Cardiovascular Disease
Micronutrient Nutritional Losses in Patient’s Receiving Diuretic Pharmacotherapy for the Reduction of Hypertension
Despite major breakthroughs in the biological sciences, cardiovascular disease (CVD) continues to dominate the spotlight as one of the nation’s number top killers, claiming 950,000 lives a year, and 260 billion dollars annually in health care costs. A long list of risk factors contribute to the disease’s extremely variable etiology. Obesity, hypertension, hypercholesterolemia, sedentary lifestyle, poor nutrition, smoking, and alcohol intake are a few of the modifiable factors toward which therapies have been aimed. Standard treatment protocols include lifestyle and dietary changes, exercise implementation, and pharmacotherapy.
Primary preventative drug therapy in CVD is aimed at the reduction of hypertension and hypercholesterol, and control of blood glucose levels in diabetics. The efficacy of these therapies in reducing morbidity rates for CVD have been demonstrated in multiple trials. The subsequent decrease in premature mortality from CVD in these patients leads to issues revolving around quality of life, chronic medication use, and consequently an increase in adverse reactions, and alterations in normal biochemistry.
Modifiable risk factors are the target for treatment of patient’s at risk for CVD. Counseling for diet and behavior (i.e. stress reduction) modification, exercise, cessation of smoking and alcohol consumption are all first line defenses in treatment protocols. The problem herein lies with managed care. Preventative strategies and behavioral modification are not covered by many managed care organizations (MCO) despite the proven efficacy of these intervention strategies in lowering health risks and health care dollars spent. As a consequence, many patients are placed on pharmaceutical agents without adequate counseling despite treatment guidelines. This review will discuss nutritional losses in patients receiving pharmaceutical agents for the treatment of hypertension.
The Effect of Anti-Hypertensive Medications on Micronutrient Status
Diuretics represent the foundation for modification of high blood pressure. As well, they are highly utilized in the treatment of congestive heart failure (CHF). Even so, their use has been shown to have detrimental effects on the body’s nutritional status. All diuretics promote sodium and volume excretion from the kidneys. Depending on the type of diuretic and its site and mode of action, increased excretion of potassium, chloride, calcium, bicarbonate, and magnesium can all be present. Complications can include prerenal azotemia, acid-base balance disturbances, neurological damage, glucose intolerance, ototoxicity, interstitial nephritis, pancreatitis, and myalgia.
Potassium-sparing diuretics (PSD) have been implicated in increasing urinary clearance of calcium, sodium, zinc, and folic acid. Hanze et al reported an increase in urinary excretion of calcium with triamterene (a PSD) administration. This same drug was also found to have competitive inhibition against folic acid in rat jejunum. In a case study, Joosten and Pelemans report an elderly patient with megaloblastic anemia. Their speculation points to folic acid deficiency induced by triamterene. Lambie and Johnson review folate antagonist drugs (to include triamterene), and suggest treatment with folic acid to prevent megaloblastic anemia. Other nutritionally related side effects of PSD’s can include hyperkalemia, elevated blood urea nitrogen (BUN), glucose intolerance, and gastrointestinal disturbances. Loop diuretics act on the thick ascending limb by inhibiting luminal cotransport of sodium, potassium and chloride. Administration of these medications has been associated with deficiencies in calcium, magnesium, sodium, potassium, zinc, and vitamins B1, B6, and C. The 2001 PDR states that serum electrolytes (in reference to calcium, magnesium, and potassium) should be monitored when loop diuretics are prescribed. A study published by Suki et al reported the successful treatment of hypercalcemia with intravenous furosemide therapy. Ryan et al found in patients with congestive heart failure being treated with furosemide that both magnesium and potassium levels were inadequate. Schwinger et al recommend electrolyte replacement when treating heart failure patients with loop diuretics. In a controlled trial, Lucker et al utilized furosemide in potassium and magnesium deplete patients. The administration of the diuretic led to an even greater intracellular deficiency of the two minerals. A review by Quamme states that furosemide inhibits passive magnesium uptake as well as increases renal magnesium excretion. Seligmann et al found a causal thiamine deficiency which contributed to impaired heart function in patients receiving long-term loop diuretic (furosemide) therapy. Another study demonstrated improved left ventricular function (as measured by ejection fracture) in patients being treating by furosemide for at least three months after repletion of thiamine (200mg/day for 6 weeks). Rieck et al found that furosemide in 1, 3, and 10mg doses doubled thiamine excretion in healthy volunteers before returning to baseline levels at 18 hours after drug administration. Using the erythrocyte transketolase activity coefficient assay (ETKAC), Brady et al found biochemical evidence of thiamin deficiency and inadequacy in 21% and 25% respectively in 38 congestive heart failure (CHF) patients receiving loop diuretics as treatment. Suter and Vetter propose that chronic diuretic use in patients at risk (elderly and alcohol abusers) may lead to subclinical thiamine deficiency which in turn might play a metabolic role in the prevalence and severity of heart failure. In a prospective trial looking at ETKAC on admission and discharge Suter et al found that 149 elderly hospitalized patients were at an increased risk for thiamine malnutrition which was highly correlated with furosemide therapy. The group further recommends low-dose thiamine to prevent subclinical ber-beri. Inhibition of cellular uptake of thiamin was found by Zangen et al after they exposed cardiac cells in culture to furosemide. In separate studies, Mydlik et al found an increase in urinary excretion of vitamin C and B6 after in intravenous injection of 20 mg furosemide in patients with chronic renal failure. Subsequently the authors recommend future monitoring of plasma vitamin C and B6 in chronic renal failure patients on long-term high dose furosemide therapy.
