An Overview of Clinically Imperative and Pharmacodynamically Significant Drug Interactions of Renin-Angiotensin-Aldosterone System (RAAS) Blockers

Abstract

Introduction: Hypertension is a leading cause of cardiovascular disease and chronic kidney disease, resulting in premature death and disability. The Renin-Angiotensin-Aldosterone System (RAAS) blockers, including Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs), are used as first-line antihypertensive therapy to treat hypertensive patients with comorbidities, including diabetes, ischemic heart disease, heart failure, and chronic kidney disease. The use of RAS blockers is associated with the risks, such as hyperkalemia, angioedema, etc. The drugs potentiating them interact pharmacodynamically, resulting in adverse consequences. This review article focuses on the clinically important drug interactions of RAAS blockers.

Materials and Methods: The electronic databases, such as Medline/PubMed Central/PubMed, Google Scholar, ScienceDirect, Cochrane Library, Directory of Open Access Journals (DOAJ), Embase, and reference lists were searched to identify relevant articles.

Results: The risk of hyperkalemia may be enhanced potentially in patients receiving a RAS blocker and potassium-sparing diuretics, potassium supplements, trimethoprim, adrenergic beta-blockers, antifungal agents, calcineurin inhibitors, pentamidine, heparins or an NSAID, concomitantly. The patients taking ACE inhibitors and mTOR inhibitors, DPP4 inhibitors, alteplase, or sacubitril/valsartan concurrently may be at increased risk of developing angioedema.

Conclusion: Clinicians, pharmacists, and other healthcare practitioners should be accountable for medication safety. To avoid adverse implications, prescribers and pharmacists must be aware of the drugs that interact with RAAS blockers.

1. INTRODUCTION

Renin-Angiotensin-Aldosterone System (RAAS) blockers include Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), Direct Renin Inhibitors (DRIs), and Aldosterone receptor antagonists. Patients with hypertension, acute myocardial infarction, congestive heart failure, chronic kidney disease, stroke, and diabetic nephropathy might be benefited from the blockade of the RAAS system [1]. Renin is a hormone enzyme, which is produced by the juxtaglomerular cells of the kidney, and it is involved in the conversion of angiotensinogen to angiotensin I [2]. Angiotensin-Converting Enzyme (ACE) is responsible for the conversion of angiotensin I to angiotensin II [3]. Angiotensin- II can elevate blood pressure through many mechanisms (Fig. 1).

Fig. (1).

Renin-angiotensin-aldosterone system.

ACE inhibitors are the most widely prescribed antihypertensive agents across the globe. They are recommended as first-line antihypertensive therapy to treat hypertensive patients with comorbidities, including diabetes, ischemic heart disease, heart failure, and chronic kidney disease, by evidence-based clinical practice guidelines approved by Eighth Joint National Committee (JNC 8) [4]. ACE inhibitors include sulfhydryl derivative (captopril), dicarboxylate derivatives (lisinopril, perindopril, pnalapril, ramipril, trandolapril, cilazapril), and phosphonate derivative (fosinopril) [5].

ARBs block the binding of angiotensin- II with angiotensin (AT₁) receptors and prevent their activation [6]. Similar to ACE inhibitors, ARBs are also recommended as first-line antihypertensive therapy to treat hypertensive patients with comorbidities, including diabetes, ischemic heart disease, heart failure, and chronic kidney disease [4]. ARBs are preferred in patients who cannot tolerate ACE inhibitor therapy due to persistent dry cough, angioedema, and other adverse effects [7]. ARBs include losartan, valsartan, candesartan, olmesartan, irbesartan, and telmisartan [8].

Aliskiren is a DRI; it is useful as an add-on therapy to treat hypertensive diabetic patients [9]. Aldosterone receptor antagonists are used as potassium-sparing diuretics, including spironolactone (nonselective blocker) and eplerenone (selective blocker). Usually, they are indicated in congestive heart failure, hypertension, and chronic kidney disease [10].

Hypertension is a leading cause of cardiovascular disease and chronic kidney disease resulting in premature death and disability [11]. The prevalence of hypertension among the global population is increasing. It has been estimated that 972 million adults of the world population were affected by hypertension in 2000 [12] and 1.39 billion in 2010 [13]. It is predicted to reach 1.56 billion by 2025 [12].

