Angiotensin Receptor Blockers and HCTZ Combination Drugs

Mechanism of Action

Excessive and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) is a critical component of hypertension development. Various elements of RAAS are targets for blood pressure therapy. Prorenin (a precursor of renin) is stored in juxtaglomerular cells (JG cells) within the renal afferent arterioles. Prorenin is enzymatically cleaved to form renin under specific stimuli such as renal hypoperfusion, reduced delivery of sodium and chloride to the distal convoluted tubule (DCT), or increased sympathetic flow through the β-1 adrenergic receptors.[18]

Renin is produced by the liver and initiates the conversion of angiotensinogen into angiotensin I. In the lungs, angiotensin-converting enzyme (ACE) removes 2 amino acids from the C terminal of angiotensin I to form angiotensin II, which regulates blood volume through the AT1 receptor. By inhibiting the binding of angiotensin II to AT1 receptors in the kidneys and adrenal glands, angiotensin receptor blockers impede vasoconstriction and the involvement of aldosterone in the progression of cardiovascular diseases.[19][20] HCTZ is a diuretic agent that acts on the DCTs. Sodium is absorbed in the DCTs and transported to the basolateral aspect of the interstitium through the activity of a sodium-potassium ATPase pump. This process establishes a concentration gradient across the epithelial cells and the DCTs, facilitating water reabsorption. HCTZ hinders sodium and chloride transport by targeting the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Through this interruption, HCTZ reduces the concentration difference between the DCT and epithelial cells, reducing water reabsorption and increasing diuresis.[8][21]

ARBs selectively target the AT1 receptor, reducing vasoconstriction and aldosterone secretion induced by angiotensin II. Meanwhile, HCTZ inhibits sodium and water reabsorption in the proximal DCT, promoting diuresis. These mechanisms synergistically reduce blood pressure by mediating vascular tone and fluid volume. This approach optimizes therapeutic efficacy while mitigating the risk of electrolyte imbalances and other adverse effects associated with higher doses of individual agents. A meta-analysis compared ARB-HCTZ therapy to ARB alone in patients with uncontrolled hypertension. Results from 16 RCTs (12,055 participants) indicated that ARB-HCTZ achieved significantly improved systolic and diastolic blood pressures than ARB alone. The combination also increased the likelihood of reaching target blood pressure goals. ARB-HCTZ is associated with rates of adverse events similar to ARB alone.[22]

Pharmacokinetics

Absorption: Valsartan is rapidly absorbed following oral administration and reaches peak plasma concentration after 1 to 2 hours.[23] Olmesartan is esterified with medoxomil to increase its bioavailability, allowing it to reach peak plasma concentration within 1 to 3 hours.[24] According to FDA-approved product labeling, telmisartan (20 to 160 mg) follows non-linear pharmacokinetics, and its dose-dependent bioavailability ranges from 42% to 58%. The bioavailability of irbesartan is 60% to 80% after a dose. Food intake does not affect its bioavailability. The prodrug candesartan cilexetil is rapidly activated after absorption from the gastrointestinal tract, and its bioavailability is 40% after an oral dose.[25] The bioavailability of losartan is 33%, and concurrent food intake reduces its absorption.[26] The bioavailability of eprosartan after an oral dose of 300 mg is 13%. The bioavailability of HCTZ ranges from 65% to 75%. However, this availability is reduced by 10% when HCTZ is consumed with a meal.[27]

Distribution: Valsartan and olmesartan bind strongly to plasma proteins, primarily albumin, which significantly reduces their volume of distribution. The volume of distribution for both drugs is 17 L, implying these medications are not distributed extensively throughout the body. Angiotensin receptor blockers such as telmisartan are highly bound to plasma proteins (>99.5%) regardless of dose amount. Telmisartan's distribution volume is 500 L.[28] Irbesartan is 90% bound to plasma proteins (primarily albumin and α-1-acid glycoprotein), and its volume of distribution ranges from 53 to 93 L. Candesartan is highly bound to plasma proteins and has been shown to cross the blood-brain barrier in animal models; its volume of distribution is 0.13 L/kg. Losartan is 99.7% bound to plasma proteins, giving it poor tissue distribution.[26] Eprosartan at any concentration binds strongly to plasma proteins. HCTZ is 40% to 68% bound to albumin in the serum and extensively distributed throughout the body.[29]

