REVIEW

Drug-induced Hypertension: An Unappreciated Cause of Secondary Hypertension

Ehud Grossman, MD,a,b Franz H. Messerli, MDc,d
Department of Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel Hashomer, Israel; bDepartment of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; cDivision of Cardiology, St. Lukes-Roosevelt Hospital, New York, NY; dColumbia University College of Physicians and Surgeons, New York, NY.
a

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 dened 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 patients drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identied, discontinuation of the causative agent is recommended, although hypertension can often be managed by specic 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. 2012 Elsevier Inc. All rights reserved. The American Journal of Medicine (2012) 125, 14-22 KEYWORD: Hypertension

Most patients with high blood pressure (BP) have essential hypertension (HTN) or well-known forms of secondary HTN such as renal parenchymal disease, renal artery stenosis, hyperaldosteronism, or pheochromocytoma. Most physicians are less aware of other secondary forms of HTN such as drug-induced HTN. For a comprehensive clinical
Funding: None. Conict of Interest: Ehud Grossman has received ad hoc consultant and speaker fees from Novartis, Sano-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, Pzer, 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. Requests for reprints should be addressed to Ehud Grossman, MD, Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail address: grosse@post.tau.ac.il

work-up, an accurate and detailed medical history should include foods, poisons, and all medications; even medications that patients do not consider to be drugs and therefore frequently omit from their history. Identication of the intake of these substances may be important because their elimination can obviate the need for unnecessary, costly, and potentially dangerous evaluations, treatments, or both.1,2 In this manuscript we review the therapeutic agents or chemical substances that may elevate BP by different mechanisms of action (Table). For some agents that are more commonly used, we will review the available data.

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 malig-

0002-9343/$ -see front matter 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2011.05.024