Lifestyle modifications and antihypertensive drugs could manage patients with hypertension [14]. ACE inhibitors or ARBs are used as first-line antihypertensive drugs in non-black patients aged less than 60 years and as second-line add-on drugs in black patients [4].

Interference of effects of one drug by the co-administered drugs, herbs, alcohol, or tobacco smoke is termed “Drug Interaction” [15]. The interaction resulting in enhanced risk of adverse effects or diminished therapeutic efficacy of a drug is known as adverse drug interaction [16], which can enhance the healthcare costs by increasing the number of emergency room visits, hospitalizations, and lengths of stay [17]. It has been estimated that 2-5% and 1% of hospitalizations occur in elderly patients and general populations, respectively, due to drug interactions. About 245 000 hospitalizations (2.8% of all hospitalizations) occurring in the United States are caused by drug interactions, which cost about 1.3 billion US dollars [18]. In addition, a registered study from Sweden determined that about 7% of dispensing resulted in potential drug interactions [19]. Moreover, a drug-drug interaction prevalence study conducted in France estimated that 0.2% of contraindicated codispensing and 1.4% of discommended codispensing occurred in out-hospital drug dispensing [20]. Although most of the drug-drug interactions are theoretical, some may result in serious or life-threatening consequences. It has been found that drugs associated with hyperkalemia or angioedema can interact pharmacodynamically with RAAS blockers as they are well-known adverse effects of RAAS blockers Table 1. The prescribers and pharmacists should be aware of such drugs enhancing the risk of hyperkalemia or angioedema to prevent adverse consequences. Generally, the risk of drug interactions could be minimized by considering non-pharmacologic therapy, decreasing the number of drugs, monitoring for signs and symptoms of toxicity, considering dosage adjustments if needed, evaluating therapy, and adjusting the time of administration [21]. Patients with multimorbid conditions are forced to take multiple medications, which leads to polypharmacy. Inappropriate use of multiple medications is termed polypharmacy, which is an important risk factor for drug interactions [22]. Chronic patients with conditions like hypertension, diabetes, hyperlipidemia, depression, pain, and many others usually take more medications to treat different comorbidities, leading to polypharmacy. The risk of drug interaction increases as the number of concomitant medications raises [23].

Table 1.

Drug interactions of RAAS blockers with commonly used medications.

S. No.	Interacting Drug	Outcome	Probable Mechanism
1	Spironolactone	Severe hyperkalemia in patients taking a higher dose of spironolactone [34]	Additive hyperkalemia
2	Amiloride	Dangerous elevation of blood levels of potassium [37]	Additive hyperkalemia
3	Potassium supplements	Serious hyperkalemia [39, 40]	Additive hyperkalemia
4	Trimethoprim	Dangerous elevation of blood levels of potassium [43]	Additive hyperkalemia
5	Beta-blockers	Hyperkalemia occurred in patients taking propranolol [47], carvedilol [48], Nebivolol [49] and metoprolol [50]	Additive hyperkalemia
6	Calcineurin inhibitors (Cyclosporine and Tacrolimus)	Severe hyperkalemia [52]	Additive hyperkalemia
7	Pentamidine	Higher risk of hyperkalemia [55]	Additive hyperkalemia
8	Heparin	Enhanced risk of hyperkalemia [56]	Additive hyperkalemia
9	NSAIDs	Enhanced risk of hyperkalemia [58, 59]	Additive hyperkalemia
10	Dual RAS blockade	Increased risk of hyperkalemia, hypotension, and renal failure [63]	Additive hyperkalemia
11	Triple RAAS blockade	Severe hyperkalemia [68]	Additive hyperkalemia
12	mTOR inhibitors	Elevated risk of angioedema [80]	Additive effects on angioedema
13	DPP4 inhibitors	Elevated risk of angioedema [85, 86]	Additive effects on angioedema
14	Alteplase	Enhanced risk of angioedema [91-93]	Additive effects on angioedema
15	Sacubitril /Valsartan	Increased risk of angioedema [98]	Additive effects on angioedema
16	Sulfonylureas	Enhanced risk of hypoglycemia [102-105]	Additive blood glucose-lowering effects
17	Lithium	Increased risk of hospitalization for lithium toxicity [107-111]	ACE inhibitors and ARBs may induce lithium retention via the blockade of aldosterone release [107]
18	Azathioprine	Concomitant use of Azathioprine and ACE inhibitors resulted in anemia [115] and leucopenia [116]	ACE inhibitors may decrease the circulating erythropoietin and induce anemia [112]
19	Allopurinol	Elevated risk of hypersensitivity reactions [118, 119]	Unknown.
20	Bupivacaine	Profound bradycardia and hypotension [120]	Reduction of Angiotensin II via ACE inhibition
21	Antifungal Drugs Fluconazole Ketoconazole	Decreased conversion of losartan to its active metabolite due to inhibition by fluconazole and ketoconazole, resulting in elevated plasma concentrations of losartan [121, 122]	Inhibition of Losartan metabolism
22	Magnesium supplements	Enhanced ARB induced blood pressure reduction [123]	Additive antihypertensive effects