Metabolism: Candesartan cilexetil, olmesartan medoxomil, and azilsartan medoxomil are prodrugs requiring metabolic activation in the GIT and liver to form their active counterparts. In contrast, eprosartan, irbesartan, telmisartan, and valsartan are active immediately after administration.[30] Valsartan undergoes minimal metabolism.[23] Olmesartan medoxomil is activated into its pharmacologically active form through ester hydrolysis in the gastrointestinal tract; active olmesartan undergoes negligible metabolism.[31] Telmisartan is minimally metabolized through conjugation into the pharmacologically inactive compound acyl-glucuronide without P450 isoenzymes.[28] Irbesartan is primarily metabolized in the liver through glucuronidation and oxidation by CYP2C9. Candesartan cilexetil undergoes ester hydrolysis to form the pharmacologically active candesartan, which is not mainly metabolized in the body. However, <20% of the drug undergoes hepatic metabolism through O-deethylation. The maximum amount of candesartan is excreted unchanged in stools. Losartan undergoes a metabolic transformation into an aldehyde intermediate, producing active metabolites.[26] Eprosartan is not metabolized in the body. HCTZ is also not metabolized in the body and is excreted unchanged in the urine.

Elimination: Valsartan demonstrates bi-exponential decay kinetics, has a half-life of 6 hours, and is excreted almost unchanged in the feces.[23][32] The steady-state concentration of valsartan is achieved after 7 days of twice-daily dosing.[33] Olmesartan has a half-life of 10 to 15 hours, takes 3 to 5 days to attain steady-state concentration (once-daily dosing regimen), and 90% of the dose is excreted in feces, with the remainder excreted in the urine.[24] Telmisartan is widely regarded as the longest-acting ARB, featuring a mean half-life of 24 hours, which conveniently allows for once-daily dosing.[30] This drug demonstrates bi-exponential decay kinetics, has a half-life of 24 hours, and takes 7 daily doses to achieve a steady state.[34] Irbesartan has a half-life of 11 to 15 hours, achieves steady-state concentration in 3 days, and 80% of the dose is excreted in feces, with the remaining excreted in urine. Candesartan reaches its peak concentration in 3 to 4 hours, and its half-life is 9 hours. The active metabolite of losartan has a half-life of 6 to 8 hours. Eprosartan's terminal half-life is 5 to 9 hours. The other ARBs are also eliminated primarily through feces. Hydrochlorothiazide peaks 4 hours after administration and remains effective for approximately 6 to 12 hours; its half-life is 5.6 to 14.8 hours. HCTZ is actively secreted into the proximal tubule by renal organic anion transporters and is eliminated through urine.[29]

Administration

Available Dosage Forms

The single-pill combination of angiotensin II receptor blockers (ARBs) and hydrochlorothiazide (HCTZ) is available in oral tablet formulations.

Adult Dosage and Strengths

Valsartan and hydrochlorothiazide

Available doses:

• 80 mg/12.5 mg
• 160 mg/12.5 mg
• 320 mg/12.5 mg
• 160 mg/25 mg
• 320 mg/25 mg

Initial dose: 160 mg/12.5 mg once daily

Maximum dose: 320 mg/25 mg once daily

The dose of the valsartan-HCTZ combination can be titrated 1 to 2 weeks after therapy is initiated, and maximum antihypertensive effects are achieved 2 to 4 weeks after treatment initiation.

Olmesartan and hydrochlorothiazide

Available doses:

• 20 mg/12.5 mg
• 40 mg/12.5 mg
• 40 mg/25 mg

Initial dose: 20 mg/12.5 mg once daily

Maximum dose: 40 mg/25 mg once daily

The dose of olmesartan-HCTZ combination should be titrated every 2 to 4 weeks until blood pressure is controlled.

Telmisartan and hydrochlorothiazide

Available doses:

• 40 mg/12.5 mg
• 80 mg/12.5 mg
• 80 mg/25 mg

Initial dose: 40 mg/12.5 mg once daily

Maximum dose: 160 mg/25 mg once daily

The medication should be started at the lowest possible dose and titrated every 1 to 2 weeks according to the patient's blood pressure.

Irbesartan and hydrochlorothiazide

Available doses:

• 150 mg/12.5 mg
• 300 mg/12.5 mg

Initial dose: 150 mg/12.5 mg once daily

Maximum dose: 300 mg/25 mg once daily

The dosage should be titrated every 1 to 2 weeks. The maximum antihypertensive effect is seen 3 to 4 weeks after treatment is initiated.

