In a 61-year-old woman taking an estradiol transdermal patch 0.025 mg twice weekly, oral progesterone 100 mg, Cordone 25 mg, atenolol 25 mg, and venlafaxine extended‑release 75 mg with a blood pressure of 140/90 mm Hg, what additional medication should be added to control her hypertension?

Blood Pressure Management: Adding Medication to Current Regimen

Add a thiazide-like diuretic—specifically chlorthalidone 12.5-25 mg daily or hydrochlorothiazide 25 mg daily—as your third antihypertensive agent to achieve guideline-recommended triple therapy. 1

Current Situation Assessment

Your patient has uncontrolled stage 1 hypertension (140/90 mmHg) despite dual therapy with atenolol 25 mg and Cordone 25 mg (assuming this is amiodarone or a similar agent). 1 The blood pressure remains above the target of <130/80 mmHg for most adults, particularly those with cardiovascular risk factors. 1

Important consideration: Venlafaxine can elevate blood pressure in some patients, particularly at higher doses, though 75 mg ER is relatively low. 1 Monitor whether this medication is contributing to treatment resistance.

Recommended Treatment Algorithm

First-Line Addition: Thiazide Diuretic

The combination of a beta-blocker + thiazide diuretic represents a rational dual therapy approach, but you need to add a third agent from a complementary class. 1 The most evidence-based approach is:

• Start chlorthalidone 12.5-25 mg once daily in the morning (preferred due to longer half-life and superior cardiovascular outcomes data) 2, 3
• Alternative: hydrochlorothiazide 25 mg once daily if chlorthalidone is unavailable 2, 3

Rationale: Thiazide diuretics provide complementary mechanisms—volume reduction that enhances the effectiveness of beta-blockers. 1 Chlorthalidone has demonstrated superior 24-hour blood pressure control compared to hydrochlorothiazide and has stronger evidence for cardiovascular event reduction. 2, 3

Alternative Addition: ACE Inhibitor or ARB

If there are compelling reasons to avoid a diuretic initially (such as gout, severe hypokalemia risk, or patient preference), consider:

• Lisinopril 10 mg once daily (can titrate to 20-40 mg) 4
• Or an ARB such as losartan 50 mg once daily (can titrate to 100 mg) 1

This combination (beta-blocker + ACE inhibitor/ARB) is particularly beneficial if the patient has:

• Coronary artery disease 1
• Heart failure with reduced ejection fraction 1
• Chronic kidney disease 1
• Diabetes mellitus 1

If Blood Pressure Remains Uncontrolled on Triple Therapy

Add a calcium channel blocker (amlodipine 5-10 mg daily) as the fourth agent to achieve the evidence-based four-drug combination: beta-blocker + ACE inhibitor/ARB + thiazide diuretic + calcium channel blocker. 1, 5

Monitoring After Adding Medication

• Check serum potassium and creatinine 2-4 weeks after initiating a diuretic to detect hypokalemia or changes in renal function 1
• Reassess blood pressure within 2-4 weeks after adding the new agent 1
• Target blood pressure: <130/80 mmHg for most adults, with a minimum acceptable target of <140/90 mmHg 1
• Goal: achieve target blood pressure within 3 months of treatment modification 1

Special Considerations for This Patient

Hormone Replacement Therapy Interaction

The estradiol patch and progesterone may have modest effects on blood pressure control: 6, 7

• Estrogen can cause sodium and water retention, potentially raising blood pressure 6
• However, progesterone has antialdosterone activity that may counteract this effect 6
• The combination of estrogen plus progestin with thiazide diuretics has been shown to have additive blood pressure-lowering effects in postmenopausal women 6, 7
• Estrogen plus progestin therapy can counteract the unfavorable metabolic effects of thiazide diuretics (such as insulin resistance and increased uric acid) 7

Clinical implication: The hormone therapy should not prevent you from adding a thiazide diuretic—in fact, the combination may be beneficial. 6, 7

Beta-Blocker Considerations

Atenolol 25 mg is a relatively low dose (usual range 25-100 mg daily for hypertension). 8 However, rather than simply increasing the atenolol dose, adding a complementary agent is more effective for achieving blood pressure control. 1

Important caveat: Beta-blockers should be avoided or used cautiously in patients with metabolic syndrome due to adverse effects on glucose metabolism and lipid profiles. 1 If your patient has metabolic syndrome features (obesity, prediabetes, dyslipidemia), consider switching from atenolol to a vasodilating beta-blocker like carvedilol or nebivolol, or transitioning to a different drug class entirely. 1

Critical Steps Before Adding Medication

Verify Medication Adherence

Non-adherence is the most common cause of apparent treatment resistance. 1, 9 Directly ask about:

• Prescription fills and refills 9
• Cost barriers 9
• Side effects causing discontinuation 9
• Confusion about dosing schedules 9

Confirm True Hypertension

Arrange home blood pressure monitoring or 24-hour ambulatory monitoring to rule out white coat hypertension. 1, 5 Home BP ≥135/85 mmHg or 24-hour ambulatory BP ≥130/80 mmHg confirms true hypertension requiring treatment intensification. 1

Rule Out Interfering Medications

Review for drugs that can elevate blood pressure: 9

• NSAIDs (most common culprit) 9
• Decongestants 9
• Systemic corticosteroids 9
• Herbal supplements (ephedra, St. John's wort) 9

Screen for Secondary Hypertension

If blood pressure remains severely elevated (≥160/100 mmHg) despite optimal therapy, evaluate for: 1, 9

• Primary aldosteronism 9
• Renal artery stenosis 9
• Obstructive sleep apnea 9
• Pheochromocytoma 5

Lifestyle Modifications to Reinforce

These provide additive blood pressure reductions of 10-20 mmHg: 1, 9

• Sodium restriction to <2 g/day (provides 5-10 mmHg systolic reduction) 1, 9
• Weight loss if overweight (10 kg weight loss associated with 6.0/4.6 mmHg reduction) 9
• DASH diet (reduces systolic/diastolic BP by 11.4/5.5 mmHg) 1, 9
• Regular aerobic exercise (minimum 30 minutes most days produces 4/3 mmHg reduction) 1, 9
• Alcohol limitation to ≤1 drink/day for women 1, 9

Common Pitfalls to Avoid

• Do not add a second beta-blocker or simply increase atenolol dose as the primary strategy—combination therapy with different drug classes is more effective than monotherapy dose escalation 1, 9
• Do not combine an ACE inhibitor with an ARB—dual RAS blockade increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 1, 5
• Do not delay treatment intensification—the patient has uncontrolled hypertension requiring prompt action to reduce cardiovascular risk 1, 9
• Do not assume treatment failure without first confirming adherence and ruling out secondary causes 1, 5