This review article focuses on possible interactions of ACE inhibitors or ARBs coadministered with clinically used drugs, which would help clinicians and healthcare personnel to minimize or prevent adverse drug interactions.

2. METHODS

The electronic databases, such as Medline/PubMed Central/PubMed, Google Scholar, ScienceDirect, Cochrane Library, Directory of Open Access Journals (DOAJ), Embase, and reference lists were searched to identify relevant articles using the following keywords: Drug Interactions, RAAS Blockers, ACE Inhibitors, Angiotensin Receptor Blockers, Aliskiren, Aldosterone Receptor Antagonists, and Pharmacodynamic Interactions. In this review, clinical case reports, case series, prospective and retrospective observational studies written in English language were included and duplicates were excluded.

3. DRUG-RAAS BLOCKER INTERACTIONS

The use of RAAS blockers is associated mainly with the risks, such as hyperkalemia and angioedema, and the drugs potentiating these effects would be expected to interact with them pharmacodynamically. Healthcare professionals, including prescribers and pharmacists, must be aware of the drugs interacting with RAAS blockers to avoid adverse consequences.

3.1. RAS Blockers Associated Hyperkalemia

RAS blockers, such as ACE inhibitors, ARBs, and DRIs, decrease aldosterone concentrations, renal blood flow, and Glomerular Filtration Rate (GFR) by blocking angiotensin II activity, resulting in reduced renal potassium excretion and hyperkalemia (Fig. 2) [24-26]. RAS blockers may also block gastrointestinal potassium secretion, as noted in anuric dialysis patients [27]. Up to 10% of patients taking an ACE inhibitor or an ARB may get affected by at least mild hyperkalemia [28].

Fig. (2).

ACE inhibitors associated angioedema.

Main mechanisms contributing to hyperkalemia with ACEi/ARB include decreased aldosterone concentrations, decreased delivery of sodium to the distal nephron, abnormal collecting tubule function, and excessive potassium intake.

Hyperkalemia is associated with ECG changes, such as peaked T waves, prolongation of the PR interval, and QRS widening [29]. Hyperkalemia may lead to ventricular fibrillation and asystole by decreasing myocardial resting membrane potential, increasing cardiac depolarization, myocardial excitability, cardiac instability, and conduction system abnormalities (Fig. 3) [30].

Fig. (3).

ACE inhibitors associated hypoglycemia.

RAAS blockers may interact pharmacodynamically with the drugs inducing hyperkalemia and increase the risk of hyperkalemia further in those patients taking them concomitantly.

3.1.1. Potassium Sparing Diuretics

Potassium-sparing diuretics include aldosterone receptor antagonists (spironolactone and eplerenone) and epithelial sodium channel blockers (amiloride and triamterene) [31].

Spironolactone and eplerenone can elevate the blood levels of potassium by decreasing the excretion of potassium through the inhibition of the aldosterone receptor. Patients with heart failure, chronic kidney, or hypertension disease may receive the combination of an aldosterone receptor antagonist and an ACE inhibitor or an ARB. The risk of morbidity and mortality in patients with severe heart failure has been shown to be reduced by such a combination. In addition, proteinuria in patients with chronic kidney disease was also found to be decreased by similar combinations [32]. The addition of eplerenone to the patients on RAS blocker lowers the blood pressure significantly [33].