Candesartan and hydrochlorothiazide

Available doses:

• 16 mg/12.5 mg
• 32 mg/12.5 mg
• 32 mg/25 mg

Initial dose: 16 mg/12.5 mg once daily

Maximum dose: 32 mg/25 mg once daily

The maximal antihypertensive effect of candesartan and HCTZ is observed 4 weeks after initiating the medication. A patient with uncontrolled blood pressure on 25 mg of HCTZ would only benefit from the combination of 16 mg of candesartan and 12.5 mg of HCTZ. A patient who develops hypokalemia on 25 mg of HCTZ can expect potassium levels to improve after initiating a combination of candesartan and HCTZ.

Losartan and hydrochlorothiazide

Available doses:

• 50 mg/12.5 mg
• 100 mg/12.5 mg
• 100 mg/25 mg

Initial dose: 50 mg/12.5 mg

Maximum dose: 100 mg/25 mg daily (ie, 100 mg/25 mg once daily or 50 mg/12.5 mg twice daily)

The typical starting dose of losartan and HCTZ is 50 mg/12.5 mg. If blood pressure remains uncontrolled after 3 weeks of therapy, the dose can be increased to 100/25 mg once daily.

Eprosartan and hydrochlorothiazide

Available doses:

• 600 mg/12.5 mg
• 600 mg/25 mg

Initial dose: 600 mg/12.5mg once daily

Maximum dose: 600 mg/25 mg once daily

The dose of eprosartan and HCTZ combination can be increased to a maximum of 600 mg/25 mg if blood pressure readings remain high 3 weeks after starting therapy.[22][35]

Specific Patient Populations

Renal impairment: No dosage changes are required for patients with mild and moderate renal impairment. However, combination ARB-HCTZ medications are contraindicated for patients with end-stage renal disease, as hydrochlorothiazide can induce azotemia in patients with severe renal impairment. According to KDIGO guidelines, hypertension is a significant risk factor for the development and progression of chronic kidney disease (CKD). A diagnosis of CKD is made for patients with an estimated glomerular filtration rate <60 mL/min/1.73 m² and a urinary albumin-to-creatinine ratio ≥300 mg/g for 3 months or longer. Among patients with type 1 or type 2 diabetes and CKD, treatment with an ACE inhibitor or ARB reduces the risk of progressing to end-stage renal disease (ESRD). Additionally, antihypertensive therapy mitigates the risk of cardiovascular events.[36] 

Hepatic impairment: Minor electrolyte imbalances can precipitate hepatic encephalopathy in patients with cirrhosis; electrolyte levels should be carefully monitored in these patients.[37] Valsartan should be avoided for patients with marked hepatic dysfunction. However, if valsartan must be administered, the daily dose should not exceed 80 mg.[23] Losartan undergoes extensive first-pass metabolism in the liver mediated by the cytochrome P450 system; initial dosing should be half the standard in patients with severe hepatic impairment.[30] ARBs inhibit the renin-angiotensin-aldosterone system (RAAS), reducing vasoconstriction. Compensatory vasoconstriction is critical for maintaining blood pressure in patients with cirrhosis. The American Association for the Study of Liver Diseases (AASLD) guidelines recommend avoiding ARBs for patients with cirrhosis-related ascites due to potential adverse effects on systemic hemodynamics and renal function.[38][39] Thiazide diuretics can cause hypovolemic hyperosmolar hyponatremia in patients with cirrhosis and ascites, especially older patients. The concomitant use of aldosterone antagonists exacerbates this complication.[40]

Pregnancy considerations: Medications that target the RAAS can result in fetal renal dysfunction, pulmonary hypoplasia, patent ductus arteriosus, hypocalvaria, and musculoskeletal deformities. HCTZ crosses the placenta and has adverse effects on the fetus, such as hyperbilirubinemia, thrombocytopenia, and oligohydramnios.[41] HCTZ also causes diuresis, which can potentially lead to hypoperfusion of the placenta and subsequent intrauterine growth restriction and fetal distress. According to AHA/ACC guidelines, women with hypertension who are pregnant or planning to become pregnant should switch to methyldopa, nifedipine, or labetalol. Clinicians are advised to avoid prescribing ACE inhibitors, ARBs, or direct renin inhibitors to pregnant women.[8] According to ISH guidelines, renin-angiotensin system (RAS) blockers, including ACE inhibitors, ARBs, and direct renin inhibitors, are contraindicated for pregnant women due to adverse fetal and neonatal outcomes.[10]

