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Recent Advances in Chest Medicine |

Medication and Dosage Considerations in the Prophylaxis and Treatment of High-Altitude Illness* FREE TO VIEW

Andrew M. Luks, MD; Erik R. Swenson, MD
Author and Funding Information

*From the Division of Pulmonary and Critical Care Medicine (Dr. Luks), University of Washington; and Division of Pulmonary and Critical Care Medicine (Dr. Swenson), Puget Sound Veterans Health Care System, Seattle, WA.

Correspondence to: Andrew M. Luks, MD, Acting Instructor, Division of Pulmonary and Critical Care Medicine, University of Washington, Box 356522, 1959 NE Pacific Ave, Seattle, WA 98195-6522; e-mail: aluks@u.washington.edu


Chest. 2008;133(3):744-755. doi:10.1378/chest.07-1417
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Published online

With increasing numbers of people traveling to high altitude for work or pleasure, there is a reasonable chance that many of these travelers have preexisting medical conditions or are receiving various medications at the time of their sojourn. As with all travelers to high altitude, they are at risk for altitude illnesses such as acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. While there are clear recommendations for pharmacologic measures to prevent or treat these illnesses, these recommendations are oriented toward healthy individuals and do not take into account the presence of preexisting medical conditions. In this review, we consider how the choice and dose of the medications used in the management of altitude illness—acetazolamide, dexamethasone, nifedipine, tadalafil, sildenafil, and salmeterol—are affected by a patient’s underlying medical conditions. We discuss the indications and current dosing recommendations for individuals without underlying disease, and then consider how drug selection or dosing regimens will be affected by the presence of renal insufficiency, hepatic insufficiency, other important medical conditions, and the potential for serious drug interactions. We include comments about interactions with antimalarial medications and antibiotics used in the treatment of traveler’s diarrhea, as well as the safety of use during pregnancy. By giving these issues adequate consideration, clinicians can increase the chances that properly evaluated patients with underlying medical conditions will enjoy a safe trip to high altitude.

Individuals who ascend to altitudes > 2,350 m (8,000 feet) are at risk for one of three forms of high-altitude illness: acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). Clinical studies15 have established the effective doses of different medications for the prevention and treatment of these diseases, and several major reviews67 also provide dosing recommendations.

An often-overlooked limitation of the clinical studies, however, is the fact that they generally include only healthy individuals with no underlying medical problems. Similarly, the main review articles do not address how the pharmacologic options are affected by a patient’s medical history or the potential for drug interactions. While it is true that the majority of people who ascend to high altitude are fit individuals without significant medical illness, it would be a mistake to assume that all high-altitude travelers fit this description, particularly when one considers the high prevalence of clinical conditions such as diabetes, hypertension, atrial fibrillation, or depression in the general population. Despite the facts that many such patients may be traveling to high altitude and the potential for significant adverse drug interactions exists, there is little information to guide drug selection for management of altitude illness in these people.

The purpose of this review is to address this issue. For each of the medications used to manage altitude illness—acetazolamide, dexamethasone, nifedipine, tadalafil, sildenafil, and salmeterol—we discuss the indications and current dosing recommendations for healthy individuals, and then consider how drug selection or dosing regimens will be affected by various underlying medical conditions and the potential for important drug interactions. We also provide information about the safety of use in pregnancy and, because many travelers worry about the potential for interactions with medications used for travel in the developing world, antimalarials and antidiarrheal antibiotics, we include information about these clinical situations as well.

Before considering how to properly prescribe high-altitude medications for people with underlying medical conditions, it is important to state two caveats. First, we are in no way arguing that all such patients are, in fact, safe to travel to this environment. These patients should undergo a thorough pretrip evaluation to determine their fitness for travel to high altitude. Only after such an evaluation is conducted and the patient is deemed safe, can they travel to these environments; it is then that dose considerations for high-altitude medications should be considered. The details of appropriate pretrip evaluations are beyond the scope of this review and are not considered. For such information, the reader is referred to reviews that discuss issues relevant for patients with various underlying medical conditions8including lung disease,9heart disease,10pregnancy,11neurologic conditions,12diabetes,1314 and ocular conditions.15

Second, because the main risk factor for high-altitude illness is an overly rapid ascent,16 the single best way to prevent altitude illness is by ascending at an appropriately slow rate. By adhering to published recommendations6 regarding safe ascent rates—at > 2,000 m individuals should not increase their sleeping elevation by > 300 to 500 m/d and should include rest days every 3 to 4 days—the majority of individuals should be able to ascend without the need for prophylactic medications. This is a particularly important point to keep in mind regarding patients with severe renal disease (glomerular filtration rate [GFR] < 10 mL/min), liver disease (portal hypertension), lung disease (FEV1 < 25% of predicted), and pregnancy. These individuals will rarely ascend > 2,500 to 3,000 m in elevation, where AMS and HAPE are much less common than at higher altitudes and HACE is essentially not seen. For that reason, a slow ascent should be sufficient to prevent altitude illness in these patient groups. Nevertheless, with the ease of car or plane travel to high elevations, it is expected that some people with severe disease may exceed recommended ascent rates and the need for prophylactic or treatment medications will come into play. It is for that reason that we provide recommendations for patients with severe disease who might not otherwise be expected to require their use.

Medications Used in the Treatment of Altitude Illness

In the space that follows, we consider each of the medications used in the treatment of high-altitude illness. For each drug, we discuss the basic indications for its use and then review use of the medication in patients with renal insufficiency, hepatic insufficiency, and other important medical conditions, as well as the potential for drug-drug interactions. Other information is summarized in tabular form apart from these discussions. The doses used for management of altitude illness in normal individuals are presented in Table 1 and have been reviewed elsewhere.67,17 Information about the use of these drugs in pregnant or lactating women is presented in Table 2 , and the use of these medications in travelers who might be receiving malaria prophylaxis or medication for traveler’s diarrhea is presented in Table 3 . We will not discuss the clinical features of the high-altitude diseases themselves because these have been well described in earlier reviews.,67,18

Acetazolamide

The carbonic anhydrase inhibitor (CAI) acetazolamide is the mainstay for prevention and treatment of AMS and HACE. Research studies in several animals2122 and a single study in humans23 have shown that acetazolamide can block hypoxic pulmonary vasoconstriction and may play a role preventing HAPE, but in the absence of studies demonstrating a prophylactic effect in HAPE it cannot be recommended for this purpose as this time. The dosing of acetazolamide in normal individuals is provided in Table 1.

Renal Insufficiency:

Because up to 90% of acetazolamide elimination occurs via the kidney24and 50% of clearance depends on tubular secretion,25dose adjustments are necessary in renal insufficiency and failure. Patients with a GFR of 10 to 50 mL/min should not take the medication more frequently than every 12 h, while patients with GFR < 10 mL/min should not use the drug.26Patients with preexisting metabolic acidosis should also avoid acetazolamide because it will cause a greater degree of acidosis that may increase minute ventilation needs to levels that are uncomfortable for the patient, or for which they may not be able to generate effective respiratory compensation. Finally, patients with hypercalcemia and hyperphosphatemia or patients with a history of nephrolithiasis should avoid acetazolamide because there have been reports2728 of calcium-phosphate stone formation during CAI therapy as a result of urinary alkalinization and suppression of citrate excretion.