Pharmacologic Action of Thiazide Diuretics.
The main pharmacologic action of thiazide diuretics is inhibition of sodium and chloride transport in the distal convoluted tubule. Thiazide-induced depletion of magnesium, sodium, and potassium has been well documented. Franse et al analyzed data from the Systolic Hypertension in the Elderly Program (SHEP) trial, and found that patients who experienced hypokalemia after a year of diuretic treatment did not share the beneficial reduction in cardiovascular events with patients who had normal potassium levels. Thiazide diuretics have been shown to inhibit CoQ10 enzymes succinooxidase and NADH-oxidase which play a role in heart mitochondrial energy production. In two separate studies, Reyes et al found thiazides to induce zinc deficiencies during long-term diuretic therapy. The group goes on to state the importance of monitoring patients for signs and symptoms of zinc deficiency. Another study showed a decreased mean hair zinc content in patients receiving long term (6-36 months) thiazide drugs. The authors note the decrease to be caused by increased urinary output of zinc. Additional nutritional side effects encountered with thiazide treatment include hyperglycemia, hyperlipidemia, and insulin resistance all of which are signs and symptoms of diabetes which is known to increase the risk of CVD two-fold.
Possible Side Effects of Depleted Nutrients
Drug induced reduction of potassium, magnesium, zinc, calcium, thiamin, B6, and vitamin C as well as the inhibition of CoQ10 and folic acid have all been documented. Deficiencies of these nutrients can have deleterious side effects. Some of these side effects may create additional risk factors for cardiovascular disease as well as other health sequelae. It is not within the scope of this paper to discuss the full range of known deficiency symptoms, therefore I will focus only on select symptoms. Simply looking at the physio-chemical function of nutrients gives great insight into the affects of nutrients on cardiovascular physiology.
Examples:
Potassium is a necessary electrolyte to maintain normal heart conduction.
Magnesium is involved in greater than 300 metabolic reactions in the body. For this reason widespread side effects may manifest clinically. Some clinical symptoms include: abnormal EKG, arrhythmias, an increase in blood lipids, increased platelet aggregation, thyroid abnormalities, poor bone mineralization, mood alterations, ataxia, and other neuromuscular manifestations (i.e. depressed deep tendon reflexes, myoclonus, and myospasm). In addition, magnesium is a known mild calcium channel blocker and vaso-relaxant. Therefore a deficiency may potentially lead to cardiovascular symptoms.
Zinc functions as a coenzyme for carbonic anhydrase (an enzyme in the blood stream which helps regulate the acid/base balance of the body) to help regulate the systemic pH. Additionally zinc is responsible for running the superoxide dismutase (SOD) enzyme which has potent antioxidant properties. Poor antioxidant status is associated with a higher risk of cardiovascular disease. Zinc represents the center molecule of the insulin polypeptide. Diabetics commonly have zinc deficiencies. Zinc is necessary to form collagen cross links. Because of this, a deficiency may lead to weakened arterial walls.
Calcium regulates cardiovascular smooth muscle tonicity and is necessary for normal nerve conduction. Deficiencies can manifest as hypertension, chronic muscle pain and spasm, joint pain, poor bone mineralization, and depression.
