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Hydrochlorothiazide (Hydrodiuril): Drug Whys

Generic name: Hydrochlorothiazide (multiple generic manufacturers)
Common U.S. brand names: Hydrodiuril (Merck & Co.), Microzide (Watson Laboratories)
Popularity: Sixth most commonly prescribed drug between 2002 – 2007 (U.S.)
Class: Thiazide diuretic

Treatment Uses – For treatment of [mild to moderate] hypertension; edema associated with congestive heart failure, liver disease, kidney dysfunction, steroids, or estrogen therapy. Hydrochlorothiazide is also used to treat bronchopulmonary dysplasia (BPD) in infants, hypercalciuria (to prevent formation of calcium oxalate kidney stone formation), diabetes insipidus (especially lithium induced) and Meniere’s disease. It may be effective for treatment of osteoporosis (for which effects appear stronger in women than men).

Hydrochlorothiazide belongs to a family of drugs called thiazide diuretics. The differences between thiazide and loop diuretics result from where they act in the kidney. Thiazides work by inhibiting reabsorption of sodium in the early part of the kidney’s distal tubules causing increased excretion of sodium and water. Loop diuretics (such as furosemide) work by inhibiting sodium reabsorption from the Loop of Henle, a more important sodium reabsorption site.

Thiazides cause a gentler and sustained diuretic effect whereas loop diuretics produce an aggressive and shorter lived diuresis. Thiazides are more effective than loop diuretics for treating hypertension. All thiazides can be dosed once daily for treatment of hypertension except chlorthiazide, which requires twice daily dosing.

For most patients with Stage 1 hypertension (SBP 140 to 159 or DPB 90 to 99), thiazide diuretics are the drug of choice. Use of angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARBs), beta blockers (BB), calcium channel blockers (CCB), or a combination may also be considered. Patients with Stage 2 hypertension (SBP > 160 or DBP > 100) typically require a two-drug combination, adding one of these other agents to the diuretic, often based on other factors such as race, heart failure, age, diabetes, COPD or cost. Black patients tend to respond better to thiazide diuretics and CCBs than to ACEIs, ARBs, or BBs.

Dosing and Administration – For treatment of hypertension in adults, the recommended starting oral dose of hydrochlorothiazide is 12.5 to 25 milligrams, in a single daily dose. Titrations, according to blood pressure response, are usually made at two to three week intervals up to a maximum of 100 milligrams twice daily in either single or divided doses. Dosages should be reduced to 50 milligrams daily or less when used in combination with other antihypertensives. For management of edema in adults, dosing typically starts at 25 milligrams once daily. Many patients with edema will respond quite nicely to intermittent (every other day or three to five times each week) therapy. Diabetes insipidus (DI) treatment in adults normally requires 50 to 150 milligrams in divided daily doses. DI patients intolerant of, or allergic to, vasopressin often find hydrochlorothiazide a useful alternative. A 50 percent or greater reduction in urine output is considered a good response.

Pediatric dosing recommendations vary somewhat. For neonates and infants under 6 months old, 2 to 4 milligrams per kilogram of the child’s body weight divided into two daily doses, up to a maximum total of 37.5 milligrams per day of hydrochlorothiazide, is recommended. In children older than 6 months, recommendations range from 1 milligram per kilogram of the child’s body weight in a single daily dose to 2 milligrams per kilogram divided into two daily doses. Maximum daily pediatric doses should not exceed 37.5 milligrams for children less than 2 years of age and 100 to 200 milligrams between 2 and 12 years of age. As with adult patients, pediatric dosing of hydrochlorothiazide should be reduced when used with other antihypertensive agents.

Although most drug references say that hydrochlorothiazide can be taken with food or milk, oral doses taken with meals may result in reduced plasma drug levels. To avoid nocturia (nighttime urination), hydrochlorothiazide should be taken early in the day, and preferably before breakfast (for maximal drug levels). Once-daily dosing also appears to have less influence on blood potassium levels and may result in less hydrochlorothiazide-caused hypokalemia (low blood potassium levels).

Dose reductions are not necessary for patients with kidney dysfunction, but note that patients with renal failure are usually refractory (won’t respond) to hydrochlorothiazide. Current recommendations suggest hydrochlorothiazide not be used in patients with serum creatinine levels above 2.5 (mg/dL) and, because the drug itself can aggravate renal failure, it should be stopped if progressive renal failure becomes evident.