Hepatic Insufficiency:

Patients with liver disease should not receive acetazolamide.29Because acetazolamide alkalinizes the urine, ammonium ion (NH4+) is diverted from the urine to the bloodstream. In the setting of impaired synthetic liver function, the extra NH4+ cannot be converted to urea and accumulates to levels that can provoke encephalopathy.30 Any degree of hypokalemia that results from acetazolamide may exacerbate this process because hypokalemia accelerates diffusion of NH4+ into cells. Finally, evidence suggests that CAI therapy can reduce urea synthesis itself and lead to accumulation of NH4+.31 It is not clear what degree of liver dysfunction is necessary to cause such problems with acetazolamide, but given its potential problems and the lack of such side effects with dexamethasone in these patients, we recommend that patients with any degree of underlying liver disease (Child’s class A through C cirrhosis) avoid acetazolamide.

Other Medical Conditions:

Care should be taken when administering acetazolamide to patients with severe COPD or other disorders associated with ventilatory limitation (FEV1 < 25% of predicted). In addition to the fact that acetazolamide increases ventilation by creating a metabolic acidosis, doses > 2 mg/kg can begin to cause significant red cell carbonic anhydrase inhibition and, as a result, impair carbon dioxide (CO2) excretion.32In patients with limited ventilatory reserve, increased ventilatory demand and CO2 retention may lead to worsened dyspnea and/or respiratory failure.33 In such patients, we recommend limiting the dose to 125 mg bid or using dexamethasone instead.

Caution should also be used in patients with a sulfa allergy because acetazolamide contains a sulfonamide and the potential exists for cross-reactivity. The likelihood of a reaction in patients with self-reported “sulfa allergy” is low (7 to 10%),3435 but case reports3637 have described anaphylactic reactions in patients with documented sulfa allergies who received acetazolamide. In addition, remote regions of the mountains are not the place to discover that a patient is one of the rare people who do, in fact, cross-react and have anaphylaxis. For that reason, we recommend that patients with documented sulfa allergy undergo a physician-supervised trial of acetazolamide at sea level prior to their trip to document the presence or absence of a reaction. If there is any uncertainty, the patient should simply use dexamethasone instead.

Because pregnant women already have increased ventilation due to higher circulating levels of progesterone, the metabolic acidosis generated by acetazolamide, a pregnancy class C medication, might increase a pregnant woman’s sensation of dyspnea. It has been demonstrated to have teratogenic effects in animals during the first trimester38and may cause neonatal jaundice when used after 36 weeks of pregnancy.39

Drug Interaction Issues:

Acetazolamide should be avoided in patients receiving long-term high doses of aspirin. By decreasing protein binding and renal tubular secretion of acetazolamide, concurrent aspirin use can impair acetazolamide elimination.40This leads to a greater degree of metabolic acidosis, which, in turn, increases CNS penetration of aspirin, thereby increasing the risk of aspirin toxicity.41Acetazolamide should also be avoided in patients receiving ophthalmic CAIs such as dorzolamide because the combination of drugs may have an additive effect.42Finally, patients receiving topiramate for seizure management or migraine prophylaxis should avoid acetazolamide because topiramate has CAI activity, and the combined use of the medications may increase the risk of renal stone formation.43Clinically significant interactions have also been described with carbemazepine.44

Because acetazolamide is a diuretic with kaliuretic effects, care is necessary when administering it to people already receiving diuretic drugs (eg, furosemide or hydrochlorothiazide) because this may increase the risk of electrolyte abnormalities and dehydration. The kaliuretic effects mandate caution when administering acetazolamide to people receiving digoxin for atrial fibrillation or cardiomyopathy because hypokalemia increases the risk for junctional bradycardia or other forms of digoxin toxicity.45The kaliuretic effects of acetazolamide may also affect administration of antiemetics to patients with GI symptoms; concurrent use of droperidol and potassium-wasting diuretics increases the risk of QT-interval prolongation and subsequent arrhythmia.46

Because of its ability to alkalinize the urine, acetazolamide may increase the excretion of acidic drugs such as barbiturates while decreasing the excretion of alkaline drugs such as ephedrine, ephedra, or amphetamines.47Acetazolamide can also increase serum cyclosporine concentrations, although the mechanism of this effect does not appear related to urinary alkalinization.48

Dexamethasone

The corticosteroid dexamethasone is an alternative to acetazolamide for the prevention and treatment of AMS and is the primary drug in the management of HACE. Maggiorini et al4 demonstrated that it may also be effective for prevention of HAPE in known susceptible individuals, but given that this result is from a single trial with eight individuals per arm of the study, it has yet to become a standard part of the regimen for HAPE prevention. It should be noted that, unlike acetazolamide, dexamethasone does not facilitate acclimatization. As a result, abrupt cessation of dexamethasone may lead to a rebound effect and the manifestation of altitude illness symptoms that were not present while receiving the medication.

Renal Insufficiency:

Dexamethasone is an ideal drug for the management of altitude illness in patients with underlying renal insufficiency. There are no contraindications to its use, and dose adjustments are not necessary in patients with impaired glomerular filtration. Based on the problems noted above regarding acetazolamide use in the setting of renal insufficiency, dexamethasone should be the drug of choice for prevention and treatment of AMS and HACE for this patient population.

Hepatic Insufficiency:

Dose adjustments are also not necessary for patients with hepatic insufficiency. Given the risks of acetazolamide use in such patients, dexamethasone is the drug of choice for preventing and treating AMS and HACE in this patient population as well. If further research supports the findings of Maggiorini et al4 on dexamethasone and HAPE prevention, it may also become the drug of choice for HAPE prevention in cirrhotic patients because, as discussed below, there are important dose considerations in patients with hepatic insufficiency for each of the other oral agents used for this purpose.

Other Medical Conditions:

Patients with diabetes mellitus may have higher blood glucose levels while receiving dexamethasone and should be provided with instructions for managing the dose of oral diabetes medications and/or insulin at altitude. For a full discussion on diabetes at high altitude, the reader is referred to several reviews1314 on this topic.

Patients suspected of having amebiasis or strongyloidiasis should consider avoiding dexamethasone. In the case of amebiasis, concurrent steroid use can lead to acute amebic dysentery and potentially fulminant hepatic disease49; while in the presence of strongyloides infection, corticosteroid use can provoke a hyperinfection syndrome.50 Individuals who have spent considerable time traveling in the developing world are at high risk for these infections; if they plan to use dexamethasone for AMS prophylaxis, they should be screened for the presence of these infections prior to initiating dexamethasone or consider using acetazolamide instead.

Finally, patients with active peptic ulcer disease or recent upper-GI tract bleeding should avoid dexamethasone because corticosteroids have been shown to increase the risk of both problems.5152 This risk may be further increased by concurrent use of alcohol, aspirin, or other nonsteroidal antiinflammatory drugs (NSAIDs).53This concern is important in light of a recent report54 suggesting that the risk of GI bleeding may be increased at altitude.

Drug Interactions:

The effectiveness of dexamethasone may be decreased in patients being treated with antiseizure medications such as phenobarbital, carbemazepine, and phenytoin because these agents have been shown to increase corticosteroid metabolism.5557 According to the product information58 for the fluoroquinolone levofloxacin, postmarketing surveillance studies demonstrated that concomitant use of the antibiotic and corticosteroids may increase the risk of tendon rupture. The literature does not contain any reports of such events, and it is unclear if the risk is increased during the short duration someone might be receiving dexamethasone at high altitude; but given the central role levofloxacin, ciprofloxacin, and other fluoroquinolones play in management of traveler’s diarrhea in the developing world, careful attention should be paid to symptoms suggestive of tendon injury if dexamethasone is used concurrently with these agents.

