Hypertension: Proper Use of the Laboratory to Monitor Drug Therapy
Lionel U. Mailloux, MD
North Shore University Hospital
Mailloux LU. Hypertension: proper use of the laboratory to monitor drug therapy. Consultant. 1985;25(10):75-85.
Antihypertensive drugs are in widespread use. Many of them, especially the diuretics, may produce abnormal findings on urine and blood analysis that reflect toxic reactions or exaggerated pharmacologic effects. Once we prescribe these agents, we should routinely use laboratory test results to monitor the safety of the medical regimen and make rational changes in our selections if indicated.
In this article, I discuss which abnormalities to especially look for and suggest a practical schedule of testing, leaving the formulation of the drug regimen to the practitioner. The focal point will be the oral antihypertensives most commonly used, the diuretics; and I will mention briefly the other oral drugs as well (see Table 1).
Oral diuretics may be grouped according to the portion of the nephron at which they have their greatest action. Knowing the drugs’ sites of action helps us anticipate the electrolyte and acid-base abnormalities that are most likely to occur.
In the order in which they act on the nephron, they are the carbonic anhydrase inhibitors (proximal tubule), the loop diuretics (Henle’s loop), the thiazide diuretics (distal tubule), and the potassium-sparing agents (aldosterone sensitive site in the distal tubule). The most frequently occurring complications are listed in Table 2.
Carbonic anhydrase inhibitors
Though widely used in the treatment of glaucoma, carbonic anhydrase inhibitors are rarely used in the treatment of hypertension. These agents interfere with the absorption of bicarbonate in the proximal tubule, thus causing a urinary loss of sodium, potassium, and bicarbonate.
The result is a hypokalemic metabolic acidosis and an alkaline urine such as would be seen in proximal renal tubular acidosis. A typical laboratory profile that reflects this state would be the following: sodium, 134 be the mEq/L; chloride, 115 mEq/L; carbon dioxide, 8 mEq/L; BUN 32 mg/dL; potassium, 2.8 mEq/L; glucose, 105 mg/dL; and creatinine, 1.6 mg/dL. The patient may feel weak, but serious symptoms are uncommon, and the most immediate clue is provided by your test results.
This biochemical abnormality is treated effectively with potassium bicarbonate, potassium gluconate, or any other organic potassium compound.
The three oral loop diuretics—furosemide, ethacrynic acid, and bumetanide—block the reabsorption of chloride and sodium in Henle’s loop, affecting both concentrating and diluting mechanisms.
Because the drugs have a short duration of action, patients must take them several times a day for hypertension. These are the most potent diuretics available and are most frequently used when hypertensive patients have severe edema-forming conditions. They are, therefore, generally used when the hypertension is associated with severe edema or renal insufficiency; and as a result, the laboratory abnormalities may be complex.
Used in uncomplicated hypertension, these potent short-acting diuretics may cause hypokalemic hypochloremic metabolic alkalosis, which I discuss with complications of thiazide diuretics.
Thiazides and related sulfonamides
Thiazide diuretics are the most frequently used agents that have an effect on the distal tubule. There are minor variations in length of action among the thiazide and other sulfonamide derivatives, but they are equipotent and they prove equally beneficial in the treatment of essential hypertension.
Another sulfonamide, metolazone, appears to be more potent. Like the loop diuretics, it can be used by patients with renal insufficiency and may be used to potentiate the action of loop diuretics in the treatment of resistant fluid retention. Indapamide is a longacting sulfonamide diuretic that appears to have some vasodilating properties. It may cause less elevation of the uric acid level than the other diuretics.
Complications of treatment. The loop agents and thiazidetype agents may all lead to the following untoward effects: fluid depletion, hyponatremia, hypokalemic hypochloremic alkalosis, hyperuricemia, and carbohydrate intolerance. The combined use of drugs from these two groups—metolazone plus a loop diuretic, for example—potentiates the pharmacologic effects of both agents, potentially leading to severe fluid depletion and marked biochemical abnormalities. Such combinations have led to hyperosmotic states in diabetic persons and to life-threatening hypokalemia.
The volume depletion and hypokalemic hypochloremic alkalosis occur because either type of diuretic produces natriuresis and chloruresis with a mild depletion of fluid volume (Flowchart). The volume depletion stimulates the renin-angiotensin system to produce a state of secondary aldosteronism. The chloruresis results in a slight decrease in chloride in the glomerular filtrate, causing less sodium to be reabsorbed in the proximal tubule. As a result, the fluid in Henle’s loop and the distal tubule contains more sodium. The patient develops kaliuresis and a mild decrease in serum potassium level.
