NRP/507 Week 3: Cardiovascular Drug Therapy Case, sample paper

The Fourth Drug: Adding Spironolactone for Resistant Hypertension in a 64-Year-Old Bus Mechanic After Ruling Out the Reasons Three Drugs Were Not Working

[Student Name]

University of Phoenix

NRP/507: Advanced Pharmacology

Week 3 Assignment

[Instructor Name]

[Date]

The patient is a composite written for a model paper.

Mr. T., a 64-year-old bus mechanic, has hypertension and type 2 diabetes. For eight months his office blood pressure has ranged from 152 to 158 systolic and 88 to 92 diastolic despite taking lisinopril 40 mg, amlodipine 10 mg and chlorthalidone 25 mg every morning. Recent labs show kidney function in the low-normal range, an eGFR of 64, with potassium at 4.3 mmol/L. He asks whether he needs "a stronger pill." This paper explains why the answer begins with questions and ends with a fourth drug chosen for a reason.

Is This Truly Resistant Hypertension?

Resistant hypertension is blood pressure above goal despite three drugs of different classes, usually including a diuretic, at maximally tolerated doses (Carey et al., 2018). Mr. T. meets this definition on paper, but pseudoresistance must be ruled out first. Carey et al. (2018) identify its common causes: inaccurate measurement, white-coat effect and poor adherence. My clinic repeats his readings with correct technique, a proper cuff size and five minutes of rest, and they remain near 150/88 mm Hg. A week of home readings averages 146/86 mm Hg, confirming that his blood pressure is high outside the office as well.

Is He Taking the Drugs?

Nonadherence is common and often hidden. I ask without judgment how often he misses doses, and review pharmacy fill dates, which show consistent monthly fills. He takes all three pills each morning with breakfast. Adherence appears good.

Is Something Raising His Blood Pressure?

I review substances that raise blood pressure (Carey et al., 2018). Mr. T. takes naproxen 500 mg twice a day for knee pain most days, which can raise blood pressure and blunt the effect of his lisinopril and diuretic; he drinks four to five beers most evenings; and he eats lunch from a fast-food counter near the garage almost daily, a high-sodium diet. He does not use decongestants or stimulants.

Could There Be a Secondary Cause?

Secondary causes are more common in resistant hypertension than in other hypertension. His snoring, daytime sleepiness and a neck circumference of 44 cm suggest obstructive sleep apnea, and I refer him for a sleep study. Primary aldosteronism is a frequent and underrecognized cause of resistant hypertension, and screening with a plasma aldosterone-to-renin ratio is recommended (Carey et al., 2018); I order it before starting any drug that would interfere with the result. His kidney function and urine albumin will also be rechecked.

First Steps Without a New Drug

Before adding a drug, I recommend replacing naproxen with acetaminophen and a topical anti-inflammatory for his knee, reducing alcohol to no more than two drinks a day and choosing lower-sodium lunch options, with a referral to a dietitian. These changes alone could lower his blood pressure meaningfully. We agree to recheck in four weeks.

Four Weeks Later

Mr. T. stopped naproxen and cut his drinking to two beers most nights. His home average is now 142/84 mm Hg, better but above his goal of under 130/80 mm Hg (Whelton et al., 2018). His aldosterone-to-renin ratio is not elevated, and his sleep study is scheduled. It is now reasonable to add a fourth drug.

Choosing the Fourth Drug

PATHWAY-2, a randomized crossover trial in patients with resistant hypertension on three drugs, compared spironolactone, bisoprolol, doxazosin and placebo. Spironolactone reduced home systolic blood pressure by 8.7 mm Hg more than placebo and by about 4.3 mm Hg more than the average of the other two active drugs, and it was the most effective drug across the range of baseline renin (Williams et al., 2015). The authors concluded that sodium retention plays a primary role in resistant hypertension. The American Heart Association statement recommends a mineralocorticoid receptor antagonist as the preferred fourth agent (Carey et al., 2018). When three drugs fail, the fourth should target the mechanism most likely to be driving the pressure, and in most patients that mechanism is retained salt and water.

Mechanism

Spironolactone blocks the mineralocorticoid receptor in the distal nephron, preventing aldosterone from promoting sodium reabsorption and potassium excretion. The result is a modest natriuresis and a fall in blood pressure, with a tendency to raise potassium.