When using hydrochlorothiazide in liver failure patients (to decrease edema), close attention to potassium levels is warranted. Potassium and sodium losses are closely correlated to increased blood ammonia levels, which lead to coma.

For geriatric patients, use lower starting doses of hydrochlorothiazide initially (i.e. 12.5 to 25 milligrams once daily) with slower upward titration (both in dose and time interval) than for younger patients.

Overdoses of hydrochlorothiazide generally result in gastrointestinal symptoms, weakness, confusion, and (of course) diuresis. Toxic effects are due primarily to volume depletion and electrolyte loss. There is no specific antidote for hydrochlorothiazide overdoses; treatment should be supportive. As with other thiazide diuretics, hemodialysis is largely ineffective in removing hydrochlorothiazide from the body. Despite this, daily doses should be held until after dialysis.

Pharmacology/Pharmacokinetics/Stability – Oral hydrochlorothiazide is rapidly absorbed. Diuretic effects occur within two hours, peaking at three to six hours, and lasting from six to 12 hours after each dose. Blood pressure effects occur within three to four days and persist for up to one week following discontinuation of therapy. The full blood pressure lowering effects of hydrochlorothiazide dose adjustments may take four weeks to appear. The kidneys excrete 50 to 70 percent of each hydrochlorothiazide dose as unchanged drug. There is little to no appreciable metabolism of hydrochlorothiazide – it acts directly on the kidney and is excreted near completely in the urine as unchanged drug.

Hydrochlorothiazide is excreted in breast milk in low concentrations; blood samples from breast fed infants have not revealed detectable hydrochlorothiazide concentrations. The American Academy of Pediatrics rates hydrochlorothiazide as compatible with breastfeeding. Limited data suggest that thiazide diuretics may decrease milk production.

There have been no well-designed studies evaluating risks of hydrochlorothiazide during pregnancy. However, thiazide diuretics pose risks of congenital defects and other complications to the fetus. Hydrochlorothiazide does cross the placenta. As a class, thiazide diuretics are not recommended for use during pregnancy. Alternative agents include methyldopa (widely accepted as safe for use during pregnancy), and some beta blockers.

Hydrochlorothiazide works in the body by inhibiting reabsorption of sodium and chloride (in equal amounts) in the distal tubules of the kidney, resulting in increased excretion of sodium, water, potassium and hydrogen ions. Water follows sodium into, through, and out of the body. Thiazide diuretic effects depend on sodium reaching the distal tubule which may not happen in patients with significant renal disease, heart failure, or liver failure. The exact mechanism by which thiazides lower blood pressure is unknown. It is theorized that resultant hypovolemia initially lowers blood pressure and, following normalization of sodium and water levels that occurs after the first month of treatment, arterial vasodilatation may be responsible for maintaining lowered blood pressure.

Hydrochlorothiazide tablets come in 25, 50 and 100 milligram strengths. A 12.5 milligram capsule is also available in the United States. Color, shape and size of tablets and capsules vary by manufacturer. Tablets and capsules should be stored in a tight, light resistant container at room temperature between 68-77 F with occasional variations to 59-86 F permitted. Tablets should be protected from freezing. A compounding pharmacy can prepare hydrochlorothiazide liquid suspension (for children) that will remain stable for up to 10 weeks at room temperature. Commercially prepared suspensions are also widely available; normal concentration is 2 milligrams per milliliter.

Cautions and Warnings – It is suggested that patients allergic to sulfonamide antibiotics are likely to have cross allergic sensitivity to hydrochlorothiazide and other sulfonamide derived diuretics. This theory is weak at best and clinical practice demonstrates that most sulfa allergic patients tolerate hydrochlorothiazide without adverse effects.

As mentioned previously, hydrochlorothiazide is contraindicated in anuric patients (patients without any urine output, usually due to renal failure).

Hydrochlorothiazide is often abbreviated as HCTZ. This is a dangerous, error prone abbreviation mistaken at times for hydrocortisone. Writing out drug names rather than using abbreviations could prevent thousands of medication errors annually in the United States alone. While you might think this advice applies only to prescribers and hospital staff, take note: Several high profile medication errors have been traced to hospital staff copying patient medications from prehospital care reports. Misinterpretation of the medic’s drug name abbreviations have resulted in wrong drugs being administered to patients. At least one patient death has resulted from this practice and, with recent pressure from the Joint Commission on the health care system to improve medication reconciliation, more are likely.

