophylline. Famotidine, however, has been reported to interfere with phosphate absorption, leading to the development of hypophosphatemia.47 Impairment of renal theophylline clearance with cimetidine is probably negligible compared with impairment of the hepatic metabolism of theophylline.
All four H2-receptor antagonists have the potential to alter the absorption of some drugs by increasing the gastric fluid pH. Cimetidine has been reported to enhance the absorption of ethanol from the stomach as a result of inhibition of gastric alcohol dehydrogenase.
In addition to drug interactions produced by H2-receptor antagonists, several drugs alter the disposition of the antagonists. Magnesium and aluminum hydroxide antacids decrease by 30% to 40%, respectively, the bioavailability of cimetidine, ranitidine, and famotidine. Despite this impaired absorption, therapeutic blood levels of the H2 antagonist can still be achieved, and rigorous separation of dosage schedules during combined drug therapy is probably unnecessary.48 Hepatic metabolism of cimetidine may be enhanced if phenobarbital is administered concurrently.
Proton Pump Inhibitors
Proton pump inhibitors (PPIs) (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) are the most effective drugs available for controlling gastric acidity and volume (Table 35-5). The final step in gastric acid secretion is the membrane enzyme proton pump (hydrogen-potassium-ATPase) that moves hydrogen ions across the gastric parietal cell membranes in exchange for potassium ions. The secretion of hydrochloric acid by gastric parietal cells ultimately depends on the function of the proton (hydrogen ion) pump. PPIs are more effective than H2-receptor antagonists for healing esophagitis and preventing relapse. PPIs also appear to be more effective than H2-receptor antagonists for relieving heartburn, the cardinal feature of “gastroesophageal reflux disease.”49 However, for patients without esophagitis and infrequent symptoms H2-receptor antagonists are probably more cost effective.
Omeprazole
Omeprazole is a substituted benzimidazole that acts as a prodrug that becomes a PPI.50,51 (Fig. 35-7) As a weak base, omeprazole is concentrated in the secretory canaliculi of the gastric parietal cells. It is at this site that omeprazole is pronated to its active form, which inhibits the enzyme pump. The initial dose of omeprazole will only inhibit those proton pumps present and working on the luminal surface. As pumps are generated and inserted into the luminal surfaces, additional doses are required to inhibit these new pumps. Therefore, omeprazole takes several days to exert its maximal inhibitory effect on gastric acid secretion. Daily administration results in about 66% inhibition of gastric acid secretion by about 5 days. Likewise, discontinuation of omeprazole is not followed immediately by return of gastric acid secretion.52
Omeprazole provides prolonged inhibition of gastric acid secretion, regardless of the stimulus, and it inhibits daytime and nocturnal acid secretion and meal-stimulated acid secretion to a significantly greater degree than do the H2-receptor antagonists. This drug heals duodenal and possibly gastric ulcers more rapidly than do the H2-receptor antagonists. In patients with bleeding peptic ulcers and signs of recent bleeding, treatment with omeprazole decreases the rate of bleeding and the need for surgery.53 Omeprazole is superior to H2-receptor antagonists for the treatment of reflux esophagitis49 and is the best pharmacologic treatment of Zollinger-Ellison syndrome.50
Preoperative Medication
As preoperative medication, omeprazole effectively increases gastric fluid pH and decreases gastric fluid volume in children and adults.54,55 In this regard, the onset of the gastric antisecretory effect of omeprazole after a single oral dose (20 mg) occurs within 2 to 6 hours. The duration of action is prolonged (>24 hours) because the drug is concentrated selectively in the acidic environment of gastric parietal cells. Omeprazole, 20 mg orally administered the night before surgery, increases gastric fluid pH, whereas administration on the day of surgery (up to 3 hours before induction of anesthesia) fails to improve the environment of the gastric fluid.55 This suggests that oral omeprazole should be administered >3 hours before anticipated induction of anesthesia to ensure adequate chemoprophylaxis.
Side Effects
Omeprazole crosses the blood–brain barrier and may cause headache, agitation, and confusion. Gastrointestinal side effects include abdominal pain, flatulence, nausea, and vomiting. Small bowel bacterial overgrowth may occur owing to acid suppression. The loss of the inhibitory effect of gastric acid results in increased plasma concentrations of gastrin. There is no need to decrease the dose of PPIs in the presence of renal or hepatic dysfunction.
