Why does Florinef (fludrocortisone) for orthostatic hypotension oppose the effects of HCTZ (hydrochlorothiazide) for hypertension?

From the Guidelines

The combined use of Florinef and HCTZ for orthostatic hypotension and hypertension, respectively, is not recommended due to their opposing effects on blood pressure regulation, which can lead to worsening of orthostatic symptoms and diminished antihypertensive benefits. Florinef (fludrocortisone) is prescribed for orthostatic hypotension because it increases sodium retention and blood volume, which raises blood pressure when standing, by mimicking aldosterone and enhancing sodium reabsorption in the kidneys and increasing fluid retention 1. In contrast, HCTZ is a diuretic used to treat hypertension by promoting sodium and water excretion, reducing blood volume and lowering blood pressure. When used together, HCTZ can diminish Florinef's volume-expanding effects, potentially worsening orthostatic symptoms, while Florinef may counteract HCTZ's antihypertensive benefits.

According to the 2024 ESC guidelines for the management of elevated blood pressure and hypertension, it is recommended to pursue non-pharmacological approaches as the first-line treatment of orthostatic hypotension among persons with supine hypertension, and to switch BP-lowering medications that worsen orthostatic hypotension to an alternative BP-lowering therapy and not to simply de-intensify therapy 1. Alternative approaches might include using non-diuretic antihypertensives (like ACE inhibitors or calcium channel blockers) alongside Florinef, or carefully titrating both medications with close blood pressure monitoring in both sitting and standing positions to achieve an optimal balance. The treatment goals for orthostatic hypotension include prevention of symptom recurrence and associated injuries, and improved quality of life, as stated in the guidelines on management (diagnosis and treatment) of syncope 1.

Some key points to consider when managing patients with both orthostatic hypotension and hypertension include:

• Establishing the underlying diagnosis is crucial in patients with orthostatic hypotension
• Elimination of offending agents, such as diuretics and vasodilators, is the principal treatment strategy for drug-induced autonomic failure
• Non-pharmacological approaches should be pursued as the first-line treatment of orthostatic hypotension among persons with supine hypertension
• BP-lowering medications that worsen orthostatic hypotension should be switched to an alternative BP-lowering therapy.

From the FDA Drug Label

BECAUSE OF ITS MARKED EFFECT ON SODIUM RETENTION, THE USE OF FLUDROCORTISONE ACETATE IN THE TREATMENT OF CONDITIONS OTHER THAN THOSE INDICATED HEREIN IS NOT ADVISED... however, since fludrocortisone acetate is a potent mineralocorticoid, both the dosage and salt intake should be carefully monitored in order to avoid the development of hypertension, edema or weight gain. Hydrochlorothiazide blocks the reabsorption of sodium and chloride ions, and it thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted.

The combination of Florinef (fludrocortisone) and HCTZ (hydrochlorothiazide) may seem counterintuitive because they have opposing effects on sodium retention.

• Fludrocortisone promotes sodium retention, which can increase blood pressure.
• HCTZ increases sodium excretion, which can decrease blood pressure. However, in the context of treating orthostatic hypotension with Florinef and hypertension with HCTZ, the doses and patient conditions are carefully managed to balance these effects 2 3.

From the Research

Orthostatic Hypotension and Hypertension Treatment

• Orthostatic hypotension (OH) is a condition where blood pressure drops when standing up, which can be treated with fludrocortisone, a mineralocorticoid that increases blood volume and blood pressure 4.
• Hypertension (HTN) is often treated with diuretics like hydrochlorothiazide (HCTZ), which can help lower blood pressure by increasing urine production.
• The combination of fludrocortisone for OH and HCTZ for HTN may seem counterintuitive, as fludrocortisone can increase blood volume and pressure, while HCTZ can decrease blood volume and pressure.

Mechanisms and Interactions

• Fludrocortisone works by increasing blood volume and blood pressure, which can help alleviate OH symptoms 4.
• HCTZ, on the other hand, works by increasing urine production, which can help lower blood pressure in patients with HTN.
• However, the use of HCTZ in patients with OH can exacerbate the condition, as it can further decrease blood volume and pressure 5.
• The treatment of OH in hypertensive patients should focus on removing drugs that can worsen OH, and using antihypertensives that are less likely to exacerbate the condition, such as angiotensin receptor blockers and calcium channel blockers 5.

Clinical Considerations

• The management of OH in hypertensive patients is challenging, and requires a careful balance of treatments to avoid worsening one condition while treating the other 5.
• Non-pharmacological interventions, such as lifestyle modifications and physical countermaneuvers, should be used as first-line treatments for OH, with pharmacological interventions added as needed 6.
• The treatment goal in OH should be to improve symptoms and functional status, rather than targeting arbitrary blood pressure values 6.