Nifedipine

Nifedipine is a calcium-channel antagonist that plays a primary role in the prevention and treatment of HAPE.6 By its ability to inhibit hypoxic pulmonary vasoconstriction, it blunts the rise in pulmonary artery pressures that is responsible for the development of pulmonary edema.

Renal Insufficiency:

Because plasma concentrations are the same in patients with and without renal insufficiency,5960 dose adjustments are not necessary in the setting of renal disease.61 As a result, nifedipine represents an ideal drug for prophylaxis or treatment of HAPE in patients with underlying renal disease, particularly given the issues noted below with the other agents, tadalafil and sildenafil, that are now also used in the management of this disease.

Hepatic Insufficiency:

Unlike the lack of issues in the setting of renal insufficiency, use of nifedipine in the presence of hepatic insufficiency is potentially problematic. Several studies have demonstrated that despite having similar rates of absorption and peak plasma concentrations as normal patients, cirrhotic patients have a fourfold increase in the elimination half-life, a twofold increase in the area under the plasma concentration-time curve,62and increased systemic bioavailability63 when compared to normal patients. Despite this evidence of increased risk of drug accumulation, these studies do not provide guidance on the best means for adjusting drug dosage. As a result, it is difficult to determine the proper dose for prophylaxis and treatment of HAPE. At a minimum, we recommend halving the dose and using only 10 mg of the long-acting version every 12 h for HAPE prevention and treatment with careful follow-up of BP.

Other Medical Conditions:

There are no other major diseases in which nifedipine use appears to be a problem, but it is worthwhile to comment on its use in patients with preexisting cardiovascular disease. In the 1990s, there was debate about the safety of calcium-channel blockers in patients with hypertension and coronary artery disease64after several studies demonstrated an increased risk of myocardial infarction65and even death66in patients with hypertension or coronary artery disease receiving calcium-channel blockers. This concern has since dissipated. A report67following the release of these studies documented an insufficient degree of evidence to conclude that calcium-channel blockers increased the risk of adverse cardiovascular events, and several trials6869 have demonstrated that long-acting dihydropiridine calcium-channel blockers are, in fact, safe in patients with stable coronary artery disease. While the evidence does suggest that long-acting nifedipine is safe for use in patients with stable coronary artery disease traveling to high altitude, we must stress again that such patients must be evaluated prior to high altitude travel to determine their fitness for this environment.

Drug Interaction Issues:

Several potential drug interactions warrant attention. Nifedipine is eliminated via the cytochrome P450 3A4 pathway. As a result, drug concentrations may be reduced if it is administered in conjunction with inducers of these enzymes, including rifampin or seizure medications such as phenobarbital, phenytoin, and carbemazepine. Alternatively, inhibitors of the 3A4 pathway such as azole antifungal agents, protease inhibitors, doxycycline, and macrolide antibiotics may increase nifedipine concentrations. Nifedipine also inhibits the 1A2 pathway and, as a result, may cause increased levels of agents, such as aminophylline, theophylline, or mirtazapine, that are metabolized by this pathway.

Because of its effects on BP, caution should also be exercised when administering nifedipine to patients receiving antihypertensive agents, such as β-blockers or α-blockers, because the combination may precipitate hypotension. Patients receiving nifedipine should also avoid grapefruit juice, which can decrease systemic bioavailability,70 and calcium supplements, which may inhibit its effects at the site of action in vascular smooth muscle.

Given the results of a prior study71 that demonstrated that calcium-channel blockers may increase the risk of GI bleeding, it would be reasonable to avoid other medications, such as NSAIDs, that are also known to increase the risk of this problem, particularly in light of the report by Wu et al54 of an increased risk of GI bleeding associated with altitude exposure itself. The link between calcium-channel blockers and GI bleeding is not a strong one, however, as other studies7273 have not found a relationship between this class of medications and increased risk of GI hemorrhage. Patients with gastroesophageal reflux disease should also exercise caution when using nifedipine because the drug can decrease lower esophageal sphincter tone and promote increased reflux of gastric contents into the esophagus.7475

Finally, it is worth discussing the potential interaction with gingko biloba. Although several trials7677 have shown that the supplement is no better than placebo at preventing altitude illness, earlier studies7879 were suggestive of a benefit, and it is conceivable that people traveling to high altitude will use this medication for AMS prophylaxis. Two studies8081 have shown that plasma concentrations of nifedipine may be increased by concurrent use of gingko biloba and, as a result, the risk of hypotension on nifedipine may be increased. Rather than stopping nifedipine, however, we recommend avoiding gingko biloba because the data are not sufficient to support its use at high altitude.

Phosphodiesterase Inhibitors: Tadalafil and Sildenafil

Because of its pulmonary vasodilatory effects, the phosphodiesterase inhibitor tadalafil can be used for prevention of HAPE. Maggiorini et al4 demonstrated that tadalafil prevents the disease in known HAPE-susceptible individuals. No studies have examined whether the drug can also be used to treat HAPE. Although no systematic studies have examined whether sildenafil is effective in the prevention and treatment of HAPE, it is worth considering this medication as well because it has a similar mechanism of action and should exert a similar benefit as tadalafil and because there are reports of its use in clinical practice as treatment for HAPE82or prevention in children with underlying cardiopulmonary disease and HAPE.83

Renal Insufficiency:

Despite the fact its renal clearance is minimal, the half-life of tadalafil is prolonged in patients with renal insufficiency.84 Patients with creatinine clearance > 50 mL/min do not require dose adjustments, but patients with creatinine clearance between 30 and 50 mL/min should receive a maximum of 5 mg/d and should not receive > 10 mg in 48 h.84 Back pain and myalgias have also been reported in patients with creatinine clearance 30 to 50 mL/min receiving 10-mg doses of tadalafil. Patients with creatinine clearance < 30 mL/min should not receive > 5 mg of the medication.84The pharmacokinetics of sildenafil appear to be the same in patients with mild-to-moderate renal impairment (creatinine clearance > 30 mL/min) as in normal individuals, but in patients with creatinine clearance < 30 mL/min drug clearance is reduced and bioavailability is increased, necessitating dose reductions.85Interestingly, in dialysis-dependent patients, the pharmacokinetic profile again resembles that observed in volunteers with normal renal function.86It should be noted, however, that most studies of sildenafil dosing in renal failure have examined single-dose administration in dialysis-dependent patients; no studies have examined whether dose adjustments are necessary with repeated drug administration as would be used in a HAPE-prevention regimen, although the package insert87 for the drug does mention that no dose adjustment is necessary for treatment of pulmonary hypertension in patients with renal insufficiency. Given these considerations and the lack of problems associated with nifedipine use in renal insufficiency, we recommend that patients with moderate-to-severe renal insufficiency avoid tadalafil and sildenafil at high altitude.

