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hydrochlorothiazide (HCTZ) / Esidrex^TM , Hydrodiuril^TM , Oreric^TM

DIURETIC:

Description: Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in the management of edema and hypertension. In hypertension, thiazide diuretics are often used as initial therapy, either alone or in combination with other agents. Unlike the loop diuretics, their efficacy is diminished in patients with renal insufficiency. Hydrochlorothiazide also has been used to treat diabetes insipidus and hypercalciuria, although these are not FDA-approved indications. Hydrochlorothiazide was approved by the FDA in 1959. (Continued below video)

Mechanism of Action: Thiazide diuretics increase the excretion of sodium, chloride, and water by inhibiting sodium ion transport across the renal tubular epithelium. Although thiazides may have more than one action, the major mechanism responsible for diuresis is to inhibit active chloride reabsorption at the distal portion of the ascending limb or, more likely, the early part of the distal tubule (i.e., the cortical diluting segment). Exactly how chloride transport is impaired is unknown. Thiazides also increase the excretion of potassium and bicarbonate, and decrease the elimination of calcium and uric acid. By increasing the sodium load at the distal renal tubule, hydrochlorothiazide indirectly increases potassium excretion via the sodiumpotassium exchange mechanism. Hypochloremia and hypokalemia can cause mild metabolic alkalosis. The diuretic efficacy of hydrochlorothiazide is not affected by the acid-base balance of the patient. Hydrochlorothiazide is not an aldosterone antagonist, and its main action is independent of carbonic anhydrase inhibition.

The antihypertensive mechanism of hydrochlorothiazide is unknown. It usually does not affect normal blood pressure. Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Cardiac output eventually returns to normal, plasma and extracellular fluid values return to slightly less than normal, but peripheral vascular resistance is reduced, resulting in lower blood pressure. These diuretics also decrease the glomerular filtration rate, which contributes to the drug's lower efficacy in patients with renal impairment. The changes in plasma volume induce an elevation in plasma renin activity, and aldosterone secretion is increased, contributing to the potassium loss associated with thiazide diuretic therapy.

Pharmacokinetics: Hydrochlorothiazide absorption from the GI tract varies depending on the formulation and dose. Bioavailability is approximately 50-60%. The drug crosses the placenta but not the blood-brain barrier and is distributed in breast milk. Hydrochlorothiazide is not metabolized and is excreted unchanged in the urine. The half-life of the drug ranges from 5.6-14.8 hours. The onset of action of the drug is 2 hours following oral administration, with peak effects occurring at 4 hours. The duration of action ranges from 6-12 hours.

CONTRAINDICATIONS/PRECAUTIONS: Hydrochlorothiazide-induced fluctuations in serum electrolyte concentration can occur rapidly and precipitate hepatic coma in susceptible patients. Therefore, the drug should be used with caution in patients with hepatic disease.

Hyperglycemia, impaired glucose tolerance, and glycosuria can occur during hydrochlorothiazide therapy, and blood and/or urine glucose levels should be assessed more carefully in patients with diabetes mellitus who are receiving hydrochlorothiazide.

Hydrochlorothiazide should be used cautiously in patients with renal disease such as severe renal impairment because the drug decreases the glomerular filtration rate and may precipitate azotemia in these patients. Therapy should be interrupted or discontinued if renal impairment worsens, as evidenced by an increase in concentrations of BUN, serum creatinine, or nonprotein nitrogen. With the exception of metolazone, thiazide diuretics are considered ineffective when the creatinine clearance is less than 30 ml/minute. Hydrochlorothiazide is contraindicated in patients with anuria.

The safety of hydrochlorothiazide administration during pregnancy has not been established, so the drug should be administered to pregnant women only when absolutely necessary. Thiazides cross the placenta, and jaundice can occur in the fetus or neonate. Hydrochlorothiazide is classified as pregnancy category D. Thiazide diuretics distribute into breast milk, and it has been recommended by some manufacturers that women should not nurse while receiving thiazide diuretics. The American Academy of Pediatrics recommends breast-feeding be avoided during the first month of lactation in patients receiving thiazide diuretics, because suppression of lactation has been reported.