Concomitant use of spironolactone and an ACE inhibitor or an ARB may induce severe hyperkalemia in patients with reduced renal function, type 2 diabetes mellitus, older age, and taking a higher dose (> 25 mg daily) of spironolactone [34]. Frequent monitoring of plasma potassium concentrations is recommended in patients taking spironolactone and an ACE inhibitor or an ARB, and they should be advised to seek medical attention if they develop dehydration [35, 36].

Amiloride and triamterene can induce hyperkalemia by reducing the excretion of potassium through the inhibition of reabsorption of sodium by blocking epithelial sodium channels. The addition of amiloride to the patients taking an ACE inhibitor elevated the blood levels of potassium dangerously. Monitoring serum potassium, renal function, and ECG is recommended in patients taking this combination [37].

3.1.2. Potassium Supplements

The risk of hyperkalemia might be elevated by the addition of potassium supplements in patients taking RAAS blockers. Patients with hypertension may receive potassium supplements, and adding captopril to those patients elevates the blood potassium levels significantly [38]. It was reported that concurrent use of captopril (ACE inhibitor), potassium supplements, and frusemide in an elderly patient with congestive heart failure led to serious hyperkalaemia [39]. The serum potassium was also found to be elevated in hypertensive patients using salt substitute (Lo salt) and taking an ACE inhibitor [40]. The patients taking RAAS blockers should be advised of the dangers of excessive dietary potassium, including potassium supplements and potassium-containing salt substitutes.

3.1.3. Trimethoprim

Trimethoprim is a synthetic antibacterial, and it is prescribed either alone or as co-trimoxazole (Trimethoprim–Sulfamethoxazole) to treat infections, including uncomplicated urinary tract infections and others [41]. Trimethoprim can elevate serum potassium levels by inhibiting potassium excretion through the blockade of epithelial sodium channels in the distal nephron [42]. It has been reported that the administration of co-trimoxazole in older patients receiving ACE inhibitors or ARB was associated with an increased risk of sudden death, which might be induced by unrecognized severe hyperkalemia. The prescribers may use alternative antibiotics [43], or serum potassium is required to be closely monitored when trimethoprim is used in patients on RAAS blockers [44, 45].

3.1.4. Adrenergic β-blockers

Adrenergic β-blockers may be used in combination with ACE inhibitors and ARB to treat patients with heart failure, and triple therapy is found to be effective in slowing the progression of heart failure [46]. Adrenergic β-blockers may cause hyperkalemia by inducing potassium retention by inhibiting catecholamine-induced renin release, leading to decreased angiotensin II and aldosterone levels and altering transmembrane potassium movement by inhibiting cell membrane Na-K-ATP pump [47].

It has been reported that hyperkalemia occurred in patients taking beta-blockers, such as propranolol [47], carvedilol [48], nebivolol [49], and metoprolol [50]. The risk of hyperkalemia was high among patients taking beta-blockers and with concurrent risk factors like diabetes and chronic renal failure. The risk of hyperkalemia may further be elevated by the concurrent use of β-blockers and RAAS blockers, and the patients taking such a combination may be required to be monitored closely.

3.1.5. Calcineurin Inhibitors

The calcineurin inhibitors, including cyclosporine and tacrolimus, are effective in postoperative immunosuppression. The use of calcineurin inhibitors is associated with hyperkalemia. It has been observed that potassium excretion is commonly decreased in patients treated with cyclosporine [51], leading to the elevation of plasma concentrations of potassium. Concurrent administration of an ACE inhibitor or an ARB with calcineurin inhibitors may induce severe hyperkalemia [52]. Close monitoring of potassium levels is advised in patients taking such a combination.

3.1.6. Pentamidine

Pentamidine is an antimicrobial agent used in the prophylaxis and treatment of pneumocystis pneumonia [53, 54]. Pentamidine decreases the potassium secretion in the distal nephron through the blockade of epithelial sodium channels, resulting in hyperkalemia [55]. The risk of hyperkalemia might be elevated due to the addition of pentamidine in a patient taking a RAAS blocker; therefore, monitoring patients taking this combination is recommended.

3.1.7. Heparins

Heparin is an injectable anticoagulant that activates antithrombin III and is indicated for prophylaxis and treatment of venous thrombosis, post-operative deep venous thrombosis (DVT), pulmonary embolism (PE), and prevention of clotting in arterial and cardiac surgery.