Esomeprazole
Esomeprazole is the levorotatory isomer of omeprazole. This levoisomer is metabolized differently in the liver, resulting in greater plasma concentrations of the drug compared with the racemic drug, omeprazole.
Pantoprazole
Pantoprazole is a potent and fast-acting PPI. Memis et al.56 studied two groups of 30 patients each and administered pantoprazole (40 mg) or ranitidine (50 mg) IV 1 hour before the induction of anesthesia and found that both were equally effective in decreasing gastric fluid volume and pH.
Gastrointestinal Prokinetics
Motility-modulating drugs exert their therapeutic effects by increasing lower esophageal sphincter tone, enhancing peristaltic contractions and accelerating the rate of gastric emptying.
Dopamine Blockers
Metoclopramide
Metoclopramide acts as a gastrointestinal prokinetic drug that increases lower esophageal sphincter tone and stimulates motility of the upper gastrointestinal tract in normal persons and parturients.57 It is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of diabetic gastroparesis.58 Gastric hydrogen ion secretion is not altered. The net effect is accelerated gastric clearance of liquids and solids (decreased gastric emptying time) and a shortened transit time through the small intestine.
Domperidone
Domperidone is a benzimidazole derivative that, like metoclopramide, acts as a specific dopamine antagonist that stimulates peristalsis in the gastrointestinal tract, speeds gastric emptying, and increases lower esophageal sphincter tone (Fig. 35-8).59 Domperidone is currently not marketed in the Unites States.60
Unlike metoclopramide, domperidone does not easily cross the blood–brain barrier and does not appear to have any anticholinergic activity. Its gastrokinetic actions have therefore been attributed to its peripheral dopaminergic activity. Because it lacks dopaminergic effects in the CNS, this drug is not associated with extrapyramidal symptoms. However, it does effect prolactin secretion by the pituitary. The FDA refused to give approval for domperidone’s sale in the United States because of concerns about lactating women using dromperiodone to increase breast milk production because of the cardiac risks associated with domperidone use (e.g., cardiac arrhythmias, cardiac arrest, and sudden death). It is possible to obtain permission from the FDA for nonlactating adults with gastrointestinal motility disorders that are difficult to manage with available therapy, in whom domperidone’s potential benefits outweigh its cardiac risks. The value of domperidone as prophylaxis against or treatment of postoperative nausea and vomiting is unclear.61
Mechanism of Action
Metoclopramide produces selective cholinergic stimulation of the gastrointestinal tract (gastrokinetic effect) consisting of (a) increased smooth muscle tension in the lower esophageal sphincter and gastric fundus, (b) increased gastric and small intestinal motility, and (c) relaxation of the pylorus and duodenum during contraction of the stomach.62 The cholinergic stimulating effects of metoclopramide are largely restricted to smooth muscles of the proximal gastrointestinal tract and require some background cholinergic activity. There is evidence that metoclopramide sensitizes gastrointestinal smooth muscles to the effects of acetylcholine, which explains the observation that metoclopramide, unlike conventional cholinergic drugs, requires background cholinergic activity to be effective. Postsynaptic activity results from the ability of metoclopramide to cause the release of acetylcholine from cholinergic nerve endings. Indeed, atropine opposes metoclopramide-induced increases in lower esophageal sphincter tone and gastrointestinal hypermotility, indicating that metoclopramide acts on postganglionic cholinergic nerves intrinsic to the wall of the gastrointestinal tract.
Metoclopramide acts as a dopamine-receptor antagonist, but any effects on dopamine-induced inhibition of gastrointestinal motility are not considered to be clinically significant.63 However, metoclopramide does cross the blood–brain barrier and, within the CNS, metoclopramide inhibiton of dopamine receptors can produce significant extrapyramidal side effects.58 Metoclopramide’s dopamine receptor antagomism also stimulates prolactin secretion but its risk-benefit ratio is considered safer than that of a domperidone. Metoclopramide-induced antagonism of dopamine-agonist effects on the chemoreceptor trigger zone (located outside the blood–brain barrier) contributes to an antiemetic effect.
