Drug-induced hypertension is a serious and underappreciated problem—especially in those already taking antihypertensive drugs. As most physicians know, high blood pressure is classified as either essential, or secondary to another medical condition. One form of secondary hypertension that is gaining more attention is hypertension induced by prescription or over-the-counter drugs.
High blood pressure is still the world’s leading mortality risk factor. Disconcertingly, one in three American adults has high blood pressure, but only 35% of patients have adequate blood pressure control—despite evidence that strategies to lower blood pressure greatly reduce cardiovascular risk. It makes sense that medications, especially those that interfere with antihypertensive drugs a patient is already taking, should be considered a factor with uncontrolled hypertension.
The following is a look at drugs that can cause this unwanted adverse effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can interfere with the control of blood pressure in hypertensive patients and may increase associated mortality and morbidity risks, as well as cost of care. Results from a retrospective cohort study published in BMC Cardiovascular Disorders shed light on the comparative hypertensive effects of different NSAIDs.
In a sample of 1,340 patients, researchers found that those receiving NSAIDs exhibited a 2 mmHg increase in systolic blood pressure vs acetaminophen users. The rise in systolic blood pressure was 3 mmHG among those taking ACE inhibitors and calcium-channel blockers and 6 mmHg in those taking beta-adrenergic blockers. Ibuprofen raised blood pressure 3 and 5 mmHg over naproxen and celecoxib, respectively. The researchers also noted that these increases did not trigger clinicians to change therapy, which meant that increases in blood pressure were subtle, but, nonetheless, harmful. Importantly, blood pressure changes were negligible in those who were prescribed diuretics or multiple antihypertensive agents.
As for mechanisms, the researchers suggested the following: “The inhibition of PGs by NSAIDs is proposed as the mechanism that explains the loss of the blood pressure lowering effect of ACE-I [ACE inhibitors]. Because PGs mediate the antihypertensive effect of ACE-I at least in part, inhibition of PGs by NSAIDs could disrupt the blood pressure control achieved by ACE-I,” they wrote.
“These observations may be particularly important in patients with diabetes. Antihypertensive treatment is often intensified in patients with diabetes mellitus; in addition, patients with diabetes mellitus who are diagnosed with hypertension are more likely to receive an ACE-I rather than other antihypertensive medications to preserve renal function. Therefore, it is important to monitor blood pressure closely in diabetic patients who are prescribed NSAIDs to ensure adequate blood pressure control,” they added.
Cyclosporine and other immunosuppressants
The calcineurin inhibitor cyclosporine, as well as other immunosuppressant agents including corticosteroids, can increase blood pressure. These effects are especially concerning in kidney and other transplant patients because they can lead to graft rejection.
According to the authors of a review article published in Current Medical Chemistry, “Calcineurin inhibitors induce hypertension by a mechanism related to the imbalance of vasoactive substances endothelin and nitric oxide, and probably by causing overactivity of thiazide-sensitive sodium-chloride-cotransporter. Corticosteroids are well known for their hypertensive effects. The interactions of calcineurin inhibitors and mammalian target of rapamycin inhibitor sirolimus also promote hypertension.”
The management of arterial hypertension in kidney transplant recipients is complex, with target values below 130/80 mmHg recommended by the National Kidney Foundation.
As for treatment of secondary hypertension due to specific immunosuppressive agents, the authors concluded, “Calcium channel blockers may be useful in antagonizing the vasoconstrictive effects of calcineurin inhibitors. The renin-angiotensin system inhibitors seem a good option, especially in patients with proteinuria, however their effects on long-term graft and patient survival are controversial. β-Blockers could be beneficial in patients with coronary heart disease, but caution is required due to metabolic adverse effects. Thiazide diuretics could be the reasonable option for patients with glomerular filtration rate ≥30 mL/min/1.73 m2, also with caution regarding hypokalemia and glycemia.” Of note, the authors cautioned that more studies are needed on the topic, and advised that the choice of optimal antihypertensive agents following kidney transplant should be based on tolerability, efficacy, comorbidities, other medications, and post-transplant kidney function.