Heparin can induce hyperkalemia by inhibiting the secretion of aldosterone through decreased affinity and the number of angiotensin II receptors [56]. Concomitant use of heparin and a RAAS blocker may increase the risk of hyperkalemia further. It may require monitoring the serum levels of potassium in patients taking this combination.

3.1.8. Non-steroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs decrease renin secretion and renal blood flow by inhibiting both prostaglandin E and prostacyclin synthesis, resulting in decreased angiotensin II and aldosterone levels, leading to elevated potassium levels [57]. The risk of hyperkalemia may further be enhanced by the coadministration of a RAAS blocker, and the risk of acute kidney injury is enhanced in patients taking the combination of NSAIDs, diuretics, and an ACE inhibitor or an ARB [58. 59].

NSAIDs inhibit the synthesis of prostaglandins, leading to increased sensitivity of renal blood vessels to angiotensin II [60]. NSAID treatment in patients taking ACE inhibitors or ARBs may attenuate their antihypertensive efficacy [61]. The hypertensive patients taking ACE inhibitors or ARBs and NSAIDs to treat pain and inflammation are monitored for antihypertensive efficacy, renal function, and hyperkalemia.

3.1.9. Dual RAS Blockade

An ACE inhibitor or an ARB could be used successfully to prevent or treat diabetic nephropathy. However, the dual RAS blockade is not recommended in patients with diabetic nephropathy [62]. The risk of hyperkalemia, hypotension, and renal failure is increased in patients taking dual RAS blockade therapy through the concomitant use of an ACE inhibitor with an ARB or aliskiren. However, patients with heart failure [63] and advanced proteinuric nephropathy [64] may receive an ACE inhibitor and an ARB with close monitoring of electrolytes, blood pressure, and renal function.

The regulatory agencies, such as the US FDA and the European Medicines Agency, recommended a contraindication against the use of dual RAS blockade (Aliskiren with ACE inhibitors or ARBs) in patients with diabetes because of the risk of hyperkalemia, hypotension, and renal impairment. Moreover, they issued a warning to avoid the use of RAS blockade (Aliskiren with ACE inhibitors or ARBs) in patients with moderate to severe renal impairment [65].

The incidence of hyperkalemia with a single RAAS inhibitor treatment is 2%, while dual RAAS inhibition causes approximately 5% incidence of hyperkalemia. Patients with chronic kidney disease (CKD) or heart failure (HF) have a higher (5-10%) risk of developing hyperkalemia. Hence, the use of RAAS blockers in patients with CKD and HF should be monitored closely [24].

3.1.10. Triple RAAS Blockade

Triple RAAS blockade might be associated with severe hyperkalemia compared to dual RAS blockade. The addition of an aldosterone receptor antagonist (spironolactone or eplerenone) to a patient taking dual RAS therapy (an ACE inhibitor and an ARB) may reduce albuminuria by 30%–40% [66]. However, this triple RAAS therapy is not recommended for patients with glomerular filtration rates below 40ml/min [67]. Caution is advised to avoid severe hyperkalemia in patients receiving triple RAAS therapy.

3.2. ACE Inhibitors Associated Angioedema

The use of ACE inhibitors is the leading cause of drug-induced angioedema. It has been estimated that 0.1% to 6% of users of ACE inhibitors are affected by angioedema [68]. ACE inhibitors block the enzyme ACE (Kininase II), which is involved in the degradation of bradykinin, resulting in elevated levels of plasma bradykinin, inducing continued prostaglandin E2 synthesis, vasodilation, increased vascular permeability, and increased interstitial fluid, leading to ACE inhibitor-associated angioedema (Fig. 4) [69, 70].

Fig. (4).

RAS blockers associated hyperkalemia.

Most commonly, angioedema associated with ACE inhibitors may occur in the lips, face, tongue, and upper airway. If severe laryngeal edema occurs, it may become life-threatening and cause respiratory distress and death [71, 72]. Patients with a history of ACE inhibitor-associated angioedema may also have a lesser risk of angioedema using an ARB than ACE inhibitors [73, 74]. It has been reported that the administration of Aliskiren is also associated with angioedema [75, 76].

The drugs inducing angioedema may interact pharmacodynamically with RAS blockers and enhance the risk of angioedema further.

