Secondary hypertension due to drugs and toxins--a challenge for research on harm.

Hypertension is a major independent risk factor for cardiovascular disease and mortality. Despite more than five decades of the expansion of therapeutic regimens for hypertension, the treatment of hypertension still remains a therapeutic challenge. Data from the third National Health and Nutrition Survey (NHANES III) suggest that only 29 to 34% of hypertensive patients are adequately controlled. (1)

Secondary hypertension comprises nearly 5 to 10% of hypertensive patients. Factors that pose a special dilemma for clinicians include a lack of patient understanding, financial burden, inappropriate therapeutic regimens to control blood pressure, as well as secondary hypertension due to drugs and toxins.

Many classes of pharmacological agents can cause secondary hypertension. Nonsteroidal anti-inflammatory drugs are the most common medicines that diminish the effect of all antihypertensive medications (except for calcium channel blockers), due to sodium retention by inhibiting vasodilatory and natriuretic prostaglandins. (1,2) Some drugs directly cause secondary hypertension (erythropoietin), whereas other drug classes (NSAIDs) usually exacerbate pre-existing essential hypertension. A wide variety of agents, including immunosuppressants, such as cyclosporine and tacrolimus, sympathomimetic weight loss agents (ephedra and sibutramine), over-the-counter decongestants (pseudoephedrine), herbal medicines such as yohimbine and ginseng, and illicit substances such as cocaine, methamphetamines and alcohol, can cause hypertension.

In this issue of the Journal, Geeta Gyamlani and colleagues provide us with a comprehensive review on drugs and toxins which cause secondary hypertension. (3) To identify patients with secondary hypertension due to drugs and toxins, the authors recommend that a thorough medication history of over-the-counter medications and herbal supplements be elicited. Clinicians should remain vigilant at identifying certain subgroups of patients who may be at increased risk. These patients include those with no prior history of hypertension, females in the reproductive age group on oral contraceptive pills, patients with migraines on ergot derivatives, patients on prescription steroids or NSAID agents, and hospitalized patients who develop postoperative hypertension triggered by anesthetic agents. They emphasize that these cases of hypertension are easily correctable by prompt withdrawal of the offending agent.

Although the hypertension caused by most of these drugs is transient, the risks that these drugs pose are not trivial. Our recent experience with an increased risk of stroke with over-the-counter decongestants (4) confirms that these drugs may carry risks beyond hypertension. It is prudent to assume that secondary hypertension due to these agents carries cardiovascular disease and mortality risks that are similar to essential hypertension until we have better evidence to the contrary.

Despite Gyamlani et al's exhaustive review of the literature, several unanswered questions remain. The proportion of hypertensive patients whose hypertension can be attributed to these drugs and toxins is unknown, limiting any estimation of the burden of this problem. This is especially challenging as some of the drugs are available without prescription (over-the-counter and herbal supplements) and may not be brought to the attention of the provider. A precise estimate of the magnitude of the risk of hypertension with these agents, the dose at which it occurs, the duration of use needed to precipitate hypertension, as well as the long-term risks of hypertension recurrence once these agents are withdrawn is also unknown. Precise biologic pathways that explain within-class differences in the risk of hypertension among these agents, and the optimal therapeutic strategy for patients in whom the offending agent cannot be withdrawn (eg, patients on immunosuppressants) are not well elucidated.

To make rational clinical decisions at the bedside, clinicians need to be aware of the benefits and risks of therapeutic agents. Our current research model has failed to provide us with timely information on the risk of several therapeutic agents. Randomized controlled trials are notoriously poor at evaluating certain adverse events. Future research in this area should go beyond identifying secondary hypertension from drugs and toxins to determining their dose-time susceptibility characteristics and the magnitude and strength of this association. Only a comprehensive teleo-analytical approach combining data from spontaneous published reports, unpublished reports submitted to the regulatory agencies (such as the FDA Adverse Event Database), observational studies and randomized controlled trials will enable us to determine the clinical, epidemiologic and prognostic significance of the risk of hypertension and its consequences with these agents. (5) Until we devise better strategies to estimate the harm of therapeutic agents, clinicians will continue to struggle with decision-making in the face of uncertain evidence.

References

1. Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med 2001;345:479-486.

2. Papadopoulos DP, Papademetriou V. Resistant hypertension: diagnosis and management. J Cardiovasc Pharmacol Ther 2006;11:113-118.

3. Gyamlani G, Geraci SA. Secondary hypertension due to drugs and toxins. South Med J 2007; 100:665-666.

4. La Grenade L, Graham DJ, Nourjah P. Underreporting of hemorrhagic stroke associated with phenylpropanolamine. JAMA 2001;286:3081.

5. Wald NJ, Morris JK. Teleoanalysis: combining data from different types of study. BMJ 2003;327:616-618.

Sonal Singh, MD, and Amit Nautiyal, MD

From the Section on General Internal Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; the MPH Program Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; and the Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA.

Reprint requests to Sonal Singh, MD, Section on General Internal Medicine, Department of Medicine, One Medical Center Blvd. Wake Forest University Health Sciences, Winston-Salem, NC 27157. Email: [e-mail]

Accepted March 28, 2007.

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