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).26 Nizatidine 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.34 Most of the described arrhythmias have occurred after chronic administration. Rare descriptions of prolonged QT interval and fatal cardiac arrest with famotidine have been reported.35 Cardiac 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.
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