CME Topic

Secondary Hypertension due to Drugs

and Toxins
Geeta Gyamlani, MD, and Stephen A. Geraci, MD

atypical (by age and risk profile) hypertension, before per-

Abstract: This review summarizes the current state of knowledge
formance of expensive or invasive tests for other etiologies.
about drugs, other chemical substances, and toxins on blood pres-
sure. Many classes of drugs, such as steroids, sympathomimetic
amines, immunosuppressive agents, nonsteroidal anti-inflammatory
Steroids
agents, antidepressants, erythropoietin, substances of abuse and other Corticosteroids
agents can induce transient or sustained hypertension, exacerbate Although hypertension develops in 70 to 80% of patients
well-controlled hypertension, antagonize the effects of antihyperten- with Cushing syndrome, it is seen in only 15 to 20% of
sive therapy, or precipitate hypertensive emergencies. Heightened patients treated with high-dose synthetic corticosteroids,
awareness on the part of the physician is important to avoid unnec- which have less mineralocorticoid activity than cortisol.1,2 In
essary tests in search for other etiologies, and to reduce antihyper- healthy subjects, a several day infusion of cortisol or oral
tensive medication prescriptions by eliminating contributing agents ingestion of dexamethasone leads to increased systolic and
whenever possible. These agents represent an important modifiable diastolic blood pressure parallel with increased arterial resis-
cause of secondary or resistant hypertension. tance.3–5 Patients receiving therapeutic glucocorticoids also
have a greater sensitivity to catecholamines from a direct
Key Words: hypertension, toxins, secondary, resistant, drugs
effect of the drugs on vascular tissue.5 Natural licorice and its
derivative carbenoxonole cause a syndrome of apparent min-
D rugs, herbal preparations and environmental toxins are
important and modifiable causes of hypertension. The
presence of other drugs or chemicals which elevate blood
eralocorticoid excess, with hypertension, hypokalemic metabolic
alkalosis, and suppression of the renin-angiotensin-aldosterone
system.6 The mechanism is inhibition of 11 ␤-hydroxysteroid
pressure directly or through secondary phenomena (drug in- dehydrogenase (11 ␤–HSD),7 preventing the deactivation of cor-
teractions, renal impairment) can produce resistant hyperten- tisol to cortisone, permitting circulating endogenous glucocorti-
sion (blood pressure remaining above goal despite treatment coids to bind to mineralocorticoid (and possibly glucocorticoid)
with three or more antihypertensive medications at or near receptors, and inducing a mineralocorticoid-like response.8 Flu-
maximal doses), increase antihypertensive drug requirements, oroprednisolone and 9␣–fluorocortisol have considerable direct
or cause loss of blood pressure control in previously con- mineralocorticoid activity; in large amounts they produce arte-
trolled hypertensives. A thorough history, addressing present rial hypertension with a clinical picture of pseudohyperaldoste-
and past medication use, over-the-counter and “natural” sup- ronism (increased exchangeable sodium and blood volume, hy-
plements, as well as environmental exposures, should be part pokalemic metabolic alkalosis, and suppressed plasma renin and
of every evaluation of patients with marked, refractory, or

From the Department of Internal Medicine, University of Mississippi School

Key Points
of Medicine, G.V. (Sonny) Montgomery VAMC, Jackson, Mississippi. • Certain drugs, herbal preparations and environmental
Reprint requests to Dr. Geeta Gyamlani, University of Mississippi School of toxins are important and modifiable causes of hyper-
Medicine, G.V. (Sonny) Montgomery VAMC, 1500 E. Woodrow Wilson tension, sometimes contributing to hypertensive emer-
Drive, Jackson, MI 39216. Email: [email protected] gencies.
Research for this review was gathered from PubMed (years 1974 to 2006) • These agents can induce transient or sustained hyper-
using keywords “drug-induced hypertension,” “resistant hypertension,”
“hypertension and toxins” and “secondary hypertension.” A search was tension, exacerbate well-controlled hypertension, or
also performed of the MicroMedex database (version 5.1). antagonize the effects of antihypertensive therapy.
Neither Dr. Gyamlani nor Dr. Geraci have any financial disclosures to declare. • Heightened awareness on the part of the treating phy-
Accepted February 22, 2007. sician is important to avoid unnecessary and expen-
Copyright © 2007 by The Southern Medical Association sive testing.
0038-4348/0⫺2000/10000-0692

