CHEST Recent Advances in Chest Medicine

Medication and Dosage Considerations

in the Prophylaxis and Treatment of
High-Altitude Illness*
Andrew M. Luks, MD; and Erik R. Swenson, MD

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. (CHEST 2008; 133:744 –755)

Key words: acetazolamide; acute mountain sickness; altitude; dexamethasone; high-altitude cerebral edema; high-
altitude pulmonary edema; nifedipine; sildenafil; tadalafil

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 antiin-
flammatory drug

ndividuals who ascend to altitudes ⬎ 2,350 m

I (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 studies1–5
have established the effective doses of different medi-
cations for the prevention and treatment of these
diseases, and several major reviews6,7 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 prob-
lems. 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 descrip-
tion, particularly when one considers the high preva-
lence of clinical conditions such as diabetes, hyperten-
sion, 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

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 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 infor-
mation 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 clin-
ical 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 environ-
ment. 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 conditions8
including lung disease,9 heart disease,10 pregnancy,11
neurologic conditions,12 diabetes,13,14 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 particu-
larly important point to keep in mind regarding
patients with severe renal disease (glomerular filtra-
tion rate [GFR] ⬍ 10 mL/min), liver disease (portal
*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.
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.
Manuscript received June 6, 2007; revision accepted June 28,
2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
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
DOI: 10.1378/chest.07-1417
www.chestjournal.org
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hypertension), lung disease (FEV1 ⬍ 25% of pre-
dicted), 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 recommen-
dations 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 indica-
tions for its use and then review use of the medica-
tion in patients with renal insufficiency, hepatic
insufficiency, and other important medical condi-
tions, as well as the potential for drug-drug interac-
tions. 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.6,7,17 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 medica-
tion 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.6,7,18
Acetazolamide
The carbonic anhydrase inhibitor (CAI) acetazol-
amide is the mainstay for prevention and treatment
of AMS and HACE. Research studies in several
animals21,22 and a single study in humans23 have
shown that acetazolamide can block hypoxic pulmo-
nary vasoconstriction and may play a role preventing
HAPE, but in the absence of studies demonstrating
a prophylactic effect in HAPE it cannot be recom-
mended 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 acet-
azolamide elimination occurs via the kidney24 and
50% of clearance depends on tubular secretion,25
CHEST / 133 / 3 / MARCH, 2008 745
 Table 1—Dosing Recommendations for the Primary Medications Used in the Management of Altitude Illness for
People With No Underlying Medical Issues

Medications* Indication Route Prevention Dose Treatment Dose

Acetazolamide AMS Oral 125 or 250 mg bid 250 mg bid

Dexamethasone AMS Oral, IM, or IV 2 mg q6h or 4 mg q12h 4 mg q6h
HACE Oral, IM, or IV 2 mg q6h or 4 mg q12h 8 mg initially then 4 mg q6h
Nifedipine HAPE Oral 20 to 30 mg of sustained- 20 to 30 mg of sustained-
release version q12h release version q12h
Tadalafil HAPE Oral 10 mg bid Unknown
Sildenafil HAPE Oral 50 mg q8h Unknown
Salmeterol HAPE Inhaled 125 ␮g bid Unknown
*Recommended doses for acetazolamide, dexamethasone, and nifedipine adapted from Hackett and Roach.6

dose 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.26 Patients 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 neph-
rolithiasis should avoid acetazolamide because there
have been reports27,28 of calcium-phosphate stone for-
mation during CAI therapy as a result of urinary
alkalinization and suppression of citrate excretion.
stream. 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 accumula-
tion 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.