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Drug-induced Hypertension

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nancies. This group includes mainly monoclonal antibodies sorafenib was 23.4%, and that of severe HTN 5.7%.12 Resuch as bevacizumab (Avastin; Roche, Basel, Switzerland), cently, Maitland et al13 showed that by using 24-hour ambuor orally available small molecules that inhibit the tyrosine latory BP monitoring, sorafenib 400 mg twice a day increased kinases stimulated by VEGF, such as lapatinib (Tykerb; systolic BP by 8.2 mm Hg, and diastolic BP by 6.5 mm Hg GlaxoSmithKline, Philadelphia, Penn); sunitinib (Sutent; within 24 hours of treatment. Pzer Inc., New York, NY); Sunitinib also has been associsorafenib (Nexavar; Bayer, Pittsated with HTN.14 In a recent metaburgh, Penn/Onyx, San Francisco, analysis, the incidence of all HTN CLINICAL SIGNIFICANCE Calif); axitinib, and pazopanib. and severe HTN were 21.6% and Hypertension has evolved as one 6.8%, respectively, among patients Transient or sustained blood pressure of the most common adverse efreceiving sunitinib.14 Sunitinib was elevation has been identied as a powfects of these drugs. The recognition associated with a signicantly inerful risk factor for cardiovascular morand management of HTN is increased risk of severe HTN (relative bidity and mortality. creasingly important in patients risk 22.7, 95% condence interval, Although in most patients, blood preswith malignancies because che4.48-115.29, P .001) in comparimotherapy reduces cancer-related son with controls. sure elevation is essential, it not unmorbidity and mortality and paHypertension should be considcommonly is inuenced by chemical tients are expected to live longer. ered as a class adverse effect of all substances. Therefore, the impact of poorly antiangiogenic therapies, and it A myriad of drugs and poisons has been controlled HTN on cardiovascular seems that the risk of HTN is simdocumented to increase blood pressure. morbidity and mortality may beilar with all the agents.12 The use This overview on chemically induced hycome a major issue. Bevacizumab of VEGF signaling inhibitors is pertension will allow the clinician to (Avastin) is used to treat metausually associated with mild BP static cancers of the colon, rectum, increase. However, it may be asrecognize this entity and to take the kidney, breast, and glioblastoma sociated with severe HTN and Reappropriate therapeutic measures. multiforme. In clinical trials, modversible Posterior Leukoencephaerate HTN that requires antihyperlopathy Syndromea signicant tensive treatment was more prevevent likely secondary to HTN.15 alent in the bevacizumab-treated groups than in the placebo. About 1% of all patients on antiangiogenic therapy develop The incidence of severe HTN (BP 200/100 mm Hg) was life-threatening HTN crisis. 3- to 5-fold higher in the bevacizumab groups compared The mechanism of elevated BP in patients treated with with placebo.3,4 Hypertension had an overall incidence of antiangiogenesis agents is likely to be multifactorial and up to 32%; 11%-16% of patients required therapy with may include a decrease in nitric oxide (NO) production, a multiple drugs, but only 1% had grade-4 life-threatening reduction in the density of microvascular beds, a phenomhypertensive crisis.5 In the Bevacizumab Regimens Invesenon called rarefaction, loss of antioxidative effect, and tigation of Treatment Effects (BRiTE) study, de novo HTN activation of the endothelin-1 system.16-18 requiring medication was reported in 22% of the patients, What is the clinical signicance and therapeutic appeal to and 18.7% of patients who had HTN had experienced worsHTN induced by systemic VEGF inhibition? Several studies 6 ening of their HTN. The incidence of HTN is dose related, have suggested that HTN may predict a benecial response to and half of the patients developing HTN on bevacizumab antiangiogenics.19 Anti-VEGF therapy-associated HTN is of7 have a history of HTN. Intravitreal bevacizumab injection ten transient and typically resolves with discontinuation of the is safe in terms of BP in both hypertensive and normotenprovoking agent. Elevated BP is usually easily controlled, and 8 sive patients; however, in a recent study, 27 of 768 patients the immediate risk of hypertensive target organ diseases is low (3.5%) reported a new episode of HTN during intraocular in most patients. However, one should keep in mind that 9 injections of bevacizumab. hypertensive crisis may occur, and therefore a close monitorSorafenib, which is approved for advanced renal cell ing of BP and early initiation of anti-HTN agents when neccarcinoma and hepatocellular carcinoma, also can increase essary is recommended. BP. In the Treatment Approaches in Renal Cancer Global Renin angiotensin system inhibitors, diuretics, betaEvaluation Trial (TARGET), treatment-related HTN was reblockers, and calcium antagonists can be used to lower BP. ported in 17% of the patients. Stage 2 HTN was reported in 4% The nondihydropyridine calcium antagonists such as veraof the sorafenib-treated patients, compared with 1% in the pamil and diltiazem are CYP3A4 inhibitors, and nifedipine, controls.10 Unlike the ndings of the TARGET trial, in the a dihydropyridine calcium antagonist, has been shown to Sorafenib Hepatocellular Carcinoma Assessment Randomized induce VEGF secretion, and therefore should be used with Protocol (SHARP), patients with advanced hepatocellular carcaution in combination with oral angiogenic inhibitors.5 cinoma who were treated with sorafenib 400 mg twice a day 11 Nitrates can increase the production of endogenous NO, did not develop more HTN than the control group. In a recent meta-analysis, the overall incidence of HTN in patients on thereby facilitating BP control.20 A favorable BP response