3.2.1. Mechanistic (Mammalian) Target of Rapamycin (mTOR) Inhibitors

The mechanistic (Mammalian) target of rapamycin (mTOR) is involved in the regulation of cellular metabolism, growth, and proliferation, and the drugs inhibiting mTOR include sirolimus, everolimus, temsirolimus, etc. The mTOR inhibitors are used in the treatment of renal cancer [77]. It has been reported that mTOR inhibitors are associated with the incidence of angioedema [78, 79].

The risk of angioedema is further elevated in patients taking the combination of ACE inhibitors and mTOR inhibitors [80]. The prescribers and patients are required to be aware of this potentially dangerous drug interaction, and caution is advised while administering an mTOR inhibitor to a patient taking an ACE inhibitor [81].

3.2.2. Dipeptidyl Peptidase-4 (DPP4) Inhibitors

1. Dipeptidyl peptidase-4 (DPP4) inhibitors, such as sitagliptin, saxagliptin, vildagliptin, etc., are useful in the treatment of type 2 diabetes mellitus [82]. The use of DPP4 inhibitor has been reported to be associated with angioedema [83]. The angioedema associated with DPP4 inhibitors may result from the accumulation of vasoactive kinins through the prevention of inactivation of substance P and bradykinin by DPP4 inhibitors [84].

2. Hence, concomitant use of an ACE inhibitor along with a DPP4 inhibitor may elevate the risk of angioedema through the accumulation of vasoactive kinins. The patients taking this combination of drugs should be monitored carefully [85, 86].

3.2.3. Alteplase

Alteplase is a recombinant tissue plasminogen activator (rt-PA), and it is indicated in the conditions like acute ischemic stroke (AIS), acute myocardial infarction (AMI), and acute massive pulmonary embolism [87]. Alteplase use can induce orolingual angioedema [88, 89]. Alteplase may increase the levels of bradykinin by generating plasmin, which cleaves kininogen into bradykinin [90], thus resulting in angioedema.

Hence, the concomitant administration of alteplase in patients receiving an ACE inhibitor enhances the risk of angioedema further [91-93]. It has been reported that orolingual angioedema was observed in 5.1% of patients taking alteplase and an ACE inhibitor [94]. To avoid serious adverse consequences, close monitoring of the signs of orolingual angioedema is recommended in patients receiving alteplase and ACE inhibitors concurrently [95].

3.2.4. Sacubitril/Valsartan (Entresto)

Sacubitril/Valsartan is a single crystalline complex composed of two molecular moieties (sacubitril and valsartan). Sacubitril is a prodrug neprilysin inhibitor, and valsartan is an ARB. Sacubitril/Valsartan is the first drug approved in the class of Angiotensin Receptor-Neprilysin Inhibitor (ARNi) [96]. It is used to treat heart failure patients with preserved ejection fraction and mild to moderate arterial hypertension [97].

The risk of angioedema may be enhanced in patients taking Sacubitril/Valsartan and an ACE inhibitor concurrently, and it is recommended to discontinue the ACE inhibitor at least 36 hours before starting valsartan/sacubitril [98].

3.3. ACE Inhibitors Associated Hypoglycemia

In diabetic patients, insulin sensitivity was found to be increased by the administration of ACE inhibitors [99]. It has also been reported that ACE inhibitors may improve insulin sensitivity through raised bradykinin levels (Fig. 5) [100, 101].

Fig. (5).

Risks of hyperkalemia.

3.3.1. Sulfonylureas

Concomitant use of ACE inhibitors and sulfonylureas in diabetic hypertensive patients may enhance the risk of hypoglycemia [102-105]. It is recommended to monitor the blood glucose levels of the patients taking ACE inhibitors and sulfonylureas or insulin concurrently.

3.4. Other Possible Interactions

3.4.1. Lithium

Lithium is an antipsychotic medication primarily used to treat bipolar disorders, and it has a narrow therapeutic index [106]. Concomitant use of ACE inhibitors with lithium can significantly increase the risk of hospitalization for lithium toxicity [107-109]. The use of ARBs in patients receiving lithium therapy may also induce lithium intoxication [110, 111].

ACE inhibitors and ARBs prevent sodium and water reabsorption in the proximal tubule through the blockade of the release of aldosterone, resulting in natriuresis, which may lead to more lithium retention [112]. Close monitoring of signs and symptoms of lithium toxicity is recommended in patients taking an ACE inhibitor [113] or an ARB [114] and lithium concurrently.