Thiazide diuretics, including hydrochlorothiazide, should be used with caution in patients with sulfonamide hypersensitivity or carbonic anhydrase inhibitor hypersensitivity because of the risk of cross-sensitivity. Although furosemide and, to a lesser extent, bumetanide are chemically related to the sulfonamides and theoretically should also be used cautiously, in fact, crosssensitivity with furosemide is an extremely rare occurence.D¥

Caution should be used when hydrochlorothiazide is administered to patients with gout or hyperuricemia since thiazide diuretics have been reported to reduce the clearance of uric acid.

Hydrochlorothiazide has been reported to activate or exacerbate systemic lupus erythematosus (SLE).

Patients with severe electrolyte imbalances, such as hyponatremia and hypokalemia, should have their condition corrected before hydrochlorothiazide is initiated. Initiation of thiazide diuretics under these circumstances can produce life-threatening situations such as cardiac arrhythmias, hypotension, and seizures. Hydrochlorothiazide can cause increase in serum calcium concentrations and should be used with caution in patients with hypercalcemia.

Thiazide diuretics have been associated with a slight increase in serum cholesterol and triglyceride concentrations. Data from long-term studies, however, suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk.¥

Thiazides should be avoided in neonates with jaundice. Thiazideinduced hyperbilirubinemia is greater in this patient population.

Thiazide diuretics have been reported to cause pancreatitis. They should be used with caution in patients with a history of pancreatitis.

Antihypertensive effects of thiazide diuretics may be enhanced in patients with a sympathectomy.

DRUG INTERACTIONS: Hydrochlorothiazide can have additive effects when administered with other antihypertensive drugs or diuretics. In some patients, these effects may be desirable, but orthostatic hypotension is possible. Dosages must be adjusted accordingly. In addition, amiloride hydrochloride, spironolactone, and triamterene can reduce the risk of developing hypokalemia because of their potassium-sparing effects; these agents have been used as therapeutic alternatives to potassium supplements.

Hydrochlorothiazide-induced electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) can predispose patients to digoxin toxicity, resulting in possibly fatal arrhythmias. Electrolyte balance should be corrected prior to initiating digoxin therapy.

The risk of developing severe hypokalemia can be increased when other hypokalemia-causing agents (e.g., corticosteroids, corticotropin, amphotericin B, other diuretics) are coadministered with hydrochlorothiazide. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.

Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers can cause prolonged neuromuscular blockade due to hydrochlorothiazideinduced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.

Thiazide diuretics reduce lithium renal clearance and can increase lithium serum concentrations. In some cases, thiazide diuretics can be used to counteract lithium-induced polyuria. Lithium dosage should be reevaluated and serum lithium concentrations monitored when a thiazide is added.

Hydrochlorothiazide can interfere with the hypoglycemic effects of oral hypoglycemics, which could lead to a loss of diabetic control. Additionally, the concurrent use of diazoxide and thiazide diuretics has resulted in enhanced hyperglycemia.

Hydrochlorothiazide-induced hypovolemia could cause an increased concentration of procoagulant factors in the blood, which could decrease the effects of concomitantly administered anticoagulants and require dosage adjustments of these agents; these effects, however, have not been reported to date.

Hydrochlorothiazide can reduce the renal clearance of amantadine, with subsequent increased serum concentrations and possible toxicity. This interaction has been reported with a combination product of hydrochlorothiazide and triamterene. Since it is unclear which component was responsible for the interaction, caution should be exercised when administering either drug concurrently with amantadine.

NSAIDs can decrease the diuretic, natriuretic, and antihypertensive actions of diuretics through inhibition of renal prostaglandin synthesis. Concomitant administration of NSAIDs with diuretics also can increase the risk for renal failure secondary to decreased renal blood flow. Patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.

Cholestyramine, an anion-exchange resin, may bind to acidic drugs, such as the thiazide diuretics in the GI tract, and decrease their absorption and therapeutic effectiveness. It is recommended that thiazides be administered at least 4 hours before cholestyramine. Although to a lesser extent than cholestyramine, colestipol also has been shown to inhibit the GI absorption and therapeutic response of thiazide diuretics. Administering the diuretic dose at least 2 hours before colestipol has been suggested.

