Abstract
Clinical pharmacy services aim to ensure the rational use of drugs and resolve disease/health conditions with a multidisciplinary approach. Pharmaceutical care plans need to be created to effectively provide clinical pharmacy services in the treatment of hypertension which is one of the common chronic diseases in cancer patients. In this mini-review, we examine which drugs can cause or worsen hypertension in patients receiving cancer treatment, potential drug-drug interactions between drugs used in cancer treatment and antihypertensive drugs, pharmacological and clinical studies for the treatment of hypertension in patients with hypertension before cancer diagnosis or newly diagnosed hypertension due to cancer treatment. Non-pharmacological treatment approaches are presented. We think that our study will be a resource that can be used to solve possible drug-related problems in the practice.
Introduction
Hypertension is one of the most common cardiovascular diseases. In studies conducted on cancer patients, it appears as a comorbid disease in approximately 40 % of cases [1, 2]. As supported by current studies, clinical pharmacy services in managing hypertension make important contributions in various areas, from managing potential drug-related problems (pDRPs) to detecting pre-hypertension patients and monitoring blood pressure (BP) [2, 3]. Pharmacists contribute to hypertension management with services such as monitoring BP, providing patient education, detecting, and resolving non-compliance, and titrating antihypertensive treatment to achieve target BP [4]. Patient education also includes lifestyle changes [4], [5], [6], [7].
Clinical pharmacists collaborate with the physician in this context, checking the patient’s medication history, reviewing medication, assessing the patient’s knowledge of antihypertensive medications (e.g. dosage, timing, and side effects), and addressing any obstacles the patient may encounter in achieving BP control. Clinical pharmacists can make interventions regarding drug treatment recommendations, patient education, treatment compliance, and lifestyle changes [4]. Clinical pharmacists have a greater role in this patient group during cancer treatment. This article will specifically focus on the management of hypertension in cancer patients.
Potential drug–drug interactions (pDDIs) between antihypertensive drugs and anticancer agents
Patient- and drug-related factors impact drug-drug interactions. pDDIs with anticancer agents may be observed because of the pharmacokinetic properties (especially metabolism and excretion properties) of the antihypertensive drugs. Lexicomp Drug Interaction Checker is one of the most reliable online databases. Table 1 presents brief data on potential drug interactions between antihypertensive agents and chemotherapeutics.
Potential drug interactions between antihypertensive agents and chemotherapeutics.
| Pharmacologic group of antihypertensive drugs | Potential drug–drug interaction | Mechanism | Evidence level (severity/reliability rating) | Management |
|---|---|---|---|---|
| ACE inhibitors | *Ramipril-Bortezomib | Antihypertensive agents may increase the hypotensive effect of chemotherapeutic agents (arsenic trioxide; bortezomib; dinutuximab; obinutuzumab; paclitaxel), resulting in a potentially increased risk of hypotension | Moderate/fair | These combinations may increase the risk of hypotension. Monitor patients closely for additive hypotensive effects |
| *Ramipril-Sirolimus/temsirolimus | Sirolimus/temsirolimus may increase the adverse effects of ACE inhibitors (especially, angioedema) | Moderate/good | An increased risk of angioedema has been reported with this combination. Caution patients regarding this increased risk, and urge them to report any signs or symptoms suggestive of possible angioedema immediately | |
| Although the mechanism is not clear. In a pooled analysis of everolimus oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 5 times higher than in the control arm with an ACE inhibitor | ||||
| Diuretics | *Hydrochlorothiazide-cyclophosphamide | Thiazide and thiazide-like diuretics may increase the toxicity of cyclophosphamide (especially myelosuppression) | Moderate/fair | Monitor for signs and symptoms of hematotoxicity |
| Although the mechanism is not clear, thiazides have been associated with blood dyscrasia | ||||
| *Furosemide-cisplatin | Loop diuretics may increase the nephrotoxicity and ototoxicity of cisplatin | Moderate/fair (reported in the prescribing information) | Monitor renal function and volume status and for signs or symptoms of ototoxicity | |
| Loop diuretics, especially ethacrynic acid high doses of furosemide, and cisplatin have been individually associated with ototoxicity | ||||
| Calcium channel blockers, CCB | **Verapamil/diltiazem-Doxorubicin | Moderate CYP3A4 inhibitors (verapamil, diltiazem) may increase the serum concentration of doxorubicin by inhibiting its metabolism | Moderate/good | Avoid co-administration of doxorubicin with moderate CYP3A4 inhibitors because of the risk of increased doxorubicin adverse effects |
| *Verapamil/diltiazem-Sunitinib | Moderate CYP3A4 inhibitors may increase the serum concentration of Sunitinib by inhibiting its metabolism | Moderate/fair | Monitor for increased sunitinib toxicities (e.g., QTc prolongation) |
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ACE, angiotensin-converting enzyme; *C, monitor therapy; **X, avoid combination therapy.