3.4.2. Azathioprine

Azathioprine is an immunosuppressant drug, and its administration in renal transplant recipients taking an ACE inhibitor resulted in anemia [115] and leucopenia [116]. ACE inhibitors may decrease the circulating erythropoietin and induce anemia [117]. Monitoring of patients taking azathioprine and an ACE inhibitor concomitantly for the signs of myelosuppression, such as anemia and leukopenia, is recommended.

3.4.3. Allopurinol

Allopurinol is an anti-gout drug, and it may be used prophylactically to manage gout. Coadministration of allopurinol with an ACE inhibitor may elevate the risk of hypersensitivity reactions [118, 119]. The patients taking this combination should be monitored for adverse effects.

3.4.4. Bupivacaine

Administration of bupivacaine to induce spinal anesthesia in a patient receiving ACE-inhibitor resulted in profound bradycardia and hypotension. It has been proposed that reduction of Angiotensin II by ACE inhibitor may contribute to these effects [120]. It is recommended to monitor the patients receiving bupivacaine and ACE inhibitors concurrently.

3.4.5. Antifungal Drugs

3.4.5.1. Fluconazole

Fluconazole belongs to a class of drugs called azole antifungals. It is used to prevent and treat a variety of fungal and yeast infections. Inhibitors of the hepatic CYP2C9 isoenzyme have the potential to inhibit the conversion of losartan to its active metabolite E-3174. Fluconazole coadministered with losartan has been shown to increase the AUC of losartan and E-3174 by 69% and 41%, respectively [121]. It is essential to monitor therapeutic responses to individualize losartan dosage.

Concurrent use of fluconazole and losartan may result in decreased losartan conversion to its active metabolite due to inhibition by fluconazole of losartan metabolism. At the same time, the risk or severity of hyperkalemia can be increased when fluconazole is combined with ACE inhibitors [121].

3.4.5.2. Ketoconazole

Similarly, caution is advised when using ketoconazole, a strong CYP3A4 inhibitor, together with a CYP3A4 substrate, such as losartan, as their concomitant use may result in elevated plasma concentrations of losartan, resulting in increased or prolonged therapeutic and adverse effects due to inhibition of CYP3A4-mediated metabolism of losartan by ketoconazole [122].

3.4.6. Magnesium Supplements

Magnesium (Mg) is a basic component for vascular work and blood pressure regulation. Several studies have demonstrated that dietary Mg supplementation can attenuate the blood pressure in hypomagnesemic hypertension and enhance the antihypertensive effect. In addition, Mg supplementation may be helpful in managing hypertension concomitant with hypomagnesemia [123].

Jin et al. [123] also reported that concurrent dietary Mg supplementation could reduce blood pressure in rats with hypomagnesemic hypertension and enhance the antihypertensive effect of an ARB as Mg supplementation may affect aldosterone synthesis independent of the renin-angiotensin-aldosterone system. Hence, it is recommended to take Mg supplements and ACE inhibitors 2 to 3 hours apart to minimize any potential problems.

CONCLUSION

Renin-Angiotensin-Aldosterone System (RAAS) blockers, including Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blockers (ARBs), Direct Renin Inhibitors (DRIs), and Aldosterone receptor antagonists, are useful to treat the patients with hypertension, acute myocardial infarction, congestive heart failure, chronic kidney disease, stroke, and diabetic nephropathy. It is common among chronic patients to take multiple medications to treat comorbidities, and the risk of drug interactions increases as the number of concomitant medications raises. The drugs, such as potassium-sparing diuretics, potassium supplements, trimethoprim, adrenergic beta-blockers, antifungal drugs, calcineurin inhibitors, pentamidine, heparins, and NSAIDs, can increase the risk of hyperkalemia associated with RAAS blockers. Monitoring of plasma concentrations of potassium is recommended for patients using them concurrently. In addition, the drugs like mTOR inhibitors, DPP4 inhibitors, Alteplase, and Sacubitril/valsartan can enhance the incidence rates of angioedema associated with ACE inhibitors. This article might be beneficial for the prescribers and health care professionals to understand how to effectively prevent adverse drug interactions without compromising the patient’s safety.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This research received no external funding.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.