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Table

The American Journal of Medicine, Vol 125, No 1, January 2012

Drugs and Chemical Agents that May Increase Blood Pressure Clinical Use Notes

Ingredient

BP elevation mainly by volume retention Glucocorticoid Replacement therapy, rheumatic disease Hypertension occurs more often in elderly patients and in patients with a positive family history of collagen disease, dermatologic primary HTN. Blood pressure rise is dose disease, allergic state, ophthalmic dependent, and at low doses, cortisol has less disease, inammatory bowel disease, effect on BP. respiratory disease, hematologic and neoplastic disease, nephropathies Mineralocorticoid Dose-dependent, sustained increase in BP Licorice A avoring and sweetening agent Carbenoxolone characterized by hypokalemia, metabolic Ulcer medication 9-alpha uoroprednisolone alkalosis, and suppressed plasma renin activity Skin ointments, antihemorrhoid cream 9-alpha uorocortisol and aldosterone levels. Ophthalmic drops, and nasal sprays Ketoconazole Antimycotic Sex hormones Estrogen progesterone Contraception, replacement therapy Mild, sustained BP elevation, more common in premenopausal women. History of high BP during pregnancy, a family history of HTN, cigarette smoking, obesity, black, diabetes, and renal disease increase the risk of developing HTN. Severe hypertension has been reported. Mild dose-dependent sustained increase in systolic BP. Androgens Prostate cancer Danazol (semisynthetic androgen) Anabolic effect Endometriosis, hereditary angioedema NSAIDs Analgesic, anti inammatory Mild, dose-dependent increase in BP. Elderly patients, those with pre-existing hypertension, salt-sensitive patients, patients with renal failure and patients with renovascular hypertension are at a higher risk to develop severe HTN. Calcium antagonists are the preferred choice of treatment. BP elevation mainly by activation of the sympathetic nervous system Phenylephrine hydrochloride Upper respiratory decongestant, Dose-dependent, sustained increase in BP. ophthalmic drops Dipivalyl adrenaline hydrochloride Ophthalmic drops Severe HTN has been reported. Epinephrine (with beta-blocker) Local anesthetic, anaphylactic reaction, bronchodilatation, decongestant, antihemorrhoidal treatment Phenylpropanolamine Anorexic, upper respiratory decongestant Pseudoephedrine hydrochloride Upper respiratory decongestant Tetrahydrozoline hydrochloride Ophthalmic vasoconstrictor drops Naphazoline hydrochloride Ophthalmic vasoconstrictor and nasal decongestant drops Oxymetazoline hydrochloride Upper respiratory decongestant drops Caffeine Analgesia, vascular headache, beverages The reaction to caffeine is more pronounced in males, in those with a positive family history of HTN, and in African-American subjects. Caffeine may cause persistent BP effects in persons who are regular consumers, even when daily intake is at moderately high levels. Herbal products Complementary and alternative Mainly relate to dietary supplements that contain medicine Ephedra alkaloids.

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Table Continued

Drug-induced Hypertension

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Ingredient Cocaine

Clinical Use Local anesthetics

Notes Cocaine use is associated with acute but not chronic HTN. Transient severe increase in BP, especially when used with beta-blockers. Transient severe increase in BP has been reported.

Ketamine hydrochloride Fentanyl citrate Smokeless tobacco Methylphenidate Dexmethylphenidate Amphetamine Yohimbine hydrochloride Sibutramine Clozapine Glucagon Venlafaxine Monoamine oxidase inhibitors

Anesthetic agent Narcotic analgesic and anesthetic agent Alternative to smoking Attention decit hyperactivity disorder

Impotence Weight loss Antipsychotic agent Prevent bowel spasm Antidepressive and anti-anxiety agents Antidepressive agents

Acute, dose-dependent increase in BP. Mild increase in BP. Only in patients with pheochromocytoma. At dose above 300 mg/day. Mainly with sympathomimetic amines and with certain food containing tyramine. Tranylcypromine is the most hazardous because of its stimulant action, whereas moclobemide and brofaromine are the least likely to induce hypertensive reaction. More common in patients with panic disorders. Mild dose-dependent increase in BP. In combination with selegiline. Massive overdose may cause severe HT.

Selegiline Tricyclic antidepressants Buspirone Fluoxetine Thioridazine hydrochloride Physostigmine

Ritodrine hydrochloride Disulram

Used mainly for Parkinson disease Antidepressive agent Anxiolytic agent Antidepressive agents Psychotic and depressive disorders Reverse anticholinergic syndrome, myasthenia gravis, glaucoma, Alzheimer disease Inhibition of preterm labor Management of alcoholism

Hypertensive crisis has been reported. Slight increase in BP. Severe HT may occur in alcoholic-induced liver disease.

BP elevation mainly by activation of the rennin angiotensin system Lead Industry Cholesteryl ester transfer protein Increases HDL cholesterol levels (CETP) inhibitor Torcetrapid Dalcetrapib BP elevation mainly by direct vasoconstriction Cyclosporine A Immunosuppressive agent, prophylaxis of organ rejection, autoimmune disease, dermatologic disorders

Also activates the sympathetic nervous system.

Not registered. Does not increase BP.