Important Side Effects and Interactions – Diuretics have the lowest incidence of reported side effects among the cardiovascular drugs. Diuretic effects account for the most frequently reported hydrochlorothiazide adverse reactions, which include hypotension and hypokalemia. Some 15 to 50 percent of patients taking diuretics develop hypokalemia (K+ less than 3.5 mEq/L). Although potassium supplementation may be necessary in some patients, once daily dosing often minimizes hypokalemia.

Often, consumption of potassium rich snacks such as oranges or bananas suffice to maintain normal potassium levels. Women, patients with low potassium levels prior to starting thiazide diuretics, eating a high-salt diet, and patients with low serum magnesium levels have increased risk for diuretic induced hypokalemia. Potassium supplementation should be instituted if levels fall below 3.0 mEq/L or below 3.5 mEq/L in patients taking digitalis, those with ischemic heart disease, or tendency towards ectopic rhythms. Normalizing serum potassium may also help improve blood pressure and blood glucose control.

Other adverse reactions occurring in 1 to 10 percent of patients include photosensitivity and gastrointestinal distress. Rarely, serious adverse reactions have been reported. These include arrhythmias, blood dyscrasias, exfoliative dermatitis, liver toxicity, pancreatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Hydrochlorothiazide is also known to exacerbate several pre-existing medical conditions. Patients with a history or family history of gout may develop gout when taking hydrochlorothiazide due to decreased uric acid excretion. This phenomenon seems more prevalent in women. Thiazide diuretics are implicated in difficulty regulating blood glucose levels, which is likely related to potassium depletion. When mild hyperglycemia occurs in patients taking hydrochlorothiazide, potassium supplementation often corrects the problem.

Compounding the issue are studies showing that diabetes is 2.5 times more likely to develop in hypertensive versus normotensive individuals. That begets the question of whether antihypertensive medications truly cause the hyperglycemia. For yet unknown reasons, patients taking beta blockers and hydrochlorothiazide (combination therapy) have significantly greater hyperglycemic effects. Hydrochlorothiazide has also been reported to exacerbate systemic lupus erythematosus (SLE). Patients with elevated cholesterol levels may experience increased lipid levels when starting hydrochlorothiazide although these seem to be transient, and return to baseline with prolonged hydrochlorothiazide therapy.

There are 122 drugs specifically reported to interact with hydrochlorothiazide. Most are either poorly documented or extremely uncommon. Three are worth noting: ACEI, NSAIDs (non steroidal anti-inflammatory drugs), and lithium. Severe postural hypotension has been reported when ace inhibitors are combined with diuretics. While this problem is usually transient and more commonly seen with loop diuretics, first dose hypotension often occurs when adding ace inhibitors to patients’ already volume depleted from diuretics. As mentioned previously, dose reduction is warranted when combining hydrochlorothiazide with other antihypertensive agents. NSAIDs (such as ibuprofen) reduce the diuretic and antihypertensive effects of thiazides. Careful monitoring should be exercised when patients on hydrochlorothiazide take NSAIDs. Thiazide diuretics substantially decrease urinary excretion of lithium, which can lead to elevated lithium levels and lithium toxicity. Close monitoring is indicated when these drugs are used in combination.

Licorice, well known for raising blood pressure in any person, healthy or not, is believed to reduce hydrochlorothiazide diuretic effectiveness and increase the risk of hypokalemia in patients taking hydrochlorothiazide. Hypertensive patients should completely avoid licorice; healthy people would also be wise to limit licorice consumption.

Average Costs – U.S.
250 mg /500 mg tablets and 875 mg capsule (generic)
Patient cost: $ 0.30/0.38 and 0.67 each*
Large hospital cost: $0.06/0.08 and 0.42 each
*($4.00 at Wal Mart® and Target for 1 month or $10.00 for 90 day supply)

References:

  • MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed July, 2008).
  • Albany Medical Center Pharmacy, Albany, New York.
EMS1.com columnist Mike McEvoy, is the EMS coordinator for Saratoga County and the EMS director on the Board of the New York State Association of Fire Chiefs. Mike is the Fire-EMS technical editor for Fire Engineering magazine and has authored numerous publications including the book, “Straight Talk About Stress for Emergency Responders.”
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