692 © 2007 Southern Medical Association

 CME Topic

aldosterone levels).9 Prolonged use of high-dose ketoconazole cell mass, and can occur even with no change in hematocrit.24
and other drugs that inhibit endogenous steroid catabolism can Chronic exogenous EPO results in a reduction of nitric oxide-
lead to mineralocorticoid-related hypertension.10 Discontinua- mediated vasodilation via elevated resting cytosolic calcium
tion of interacting drugs and/or steroids is recommended to ame- concentrations, and directly constricts resistance arterioles.25
liorate steroid-induced hypertension. When steroid therapy is Initially, this effect is countered by acute elevations of nitric
unavoidable, the resultant hypertension usually responds to fluid oxide and cGMP. When taken chronically however, EPO
restriction and diuretics.11 promotes vascular smooth muscle cell growth, vascular re-
modeling and medial hypertrophy, maintaining blood pres-
Sex Hormones sure elevation.25,26 Hypertension from rHuEPO is generally
Hypertension is 2 to 3 times more common in women easily controlled; in one report, 42% of patients were effec-
taking oral contraceptives than in control patients.12 It is es- tively treated with a single agent.27 In the chronic hemodial-
pecially common among individuals with a history of ele- ysis population, hypertension can also be treated with fluid
vated blood pressure during pregnancy, those with a family removal and conventional antihypertensive therapy; when un-
history of hypertension, smokers, blacks, obese women, and successful, the rHuEPO dose should be lowered, or therapy
diabetics.13 High-dose estrogens may induce sodium reten- held for several weeks. When refractory to these approaches,
tion and volume expansion through an interaction with min- phlebotomy (500 mL) can also help.28
eralocorticoid receptors or effects on 11 ␤-HSD activity.14
Sex hormones also increase plasma concentrations of angio- Nonsteroidal Anti-inflammatory Drugs
tensinogen.15 Danazol, a semisynthetic androgen used to treat Nonsteroidal anti-inflammatory drugs (NSAIDs) are the
endometriosis and hereditary angioedema (and abused as a medications most commonly prescribed to treat pain and in-
performance-enhancing androgen by athletes) can induce hy- flammation, but hypertension, renal and gastrointestinal tox-
pertension through salt and water retention; blood pressure icity can limit tolerance. NSAIDs cause sodium retention,
usually responds to low-dose diuretics if the drug cannot be enhance the vasoconstrictor response to pressor hormones,
stopped.16 and antagonize the effects of antihypertensive drugs.29 Hy-
pertension is caused by cyclooxygenase inhibition, which re-
Immunosuppressive Agents duces vasodilatory prostaglandin synthesis. These prostaglan-
dins promote natriuresis and modulate systemic and renal
Cyclosporine vasodilation, glomerular filtration, and sympathetic nerve
Hypertension is reported in as many as 50 to 70% of transmission. The net effects of NSAIDs are salt and water
patients undergoing renal, hepatic or heart transplants treated retention, loss of renal vasodilation, and increased sympa-
with cyclosporine. This drug can cause new onset, or exac- thetic activity with resultant suppression of renin activity.30
erbation of pre-existing, hypertension. Most studies have Two meta-analyses confirmed that NSAIDs increase mean
shown no association with race or gender. Typically, patients arterial pressure an average of 4 to 5 mm Hg.31,32 They can
develop mild to moderate hypertension, with severe hyper- antagonize the actions of most antihypertensive agents, ex-
tension occurring infrequently.17 Enhanced renal vasocon- cept calcium channel blockers and perhaps central sympatho-
striction with decreased excretion of salt and water produces lytics, whose effects are largely unrelated to prostaglandin
volume-dependent (low renin) hypertension.18 Blood pres- actions.33 Ibuprofen, piroxicam and naproxen demonstrate
sure may be difficult to control when cyclosporine is contin- the greatest blood pressure effects, whereas sulindac and full-
ued, and although this typically decreases after drug discon- dose aspirin exhibit the least effects.30,34 Low-dose aspirin
tinuation, it may not resolve completely.19 Although diuretics has no effect on blood pressure in hypertensive patients, but
are effective treatment, they may exacerbate prerenal azotemia. selective cyclooxygenase-2 inhibitors (rofecoxib and cele-
Calcium channel antagonists are the most consistently effective coxib) increase pressure in a dose-dependent manner.35 Both
agents, but can increase cyclosporine blood levels through cy- the incidence and severity of hypertension are greater with
tochrome P450-mediated metabolism of cyclosporine.20 rofecoxib than with celecoxib or naproxen.36 Since NSAIDs
are available over the counter, clinicians must consider their
contribution to new onset and refractory hypertension.
Recombinant Human Erythropoietin
Recombinant human erythropoietin (rHuEPO) has dra-
matically improved the care of patients with renal failure, but Therapeutic Sympathomimetic Amines
can increase blood pressure in a dose-dependent fashion and Sympathomimetic amines produce ␣-adrenergic agonism
cause hypertension in 20 to 33% of recipients.21 A family by postsynaptic receptor binding, facilitated norepinephrine
history and a prior personal history of hypertension increase release from neuronal storage sites, or both mechanisms.37
this risk.22,23 Hypertension may develop 2 to 16 weeks after Over-the-counter nasal sprays, oral decongestants, and many
starting rHuEPO,22 does not correlate with an increase in red appetite suppressants contain the vasoconstrictors ephedrine,