Breastfeeding considerations: HCTZ is secreted in human milk and is associated with adverse neonatal effects. Women who are nursing must discontinue either the drug or breastfeeding. Intense diuresis induced by HCTZ can reduce breast milk production. Neonates who ingest HCTZ in breast milk may experience acute renal injury, hypokalemia, hyperbilirubinemia, hyponatremia, and hypochloremia. The latter effect is associated with significant mortality among preterm neonates.[42] Intensive diuresis using high doses of diuretics (eg, hydrochlorothiazide 100–150 mg daily) has historically been administered to suppress postpartum lactation. However, no instances of lactation suppression have been reported in patients administered the standard antihypertensive-hydrochlorothiazide doses (25 to 50 mg daily). There is limited information on the effect of ARBs on lactation. However, since all ARBs are highly bound to plasma proteins (>98%) and are poorly absorbed when administered orally, they are thought to be unlikely to affect nursing infants.[43] 

Pediatric patients: The safety and efficacy of ARB/HCTZ single-pill combination products have not been established in the pediatric population. However, ARBs have been shown to lower blood pressure in children aged 6 months to 6 years and have a favorable safety profile.[44] Neonates exposed to the ARB-HCTZ combination may require exchange transfusions and dialysis due to renal impairment. The safety of the ARB-HCTZ combination in patients older than 28 days has not been established. 

Older patients: No difference in safety, efficacy, or adverse effects profile has been documented in older adults. Diuretic agents may cause orthostatic hypotension in these patients; however, there is no evidence that ARB-HCTZ medications result in this condition in older patients.[45]

Adverse Effects

The incidence and severity of adverse reactions were reported lower for patients on ARB-HCTZ combination therapy than for patients taking individual drugs. The incidence of adverse reactions is independent of age, race, or sex. During clinical trials, ARB-HCTZ was discontinued in 2.3% of patients due to adverse effects.

Severe adverse effects associated with hydrochlorothiazide administration include:

• Systemic lupus erythematosus (SLE) flares
• Hyperuricemia
• Worsening dyslipidemia
• Acute angle closure glaucoma
• Urea level elevations in patients with renal dysfunction
• Electrolyte imbalances (eg, hypokalemia, hyponatremia, and hypercalcemia)

Hydrochlorothiazide diuretics are also known to cause hyperglycemia, pancreatitis, hyperbilirubinemia, gastroenteritis, aplastic anemia, hemolytic anemia, pulmonary edema, bleeding dyscrasia, headache, vertigo, and blurred vision. The risk of squamous cell carcinoma (non-melanoma skin cancer) was found to be higher for White patients receiving HCTZ compared to the general population.[30][46] There is a significantly higher risk of drug-induced liver injury (DILI) for patients receiving azilsartan compared to valsartan.[47]

The adverse effects associated with ARBs include dizziness, hyperkalemia, sinusitis, angioedema, cough, and enteropathy. The incidence and severity of hypotension increase with the concurrent administration of diuretics such as HCTZ. Providers should avoid prescribing candesartan to patients with hyperuricemia.[48]

• Cough: ARBs increase bradykinin levels, which stimulate the production of prostaglandins that cause bronchial irritation.
• Hypotension: Hypotension is observed more commonly in patients receiving telmisartan. The ONTARGET trial highlighted the impact of hypotension in these patients, leading to the discontinuation of this drug.[49]
• Enteropathy: The administration of olmesartan can cause a sprue-like enteropathy.[50] Chronic diarrhea, weight loss, and villous atrophy have been documented. These patients typically test negative for celiac disease, and the symptoms recur if olmesartan is restarted.
• Hyperkalemia: Aldosterone is a significant regulator of potassium excretion. Since ARBs prevent the effects of angiotensin and aldosterone, patients receiving these medications are at an increased risk of hyperkalemia. This adverse effect is more common in patients with chronic kidney disease who are taking potassium-sparing diuretics such as aldactone. To a certain extent, the hypokalemia induced by hydrochlorothiazide is countered by ARB-induced hyperkalemia.[51]