Adapting the Dose to Mr. T.

Mr. T. takes lisinopril, which also raises potassium, and has diabetes and mildly reduced kidney function, all of which increase the risk of hyperkalemia. His potassium of 4.3 mmol/L and eGFR of 64 permit spironolactone with caution. I start at 12.5 mg daily rather than 25 mg, with a plan to increase to 25 mg if potassium remains below 5.0 mmol/L and blood pressure remains above goal.

Why Not Bisoprolol or Doxazosin?

A beta blocker or an alpha blocker would be reasonable if spironolactone could not be used. In PATHWAY-2, each lowered blood pressure less than spironolactone (Williams et al., 2015), and neither targets volume. Mr. T. has no angina, prior heart attack or heart failure that would give a beta blocker a separate reason, and doxazosin can cause dizziness on standing, a concern for a man who works under buses and climbs in and out of service pits. If his potassium rises and spironolactone must stop, a beta blocker or a loop diuretic in place of chlorthalidone would be the next options to discuss.

Monitoring

Potassium and creatinine will be checked at one week, four weeks and then every three months. Spironolactone will be held if potassium exceeds 5.5 mmol/L. I will ask about breast tenderness or enlargement, a known adverse effect that may prompt a switch to eplerenone. Home blood pressure readings will be reviewed at four weeks.

Treating the Whole Risk Profile

Blood pressure is one part of Mr. T.'s cardiovascular risk. He has diabetes, and the hypertension guideline recommends assessing overall risk and treating other factors, such as lipids and glucose, together (Whelton et al., 2018). His statin therapy and diabetes control will be reviewed at the same visit, and lowering his blood pressure to goal will also protect his kidneys, where albuminuria would signal early damage.

Teaching

Mr. T. will learn to avoid potassium supplements and salt substitutes that contain potassium, to avoid nonsteroidal anti-inflammatory drugs, to report muscle weakness or palpitations and to continue home monitoring. He will bring his home log to each visit.

What Success Looks Like

The goal is a home average below 130/80 mm Hg within three months without hyperkalemia or a meaningful fall in kidney function. A small rise in creatinine after starting spironolactone is expected and acceptable; a rise of more than about 30% would prompt a dose reduction and a closer look. If his sleep study confirms obstructive sleep apnea, treatment may lower his pressure further, and the need for four drugs will be reconsidered.

Conclusion

Mr. T. appeared to need a stronger pill, but the first gains came from stopping naproxen and reducing alcohol. When a fourth drug was still needed, spironolactone was chosen because trial evidence showed it to be the most effective add-on in resistant hypertension, and its dose and monitoring were adapted to his kidney function, diabetes and use of an ACE inhibitor.

References

Carey, R. M., Calhoun, D. A., Bakris, G. L., Brook, R. D., Daugherty, S. L., Dennison-Himmelfarb, C. R., Egan, B. M., Flack, J. M., Gidding, S. S., Judd, E., Lackland, D. T., Laffer, C. L., Newton-Cheh, C., Smith, S. M., Taler, S. J., Textor, S. C., Turan, T. N., & White, W. B. (2018). Resistant hypertension: Detection, evaluation, and management: A scientific statement from the American Heart Association. Hypertension, 72(5), e53-e90. https://doi.org/10.1161/HYP.0000000000000084

Whelton, P. K., Carey, R. M., Aronow, W. S., Casey, D. E., Jr., Collins, K. J., Dennison Himmelfarb, C., DePalma, S. M., Gidding, S., Jamerson, K. A., Jones, D. W., MacLaughlin, E. J., Muntner, P., Ovbiagele, B., Smith, S. C., Jr., Spencer, C. C., Stafford, R. S., Taler, S. J., Thomas, R. J., Williams, K. A., Sr., . . . Wright, J. T., Jr. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Hypertension, 71(6), e13-e115. https://doi.org/10.1161/HYP.0000000000000065

Williams, B., MacDonald, T. M., Morant, S., Webb, D. J., Sever, P., McInnes, G., Ford, I., Cruickshank, J. K., Caulfield, M. J., Salsbury, J., Mackenzie, I., Padmanabhan, S., & Brown, M. J. (2015). Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial. The Lancet, 386(10008), 2059-2068. https://doi.org/10.1016/S0140-6736(15)00257-3