Tacrolimus Rapamycin BP elevation mainly by combined mechanisms Recombinant human erythropoietin

Prophylaxis of organ rejection Prophylaxis of organ rejection

Dose-dependent mild to moderate increase in BP. Presence of HTN before transplantation, elevated creatinine levels and maintenance therapy with corticosteroids, increase the risk of HTN. Severe HTN has been reported. Produces less hypertension than cyclosporine A. Produces little BP increase.

Anemia of renal failure and of some malignancies

Dose-related mild increase in BP. The risk to develop or worsen HTN is increased in the presence of pre-existing HTN, the presence of native kidneys, a genetic predisposition to HTN, when the initial hematocrit is low and when it increases rapidly. Hypertensive crisis with encephalopathy has been reported.

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Table Continued Clinical Use Beverage

The American Journal of Medicine, Vol 125, No 1, January 2012

Ingredient Alcohol

Notes Dose-dependent, sustained increase in BP. The BP effects of alcohol are independent from obesity, salt intake, cigarette smoking, and potassium intake.

Anti-vascular endothelial growth factor (VEGF) signaling Bevacizumab

Sorafenib

Sunitinib BP elevation by unknown mechanisms Acetaminophen Scopolamine Naloxone hydrochloride Metoclopramide Alizapride Prochlorperazine Carbamazepine Lithium Alkylating agents Paclitaxel Cis-diamminedichloroplatinum Cadmium Arsenic Bromocriptine mesylate

Metastatic cancers of the colon, rectum, The incidence of HTN is dose related and is more kidney, breast and glioblastoma pronounced in elderly patients, in those with multiforme preexisting HTN, and in those with renal cell carcinoma. Approved for advanced renal cell carcinoma and hepatocellular carcinoma Advanced gastrointestinal stromal tumor and renal cell carcinoma Analgesic and antipyretic Preanesthetic medication, Motion sickness Opioid overdose Antiemetic Antiemetic Antiemetic Bipolar depression and seizures Manic depressive illness Antineoplastic agent Antineoplastic agent Antineoplastic agent Industry Industry Suppression of lactation, and prolactin inhibition in prolactinoma

Transient BP elevation. Transient increase in BP in association with cancer.

Acute intoxication can cause severe HTN.

Only during intra-arterial administration. The association between cadmium exposure and HTN is equivocal. Severe HTN with stroke has been reported following the use for suppression of lactation. Patients with pregnancy-induced HTN are at increased risk to develop HTN.

Highly active antiretroviral therapy (HAART) Amphotericin B

BP blood pressure, HTN hypertension.

Anti-HIV treatment Fungal infections

to sublingual test dose of 5 mg isosorbide dinitrate has been used to predict response to long-acting nitrates.20

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND ANALGESICS

Nonsteroidal anti-inammatory 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 signicant 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 increased renal endothe-

lin-1 synthesis, may be the culprits and are potentially important.22 NSAIDs interfere with some antihypertensive agents such as diuretics, beta-blockers, and angiotensinconverting enzyme inhibitors, but do not interact with calcium antagonists and central-acting drugs.23,24 NSAIDs vary considerably in their effect on BP. Armstrong and Malone25 found that, among the various NSAIDs, indomethacin, naproxen, and piroxicam were associated with the greatest increase in BP. Among the selective NSAIDs, rofecoxib was more likely than celecoxib to raise systolic BP.25 Two meta-analyses showed that selective cyclooxygenase (COX)-2 inhibitors increase BP more than the nonselective agents.26,27 Unlike these ndings, Wang et al28 showed that there were similar hazard rates of

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Drug-induced Hypertension

19 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 angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers may be required, and careful monitoring of potassium is necessary.