Hepatic Insufficiency:

There are little published data on tadalafil pharmacokinetics in patients with hepatic insufficiency. Forgue et al84 demonstrated that peak and average plasma concentrations of the drug were actually lower in patients with mild-to-moderate hepatic insufficiency than in patients with normal liver function, but evidence is lacking regarding outcomes in patients with severe hepatic insufficiency. Despite these lower peak and plasma concentrations, the product information88 for tadalafil stipulates that patients with mild-to-moderate hepatic insufficiency (Child’s class A and B) should not receive > 10 mg/d. This dose is lower than that used by Maggiorini et al4 and, therefore, it is not known if it is sufficient for HAPE prophylaxis. Patients with Child’s class C cirrhosis should not receive the medication.

Eighty-five percent of sildenafil metabolism occurs in the liver, and in the setting of hepatic impairment peak plasma concentrations are elevated by as much as 47% compared to normal control subjects.85 As a result, it would be prudent to use lower starting doses for HAPE prevention (25 mg tid). While this recommendation agrees with the product information for sildenafil,89the literature does contain several reports9091 of patients with cirrhosis and portopulmonary hypertension who were treated with and tolerated 50 mg tid.

Although standard doses may be well tolerated from a BP and side effect standpoint, there is one additional risk that must be considered in these patients. Because sildenafil may increase splanchnic blood flow92at the same time that it lowers pulmonary artery pressures, patients with portal hypertension may be at increased risk for variceal bleeding while receiving sildenafil. Finley et al,93 for example, reported a fatal variceal hemorrhage in a patient with portopulmonary hypertension during treatment with sildenafil. The presence of a single case report should not preclude use of this medication in patients with cirrhosis who are traveling to high altitude, but one should consider adequate screening prior to travel and consider alternative agents for HAPE prophylaxis in patients found to have significant esophageal or gastric varices. Concurrent use of NSAIDs should also be avoided in such patients.

Other Medical Conditions:

Patients with coronary artery disease whose medication regimen includes nitrates should not receive tadalafil or sildenafil for HAPE prophylaxis because the combination of the medication classes may cause profound hypotension. In patients with stable coronary artery disease not receiving nitrates, tadalafil appears to be safe from a cardiovascular standpoint because several studies have shown that the drug does not increase the time to exercise-treadmill–induced ischemia,94or increase the risk of serious cardiovascular events such as myocardial infarction, stroke, or cardiovascular death.95Sildenafil has also been shown to have no effect on symptoms, exercise tolerance, or ischemic threshold in this patient group.9697 Like nifedipine, tadalafil and sildenafil decrease lower esophageal sphincter tone and may increase symptoms of gastroesophageal reflux.75

Drug Interactions:

In addition to concern about concurrent nitrate use, two other potential drug interactions warrant attention. Because tadalafil and sildenafil are metabolized via the cytochrome P450 3A4 pathway, high plasma concentrations of the drugs may result if they are administered in conjunction with inhibitors of this pathway, such as protease inhibitors, macrolide antibiotics, and azole antifungal agents. There is no evidence to suggest adverse consequences if the medications are used in conjunction with antimalarial agents including mefloquine, which, as noted above, is also metabolized via the 3A4 pathway. However, given the short duration of time that tadalafil has been on the market, it is possible that reports will emerge about this or other potential interactions. Caution should also be exercised in cases where the drugs are used in combination with α-blocker medications, such as doxazosin, terazosin, or prazosin, for benign prostatic hypertrophy because the combination may lead to postural hypotension.

Salmeterol

Salmeterol is a long-acting inhaled β-agonist that has been shown to be effective at preventing HAPE in known susceptible individuals.5 These results have not been validated in further studies and, at present, the drug is largely used as an adjunct to nifedipine prophylaxis rather than being used as the sole prophylactic agent. Although no studies have examined whether salmeterol may play a role in the treatment of HAPE, there is a report82 that it is being used for this purpose in clinical practice at a dose equivalent to that used for prophylaxis.

Renal Insufficiency:

Dose adjustments do not appear to be necessary in patients with renal insufficiency. When administered in inhaled form at doses recommended for the treatment of asthma (50 μg bid), low-to-undetectable plasma concentrations are achieved. It should be noted, though, that the dose used in the single HAPE prevention trial98 (125 μg bid) is much higher than the standard dose for asthma treatment, and the higher doses can lead to detectable plasma concentrations and signs and symptoms typical of systemic adrenergic activation. However, it is not clear that such concentrations are of clinical significance and, more importantly, because the kidney plays a minimal role in salmeterol elimination, renal insufficiency would not be expected to affect drug clearance or clinical effects. Because β-agonists cause cellular uptake of potassium, caution should be exercised when using the drug in patients with a predisposition toward hypokalemia, particularly when such patients are receiving other agents such as acetazolamide that can provoke hypokalemia.

Hepatic Insufficiency:

Salmeterol is metabolized predominantly through the cytochrome P450 34A pathway, with the hydroxylated metabolites being excreted through the biliary system and eliminated in the feces.99 There are no studies examining the pharmacokinetics of the drug in patients with hepatic impairment. Because, as noted above, the plasma concentrations achieved with the inhalational form are quite low, one would not expect major issues in this class of patients, but in the absence of firm data in this regard it would be prudent to avoid use of the drug in patients with underlying hepatic insufficiency.

Other Medical Conditions:

Because of its sympathomimetic effects, it is worthwhile to consider if salmeterol poses risks to patients with a history of cardiac disease or who are prone to tachyarrhythmias. Ferguson et al100conducted a metaanalysis of seven randomized studies that compared salmeterol 50 μg bid against placebo in patients with COPD and found an equal risk of cardiovascular adverse events as well as equal ventricular and supraventricular ectopic events, QT intervals, and 24-h heart rates in the placebo and salmeterol groups. The dose examined in this analysis, however, was 60% lower than that used for HAPE prevention. Other studies101102 have examined higher doses but unfortunately did not include patients who might also be at risk for cardiac disease. Given the lack of data with high doses in patients at risk for cardiac disease, it is difficult to draw firm conclusions about the risks posed by HAPE-prevention doses. For this reason, it may be prudent to avoid the medication in this class of patients.

Drug Interactions:

Patients receiving β-blockers such as metoprolol or atenolol may have decreased effectiveness of either the β-blocker or salmeterol because the two classes of medications have opposite effects on β-receptors. Caution is necessary when using salmeterol in conjunction with or shortly following discontinuation of two classes of antidepressant medications: monoamine oxidase inhibitors and tricyclic antidepressants. In the case of the monoamine oxidase inhibitors, there is concern that concurrent use of a β-agonist with sympathomimetic effects might lead to hypertensive crisis, although there are no cases of this reported effect with salmeterol.103 In the case of tricyclic antidepressants, there is concern that concurrent use of the medications could lead to increased incidence of BP elevation, tachycardia, and ECG changes. There are no case reports in the literature for such interactions, but this warning is stipulated in the drug product information.103

Salmeterol is metabolized by the cytochrome P450 CYP34A, but the likelihood of clinically relevant interactions is probably low because serum concentrations of salmeterol are low when it is used in the inhaled form.99 Caution should be exercised when using salmeterol in conjunction with chloroquine for malaria prophylaxis because the latter medication may prolong the QT interval and increase the risk of ventricular arrhythmia.104

This review demonstrates that many factors can affect the medication choices for patients with underlying medical conditions who seek pharmacologic options for the prophylaxis or treatment of altitude illness. The information discussed above for each medication has been summarized in Table 4 .