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Gyamlani and Geraci • Secondary Hypertension due to Drugs and Toxins

pseudoephedrine and oxymetazoline. They can both cause cations of amphetamines are comparable to those of cocaine
and counteract the pharmacological treatment of hyperten- and include hypertension and tachycardia.54 Methylphenidate
sion.37– 40 Hypertension has occurred with ocular administra- has been reported to cause hypertension in children treated
tion of dipivefrin (epinephrine) used to treat simple glau- for attention deficit disorder.55 Mescaline has effects very
coma, and ocular phenylephrine.41 Premature neonates, the similar to amphetamines and can increase blood pressure.54
elderly, and those with idiopathic orthostatic hypotension are Studies showing the superiority of one antihypertensive strat-
at greater risk from the latter drug.42 egy over others are lacking.
Patients frequently forget to include over-the-counter prod-
ucts in their medication history, and their ubiquitous nature Antidepressants
makes legal sympathomimetic amines frequent contributors to Monoamine oxidase inhibitors may cause severe hyper-
hypertension. Discontinuing the offending agent will usually nor- tension in patients who consume foods containing tyramine.56
malize blood pressure but when continuation is necessary, anti- Although the drugs themselves can exacerbate hypertension
hypertensive drugs are required. Treatment with ␤-blockers by increasing the half-life of norepinephrine at sympathetic
should be avoided as they may produce unopposed ␣-adrenergic nerve terminals, the effect is magnified when amine precur-
vasoconstriction.43 Postsynaptic ␣-blockers (eg, terazosin) or sors (dietary tyramine) are present.57 Of these agents, tranyl-
mixed ␣/␤ blockers (eg, labetalol) can be considered,44 as can cypromine is the most likely to raise blood pressure, as op-
vasodilators with sites of action distal to the adrenergic receptors posed to moclobemide and brofaromine, which are the least
(hydralazine, calcium channel antagonists). likely to elevate pressures. ␣-and combined ␣/␤ blockers seem
appropriate for initial management.58,59 Tricyclic antidepres-
Substances of Abuse sants increase blood pressure in patients with panic disor-
ders60 or pheochromocytoma.61 Sustained dose-dependent in-
Alcohol creases in blood pressure have been reported in patients
Excessive alcohol use can increase blood pressure and receiving therapeutic doses of venlafaxine.62 Episodes of se-
cause antihypertensive drug resistance in a dose-dependent vere hypertension have also been described in patients treated
manner.45 Several mechanisms have been proposed, includ- with other antidepressants such as fluoxetine.63
ing impaired baroreflex activity, sympathetic activation, in-
creased intracellular calcium, cortisol hypersecretion, and re- Antihypertensive Agents
versible disturbances in cellular sodium metabolism.46 – 48 Volume contracted, high-renin hypertensive patients may
Limitation of daily ethanol intake to no more than 1 ounce experience “paradoxic” blood pressure elevation when diuret-
(30 mL) of 40% ethanol for most men and 0.5 ounces for ics or vasodilators (which further stimulate renin production)
women and smaller men results in little blood pressure ef- are added to their regimens.64 Central ␣-2 agonists (clonidine)
fect.49 In some cases, blood pressure control is extremely may cause peripheral vasoconstriction via crossover stimula-
difficult without total abstinence. tion of peripheral postsynaptic ␣-1 receptors,65 while sympa-
tholytics such as methyldopa66 may cause transient hyperten-
Cocaine sive exacerbation before their hypotensive effects become
The prevalence of recreational drug use mandates that manifest. Rebound or withdrawal hypertension has been as-
cocaine be considered in all patients presenting for emer- sociated with the abrupt discontinuation of clonidine and
gency care with hypertensive complaints.50 Tachycardia and ␤-blockers (most commonly), but also minoxidil, methyl-
blood pressure elevation are common clinical manifestations dopa, nifedipine and guanethidine.67 The likely mechanism
of cocaine intoxication.51 By blocking neuronal reuptake of of clonidine withdrawal is a rapid resumption of catechol-
norepinephrine, cocaine causes neurotransmitter accumula- amine production suppressed during therapy.68 Withdrawal
tion in the synaptic cleft and results in intense sympathetic hypertension from ␤-blockers occurs due to therapy-induced
activation.52 Most of these patients do not require antihyper- receptor upregulation,69 and gradual dose tapering avoids this
tensive drug therapy, but if treatment is necessary, ␣-adren- reaction. Although not substantiated, selective ␤1 specific
ergic receptor antagonists, direct vasodilators, calcium chan- blockers70 or longer acting ␤-blockers may be associated with
nel blockers and combined ␣/␤ blockers are logical this complication less frequently.71 Concurrent use of
choices.52,53 Nitroglycerin and calcium channel antagonists clonidine and ␤-blockers place patients at particularly high
reverse cocaine-induced hypertension and coronary vasocon- risk for rebound hypertension should clonidine be stopped,
striction and are agents of choice for ischemic chest pain in due to the absence of ␤2 vasodilation and unopposed ␣-re-
this setting. ceptor stimulation in this setting.72