Hepatic Insufficiency: Patients with liver disease Other Medical Conditions: Care should be taken
should not receive acetazolamide.29 Because acet- when administering acetazolamide to patients with
azolamide alkalinizes the urine, ammonium ion severe COPD or other disorders associated with
(NH4⫹) is diverted from the urine to the blood- 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
Table 2—Use of High-Altitude Medications in Pregnant
carbonic anhydrase inhibition and, as a result, impair
or Lactating Women
carbon dioxide (CO2) excretion.32 In patients with
Safety During Safety During limited ventilatory reserve, increased ventilatory de-
Medications Pregnancy* Breastfeeding mand and CO2 retention may lead to worsened
Acetazolamide Category C; may Not established dyspnea and/or respiratory failure.33 In such pa-
increase minute tients, we recommend limiting the dose to 125 mg
ventilation needs and bid or using dexamethasone instead.
create increased
Caution should also be used in patients with a sulfa
dyspnea
Dexamethasone Category C Debate about allergy because acetazolamide contains a sulfon-
safety† amide and the potential exists for cross-reactivity.
Nifedipine Category C Compatible The likelihood of a reaction in patients with self-
Tadalafil Category B Not established reported “sulfa allergy” is low (7 to 10%),34,35 but
Sildenafil Category B Not established
case reports36,37 have described anaphylactic reac-
Salmeterol Category C Not established
tions in patients with documented sulfa allergies who
*Pregnancy category B ⫽ presumed safe based on studies in animals received acetazolamide. In addition, remote regions of
but no data from humans. Pregnancy category C ⫽ no human
studies demonstrating harm, but animal studies show evidence of
the mountains are not the place to discover that a
teratogenicity. patient is one of the rare people who do, in fact,
†Some authors19 claim compatibility with breast feeding, while cross-react and have anaphylaxis. For that reason, we
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

Medications Malaria Traveler’s Diarrhea

Acetazolamide No known interactions with prophylaxis medications; No interactions with fluoroquinolones or

can increase serum concentrations of quinine and
increase risk of quinine toxicity
Dexamethasone No known interactions with prophylaxis or treatment
medications
Nifedipine No reported interactions with prophylaxis or
treatment medications but potential interaction
with mefloquine
Tadalafil No reported interactions with prophylaxis or
treatment medications but potential interaction
with mefloquine
Sildenafil No reported interactions with prophylaxis or
treatment medications but potential interaction
with mefloquine
Salmeterol Avoid chloroquine due to increased risk of QT-
interval prolongation and ventricular arrhythmia;
other agents are safe to use
macrolides; avoid in patients with active
diarrhea or vomiting due to risk of
dehydration or hypokalemia
Potential increased risk of tendon injury when
used in conjunction with fluoroquinolones
Avoid clarithromycin; azithromycin and
fluoroquinolone use is safe
Avoid clarithromycin; azithromycin and
fluoroquinolone use is safe
Avoid clarithromycin; azithromycin and
fluoroquinolone use is safe
Avoid clarithromycin; azithromycin and
fluoroquinolone use is safe

recommend that patients with documented sulfa al-
lergy undergo a physician-supervised trial of acetazol-
amide 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 dexametha-
sone instead.
Because pregnant women already have increased
ventilation due to higher circulating levels of proges-
terone, the metabolic acidosis generated by acetazol-
amide, 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 trimester38 and 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 aspi-
rin use can impair acetazolamide elimination.40 This
leads to a greater degree of metabolic acidosis,
which, in turn, increases CNS penetration of aspirin,
thereby increasing the risk of aspirin toxicity.41 Ac-
etazolamide should also be avoided in patients re-
ceiving ophthalmic CAIs such as dorzolamide be-
cause the combination of drugs may have an additive
effect.42 Finally, 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.43
Clinically 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, furo-
semide or hydrochlorothiazide) because this may
increase the risk of electrolyte abnormalities and
dehydration. The kaliuretic effects mandate caution
when administering acetazolamide to people receiv-
ing digoxin for atrial fibrillation or cardiomyopathy
because hypokalemia increases the risk for junctional
bradycardia or other forms of digoxin toxicity.45 The
kaliuretic effects of acetazolamide may also affect ad-
ministration of antiemetics to patients with GI symp-
toms; 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, acet-
azolamide may increase the excretion of acidic drugs
such as barbiturates while decreasing the excretion
of alkaline drugs such as ephedrine, ephedra, or
amphetamines.47 Acetazolamide 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