Pharmacokinetics
Metoclopramide is rapidly absorbed after oral administration, reaching peak plasma concentrations in 40 to 120 minutes.62 Extensive first-pass hepatic metabolism limits bioavailability to about 75%. Most patients achieve therapeutic plasma concentrations of 40 to 80 ng/mL after 10 mg of metoclopramide administered orally. The elimination half-life is 2 to 4 hours. Metoclopramide readily crosses the blood–brain barrier and the placenta. The concentration of metoclopramide in breast milk may exceed the plasma concentration. Approximately 85% of an oral dose of metoclopramide appears in the urine, equally divided between unchanged drug and sulfate and glucuronide conjugates. Impairment of renal function prolongs the elimination half-life and necessitates a decrease in metoclopramide dosage.
Clinical Uses
Clinical uses of metoclopramide include (a) preoperative decrease of gastric fluid volume, (b) production of an antiemetic effect, (c) treatment of gastroparesis, (d) symptomatic treatment of gastroesophageal reflux, and (e) intolerance to enteral feedings in patients who are critically ill.64 Administration of metoclopramide, 10 to 20 mg IV, may be useful to speed gastric emptying before the induction of anesthesia, to facilitate small-bowel intubation, or to speed gastric emptying to improve radiographic examination of the small intestine. Metoclopramide has been used to improve the effectiveness of oral medication if other drugs or the patient’s underlying condition slows gastric emptying.
Preoperative Decrease in Gastric Fluid Volume
Metoclopramide, 10 to 20 mg IV over 3 to 5 minutes administered 1565 to 3066 minutes before induction of anesthesia, results in increased lower esophageal sphincter tone and decreased gastric fluid volume. More rapid IV administration may produce abdominal cramping. This gastric-emptying effect of metoclopramide may be of potential benefit before the induction of anesthesia in (a) patients who have recently ingested solid food, (b) trauma patients, (c) obese patients, (d) patients with diabetes mellitus and symptoms of gastroparesis, and (e) parturients, especially those with a history of esophagitis (“heartburn”), suggesting lower esophageal sphincter dysfunction and gastric hypomotility. Nevertheless, beneficial effects of metoclopramide on gastric fluid volume may be difficult to document in otherwise normal patients with low gastric fluid volumes who are awaiting elective surgery (Table 35-6).67
Regardless of the effects of gastric fluid volume, the administration of metoclopramide does not reliably alter gastric fluid pH. Furthermore, it is important to recognize that opioid-induced inhibition of gastric motility may not be reversible with metoclopramide. Likewise, the beneficial cholinergic stimulant effects of metoclopramide on the gastrointestinal tract may be offset by concomitant administration of atropine in the preoperative medication. Metoclopramide and other prophylactic drugs (antacids or H2 antagonists) do not replace the need for proper airway management, including placement of a cuffed tracheal tube.
Production of an Antiemetic Effect
The antiemetic effect of metoclopramide in preventing postoperative nausea and vomiting has been debated.68 However, metoclopramide has been shown to decrease chemotherapy-induced nausea and vomiting and nausea and vomiting after cesarean section, although it is less efficacious than 5-HT3 antagonsts.69–71 The antiemetic property of metoclopramide probably results from antagonism of dopamine’s effects in the chemoreceptor trigger zone. Additional antiemetic effects are provided by metoclopramide-induced increases in lower esophageal sphincter tone and facilitation of gastric emptying in the small intestine. These latter effects reverse the gastric immobility and cephalad peristalsis that accompany the vomiting reflex. Gastric stasis induced by morphine is reversed by metoclopramide, and opioid-induced nausea and vomiting, which can accompany preoperative medication or postoperative pain management, are blunted.