Cancer treatment-induced hypertension
Although newly developed anticancer drugs significantly improve survival, they can lead to cardiovascular toxicities such as heart disease, thromboembolic disease, and hypertension [6], [7], [8], [9], [10].
Table 2 presents the anticancer agents that commonly cause hypertension.
Cancer treatment-induced hypertension.
| Anticancer agents | Mechanism |
|---|---|
| VEGF inhibitors | Inhibition of the VEGF signaling pathway increases the production of reactive nitrogen and oxygen species, resulting in vascular oxidative stress [6, 8, 10]. VEGF inhibition also leads to sodium retention and extracellular volume expansion because of a shift in the pressure natriuresis relationship [6, 8, 10] |
| TKIs | The potential mechanism is TKIs suppression of the nitric oxide (NO) pathway and increased circulating levels of endothelin 1, a potent vasoconstrictor [8, 10] |
| Vinca alkaloids | Vinca alkaloids inhibit the proliferation of endothelial cells and cause caspase-mediated apoptosis, which can cause hypertension when administrated alone or in combination [8] |
| Platinum-containing agents | Especially cisplatin, has also been associated with hypertension. While the exact cause of hypertension remains unknown, nephrotoxicity and an anti-VEGF-mediated mechanism are thought to be responsible [8] |
| Proteasome inhibitors | Cardiovascular events are also observed with proteasome inhibitors (bortezomib, carfilzomib, and ixazomib). The mechanism of action that causes hypertension is endothelial dysfunction and reduction in endothelial NO bioavailability [8] |
| BTK inhibitors | BTK inhibitors (e.g. ibrutinib), are thought to decrease the VEGF signaling pathway, vascular remodeling, and endothelial dysfunction [6, 8]. This also includes a reduction in heat shock protein 70 signaling and inhibition of 3-kinase-dependent NO production [6, 8] |
| Adjuvant treatments | Adjuvant treatments include glucocorticoids (methylprednisolone, prednisone), erythropoietin (epoetin alfa, etc.), and NSAIDs (ibuprofen, indomethacin, diclofenac, celecoxib, ketorolac, etc.). Glucocorticoids contribute to hypertension development by increasing salt and water retention and sensitivity to vasoactive agents. Erythropoietin increases endothelial and vascular smooth muscle cell growth, vascular remodeling, and basal cytosolic calcium and NO resistance, all of which contribute to the development of hypertension. NSAIDs act by impaired natriuresis because of a decrease in prostaglandin synthesis [9] |
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VEGF, vascular endothelial growth factor; TKIs, tyrosine kinase inhibitors; NO, nitric oxide; BTK, Bruton kinase; NSAIDs, nonsteroidal anti-inflammatory drugs.
Management of hypertension in cancer patients
Pharmacological treatment and lifestyle changes are used to treat hypertension caused by anticancer therapy. A multidisciplinary team should optimize the patients’ hypertension treatment before the initiation of cancer treatment. Treatment can be initiated with any of the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, and calcium channel blockers [11]. For example, while ACE/ARB is the first choice in patients with proteinuria, diuretics should not be preferred in patients with gout. Beta-blockers are not the first choice unless there is ischemic heart disease or heart failure [5]. Lifestyle changes can reduce the cardiovascular risk associated with hypertension. Clinical pharmacists advise patients to limit sodium intake, alcohol consumption, and smoking. Counseling should be provided on issues that may help control blood pressure, such as quitting, non-steroidal anti-inflammatory drug use, caffeine consumption, and increasing physical activity and potassium intake [5], [6], [7].
Conclusions
In conclusion, hypertension is the most common comorbidity in reported cancer patients. The management of pre-existing or gained hypertension in oncological patients is crucial for reducing the risk of heart failure and other cardiovascular diseases in these patients. Therefore, patients should undergo a pre-treatment risk assessment to identify pre-existing hypertension and help predict the risk of developing hypertension with treatment. All patients, especially those at high risk, require careful monitoring of blood pressure throughout their treatment and after treatment ends. If prohypertensive anticancer therapy is to be started, a baseline blood pressure measurement should be made, and in case the antihypertensive drug needs to be started, the antihypertensive recommendation should be made to the physician. Management of hypertension in cancer patients requires collaborative care involving oncologists, cardiologists, primary care specialists, and pharmacists, thus ensuring the best therapeutic effect from cancer treatment while minimizing cardiovascular toxicities.
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Ethical Approval: Not applicable.
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Informed consent: Not applicable.
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Author contributions: The authors confirm contribution to the paper as follows: study conception and design: S.T., F.N.Y; literature review: S.T., F.N.Y.; draft manuscript preparation: S.T., F.N.Y. All authors reviewed the results and approved the final version of the manuscript.
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Competing interests: Authors state no conflict of interest.
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Research funding: None declared.
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