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 acetazolamide, dexamethasone does not facilitate accli-
matization. As a result, abrupt cessation of dexameth-
asone may lead to a rebound effect and the manifesta-
tion 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 pa-
tients with underlying renal insufficiency. There are
no contraindications to its use, and dose adjustments
are not necessary in patients with impaired glomer-
ular 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 Mag-
giorini 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 reviews13,14 on this topic.
Patients suspected of having amebiasis or strongy-
loidiasis should consider avoiding dexamethasone. In
the case of amebiasis, concurrent steroid use can
lead to acute amebic dysentery and potentially ful-
minant hepatic disease49; while in the presence of
strongyloides infection, corticosteroid use can pro-
voke a hyperinfection syndrome.50 Individuals who
have spent considerable time traveling in the devel-
oping world are at high risk for these infections; if
they plan to use dexamethasone for AMS prophy-
laxis, 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 dexa-
methasone because corticosteroids have been shown
to increase the risk of both problems.51,52 This risk
may be further increased by concurrent use of
alcohol, aspirin, or other nonsteroidal antiinflamma-
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tory drugs (NSAIDs).53 This 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 dexameth-
asone 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 metabo-
lism.55–57 According to the product information58 for
the fluoroquinolone levofloxacin, postmarketing sur-
veillance 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 develop-
ment of pulmonary edema.
Renal Insufficiency: Because plasma concentra-
tions are the same in patients with and without renal
insufficiency,59,60 dose adjustments are not necessary
in the setting of renal disease.61 As a result, nifedi-
pine 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,62 and 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
Recent Advances in Chest Medicine
 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 hyperten-
sion and coronary artery disease64 after several stud-
ies demonstrated an increased risk of myocardial
infarction65 and even death66 in patients with hyper-
tension or coronary artery disease receiving calcium-
channel blockers. This concern has since dissipated.
A report67 following 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
trials68,69 have demonstrated that long-acting dihy-
dropiridine 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 evalu-
ated prior to high altitude travel to determine their
fitness for this environment.
Drug Interaction Issues: Several potential drug
interactions warrant attention. Nifedipine is elimi-
nated 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 carbemaz-
epine. 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 in-
creased 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 pa-
tients receiving antihypertensive agents, such as
␤-blockers or ␣-blockers, because the combination
may precipitate hypotension. Patients receiving ni-
fedipine should also avoid grapefruit juice, which can
decrease systemic bioavailability,70 and calcium sup-
plements, which may inhibit its effects at the site of
action in vascular smooth muscle.
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Given the results of a prior study71 that demon-
strated 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 studies72,73 have not found a
relationship between this class of medications and
increased risk of GI hemorrhage. Patients with gas-
troesophageal reflux disease should also exercise
caution when using nifedipine because the drug can
decrease lower esophageal sphincter tone and pro-
mote increased reflux of gastric contents into the
esophagus.74,75
Finally, it is worth discussing the potential interac-
tion with gingko biloba. Although several trials76,77 have
shown that the supplement is no better than placebo at
preventing altitude illness, earlier studies78,79 were sug-
gestive of a benefit, and it is conceivable that people
traveling to high altitude will use this medication for
AMS prophylaxis. Two studies80,81 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 recom-
mend 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 mecha-
nism of action and should exert a similar benefit as
tadalafil and because there are reports of its use in
clinical practice as treatment for HAPE82 or preven-
tion 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 Pa-
tients with creatinine clearance ⬎ 50 mL/min do not
require dose adjustments, but patients with creati-
nine clearance between 30 and 50 mL/min should
CHEST / 133 / 3 / MARCH, 2008 749
 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.84 The
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 bio-
availability is increased, necessitating dose reduc-
tions.85 Interestingly, in dialysis-dependent patients,
the pharmacokinetic profile again resembles that
observed in volunteers with normal renal function.86
It should be noted, however, that most studies of
sildenafil dosing in renal failure have examined
single-dose administration in dialysis-dependent pa-
tients; no studies have examined whether dose ad-
justments are necessary with repeated drug admin-
istration 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 pa-
tients 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 regard-
ing outcomes in patients with severe hepatic insuffi-
ciency. Despite these lower peak and plasma con-
centrations, 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 oc-
curs 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,89 the literature
does contain several reports90,91 of patients with
750
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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 flow92 at the same time that it lowers pulmo-
nary artery pressures, patients with portal hyperten-
sion 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 pa-
tients with cirrhosis who are traveling to high alti-
tude, but one should consider adequate screening
prior to travel and consider alternative agents for
HAPE prophylaxis in patients found to have signifi-
cant 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,94 or in-
crease the risk of serious cardiovascular events such
as myocardial infarction, stroke, or cardiovascular
death.95 Sildenafil has also been shown to have no
effect on symptoms, exercise tolerance, or ischemic
threshold in this patient group.96,97 Like nifedipine,
tadalafil and sildenafil decrease lower esophageal
sphincter tone and may increase symptoms of gas-
troesophageal 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 conjunc-
tion 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 con-
junction with antimalarial agents including meflo-
quine, 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
Recent Advances in Chest Medicine
 where the drugs are used in combination with
␣-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 ␤-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 pro-
phylactic 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 insuf-
ficiency. When administered in inhaled form at
doses recommended for the treatment of asthma (50
␮g bid), low-to-undetectable plasma concentrations
are achieved. It should be noted, though, that the
dose used in the single HAPE prevention trial98 (125
␮g 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, be-
cause the kidney plays a minimal role in salmeterol
elimination, renal insufficiency would not be ex-
pected to affect drug clearance or clinical effects.
Because ␤-agonists cause cellular uptake of potas-
sium, caution should be exercised when using the
drug in patients with a predisposition toward hypo-
kalemia, particularly when such patients are receiv-
ing 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 sympa-
thomimetic effects, it is worthwhile to consider if
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salmeterol poses risks to patients with a history of
cardiac disease or who are prone to tachyarrhyth-
mias. Ferguson et al100 conducted a metaanalysis of
seven randomized studies that compared salmeterol
50 ␮g bid against placebo in patients with COPD
and found an equal risk of cardiovascular adverse
events as well as equal ventricular and supraventric-
ular 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 studies101,102
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 ␤-blockers
such as metoprolol or atenolol may have decreased
effectiveness of either the ␤-blocker or salmeterol
because the two classes of medications have opposite
effects on ␤-receptors. Caution is necessary when
using salmeterol in conjunction with or shortly fol-
lowing discontinuation of two classes of antidepres-
sant medications: monoamine oxidase inhibitors and
tricyclic antidepressants. In the case of the mono-
amine oxidase inhibitors, there is concern that con-
current use of a ␤-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 medica-
tions could lead to increased incidence of BP eleva-
tion, 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 concen-
trations 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
Conclusions
This review demonstrates that many factors can
affect the medication choices for patients with un-
derlying medical conditions who seek pharmacologic
options for the prophylaxis or treatment of altitude
CHEST / 133 / 3 / MARCH, 2008 751
 752
Table 4 —Summary of Recommendations for Primary Medications Used in the Treatment and Prevention of Altitude Illness