incident HTN with celecoxib and nonselective NSAIDs users. Several studies showed that rofecoxib (which is now off the market) increased BP more than celecoxib.26,29 Sowers et al29 showed that at equally effective doses for osteoarthritis management, treatment with rofecoxib but not celecoxib or naproxen induced a signicant increase in 24-hour systolic BP from 130.3 1.2 to 134.5 1.4 mm Hg. However, celecoxib also may increase BP in a dose-dependent way. In the studies that compared the efcacy and safety of celecoxib with placebo in reducing the rate of colorectal cancer, patients who received celecoxib 400 mg twice daily exhibited after 3 years a 5.2-mm Hg increase in systolic BP.30 No change in BP was observed in those who took the drug once daily or in the usual doses of 100-200 mg/day. Naproxcinod (NicOx, Sophia Antipolis, France) is a new NO-donating NSAID that upon absorption is rapidly cleaved to produce naproxen and an NO-donating moiety. Preliminary studies show that this compound has anti-inammatory effect without raising BP.31 The drug is not yet approved by the US Food and Drug Administration, and additional efcacy or safety data are required. Low-dose aspirin has no effect on BP control in hypertensive patients and may even lower BP when taken at bedtime.32 In patients who take NSAIDs, calcium antagonists would appear to be a preferred choice over other antihypertensive agents.33 In patients with hypertension, acetaminophen is recommended as the preferred analgesic because it is considered safe. The safety of acetaminophen in regard to BP elevation is doubtful, because several observational studies linked acetaminophen with a higher incidence of HTN.34-36 Previous interventional studies failed to show the hypertensive effect of acetaminophen.37-38 However, a recent study showed that acetaminophen induces a signicant increase in ambulatory BP in patients with coronary artery disease.39 The mechanism by which acetaminophen increases BP is not clear. It can be mediated by COX-2 inhibition or by central COX-3 inhibition,40 or by an indirect activation of cannabinoid receptors.41

LICORICE-INDUCED HYPERTENSION
The mechanism by which licorice increases BP is similar to 11-hydroxysteroid dehydrogenase deciency. This enzyme converts cortisol to cortisone and its deciency produces an excess of cortisol. Cortisol binds renal mineralocorticoid receptors with high afnity, whereas cortisone binds to a lesser extent. The inhibition of 11-hydroxysteroid dehydrogenase with glycyrrhizic acid, the main active ingredient in licorice, produces a state of mineralocorticoid excess. The clinical picture is characterized by severe HTN, hypokalemia, low plasma renin activity, and low aldosterone levels. Some other compounds may stimulate mineralocorticoid receptors and increase BP (Table).

SEX HORMONES
Oral contraceptives induce HTN in approximately 5% of users of combined high-dose compounds that contain at least 50 g 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 signicant 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 been addressed by randomized studies. Postmenopausal hormone replacement therapy has minimal if any effect on BP in normotensive women. Afnito et al showed that hormone replacement therapy can even reduce BP in postmenopausal hypertensive women.45

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 signicant only at dosages above 300 mg/day.42 Several other antidepressant agents also may increase BP by activating the sympathetic nervous system (Table).2

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 caffeine is small. Of note, caffeine content of 1 cup of coffee can vary more than 10-fold.49

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

HERBAL PRODUCTS
Some popular herbal products have the potential to increase BP and to interfere with antihypertensive treatment.50 The

20 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 thiazide.50

The American Journal of Medicine, Vol 125, No 1, January 2012 sures are unsuccessful, the dose of r-HuEPO should be lowered or therapy should be held for several weeks. Phlebotomy of 500 mL of blood may rapidly lower BP in refractory patients.2

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 annual systolic BP increase was greater in those who consumed 300 g/week or more of alcohol, corresponding to 13 glasses of wine (240 mL each), 13 bottles of beer (633 mL each), or 26 shots of whiskey (35 mL each), than nondrinkers. A reasonable approach is to limit daily alcohol consumption to 30 g.

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 signicantly reduced cocaineinduced 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 cyclosporinetreated 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 also is common in patients with autoimmune disease and in patients with psoriasis treated with cyclosporine.2 CAH is characterized by a disturbed circadian rhythm, with the absence or reversal of the normal nocturnal fall in BP.57 BP usually decreases after the withdrawal or substitution of cyclosporine immunosuppression, but may not remit completely.57 Calcium antagonists have been used successfully to lower BP, but are known to increase cyclosporine blood levels.58 If necessary, cyclosporine can be continued and multidrug therapy should be used to control CAH. Tacrolimus, another immunosuppressive agent that inhibits calcineurin, also has been associated with HTN. However, it produces less BP elevations than cyclosporin, and therefore, conversion to tacrolimus may be considered in patients with CAH. Rapamycin and mycophenolate mofetil are immunosuppressive agents that do not inhibit calcineurin and produce little if any nephrotoxicity or HTN.59,60