Amphetamines Anesthetics
Amphetamines are noncatechol sympathomimetic agents Ketamine is an anesthetic agent that increases heart rate,
with substantial abuse potential. The cardiovascular compli- systemic arterial pressure, systemic vascular resistance, pul-

694 © 2007 Southern Medical Association

 CME Topic

Table. Common hypertension-causing drugs

Medication Mechanism of action Management
Steroids
Corticosteroids Increases sensitivity to catecholamines Discontinue drug, fluid restriction, diuretics
Mineralocorticoids Increased exchangeable sodium and blood volume Discontinue drug, fluid restriction, diuretics
Sex hormones Sodium retention, volume expansion, increased plasma Discontinue drug, fluid restriction, diuretics
concentration of angiotensinogen
Immunosuppressive agents
Cyclosporine Enhanced renal vasoconstriction, volume-dependent Discontinue or switch to tacrolimus. Calcium
hypertension channel antagonists effective
Recombinant human erythropoietin Reduction in nitric oxide-mediated vasodilation and direct Dose reduction, fluid removal, conventional
(rHuEPO) vasoconstriction of the resistance arterioles antihypertensives and phlebotomy in
refractory cases
Nonsteroidal anti-inflammatory Cyclo-oxygenase inhibition reduces vasodilatory prostaglandin Discontinue drug, calcium channel blockers
drugs (NSAIDs) synthesis and central sympatholytics
Therapeutic sympathomimetic ␣-adrenergic agonism by postsynaptic receptor binding and/or Discontinue drug, postsynaptic ␣-blockers,
amines norepinephrine release from neuronal storage sites combined ␣/␤ blockers or vasodilators
Substances of abuse
Alcohol Impaired baroreflex activity, sympathetic activation, cortisol Limitation of alcohol intake
hypersecretion, increased intracellular calcium, disturbances
in cellular sodium metabolism
Cocaine Blocks neuronal uptake of norepinephrine causing intense ␣-adrenergic receptor antagonists, direct
sympathetic activation vasodilators, calcium channel blockers and
combined ␣/␤ blockers
Antidepressants Increases the half life of norepinephrine at sympathetic nerve Alpha- and combined ␣/␤ blockers
terminals
Antihypertensive agents
Diuretics or vasodilators Stimulate renin production Avoid volume depletion
Clonidine withdrawal Clonidine withdrawal causes rapid resumption of catecholamine Gradual dose tapering
production which was suppressed during therapy
Beta-blocker withdrawal Beta blocker-induced receptor upregulation Gradual dose tapering
Anesthetics
Ketamine Increases systemic vascular resistance Clonidine or ␣-blockers
Desflurane Sympathomimetic Sympatholytics (␣-blockers, ␣/␤-blockers, or
clonidine)
Miscellaneous agents
Ergot alkaloids/bromocriptine Facilitates smooth muscle constriction by increasing cytosolic Avoid use if possible
calcium
Sibutramine Serotonin-norepinephrine reuptake inhibitor elevates blood Discontinue
pressure through a similar pharmacologic effect on vascular
afferent nerves
Glucagon Sympathomimetic Sympatholytics (␣-blockers, ␣/␤-blockers, or
clonidine)
Ginseng Sympathomimetic Discontinue
Ephedra Sympathomimetic Discontinue