Medications Renal Insufficiency Hepatic Insufficiency Other Major Dosing Issues

Acetazolamide Avoid use in patients with GFR ⬍ 10 mL/min, Acetazolamide use is contraindicated Avoid in patients receiving long-term high doses of aspirin or with
metabolic acidosis, hypokalemia, hypercalcemia, ventilatory limitation (FEV1 ⬍ 25% of predicted); caution in
and hyperphosphatemia, or recurrent patients with documented sulfa allergy; avoid concurrent use of
nephrolithiasis topiramate, potassium-wasting diuretics, and ophthalmic CAI
Dexamethasone No contraindication and no dose adjustments No contraindication and no dose adjustments Expect elevated blood glucose values when used in diabetic
necessary necessary patients; avoid in patients at risk for peptic ulcer disease or
upper-GI bleeding; caution in patients at risk for amebiasis or

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strongyloidiasis
Nifedipine No contraindication and no dose adjustments Best to avoid; if use is necessary, administer Caution in patients at risk for GI bleeding or with gastroesophageal
necessary at reduced dose (10 mg bid) of sustained- reflux; caution in patients taking medications metabolized by
release version CytP450 3A4 and 1A2 pathways; caution during concurrent use
with other antihypertensive medications
Tadalafil Dose adjustments necessary if GFR ⬍ 50 mL/min; Child’s class A and B: maximum 10 mg/d; Increased risk of gastroesophageal reflux; caution in patients
if GFR is 30 to 50 mL/min, use 5-mg dose, Child’s class C: do not use tadalafil receiving medications metabolized by CytP450 3A4 pathway;
maximum 10 mg in 48 h; if GFR is ⬍ 30 mL/ avoid concurrent use of nitrates or ␣-blockers
min, no more than 5 mg
Sildenafil Dose adjustments necessary if GFR ⬍ 30 mL/min Dose reductions recommended; starting dose Increased risk of gastroesophageal reflux; caution in patients
is 25 mg tid; avoid use in patients with receiving medications metabolized by CytP450 3A4 pathway;
known esophageal or gastric varices avoid concurrent use of nitrates or ␣-blockers
Salmeterol No contraindication and no dose adjustments Insufficient data; best to avoid the Potential for adverse effects in patients with coronary artery
necessary medication in these patients disease prone to arrhythmia; avoid concurrent use of
␤-blockers; avoid concurrent use of monoamine oxidase
inhibitors or tricyclic antidepressants

Recent Advances in Chest Medicine

 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 com-
plicated medication profiles require a thorough pre-
travel 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, respec-
tively. 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 consid-
erations described in this article should come into
play.
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