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, 33 exhibited an increase in diastolic BP of 10 mm Hg or greater, and 11 patients had a new diagnosis of HTN conrmed by antihypertensive treatment. Patients on lopinavir/ ritonavir had the highest risk, and patients receiving atazanavir had the lowest risk of developing elevated BP. The effect of the treatment on BP was mainly mediated through an increase in BMI. The impact of antiretroviral medications on cardiovascular disease risk factors will increasingly inuence treatment decisions.68 One case report of severe HTN and renal atrophy associated with the protease inhibitor indinavir has been described.69 Hypertensive crisis secondary to phenylpropanolamine interacting with triple-drug therapy for human immunodeciency virus prophylaxis also has been reported.70 In addition, potential drug interactions exist between antiretroviral medications, particularly the protease inhibitors and calcium antagonists.71

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 reported.61 The BP can usually be controlled with a combination of uid removal with dialysis and conventional antihypertensive therapy. If these mea-

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

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21. Kletzel M, Jaffe N. Systemic hypertension: complication of intraarterial cis-diammine dichloroplatinum (II) infusion. Cancer. 1981; 47(2):245-247. 22. Johnson AG. NSAIDs and increased blood pressure. What is the clinical signicance? Drug Saf. 1997;17(5):277-289. 23. Krum H, Swergold G, Curtis SP, et al. Factors associated with blood pressure changes in patients receiving diclofenac or etoricoxib: results from the MEDAL study. J Hypertens. 2009;27(4):886-893. 24. Morgan T, Anderson A. The effect of nonsteroidal anti-inammatory drugs on blood pressure in patients treated with different antihypertensive drugs. J Clin Hypertens (Greenwich). 2003;5(1):53-57. 25. Armstrong EP, Malone DC. The impact of nonsteroidal anti-inammatory drugs on blood pressure, with an emphasis on newer agents. Clin Ther. 2003;25(1):1-18. 26. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005; 165(5):490-496. 27. Chan CC, Reid CM, Aw TJ, Liew D, Haas SJ, Krum H. Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? An updated meta-analysis. J Hypertens. 2009;27(12):23322341. 28. Wang J, Mullins CD, Mamdani M, Rublee DA, Shaya FT. New diagnosis of hypertension among celecoxib and nonselective NSAID users: a population-based cohort study. Ann Pharmacother. 2007; 41(6):937-943. 29. Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165(2):161-168. 30. Solomon SD, Pfeffer MA, McMurray JJ, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006;114(10):1028-1035. 31. Weber MA. Treatment of patients with hypertension and arthritis pain: new concepts. Am J Med. 2009;122(5 Suppl):S16-S22. 32. Messerli FH. Aspirin: a novel antihypertensive drug? Or two birds with one stone? J Am Coll Cardiol. 2005;46(6):984-985. 33. White WB. Cardiovascular effects of the cyclooxygenase inhibitors. Hypertension. 2007;49(3):408-418. 34. Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med. 2007;167(4):394399. 35. Montgomery B. Does paracetamol cause hypertension? BMJ. 2008; 336(7654):1190-1191. 36. Curhan GC, Willett WC, Rosner B, Stampfer MJ. Frequency of analgesic use and risk of hypertension in younger women. Arch Intern Med. 2002;162(19):2204-2208. 37. Pavlicevic I, Kuzmanic M, Rumboldt M, Rumboldt Z. Interaction between antihypertensives and NSAIDs in primary care: a controlled trial. Can J Clin Pharmacol. 2008;15(3):e372-e382. 38. Radack KL, Deck CC, Bloomeld SS. Ibuprofen interferes with the efcacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen. Ann Intern Med. 1987;107(5):628-635. 39. Sudano I, Flammer AJ, Periat D, et al. Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation. 2010; 122(18):1789-1796. 40. Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J. 2008;22(2): 383-390. 41. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12(34):250-275. 42. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998;59(10):502-508. 43. Chasan-Taber L, Willett WC, Manson JE, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation. 1996;94(3):483-489.

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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