monary arterial pressure, and pulmonary vascular resistance.73 tension in the hospital or procedure lab settings, long-term
Desflurane may also cause tachycardia and hypertension in hypertension has not been reported.
some patients sensitive to sympathetic nervous system stim-
ulation.74 Many other agents can precipitate hypertension in Miscellaneous Agents
patients with pheochromocytoma, including fentanyl, other
opiates, and neuromuscular relaxants (succinylcholine), as Ergot Alkaloids
can glucagon used during endoscopic procedures.75,76 Sym- All natural ergot compounds can cause hypertension by
patholytics (␣-blockers, ␣/␤-blockers, or clonidine) are usu- facilitating smooth muscle constriction by increasing cytosolic
ally effective treatments.77 Although contributing to hyper- calcium78; the hypertension can be quite severe and may pre-

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Gyamlani and Geraci • Secondary Hypertension due to Drugs and Toxins

cipitate myocardial infarctions.79,80 Bromocriptine, a semisyn- Heavy Metals and Other Toxins
thetic ergot alkaloid used to treat Parkinson disease and hyper- Paint and pesticides are sources of human exposure to
prolactinemia, elevates blood pressure through vasoconstriction heavy metals. A recent study showed that lead can elevate
and sympathetic nervous stimulation at the ganglionic level.81,82 blood pressure both acutely (recent dose) and chronically
Ergot-induced hypertension is more common in patients with (cumulative dosing).103 Thallium,104 cadmium,105 and ar-
previous pregnancy-induced hypertension.81 senic106 exposure also may induce hypertension in humans.
Venoms of scorpions (especially certain South American
species) and black widow spiders can produce severe hyper-
Other Therapeutic Agents tension by causing a massive discharge of preformed cat-
Sibutramine, a serotonin-norepinephrine reuptake inhib- echolamines into the circulation.107 Organophosphates in in-
itor used to treat obesity, often elevates blood pressure through secticides can elevate blood pressure acutely due to action at
a similar pharmacologic effect on vascular afferent nerves.83 nicotinic receptors.108
Although Sramek et al84 reported that the addition of sibutra-
mine did not result in blood pressure elevation in obese pa- Summary
tients whose hypertension was well controlled by a ␤ blocker, A variety of exogenous substances can induce transient
patients receiving sibutramine should have periodic blood or sustained hypertension, exacerbate pre-existing hyperten-
pressure monitoring. The drug should be withdrawn if blood sion, create resistance to previously effective antihyperten-
pressure increases. sive regimens, and/or precipitate hypertensive emergencies.
Ginseng has been associated with hypertension.85 Ephedra- Knowledge of patient use of, or exposure to, these agents is
containing dietary supplements (including ma huang), widely crucial to avoid unnecessary and expensive tests and/or treat-
used for weight loss and increased energy, produce hypertension ments. While many medications and classes of drugs can
as their most common adverse effects.86 The ephedra- and caf- have this effect, it is impossible to be all-inclusive in a single
feine-containing dietary supplement Metabolife 356 has also writing, and clinicians should take meticulous exposure his-
been linked to hypertension, sometimes severe and/or acute, and tories and regularly review new information sources when
occasionally associated with hypertensive emergencies (intra- evaluating hypertensive patients. If contributing drugs or
cranial hemorrhage).87 chemicals are identified, discontinuation or avoidance is rec-
Vitamins and their analogues (vitamin A,88 tretinoin89) ommended whenever possible, and appropriate antihyperten-
and mineral micronutrients like iron90 may exacerbate or sive therapy indicated when the offending agent is necessary
cause hypertension following overdose, or with repeated in- or cannot be avoided (Table).
gestion of supratherapeutic doses.
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I believe there are more instances of the abridgement

of freedom of the people by gradual and silent
encroachments by those in power than by violent and
sudden usurpations.
—James Madison

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