In taking these and the other recommendations into account, the reader must remember that all patients with preexisting medical conditions or complicated medication profiles require a thorough pretravel assessment to determine whether it is, in fact, safe for them to travel to this environment. Patients must be counseled about the risks of high-altitude travel, how to recognize high-altitude illnesses, and the role that slow ascent and timely descent play in prevention and treatment of these diseases, respectively. It is only after such assessment and counseling and the patient is deemed safe to make their journey that the important drug choices and dosing considerations described in this article should come into play.

Abbreviations: AMS = acute mountain sickness; CAI = carbonic anhydrase inhibitor; GFR = glomerular filtration rate; HACE = high-altitude cerebral edema; HAPE = high-altitude pulmonary edema; NSAID = nonsteroidal antiinflammatory drug

The authors have no financial interests in or relationships with companies that produce any of the medications discussed in this article. There are no other conflicts of interest to report.

Table Graphic Jump Location
Table 1. Dosing Recommendations for the Primary Medications Used in the Management of Altitude Illness for People With No Underlying Medical Issues
* 

Recommended doses for acetazolamide, dexamethasone, and nifedipine adapted from Hackett and Roach.6

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Table 2. Use of High-Altitude Medications in Pregnant or Lactating Women
* 

Pregnancy category B = presumed safe based on studies in animals but no data from humans. Pregnancy category C = no human studies demonstrating harm, but animal studies show evidence of teratogenicity.

 

Some authors19 claim compatibility with breast feeding, while others20 recommend against use in this situation.

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Table 3. Use of High-Altitude Medications in Travelers in Malaria-Prone Areas or With Traveler’s Diarrhea
Table Graphic Jump Location
Table 4. Summary of Recommendations for Primary Medications Used in the Treatment and Prevention of Altitude Illness
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Bartsch, P, Gibbs, JS The effect of altitude on the heart and lungs.Circulation2007;116,2191-2202
 
Jean, D, Leal, C, Kriemler, S, et al Medical recommendations for women going to altitude.High Alt Med Biol2005;6,22-31
 
Baumgartner, RW, Siegel, AM, Hackett, PH Going high with preexisting neurological conditions.High Alt Med Biol2007;8,108-116
 
Brubaker, PL Adventure travel and type 1 diabetes: the complicating effects of high altitude.Diabetes Care2005;28,2563-2572
 
Leal, C Going high with type 1 diabetes.High Alt Med Biol2005;6,14-21
 
Mader, TH, Tabin, G Going to high altitude with preexisting ocular conditions.High Alt Med Biol2003;4,419-430
 
Hackett, PH, Rennie, D The incidence, importance, and prophylaxis of acute mountain sickness.Lancet1976;2,1149-1155
 
Bartsch, P, Mairbaurl, H, Swenson, ER, et al High altitude pulmonary oedema.Swiss Med Wkly2003;133,377-384
 
Bartsch, P, Mairbaurl, H, Maggiorini, M, et al Physiological aspects of high-altitude pulmonary edema.J Appl Physiol2005;98,1101-1110
 
 Breastfeeding and maternal medication. 2002; World Health Organization. Geneva, Switzerland:.
 
 Product information: Decadron®, dexamethasone. 1997; Merck & Company. West Point, PA:.
 
Hohne, C, Krebs, MO, Seiferheld, M, et al Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs.J Appl Physiol2004;97,515-521
 
Hohne, C, Pickerodt, PA, Francis, RC, et al Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition.Am J Physiol Lung Cell Mol Physiol2007;292,L178-L184
 
Teppema, LJ, Balanos, GM, Steinback, CD, et al Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia.Am J Respir Crit Care Med2007;175,277-281
 
Anderson, RJ, Gambertoglio, JG, Schrier, RW. Clinical use of drugs in renal failure. 1976; Charles C. Thomas. Springfield, IL:.
 
Gomolin, IH, Chapron, DJ Elucidating the relationship between acetazolamide plasma protein binding and renal clearance using an albumin infusion.J Clin Pharmacol1992;32,1028-1032
 
Bennett, WM Drug prescribing in renal failure: dosing guidelines for adults 1st ed.1987 American College of Physicians. Philadelphia, PA:
 
Paisley, KE, Tomson, CR Calcium phosphate stones during long-term acetazolamide treatment for epilepsy.Postgrad Med J1999;75,427-428
 
Pepys, MB Acetazolamide and renal stone formation.Lancet1970;1,837
 
Friedland, BR, Maren, TH Carbonic anhydrase: pharmacology of inhibitors and treatment of glaucoma. Sears, ML eds.Handbook of experimental pharmacology1984,279-309 Springer-Verlag. Berlin:
 
Dawson, AM, De Groote, J, Rosenthal, WA, et al The effects of diamox ammonia metabolism in liver disease.Clin Sci (Lond)1957;16,413-420
 
Haussinger, D, Gerok, W Hepatic urea synthesis and pH regulation: role of CO2, HCO3-, pH and the activity of carbonic anhydrase.Eur J Biochem1985;152,381-386
 
Swenson, ER Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression.Eur Respir J1998;12,1242-1247
 
Coudon, WL, Block, AJ Acute respiratory failure precipitated by a carbonic anhydrase inhibitor.Chest1976;69,112-113
 
Lee, AG, Anderson, R, Kardon, RH, et al Presumed “sulfa allergy” in patients with intracranial hypertension treated with acetazolamide or furosemide: cross-reactivity, myth or reality?Am J Ophthalmol2004;138,114-118
 
Strom, BL, Schinnar, R, Apter, AJ, et al Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics.N Engl J Med2003;349,1628-1635
 
Gerhards, LJ, van Arnhem, AC, Holman, ND, et al Fatal anaphylactic reaction after oral acetazolamide (Diamox) for glaucoma [in Dutch].Ned Tijdschr Geneeskd2000;144,1228-1230
 
Tzanakis, N, Metzidaki, G, Thermos, K, et al Anaphylactic shock after a single oral intake of acetazolamide [letter].Br J Ophthalmol1998;82,588
 
Scott, WJ, Duggan, CA, Schreiner, CM, et al Reduction of embryonic intracellular pH: a potential mechanism of acetazolamide-induced limb malformations.Toxicol Appl Pharmacol1990;103,238-254
 
Notarianni, LJ Plasma protein binding of drugs in pregnancy and in neonates.Clin Pharmacokinet1990;18,20-36
 
Sweeney, KR, Chapron, DJ, Brandt, JL, et al Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation.Clin Pharmacol Ther1986;40,518-524
 
Hill, JB Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations.Pediatrics1971;47,658-665
 
 Dorzolamide (Trusopt®) package insert. 2004; Merck & Co. Whitehouse Station, NJ:.
 
 Topamax® (topiramate) package insert. 2005; Ortho-McNeil Pharmaceutical. Raritan, NJ:.
 
Spina, E, Pisani, F, Perucca, E Clinically significant pharmacokinetic drug interactions with carbamazepine: an update.Clin Pharmacokinet1996;31,198-214
 
 Lanoxin® (digoxin) package insert. 2001; Glaxo Smith Kline. Research Triangle Park, NC:.
 
 Product information: Inapsine®, droperidol. 2001; Akorn. Decatur, IL:.
 