Drug-Drug Interactions

Concurrent administration of ARB-HCTZ with alcohol, narcotics, and barbiturates can precipitate hypotension. Patients receiving ARB-HCTZ may develop increased responsiveness to lower doses of curare-derived muscle relaxants (eg, rocuronium). Medications that reduce gastrointestinal motility (eg, opioids, atropine) cause increased bioavailability of HCTZ. In contrast, prokinetic agents decrease the bioavailability of the drug combination. Fluconazole inhibits the activation of losartan into its active metabolite, reducing its efficacy. Simultaneous administration of HCTZ and antineoplastic agents can precipitate the latter's toxicity as their renal clearance is reduced. Elevated serum lithium levels have been observed in patients who are also receiving ARB-HCTZ. Co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) can worsen renal function, especially in older and dehydrated patients. When administered simultaneously with drugs such as NSAIDs, ARB-HCTZ can reduce the renal clearance of digoxin, leading to toxicity.[7] According to the product labeling, thiazide diuretics can reduce calcium excretion. Hydrochlorothiazide may also cause minor elevations in blood calcium levels, even in healthy patients. Significant hypercalcemia is suggestive of underlying hyperparathyroidism. Hydrochlorothiazide should be discontinued before assessing parathyroid gland function.[52][7]

Contraindications

The combination of ARBs and HCTZ should not be administered to patients with the following conditions:

• Hypersensitivity to sulfonamide-derived drugs: Individuals with a history of hypersensitivity to any component of the ARB-HCTZ combination, angioedema, or anaphylaxis should not take this medication. These conditions are absolute contraindications to the ARB-HCTZ combination.

• Pregnancy: Both ARBs and HCTZ are known to have teratogenic effects on the developing fetus. Therefore, if a woman becomes pregnant while taking this combination medication, it must be discontinued immediately.

• Receiving aliskiren: The simultaneous administration of aliskiren and ARB-HCTZ significantly increases the risk of hypotension and hyperkalemia.

• Bilateral renal artery stenosis and heart failure with hypotension: Patients with conditions such as bilateral renal artery stenosis and heart failure accompanied by hypotension rely heavily on the RAAS to regulate blood pressure and should not be administered ARBs. In patients with this or similar conditions, ARBs may precipitate renal failure and hyperkalemia.[48]

Box Warning

• Fetal toxicity: Upon detection of pregnancy, discontinue single pill combinations of ARB-HCTZ promptly. Agents affecting the renin-angiotensin system can result in fetal injury and mortality.[53]

Warning and Precautions

• Healthcare providers should remain informed about industry recalls of ARBs, including the past recalls of valsartan, irbesartan, and losartan, due to the presence of contaminants such as NMBA and NDMA. Providers should be aware of the specific batches affected and updates from regulatory agencies like the FDA regarding any new recalls related to these contaminants due to their carcinogenic potential.[54]
• Hydrochlorothiazide administration in kidney transplant recipients is associated with an increased incidence of basal cell carcinoma. This relationship underscores the importance of frequent dermatological monitoring, particularly for patients continuously exposed to sunlight or other ultraviolet sources.[55] Despite previous pharmacovigilance reports suggesting a link, a randomized, placebo-controlled trial involving 30 healthy volunteers found that HCTZ 25 mg daily for 15 days did not increase photosensitivity to UVA or UVB radiation or cause phototoxic or carcinogenic effects. In vitro studies with human keratinocytes also found no adverse effects related to phototoxicity or carcinogenesis due to HCTZ administration combined with UVB exposure.[56] A systematic review and meta-analysis on antihypertensive drugs concluded that diuretics (especially hydrochlorothiazide) are associated with an increased risk of non-melanoma skin cancer (NMSC). However, this risk was predominantly observed during studies that did not adjust for sun exposure or smoking. Cohort studies and studies that corrected these factors did not find a significantly increased risk of NMSC. Furthermore, significant publication bias was identified in some studies. In conclusion, while observational data suggest a link between HCTZ and skin cancer, the evidence from well-controlled studies correcting for confounding factors is less conclusive. Further research and ongoing surveillance is required.[57]