As more sodium is presented to the aldosterone-sensitive site of the distal tubule, especially if the patient is not restricting sodium intake, further exchange of potassium and hydrogen ion occurs because of the secondary aldosteronism. This exaggerated physiologic response to increased sodium concentration in the distal tubule leads to renal loss of potassium and hydrogen ion, resulting in metabolic alkalosis.
A typical serum electrolyte profile might be as follows: sodium, 134 mEq/L; chloride, 82 mEq/L; carbon dioxide, 33 mEq/L; BUN, 36 mg/dL; potassium, 2.8 mEq/L; glucose, 110 mg/dL. This situation is then perpetuated by increases of bicarbonate reabsorption in the proximal tubule. Even though this would appear to be a side effect of the diuretic agent, these changes really represent an exaggerated physiologic effect related to the clinical pharmacologic properties of the drug.
Correction of alkalosis. The treatment of choice for the correction of diuretic-induced hypokalemic hypochloremic alkalosis is replacement with potassium chloride. If a patient becomes severely hypokalemic rapidly (within two to three weeks) or while on a very low dose of diuretic, you should become suspicious that there is an underlying mineralocorticoid excess, such as in primary aldosteronism.
When patients are taking a moderate dose of diuretic for a more prolonged period, hypokalemia may result when the dietary sodium intake is excessive and may thus exaggerate the effect of the secondary aldosteronism. Sodium restriction will not completely prevent the development of hypokalemic alkalosis, but it will decrease its severity and may obviate potassium chloride supplementation or a changeover to potassiumsparing diuretics.
Patients who have a serum potassium level of 3.0 mEq/L or less should receive supplementation and dietary instruction while taking diuretics. If they have a history of heart disease, you would give potassium supplementation at a higher serum level. Thiazide diuretics usually cause a urinary loss of potassium that exceeds 40 to 60 mEq/d. Sodium restriction can cut these losses markedly.
Hyponaturemia may develop in patients taking diuretics, especially if kidney function is abnormal. A common example of hyponaturemia is seen when a patient using diuretics is hospitalized, given intravenous fluid, and allowed free access to drinking water. The resultant dilutional hyponaturemia can be corrected by water restriction.
Other imbalances. Carbohydrate intolerance has been rarely described in reference to patients receiving long-term thiazide treatment. The exact pathophysiologic mechanism for this abnormality is unknown but may be attributable to persistent hypokalemia. Hyperglycemia and worsened diabetes control have been reported. These phenomena have also been observed in patients taking combined potent diuretics, such as furosemide and metolazone. Since this is a rare complication, diuretics are not contraindicated for diabetic hypertensive patients.
The thiazide and loop diuretics interfere with tubular secretion of uric acid and may, therefore, induce hyperuricemia and, rarely, gout. Thiazides have been reported to produce this problem in 30% of patients. Elevated uric acid levels generally need not be treated unless patients show clinical signs of gout.
Thiazides have also been seen to increase serum cholesterol and triglyceride levels. The mechanism for these abnormalities has not been elucidated.
The three potassium-sparing diuretics available are triamterene, amiloride, and spironolactone. Although these drugs have different distal tubular sites of action and differ slightly from each other in their minor side effects, they cause nearly identical acid-base and electrolyte abnormalities.
Spironolactone is a competitive antagonist to aldosterone binding sites in the distal tubule. Triamterene and amiloride directly inhibit the exchange of sodium and potassium at the distal tubule and are not dependent upon the presence of aldosterone. All of these agents may lead to hyperkalemic acidosis by preventing the secretion of potassium and hydrogen ion.
The potassium-sparing diuretics are commonly used in combination with thiazide or loop diuretics to prevent hypokalemia and metabolic alkalosis. Because there is great variety in the proportions of those combinations, acid-base abnormalities are unpredictable. The most serious chemical abnormality that can arise is hyperkalemia, which may be life-threatening to patients with renal insufficiency or to the elderly, in whom relatively normal serum creatinine levels may represent severe renal insufficiency. You must obtain laboratory tests intermittently in the course of treatment to assess any change.
The β-adrenergic blockers were the most widely prescribed agents in 1983. They cause relatively few side effects and usually do not lead to biochemical abnormalities in young patients who have no medical problems other than hypertension. They may, however, cause hyperkalemia in certain clinical settings.