Hoffman, BB, Lefkowitz, RJ Catecholamines and sympathomimetic drugs. Gilman, AG Rall, TW Nies, ASet al eds.Goodman and Gilman’s pharmacologic basis of therapeutics1990,211-212 Pergamon Press. New York, NY:
 
Tabbara, KF, Al-Faisal, Z, Al-Rashed, W Interaction between acetazolamine and cyclosporine.Arch Ophthalmol1998;116,832-833
 
Stuiver, PC, Goud, TJ Corticosteroids and liver amoebiasis.BMJ1978;2,394-395
 
Keiser, PB, Nutman, TB Strongyloides stercoralis in the immunocompromised population.Clin Microbiol Rev2004;17,208-217
 
Nielsen, GL, Sorensen, HT, Mellemkjoer, L, et al Risk of hospitalization resulting from upper gastrointestinal bleeding among patients taking corticosteroids: a register-based cohort study.Am J Med2001;111,541-545
 
Messer, J, Reitman, D, Sacks, HS, et al Association of adrenocorticosteroid therapy and peptic-ulcer disease.N Engl J Med1983;309,21-24
 
Wu, T, Liu, J Alcohol and aspirin in combination with dexamethasone causes gastrointestinal bleeding at high altitude.Wilderness Environ Med2006;17,69-71
 
Wu, TY, Ding, SQ, Liu, JL, et al High-altitude gastrointestinal bleeding: an observation in Qinghai-Tibetan railroad construction workers on Mountain Tanggula.World J Gastroenterol2007;13,774-780
 
Olivesi, A Modified elimination of prednisolone in epileptic patients on carbamazepine monotherapy, and in women using low-dose oral contraceptives.Biomed Pharmacother1986;40,301-308
 
Gambertoglio, JG, Holford, NH, Kapusnik, JE, et al Disposition of total and unbound prednisolone in renal transplant patients receiving anticonvulsants.Kidney Int1984;25,119-123
 
McLelland, J, Jack, W Phenytoin/dexamethasone interaction: a clinical problem.Lancet1978;1,1096-1097
 
 Levofloxacin (Levaquin): full U.S. prescribing information. 2000; Ortho-McNeil. Raritan, NJ:.
 
van Bortel, L, Bohm, R, Mooij, J, et al Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure.Eur J Clin Pharmacol1989;37,185-189
 
Bogaert, MG, Rosseel, MT, Joos, R, et al Plasma concentrations of nifedipine in patients with renal failure.Arzneimittelforschung1984;34,307-308
 
Swan, SK, Bennett, WM Drug dosing guidelines in patients with renal failure.West J Med1992;156,633-638
 
Ene, MD, Roberts, CJ Pharmacokinetics of nifedipine after oral administration in chronic liver disease.J Clin Pharmacol1987;27,1001-1004
 
Kleinbloesem, CH, van Harten, J, Wilson, JP, et al Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration.Clin Pharmacol Ther1986;40,21-28
 
Horton, R Spinning the risks and benefits of calcium antagonists.Lancet1995;346,586-587
 
Psaty, BM, Heckbert, SR, Koepsell, TD, et al The risk of myocardial infarction associated with antihypertensive drug therapies.JAMA1995;74,620-625
 
Furberg, CD, Psaty, BM, Meyer, JV Nifedipine: dose-related increase in mortality in patients with coronary heart disease.Circulation1995;92,1326-1331
 
Effects of calcium antagonists on the risks of coronary heart disease, cancer and bleeding. Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension.J Hypertens1997;15,105-115
 
Lubsen, J, Wagener, G, Kirwan, BA, et al Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial.J Hypertens2005;23,641-648
 
Yui, Y, Sumiyoshi, T, Kodama, K, et al Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial.Hypertens Res2004;27,181-191
 
Bailey, DG, Dresser, GK Interactions between grapefruit juice and cardiovascular drugs.Am J Cardiovasc Drugs2004;4,281-297
 
Kaplan, RC, Heckbert, SR, Koepsell, TD, et al Use of calcium-channel blockers and risk of hospitalized gastrointestinal tract bleeding.Arch Intern Med2000;160,1849-1855
 
Lanas, A, Serrano, P, Bajador, E, et al Risk of upper gastrointestinal bleeding associated with non-aspirin cardiovascular drugs, analgesics and nonsteroidal anti-inflammatory drugs.Eur J Gostroenterol Hepatol2003;15,173-178
 
Smalley, WE, Ray, WA, Daugherty, JR, et al No association between calcium channel blocker and confirmed bleeding peptic ulcer disease.Am J Epidemiol1998;148,350-354
 
Bortolotti, M, Labriola, E, Bacchelli, S, et al “Oesophageal angina” in patients with angina pectoris: a possible side effect of chronic therapy with nitroderivates and Ca-antagonists.Ital J Gastroenterol1992;24,405-408
 
Petersen, KU, Jaspersen, D Medication-induced oesophageal disorders.Expert Opin Drug Saf2003;2,495-507
 
Chow, T, Browne, V, Heileson, HL, et al Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.Arch Intern Med2005;165,296-301
 
Gertsch, JH, Basnyat, B, Johnson, EW, et al Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT).BMJ2004;328,797
 
Gertsch, JH, Seto, TB, Mor, J, et al Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent.High Alt Med Biol2002;3,29-37
 
Roncin, JP, Schwartz, F, D’Arbigny, P EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure.Aviat Space Environ Med1996;67,445-452
 
Smith, M, Lin, KM, Zheng, YP An open-trial of nifedipine-herb interactions: nifedipine with St. John’s wort, ginseng, or gingko biloba [abstract].Clin Pharmacol Ther2001;69,86
 
Yoshioka, M, Ohnishi, N, Koishi, T, et al Studies on interactions between functional foods or dietary supplements and medicines: IV. Effects of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers.Biol Pharm Bull2004;27,2006-2009
 
Fagenholz, PJ, Gutman, JA, Murray, AF, et al Treatment of high altitude pulmonary edema at 4240 m in Nepal.High Alt Med Biol2007;8,139-146
 
Das, BB, Wolfe, RR, Chan, KC, et al High-altitude pulmonary edema in children with underlying cardiopulmonary disorders and pulmonary hypertension living at altitude.Arch Pediatr Adolesc Med2004;158,1170-1176
 
Forgue, ST, Phillips, DL, Bedding, AW, et al Effects of gender, age, diabetes mellitus and renal and hepatic impairment on tadalafil pharmacokinetics.Br J Clin Pharmacol2007;63,24-35
 
Muirhead, GJ, Wilner, K, Colburn, W, et al The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil.Br J Clin Pharmacol2002;53(suppl 1),21S-30S
 
Grossman, EB, Swan, SK, Muirhead, GJ, et al The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis patients.Kidney Int2004;66,367-374
 
 Product information Revatio (sildenafil citrate) oral tabs. 2006; Pfizer. New York, NY:.
 
 Tadalafil (Cialis) US prescribing information.  Lilly ICOS LLC. Indianapolis, IN:.
 
 Product information: Viagra, sildenafil citrate. 2000; Pfizer. New York, NY:.
 