Monitoring

Serum potassium levels should be monitored in patients with chronic kidney disease who are prescribed ARB-HCTZ. Among the patients who do not have renal dysfunction, potassium is not regularly monitored, as the incidence of new-onset hyperkalemia after ARB administration is 2% and typically rises only 0.2 mmol/L.[58] Hydrochlorothiazide increases potassium excretion and may cause hypokalemia; the hyperkalemia caused by ARBs is balanced by HCTZ-induced hypokalemia.[59] For patients receiving ARB therapy, renal parameters should be monitored routinely. Clinicians should monitor serum glucose levels in patients with diabetes mellitus and prediabetes, as HCTZ can cause hyperglycemia.[17] Patients with a past or family history of hyperuricemia should be monitored for features of an acute flare of gout, as HCTZ causes increased uric acid reabsorption.[60] According to ADA guidelines, serum creatinine elevations (up to 30% above baseline) with ARBs should not be mistaken for acute kidney injury (AKI). Therefore, ARBs should not be discontinued for these minor increases in serum creatinine unless accompanied by volume depletion.[16] According to ESC guidelines, regular patient follow-up is essential during hypertension therapy, as it allows for assessing blood pressure control, evaluating the need for lifestyle and pharmacological treatments, identifying hypertensive-mediated organ damage (HMOD), ascertaining necessary modifications to risk factors, and verifying medication adherence.[61]

Toxicity

Signs and Symptoms of Overdose

The median lethal dose (LD₅₀) of each drug combination depends on the constituent ARB. The literature does not provide toxicity data for each ARB and HCTZ combination. 

An overdose of ARB can cause hypotension, tachycardia, or bradycardia. The LD₅₀ for each ARB is listed below.

• Valsartan: >2 g/kg
• Olmesartan: >1.5 g/kg
• Telmisartan: >150 mg/kg
• Irbesartan: >2000 mg/kg
• Losartan: >2000 mg/kg

According to animal studies, the LD₅₀ of HCTZ is >10 g/kg. Hydrochlorothiazide toxicity can cause excessive diuresis, leading to hypotension and electrolyte imbalance.

Management of Overdose

The management of an ARB-HCTZ overdose involves supportive care with intravenous fluids and ensuring electrolyte balance. Terlipressin can be used to treat the patient if the hypotension is not responsive to vasopressors.[62]

Enhancing Healthcare Team Outcomes

Adequate management of hypertension is crucial for reducing cardiovascular mortality, as it is one of the major risk factors for cardiovascular diseases. Inadequate control of blood pressure poses a significant public health concern. However, patients can achieve appropriate blood pressure targets through combination therapy, such as the angiotensin receptor blocker-hydrochlorothiazide single-pill combination. This therapy improves blood pressure control and metabolic parameters while reducing other cardiovascular risk factors. Hydrochlorothiazide is available with various angiotensin receptor blockers, including telmisartan, valsartan, olmesartan, candesartan, and losartan. However, caution should be exercised when prescribing the angiotensin receptor blocker and hydrochlorothiazide combination to patients with renal impairments and electrolyte imbalances. Clinicians must rule out absolute contraindications, such as pregnancy, bilateral renal artery stenosis, and concurrent use of aliskiren, before initiating this medication.

Each healthcare provider should have a clearly defined role in optimizing treatment outcomes. Effective communication among the healthcare team members is crucial to ensuring appropriate patient care. During one prospective study, pharmacist-managed hypertension care in collaboration with physicians led to an average systolic blood pressure (SBP) reduction of 10.83 mm Hg. A greater proportion of patients in the pharmacist-managed group achieved their blood pressure goal (<130/80 mm Hg) compared to those managed solely by physicians (56.5% vs. 20.8%, P = 0.012). These findings underscore the benefit of pharmacist involvement in improving hypertension management outcomes in ambulatory care settings.[63] Evidence-based practice should guide the selection of antihypertensive therapy, and healthcare providers should thoroughly explain the potential adverse effects and benefits of the angiotensin receptor blocker and hydrochlorothiazide combination to the patient and any caregivers. By promoting coordination and communication among healthcare team members, errors are minimized, and patient outcomes are improved. Cardiologists and nephrologists should be consulted regarding secondary causes of hypertension and end-organ damage. Emergency medicine physicians should be consulted for rapid stabilization of patients who have overdosed. An interprofessional team approach and communication among clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, and nurses significantly reduces potential adverse effects, improves the disease course, and improves patient outcomes related to angiotensin receptor blocker and hydrochlorothiazide therapy.