All currently available β-blockers interfere with the production and release of renin by the juxtaglomerular apparatus of the kidney. This can lead to a state of secondary hypoaldosteronism because of interference with the exchange of sodium and potassium in the distal tubule of the kidney. β-blockers may, therefore, induce serious increases in serum potassium in individuals prone to hyporeninemic states, as are, for example, the elderly and the diabetic. This effect may be potentiated by the concomitant use of prostaglandin inhibitors such as the nonsteroidal anti-inflammatory drugs. β-blockers, like thiazides, may also alter lipid profiles.
The centrally acting adrenergic inhibitors—clonidine, methyldopa, and guanabenz—usually do not cause abnormalities in blood chemistry profiles. Methyldopa has been associated occasionally with positive Coombs' test, hepatotoxicity, and hemolytic anemia.
All the peripherally acting adrenergic inhibitors, α- and β-types, interfere with catecholamine metabolism, but this does not appear to alter biochemical levels or to cause any consistent abnormalities in laboratory test results.
Currently available vasodilators include hydralazine and minoxidil. Hydralazine may cause a syndrome resembling systemic lupus erythematosus that includes joint pain, fever, rash, and a positive antinuclear antibody titer. This occurs most frequently when patients are exposed to a great deal of sun, as during the summer months, and when doses exceed 400 mg daily.
Minoxidil causes few biochemical abnormalities by itself. Since it does cause marked sodium and water retention, however, it must be used with large doses of potent diuretics, thus resulting frequently in the fluid and electrolyte abnormalities I described previously.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Captopril is the only angiotensin converting enzyme (ACE) inhibitor currently approved by the FDA for the treatment of hypertension. Enalapril, a longer-acting ACE inhibitor, is under investigation. Proteinuria and nephrotic syndrome have occurred with captopril. Leukopenia has also been reported, especially when large doses are used by patients with collagen vascular disease or renal insufficiency. Both drugs inhibit angiotensin converting enzyme, blocking the conversion of angiotensin I to angiotensin II and causing a rapid decrease in aldosterone levels.
The most frequently observed biochemical abnormality with the ACE inhibitors is a mild increase in serum potassium levels brought about by the inhibition of aldosterone. Urinalysis may show ketones in some patients because of the reducing properties of the sulfhydryl group in the captopril molecule.
Most antihypertensive drugs may cause abnormalities in laboratory test results, either because of their mechanism of action or as a result of a toxic side effect. The hypokalemic metabolic alkalosis associated with diuretics is an example of the former, whereas hydralazine-induced lupus erythematosus is an example of the latter.
In view of the propensities of any agent you would choose, clinical judgement should be used to decide whether specific therapy is indicated. In most cases, therefore, your choice of antihypertensive agent should be based upon sound clinical criteria rather than the fear of causing laboratory abnormalities.
A routine testing schedule such as I’ve suggested in Table 3 should alert you to abnormalities before they become serious. Obviously, it may be necessary to perform the tests more often for patients you think may be more susceptible to certain problems.
The disorders I have outlined represent the more common disturbances about which every clinician needs to be aware. I have made no attempt to include all the possible abnormalities associated with these commonly used drugs since some aberrations occur extremely infrequently. Complete information about them can be learned from drug package inserts or compendiums of drug information, such as Facts and Comparisons, Physicians’ Desk Reference, or The Phycom Computer Source.
For more information:
- Abramow M, Cogan E: Clinical aspects of pathophysiology of diuretic-induced hyponatremia. Adv Nephrol. 13:1-28, 1984.
- Chobanian AV: Pathophysioment of the elderly hypertensive patient. Am J Cardiol. 52:49-53, 1983.
- Frohlich ED, Cooper RA, Lewis EJ: Review of the overall experience of captopril in hypertension. Arch Intern Med. 144:1441- 1444, 1984.
- Kurtzman NA: Metabolic alkalosis. National Kidney Foundation, Kidney. 9:27-32, 1976.
- The 1984 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med. 144:1045-1057, 1984.
- Moser M: Clinical trials, diuretics and the management of mild hypertension. Arch Intern Med. 144:789-792, 1984.
- Robinson BF, Bayley S, Dobbs RJ: Long-term efficacy of calcium antagonists in resistant hypertension. Hypertension. 5:122- 124, 1983.
- Sabatini S, Kurtzman NA: The maintenance of metabolic alkalosis; factors which decrease bicarbonate excretion. Kidney Int. 25:357-361, 1984.
- Wilcox CS, Mitch WE, Kelly RA, et al: Response of the kidney to furosemide: I. Effects of salt intake and renal compensation. J Lab Clin Med. 102:450-458, 1983.
Lionel U. Mailloux, MD, is associate professor of clinical medicine, Cornell University Medical College, New York, and co-chief, division of nephrology and hypertension, North Shore University Hospital, Manhasset, New York.