Callejas Rubio, JL, Salmeron Escobar, J, Gonzalez-Calvin, J, et al Successful treatment of severe portopulmonary hypertension in a patient with Child C cirrhosis by sildenafil.Liver Transpl2006;12,690-691
 
Makisalo, H, Koivusalo, A, Vakkuri, A, et al Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation.Liver Transpl2004;10,945-950
 
Wang, YW, Lin, HC, Yang, YY, et al Sildenafil decreased pulmonary arterial pressure but may have exacerbated portal hypertension in a patient with cirrhosis and portopulmonary hypertension.J Gastroenterol2006;41,593-597
 
Finley, DS, Lugo, B, Ridgway, J, et al Fatal variceal rupture after sildenafil use: report of a case.Curr Surg2005;62,55-56
 
Patterson, D, Kloner, R, Effron, M, et al The effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease.Br J Clin Pharmacol2005;60,459-468
 
Kloner, RA, Jackson, G, Hutter, AM, et al Cardiovascular safety update of Tadalafil: retrospective analysis of data from placebo-controlled and open-label clinical trials of Tadalafil with as needed, three times-per-week or once-a-day dosing.Am J Cardiol2006;97,1778-1784
 
Arruda-Olson, AM, Mahoney, DW, Nehra, A, et al Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial.JAMA2002;287,719-725
 
Fox, KM, Thadani, U, Ma, PT, et al Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina.Eur Heart J2003;24,2206-2212
 
Cazzola, M, Testi, R, Matera, MG Clinical pharmacokinetics of salmeterol.Clin Pharmacokinet2002;41,19-30
 
Manchee, GR, Eddershaw, PJ, Ranshaw, LE, et al The aliphatic oxidation of salmeterol to alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.Drug Metab Dispos1996;24,555-559
 
Ferguson, GT, Funck-Brentano, C, Fischer, T, et al Cardiovascular safety of salmeterol in COPD.Chest2003;123,1817-1824
 
Tranfa, CM, Pelaia, G, Grembiale, RD, et al Short-term cardiovascular effects of salmeterol.Chest1998;113,1272-1276
 
Ullman, A, Svedmyr, N Salmeterol, a new long acting inhaled β2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients.Thorax1988;43,674-678
 
 Product information: Serevent Diskus inhalation powder, salmeterol xinafoate inhalation powder. 2006; Glaxo Smith Kline. Research Triangle Park, NC:.
 
Demaziere, J, Fourcade, JM, Busseuil, CT, et al The hazards of chloroquine self prescription in West Africa.J Toxicol Clin Toxicol1995;33,369-370
 

Figures

Tables

Table Graphic Jump Location
Table 1. Dosing Recommendations for the Primary Medications Used in the Management of Altitude Illness for People With No Underlying Medical Issues
* 

Recommended doses for acetazolamide, dexamethasone, and nifedipine adapted from Hackett and Roach.6

Table Graphic Jump Location
Table 2. Use of High-Altitude Medications in Pregnant or Lactating Women
* 

Pregnancy category B = presumed safe based on studies in animals but no data from humans. Pregnancy category C = no human studies demonstrating harm, but animal studies show evidence of teratogenicity.

 

Some authors19 claim compatibility with breast feeding, while others20 recommend against use in this situation.

Table Graphic Jump Location
Table 3. Use of High-Altitude Medications in Travelers in Malaria-Prone Areas or With Traveler’s Diarrhea
Table Graphic Jump Location
Table 4. Summary of Recommendations for Primary Medications Used in the Treatment and Prevention of Altitude Illness

References

Grissom, CK, Roach, RC, Sarnquist, FH, et al (1992) Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.Ann Intern Med116,461-465
 
Basnyat, B, Gertsch, JH, Holck, PS, et al Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the Prophylactic Acetazolamide Dosage Comparison for Efficacy (PACE) trial.High Alt Med Biol2006;7,17-27
 
Oelz, O, Maggiorini, M, Ritter, M, et al Nifedipine for high altitude pulmonary oedema.Lancet1989;2,1241-1244
 
Maggiorini, M, Brunner-La Rocca, HP, Peth, S, et al Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.Ann Intern Med2006;145,497-506
 
Sartori, C, Allemann, Y, Duplain, H, et al Salmeterol for the prevention of high-altitude pulmonary edema.N Engl J Med2002;346,1631-1636
 
Hackett, PH, Roach, RC High-altitude illness.N Engl J Med2001;345,107-114
 
Basnyat, B, Murdoch, DR High-altitude illness.Lancet2003;361,1967-1974
 
Hackett, P High altitude and common medical conditions. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation2001,839-885 Marcel Dekker. New York, NY:
 
Luks, AM, Swenson, ER Travel to high altitude with pre-existing lung disease.Eur Respir J2007;29,770-792
 
Bartsch, P, Gibbs, JS The effect of altitude on the heart and lungs.Circulation2007;116,2191-2202
 
Jean, D, Leal, C, Kriemler, S, et al Medical recommendations for women going to altitude.High Alt Med Biol2005;6,22-31
 
Baumgartner, RW, Siegel, AM, Hackett, PH Going high with preexisting neurological conditions.High Alt Med Biol2007;8,108-116
 
Brubaker, PL Adventure travel and type 1 diabetes: the complicating effects of high altitude.Diabetes Care2005;28,2563-2572
 
Leal, C Going high with type 1 diabetes.High Alt Med Biol2005;6,14-21
 
Mader, TH, Tabin, G Going to high altitude with preexisting ocular conditions.High Alt Med Biol2003;4,419-430
 
Hackett, PH, Rennie, D The incidence, importance, and prophylaxis of acute mountain sickness.Lancet1976;2,1149-1155
 
Bartsch, P, Mairbaurl, H, Swenson, ER, et al High altitude pulmonary oedema.Swiss Med Wkly2003;133,377-384
 
Bartsch, P, Mairbaurl, H, Maggiorini, M, et al Physiological aspects of high-altitude pulmonary edema.J Appl Physiol2005;98,1101-1110
 
 Breastfeeding and maternal medication. 2002; World Health Organization. Geneva, Switzerland:.
 
 Product information: Decadron®, dexamethasone. 1997; Merck & Company. West Point, PA:.
 
Hohne, C, Krebs, MO, Seiferheld, M, et al Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs.J Appl Physiol2004;97,515-521
 
Hohne, C, Pickerodt, PA, Francis, RC, et al Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition.Am J Physiol Lung Cell Mol Physiol2007;292,L178-L184
 
Teppema, LJ, Balanos, GM, Steinback, CD, et al Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia.Am J Respir Crit Care Med2007;175,277-281
 
Anderson, RJ, Gambertoglio, JG, Schrier, RW. Clinical use of drugs in renal failure. 1976; Charles C. Thomas. Springfield, IL:.
 
