Review
Drug-induced Hypertension: An Unappreciated Cause of Secondary Hypertension

https://doi.org/10.1016/j.amjmed.2011.05.024Get rights and content

Abstract

A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

Section snippets

Hypertension Induced by Systemic Inhibition of Vascular Endothelial Growth Factor Signaling

Recently, anti-vascular endothelial growth factor (VEGF) drugs were introduced for the treatment of various malignancies. This group includes mainly monoclonal antibodies such as bevacizumab (Avastin; Roche, Basel, Switzerland), or orally available small molecules that inhibit the tyrosine kinases stimulated by VEGF, such as lapatinib (Tykerb; GlaxoSmithKline, Philadelphia, Penn); sunitinib (Sutent; Pfizer Inc., New York, NY); sorafenib (Nexavar; Bayer, Pittsburgh, Penn/Onyx, San Francisco,

Nonsteroidal Anti-Inflammatory Drugs and Analgesics

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce an increase in BP and interfere with antihypertensive treatment, mitigating or abolishing its effect.21 Meta-analyses from the early 1990s have demonstrated that NSAID use produces a clinically significant increment in mean BP of 5 mm Hg.22 While the mechanisms involved in BP increase remain speculative, salt and water retention through several factors operating in parallel, coupled with increased total peripheral vascular resistance via

Antidepressant Agents and Blood Pressure

Venlafaxine hydrochloride is a serotonin/norepinephrine reuptake inhibitor that is used in depression and anxiety. It can cause elevation of BP, probably through its noradrenergic mechanism. A large meta-analysis showed that BP increase with venlafaxine is more pronounced in older patients and in men, and is dose dependent. The incidence of elevated diastolic BP (>90 mm Hg) was statistically and clinically significant only at dosages above 300 mg/day.42

Several other antidepressant agents also

Steroids

Hypertension occurs in at least 20% of patients treated with synthetic corticosteroids in a dose-dependent fashion; oral cortisol at doses of 80-200 mg/day can increase systolic BP as much as 15 mm Hg within 24 hours. At low doses, cortisol has less effect on BP. Cessation of steroid therapy usually leads to normalization of BP. When steroid treatment is mandatory, a diuretic is the drug of choice, because volume overload is the main mechanism by which steroids raise BP. Addition of

Licorice-Induced Hypertension

The mechanism by which licorice increases BP is similar to 11β-hydroxysteroid dehydrogenase deficiency. This enzyme converts cortisol to cortisone and its deficiency produces an excess of cortisol. Cortisol binds renal mineralocorticoid receptors with high affinity, whereas cortisone binds to a lesser extent. The inhibition of 11β-hydroxysteroid dehydrogenase with glycyrrhizic acid, the main active ingredient in licorice, produces a state of mineralocorticoid excess. The clinical picture is

Sex Hormones

Oral contraceptives induce HTN in approximately 5% of users of combined high-dose compounds that contain at least 50 μg of estrogen and 1-4 mg of progestin.43 The increased BP is usually minimal, however, severe hypertensive episodes, including malignant hypertension, may occur. The risk of HTN decreased quickly with cessation of oral contraceptives. No significant association between HTN and use of progesterone-only pills has been found over 2-4 years of follow-up,44 but this matter has not

Caffeine

Caffeine causes a pressor response due to increased sympathetic activity and antagonism of endogenous adenosine.46 Several investigators showed that caffeine may increase BP levels.47 Caffeine in 2-3 cups of coffee can acutely raise BP by as much as 10 mm Hg in patients who are infrequently exposed to it, although the average response is an increase of about 4-5/3 mm Hg.46 Noordzij et al48 found that regular caffeine intake increases BP; however, when ingested through coffee, the BP effect of

Herbal Products

Some popular herbal products have the potential to increase BP and to interfere with antihypertensive treatment.50 The evidence is anecdotal and therefore it is impossible to estimate the true incidence of these adverse effects. Several reports have noted that dietary supplements that contain ephedra alkaloids can increase BP.51 Some herbs can interfere with bioavailability of concurrently administered drugs.52 Hypertension also has been reported after coadministration of ginkgo and a diuretic

Cocaine

Cocaine intoxication and abuse is characterized by adrenergic overactivity associated with increased BP. Cocaine use is associated with acute but not chronic HTN. In one small study, isradipine significantly reduced cocaine-induced BP elevation.53

Immunosuppressive Agents

The incidence of cyclosporine-associated hypertension (CAH) 1 year after renal transplantation varies in different studies between 32.7% and as high as 81.6%.54, 55

In recipients of bone marrow transplants, Loughran et al56 reported a 57% incidence of HTN in cyclosporine-treated patients, compared with a 4% incidence in methotrexate-treated patients. The frequency of CAH in cardiac transplant recipients is approaching 100%, and virtually all patients develop HTN soon after transplantation.2

CAH

Recombinant Human Erythropoietin

Recombinant human erythropoietin (r-HuEPO) is effective in correcting the anemia of patients with end-stage renal failure and patients with malignancies. Hypertension has been reported to develop, or to worsen, in 20%-30% of patients treated with r-HuEPO, and it may appear as early as 2 weeks and as late as 4 months after the start of treatment.2 Hypertension is usually not a serious general problem in the r-HuEPO-treated patient; however, hypertensive crisis with encephalopathy has been

Alcohol

Excessive alcohol use has clearly been shown to raise BP and also can cause resistance to antihypertensive therapy. Apart from the acute effects of alcohol, an increased prevalence of HTN has been observed in heavy drinkers.62, 63 In the Australian Risk Factor Prevalence Study,63 7% of the prevalence of HTN was attributed to alcohol consumption, whereas in the Kaiser-Permanente Study,62 the rate for men was 11%. In a prospective cohort study of 3900 Japanese men, Yoshita et al64 found that

Anti-Human Immunodeficiency Virus Treatment

Highly active antiretroviral therapy (HAART) can increase systolic BP. HAART does not usually increase BP before 6 months of use.65 The reaction to HAART is more pronounced in the elderly and in those with higher baseline systolic BP, higher baseline cholesterol levels, and low baseline CD4-cell count.66 In a large cohort study, hypertension was reported in 26.1% of the infected individuals.67

Among 444 patients who initiated HAART, 83 exhibited an increase in systolic BP of 10 mm Hg or greater,

Interaction of Drugs With Antihypertensive Treatment

Rifampicin, a bactericidal antibiotic that induces CYP3A4 and P-glycoprotein, considerably reduces the plasma concentrations and the renin-inhibiting effect of aliskiren72 and some calcium antagonists73 by decreasing its oral bioavailability. Recently it has been shown that sitagliptin, a dipeptidyl peptidase-IV inhibitor, attenuated the hypotensive effect of high-dose enalapril by stimulating the sympathetic nervous system.74

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    Funding: None.

    Conflict of Interest: Ehud Grossman has received ad hoc consultant and speaker fees from Novartis, Sanofi-Aventis, AstraZeneca, Novo Nordik, Dexon Israel, and Teva Israel Intercure, and grant support from Novartis, Bristol-Myers Squibb, Daiichi Sankyo, and Neurim Pharmaceuticals Ltd, Israel. Franz Messerli serves as a consultant to Takeda, Novartis, Bayer, Pfizer, Daiichi Sankyo and received grants from Boehringer Ingelheim, Forest.

    Authorship: Both authors had access to the data and played a role in writing the manuscript.

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