ADVERSE REACTIONS: Patients receiving hydrochlorothiazide should be monitored closely for signs of electrolyte imbalance including hyponatremia, hypokalemia, hypomagnesemia, and hypochloremia. Patients should be aware of the symptoms of these disturbances (e.g., lassitude, mental confusion, fatigue, faintness, dizziness, muscle cramps, tachycardia, headache, paresthesia, thirst, anorexia, nausea, or vomiting), and report these signs immediately. Thiazides also can decrease urinary calcium excretion, resulting in hypercalcemia.

Hypokalemia is one of the most common adverse effects associated with thiazide diuretic therapy and can lead to cardiac arrhythmias. This effect is especially important to consider in patients receiving cardiac glycoside therapy because potassium depletion increases the risk of cardiac toxicity. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose patients to hypokalemia when hydrochlorothiazide is administered. Low dietary-potassium intake, potassium-wasting states, or administration of potassium-wasting drugs also can predispose patients to hydrochlorothiazide-induced hypokalemia. Patients receiving hydrochlorothiazide therapy may require supplemental potassium to prevent hypokalemia or metabolic alkalosis.

Hypochloremic alkalosis can occur with hypokalemia during hydrochlorothiazide therapy, and it is particularly likely to occur in patients with other losses of potassium and/or chloride such as through severe vomiting, diarrhea, excessive sweating, GI drainage, paracentesis, or potassium-losing renal diseases.

Patients receiving hydrochlorothiazide can develop a dilutional hyponatremia, but it usually is asymptomatic and moderate. Withdrawal of the drug, fluid restriction, and potassium or magnesium supplementation typically will return the serum sodium concentration to normal, but severe hyponatremia can occur. Geriatric patients are especially susceptible to developing hyponatremia, so care should be taken when diuretics are administered to these patients.

Hydrochlorothiazide reportedly has caused azotemia and interstitial nephritis, resulting in reversible renal failure. These effects have occurred mainly in patients with preexisting renal disease.

Hydrochlorothiazide can produce glycosuria and hyperglycemia in diabetic patients, possibly due to potassium depletion. Blood and/or urine glucose levels should be assessed more carefully in diabetic patients receiving hydrochlorothiazide.

Thiazide diuretics are well known to cause hyperuricemia. The Framingham Study showed that acute gout occurred in only 20% of patients with hyperuricemia. Thiazide diuretics appear to interfere with proximal tubule secretion of uric acid since thiazides are also organic acids and they compete with uric acid for binding at this site. Since thiazides reduce the clearance of uric acid, patients with gout or hyperuricemia may have exacerbations of their disease.

Hypercholesterolemia and/or hypertriglyceridemia have been associated with thiazide diuretic therapy. Although elevations in total cholesterol concentrations of 8% can negate the protection against coronary heart disease provided by a 5 mmHg reduction in blood pressure, data from long-term studies suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk. After approximately one year of treatment, total serum cholesterol concentrations will subside to baseline or lower, suggesting diuretic-induced cholesterol changes are not a significant coronary heart disease risk factor.¥

Orthostatic hypotension and hypotension can occur during hydrochlorothiazide therapy and can be exacerbated by alcohol, narcotics, or antihypertensive drugs.

Thiazide diuretics have been associated with cholestatic jaundice. Caution should be used when thiazides are administered to jaundiced infants due to the risk of hyperbilirubinemia.

Adverse GI effects associated with thiazide therapy include anorexia, gastric irritation, nausea/vomiting, cramps, diarrhea, constipation, sialadenitis, and pancreatitis.

Adverse CNS effects associated with thiazide therapy include dizziness, headache, paresthesias, vertigo, and xanthopsia.

While their incidence is rare, agranulocytosis, aplastic anemia, pancytopenia, hemolysis with anemia, leukopenia, and thrombocytopenia have been reported with thiazide diuretic therapy.

Other adverse effects reported with hydrochlorothiazide include blurred vision, muscle spasm, impotence, and weakness.