Gomolin, IH, Chapron, DJ Elucidating the relationship between acetazolamide plasma protein binding and renal clearance using an albumin infusion.J Clin Pharmacol1992;32,1028-1032
 
Bennett, WM Drug prescribing in renal failure: dosing guidelines for adults 1st ed.1987 American College of Physicians. Philadelphia, PA:
 
Paisley, KE, Tomson, CR Calcium phosphate stones during long-term acetazolamide treatment for epilepsy.Postgrad Med J1999;75,427-428
 
Pepys, MB Acetazolamide and renal stone formation.Lancet1970;1,837
 
Friedland, BR, Maren, TH Carbonic anhydrase: pharmacology of inhibitors and treatment of glaucoma. Sears, ML eds.Handbook of experimental pharmacology1984,279-309 Springer-Verlag. Berlin:
 
Dawson, AM, De Groote, J, Rosenthal, WA, et al The effects of diamox ammonia metabolism in liver disease.Clin Sci (Lond)1957;16,413-420
 
Haussinger, D, Gerok, W Hepatic urea synthesis and pH regulation: role of CO2, HCO3-, pH and the activity of carbonic anhydrase.Eur J Biochem1985;152,381-386
 
Swenson, ER Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression.Eur Respir J1998;12,1242-1247
 
Coudon, WL, Block, AJ Acute respiratory failure precipitated by a carbonic anhydrase inhibitor.Chest1976;69,112-113
 
Lee, AG, Anderson, R, Kardon, RH, et al Presumed “sulfa allergy” in patients with intracranial hypertension treated with acetazolamide or furosemide: cross-reactivity, myth or reality?Am J Ophthalmol2004;138,114-118
 
Strom, BL, Schinnar, R, Apter, AJ, et al Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics.N Engl J Med2003;349,1628-1635
 
Gerhards, LJ, van Arnhem, AC, Holman, ND, et al Fatal anaphylactic reaction after oral acetazolamide (Diamox) for glaucoma [in Dutch].Ned Tijdschr Geneeskd2000;144,1228-1230
 
Tzanakis, N, Metzidaki, G, Thermos, K, et al Anaphylactic shock after a single oral intake of acetazolamide [letter].Br J Ophthalmol1998;82,588
 
Scott, WJ, Duggan, CA, Schreiner, CM, et al Reduction of embryonic intracellular pH: a potential mechanism of acetazolamide-induced limb malformations.Toxicol Appl Pharmacol1990;103,238-254
 
Notarianni, LJ Plasma protein binding of drugs in pregnancy and in neonates.Clin Pharmacokinet1990;18,20-36
 
Sweeney, KR, Chapron, DJ, Brandt, JL, et al Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation.Clin Pharmacol Ther1986;40,518-524
 
Hill, JB Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations.Pediatrics1971;47,658-665
 
 Dorzolamide (Trusopt®) package insert. 2004; Merck & Co. Whitehouse Station, NJ:.
 
 Topamax® (topiramate) package insert. 2005; Ortho-McNeil Pharmaceutical. Raritan, NJ:.
 
Spina, E, Pisani, F, Perucca, E Clinically significant pharmacokinetic drug interactions with carbamazepine: an update.Clin Pharmacokinet1996;31,198-214
 
 Lanoxin® (digoxin) package insert. 2001; Glaxo Smith Kline. Research Triangle Park, NC:.
 
 Product information: Inapsine®, droperidol. 2001; Akorn. Decatur, IL:.
 
Hoffman, BB, Lefkowitz, RJ Catecholamines and sympathomimetic drugs. Gilman, AG Rall, TW Nies, ASet al eds.Goodman and Gilman’s pharmacologic basis of therapeutics1990,211-212 Pergamon Press. New York, NY:
 
Tabbara, KF, Al-Faisal, Z, Al-Rashed, W Interaction between acetazolamine and cyclosporine.Arch Ophthalmol1998;116,832-833
 
Stuiver, PC, Goud, TJ Corticosteroids and liver amoebiasis.BMJ1978;2,394-395
 
Keiser, PB, Nutman, TB Strongyloides stercoralis in the immunocompromised population.Clin Microbiol Rev2004;17,208-217
 
Nielsen, GL, Sorensen, HT, Mellemkjoer, L, et al Risk of hospitalization resulting from upper gastrointestinal bleeding among patients taking corticosteroids: a register-based cohort study.Am J Med2001;111,541-545
 
Messer, J, Reitman, D, Sacks, HS, et al Association of adrenocorticosteroid therapy and peptic-ulcer disease.N Engl J Med1983;309,21-24
 
Wu, T, Liu, J Alcohol and aspirin in combination with dexamethasone causes gastrointestinal bleeding at high altitude.Wilderness Environ Med2006;17,69-71
 
Wu, TY, Ding, SQ, Liu, JL, et al High-altitude gastrointestinal bleeding: an observation in Qinghai-Tibetan railroad construction workers on Mountain Tanggula.World J Gastroenterol2007;13,774-780
 
Olivesi, A Modified elimination of prednisolone in epileptic patients on carbamazepine monotherapy, and in women using low-dose oral contraceptives.Biomed Pharmacother1986;40,301-308
 
Gambertoglio, JG, Holford, NH, Kapusnik, JE, et al Disposition of total and unbound prednisolone in renal transplant patients receiving anticonvulsants.Kidney Int1984;25,119-123
 
McLelland, J, Jack, W Phenytoin/dexamethasone interaction: a clinical problem.Lancet1978;1,1096-1097
 
 Levofloxacin (Levaquin): full U.S. prescribing information. 2000; Ortho-McNeil. Raritan, NJ:.
 
van Bortel, L, Bohm, R, Mooij, J, et al Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure.Eur J Clin Pharmacol1989;37,185-189
 
Bogaert, MG, Rosseel, MT, Joos, R, et al Plasma concentrations of nifedipine in patients with renal failure.Arzneimittelforschung1984;34,307-308
 
Swan, SK, Bennett, WM Drug dosing guidelines in patients with renal failure.West J Med1992;156,633-638
 
Ene, MD, Roberts, CJ Pharmacokinetics of nifedipine after oral administration in chronic liver disease.J Clin Pharmacol1987;27,1001-1004
 
Kleinbloesem, CH, van Harten, J, Wilson, JP, et al Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration.Clin Pharmacol Ther1986;40,21-28
 
Horton, R Spinning the risks and benefits of calcium antagonists.Lancet1995;346,586-587
 
Psaty, BM, Heckbert, SR, Koepsell, TD, et al The risk of myocardial infarction associated with antihypertensive drug therapies.JAMA1995;74,620-625
 
Furberg, CD, Psaty, BM, Meyer, JV Nifedipine: dose-related increase in mortality in patients with coronary heart disease.Circulation1995;92,1326-1331
 
Effects of calcium antagonists on the risks of coronary heart disease, cancer and bleeding. Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension.J Hypertens1997;15,105-115
 
Lubsen, J, Wagener, G, Kirwan, BA, et al Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial.J Hypertens2005;23,641-648
 
Yui, Y, Sumiyoshi, T, Kodama, K, et al Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial.Hypertens Res2004;27,181-191
 
Bailey, DG, Dresser, GK Interactions between grapefruit juice and cardiovascular drugs.Am J Cardiovasc Drugs2004;4,281-297
 
Kaplan, RC, Heckbert, SR, Koepsell, TD, et al Use of calcium-channel blockers and risk of hospitalized gastrointestinal tract bleeding.Arch Intern Med2000;160,1849-1855
 
Lanas, A, Serrano, P, Bajador, E, et al Risk of upper gastrointestinal bleeding associated with non-aspirin cardiovascular drugs, analgesics and nonsteroidal anti-inflammatory drugs.Eur J Gostroenterol Hepatol2003;15,173-178
 
Smalley, WE, Ray, WA, Daugherty, JR, et al No association between calcium channel blocker and confirmed bleeding peptic ulcer disease.Am J Epidemiol1998;148,350-354
 
Bortolotti, M, Labriola, E, Bacchelli, S, et al “Oesophageal angina” in patients with angina pectoris: a possible side effect of chronic therapy with nitroderivates and Ca-antagonists.Ital J Gastroenterol1992;24,405-408
 
Petersen, KU, Jaspersen, D Medication-induced oesophageal disorders.Expert Opin Drug Saf2003;2,495-507
 
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