Side Effects
Metoclopramide should not be administered to patients with known Parkinson disease, restless leg syndrome, or who have movement disorders related to dopamine inhibition or depletion.58 In patients with no known movement disorders, dystonic extrapyramidal reactions (oculogyric crises, opisthotonus, trismus, torticollis) occur in <1% of patients treated chronically with metoclopramide. Although extrapyramidal reactions may be a problem if large oral doses (40 to 80 mg daily) are administered chronically, there are reports of neurologic dysfunction related to the preoperative administration of metoclopramide.72These extrapyramidal reactions are identical to the parkinsonian syndrome evoked by antipsychotic drugs that antagonize the CNS actions of dopamine.73 Akathisia, a feeling of unease and restlessness in the lower extremities, may follow the IV administration of metoclopramide, resulting in cancellation of scheduled surgery,74 or may manifest in the postanesthesia care unit.58,75
Abdominal cramping may follow rapid IV administration (<3 minutes) of metoclopramide. IV administration of metoclopramide may also be associated with hypotension, tachycardia, bradycardia, and cardiac arrhythmias. Sedation, dysphoria, agitation, dry mouth, glossal or periorbital edema, hirsutism, and urticarial or maculopapular rash are rare side effects that have not been observed after single doses of metoclopramide. Breast enlargement, galactorrhea, or menstrual irregularities that occur rarely are presumed to reflect metoclopramide-induced increases in plasma prolactin concentrations. For this reason, patients with a history of breast cancer probably should not be treated chronically with metoclopramide.
Placental transfer of metoclopramide occurs rapidly, but adverse fetal effects with single doses have not been observed.67 The usual dopamine-induced inhibition of aldosterone secretion is prevented by metoclopramide. As a result, the possibility of sodium retention and hypokalemia should be considered, especially in patients who develop peripheral edema during chronic therapy.
Metoclopramide may increase the sedative actions of CNS depressants and the incidence of extrapyramidal reactions caused by certain drugs. For this reason, metoclopramide should probably not be administered in combination with phenothiazine or butyrophenone drugs or to patients with preexisting extrapyramidal symptoms or signs, as mentioned previously, or with seizure disorders. Patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants should likewise probably not receive metoclopramide. Metoclopramide decreases bioavailability of orally administered cimetidine by 25% to 50%.14 It would seem prudent not to administer metoclopramide to a patient with a suspected or known mechanical obstruction to gastric emptying. Likewise, metoclopramide is not administered after gastrointestinal surgery such as pyloroplasty or intestinal anastomosis because it stimulates gastric motility and may delay healing.
Metoclopramide has an inhibitory effect on plasma cholinesterase activity when tested in vivo, which may explain occasional observations of prolonged responses to succinylcholine and mivacurium in patients receiving these drugs.76,77 Parturients may be at increased risk for developing this response, considering the already decreased plasma cholinesterase activity associated with pregnancy. Likewise, the metabolism of ester local anesthetics could be slowed by metoclopramide-induced decreases in plasma cholinesterase activity.
Macrolides
The antibiotic erythromycin, as well as other macrolide antibiotics (i.e., azithromycin),78 increases lower esophageal sphincter tone, enhances intraduodenal coordination, and promotes emptying of gastric liquids and solids in patients with diabetic gastroparesis,79 in patients awaiting emergency surgery,80 in normal patients,81 and in patients in the intensive care unit with food intolerance82 (Fig. 35-9). The macrolide antibiotics’ prokinetic properties are attributed to their binding to motilin receptors in the stomach and duodenum,78 although part of their prokinetic action may be secondary to cholinergic stimulatory properties.83 Side effects of the macrolide compounds are the same as for any antibiotic, and therefore, because of concerns about tolerance, there are those that believe that erythromycin should be used if all other prokinetic agents have failed.84
5-HT4–Receptor Agonists
Nonselective 5-HT4–receptor agonists, such as cisapride and mosapride, decrease acid reflux, increase lower esophageal sphincter tone, improve gastric motility, and increase motility in the small and large intestine by enhancing the release of acetylcholine from nerve endings in the myenteric plexus of the gastrointestinal mucosa.85 Opioid-induced gastric stasis, which is an important cause of postoperative nausea and vomiting, is reversed by cisapride.86Tegaserod, a partial 5-HT4–receptor agonist improves small and large intestine transit and reduces constipation. Due to their relative nonselectivity, cisapride and mosapride are associated with prolongation of the QT interval.
Serotonin Agonists
Serotonin is involved in gastrointestinal motility and secretion, but studies of nonselective drugs that enhance serotonin action have not shown benefit.87
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