The relationship between antidepressants, such as serotonin-reuptake inhibitors (SSRIs), and blood pressure is complicated.
Sympathetic activation is a hallmark of hypertension, according to the authors of a letter to the editor published in Hypertension. The authors had previously discovered that sympathetic nervous system activity in unmedicated patients with depression yields a bimodal distribution. Thus, some of these patients have very high blood pressure values. In these patients, SSRI treatment normalizes sympathetic activity.
In others, however, SSRIs may have the opposite effect, according to the authors. “Patients with depression and those with hypertension share a common phenotype in that they both exhibit signs of a defect in function of the norepinephrine transporter in the heart. In the heart, the majority of released norepinephrine is recaptured into sympathetic nerves, so it is more sensitive than all other organs to impairments in transmitter reuptake. Blockade of norepinephrine transporter by TCAs [tricyclic antidepressants] or serotonin-norepinephrine reuptake inhibitors may further exacerbate this and could sensitize the heart to sympathetic activation, increasing cardiac output and leading to an elevation in blood pressure,” they wrote.
“Indeed, whereas TCAs have a propensity to act centrally to inhibit sympathetic outflow, in the periphery, they block the norepinephrine transporter. In healthy subjects, desipramine increases cardiac norepinephrine spillover. Whether the same occurs in patients with depression is unknown but merits further attention,” they added.
In light of these findings, the authors recommended that there is a strong hypothetical basis for avoidance of TCAs in those with a history of myocardial infarction, while SSRIs may not be suitable for those with hypertension or vascular disease. But the blanket statement that all antidepressants increase the risk of hypertension, as some have suggested, may be misleading.
The chronic administration of erythropoietin, used in treatment for anemia, is linked to increases in arterial blood pressure, as demonstrated in both clinical and preclinical studies (ie, animal models). According to the author of an article published in the American Journal of Kidney Disease, the underlying reasons are likely multifactorial, and include the following:
Rise in hematocrit and erythrocyte mass
Alterations in the production or sensitivity to endogenous vasopressors
Changes in vascular smooth-muscle ionic milieu
Disruption in the production or responsiveness to endogenous vasodilatory factors
A direct vasopressor action elicited by EPO
Arterial remodeling via stimulation of vascular cell growth
These drugs are a cornerstone in cancer treatment and block vascular endothelial growth factor (VEGF) or its receptor-signaling system. Advanced approaches to angiogenesis inhibition include VEGF/VEGF-receptor blockade via monoclonal antibodies and the inhibition of receptor signaling with tyrosine kinase inhibitors, with examples of specific drugs including bevacizumab and BAY 43-9006, respectively.
Angiogenesis inhibitors, however, carry the risk of increasing blood pressure. The authors of an article published in US Cardiology presented possible rationale for this physiologic phenomena.
“First, a number of studies in animals and humans have noted a drop in BP with angiogenic growth factor administration. For example, in the VEGF in Ischemia for Vascular Angiogenesis Trial (VIVA), both intra-coronary and intravenous infusions of recombinant human VEGF were accompanied by falls in systolic BP of up to 22% at the highest doses. Second, VEGF both enhances endothelial nitric oxide synthase (eNOS) activity and upregulates the message and protein levels of VEGF in human endothelial cells; thus, nitric oxide generation would appear to be a necessary component of the response pattern to angiogenic growth factors. Finally, angiogenic growth factors present a strong stimulus for the assembly of new capillaries and the recruitment of endothelial progenitor cells.”
They added, “It has been recognized for some time that small arteries and precapillary arterioles are important determinants of vascular resistance and a reduction in their density—so-called capillary and arteriolar rarefaction—is observed in a number of animal models of hypertension.”
Hypertension has serious repercussions. Some of the agents listed above may increase blood pressure or counteract the effects of antihypertensive drugs. When prescribing, it’s important to review medications for their potential to increase blood pressure—especially in hypertensive patients—and tailor therapy accordingly. Even smaller increases in blood pressure observed during a physical exam should be scrutinized, as these bumps could lead to serious health problems.