Folic acid and pyridoxine both play a role in the metabolism of homocysteine which when elevated is an independent risk factor for cardiovascular disease. Folic acid is also important in the regulation of Omega-3 essential fats. Lower levels of these fats can increase tissue inflammation and pose a risk factor for cardiovascular disease. Pyridoxine is necessary for blood cell formation. Pyridoxine also helps regulate serum electrolyte balance which affects heart and nerve conductivity.
Thiamine aids heart energy production and helps regulate systemic lactic acid production. A deficiency of thiamin can cause congestive heart failure as well as muscle soreness, and exercise intolerance. Exercise intolerance could potentially inhibit a person’s ability to exercise. This in turn could lead to sedentary activity. Lack of adequate exercise is also a risk factor for heart disease, high blood pressure, and high cholesterol.
Vitamin C is a powerful antioxidant and is vital to healthy collagen production (blood vessel linings). Vitamin C deficiency has been related to elevated cholesterol levels. It is also necessary to maintain adrenal function through the production of hormones such as corticosteroid and aldosterone.
CoQ10 is mandatory for energy production in all cells of the body. The myocardial mitochondria especially rely on CoQ10 for continuous energy production. A deficiency of CoQ10 has been linked to cardiomyopathy, congestive heart failure, and hypertension. Because supplementation with these nutrients is safe and cost effective, it would seem prudent for the attending physician to monitor and administer appropriate doses when deficiencies are identified.
Diet and Hypertension
In observational studies, multiple relationships have been made between dietary intake and blood pressure. Inverse associations between fat, protein, fiber, mineral intake, and hypertension have all been documented. Kromhout describes a multifactorial influence of different nutrients (low fat intake, potassium, calcium, & magnesium) used in combination to drastically reduce blood pressure. In a four year controlled trial, Stamler et al showed the effectiveness of reduced alcohol and salt intake in conjunction with moderate weight reduction to be an effective tool to reduce hypertension. In the Trial of Nonpharmacologic Interventions in the Elderly (TONE) study, showed that a reduction in blood pressure was achievable without drug intervention. Appel et al found that dietary intervention with a diet rich in fruits, vegetables, reduce saturated and total fat, and low-fat dairy products (DASH diet) was effective in lowering systolic and diastolic pressure in hypertensive patients. Reductions of systolic and diastolic pressure were 11.4 and 5.5 mm/Hg higher than in control diets. No sodium restriction, weight loss, or exercise programs were implemented. Multiple studies advocating the DASH diet with sodium restriction have found even better results.
Obesity is reportedly the most common nutritional disorder in industrialized countries. Hermansen reports that modest weight loss (in obese patients) of 3-9% can further reduce high blood pressure. A study done on ischemic heart patients by Dalgard et al concluded that in order for dietary counseling to have sustained positive effects, multiple (3) individualized counseling sessions are needed. The study also concluded that brief counseling (10 minutes) was statistically insignificant towards achieving dietary goals. The DASH Collaborative trials all used multiple counseling sessions to implement compliance with the dietary protocol as well as to educate their patients. The positive empirical data agrees with the practice of increased patient education for a more favorable prognosis.
Future studies investigating their effects on other essential nutrients (especially the water soluble variety) are still needed but the current literature justifies the use of nutritional monitoring. Where do we go from here? Nearly one in four Americans have hypertension. The numbers for severe hypertension decrease to one in 16. Because most cases are not severely life threatening, it is this author’s opinion that control of this condition be treated through lifestyle alterations. Though severe cases will require the use of medications, the goal should be short-term usage for immediate benefit, and reduction of other risk factors through patient education. Physicians prescribing antihypertensive medications should also be aware of their potential nutritional side effects and monitor patients accordingly keeping in mind that most serum lab tests are poor markers for nutrient status and that functional markers provide earlier detection and greater accuracy.
About the Author:
Peter Osborne, D.C., D.A.C.B.N has practiced integrative nutrition and chiropractic medicine for the past 6 years. He is a native Texan and received his doctorate from Texas Chiropractic College and an advanced accreditation in nutrition through the American Clinical Board of Nutrition. He has been on faculty at Texas Women’s University co-teaching neurophysiology and anatomy. He is currently teaching nutrition to the students in Houston Community College’s nursing programs. In addition, Dr. Osborne is the clinical director at Town Center Wellness in Sugar Land, TX. He is a member of the ACA Council on Nutrition, the American Association for Health Freedom, and a Diplomate with the American Clinical Board of Nutrition.
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