Adverse dermatologic reactions to hydrochlorothiazide and other thiazide diuretics are uncommon but may occur. These reactions include purpura, photosensitivity, rash, alopecia, urticaria, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis (TEN), and polyarteritis nodosa.

PATIENT INFORMATION:

What do hydrochlorothiazide tablets do?

Hydrochlorothiazide (HydroDIURIL^TM , Esidrix^TM , Oretic^TM ) is a diuretic. Diuretics increase the amount of urine passed, which causes the body to lose water and salt. Hydrochlorothiazide helps to treat high blood pressure (hypertension). It is not a cure. It also reduces the swelling and water retention caused by various medical conditions, such as heart, liver, or kidney disease. Generic hydrochlorothiazide tablets are available.

What should my doctor, dentist, or pharmacist know before I take hydrochlorothiazide?

They need to know if you have any of these conditions:

• diabetes
• gout
• kidney disease, small amounts of urine, or difficulty passing urine
• liver disease
• pancreatitis
• systemic lupus erythematosus (SLE)
• an unusual or allergic reaction to hydrochlorothiazide, sulfa drugs, carbonic anhydrase inhibitors like acetazolamide, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I take this medicine?

Take hydrochlorothiazide tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take your doses at regular intervals. Do not take your medicine more often than directed. Remember that you will need to pass urine frequently after taking hydrochlorothiazide. Do not take your doses at a time of day that will cause you problems. Do not take at bedtime.

What if I miss a dose?

If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What other medicines can interact with hydrochlorothiazide?

• amantadine
• amphotericin B
• antiinflammatory drugs (NSAIDs, such as ibuprofen)
• cholestyramine
• colestipol
• diazoxide
• digoxin
• hormones such as cortisone, hydrocortisone, prednisone
• lithium
• medicines for diabetes that are taken by mouth
• water pills

Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from taking hydrochlorothiazide?

Serious side effects with hydrochlorothiazide include:

• blood in urine or stools
• diarrhea
• dry mouth
• fever or chills, sore throat
• increased thirst
• irregular heartbeat
• lower back or side pain
• mood changes
• muscle pain or weakness, cramps
• nausea, vomiting
• severe stomach pain
• skin rash, peeling or loose skin
• tingling or numbness in the hands or feet
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellowing of the eyes or skin

Call your doctor as soon as you can if you get any of these side effects.

Minor side effects with hydrochlorothiazide include:

• constipation
• dizziness or lightheadedness
• headache
• increased sensitivity to the sun
• loss of appetite
• stomach upset, pain, or cramps

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I take hydrochlorothiazide?

Visit your doctor for regular checks on your progress. Check your blood pressure regularly. Ask your doctor what your blood pressure should be, and when you should contact him or her. You must not get dehydrated, ask your doctor how much fluid you need to drink a day. Do not stop taking hydrochlorothiazide except on your doctor's advice.

Watch your diet while you are taking hydrochlorothiazide. Ask your doctor about both potassium and sodium intake. Hydrochlorothiazide can make your body lose potassium and you may need an extra supply. Too high or too low potassium can cause problems. Some foods have a high potassium content such as bananas, coconuts, dates, figs, prunes, apricots, peaches, grapefruit juice, tomato juice, and orange juice.

You may get dizzy or lightheaded. Do not drive, use machinery, or do anything that needs mental alertness until you know how hydrochlorothiazide affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Alcohol can make you lightheaded, dizzy and increase confusion. Avoid or limit intake of alcoholic drinks.

Hydrochlorothiazide can make your skin more sensitive to sun or ultraviolet light. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen (at least SPF 15). Do not use sun lamps or sun tanning beds or booths.

If you are going to have surgery, tell your doctor or dentist that you are taking hydrochlorothiazide.

Hydrochlorothiazide can increase the amount of sugar in blood or urine. If you are a diabetic keep a close check on blood and urine sugar.

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30C (59 and 86F). Protect from light and moisture. Keep container tightly closed. Throw away any unused medicine after the expiration date.

The P-I-E-N-O Parkinsn's List Drug Database Index

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