Chlorothiazide

Common Side Effects of Diuril

Tell your doctor if any of the following side effects become severe or don't go away:

• Dizziness
• Lightheadedness
• Headache
• Blurred vision
• Numbness or tingling of the skin
• Frequent urination
• Muscle spasms
• Constipation
• Loss of appetite
• Mild diarrhea
• Hair loss
• Decreased sexual desire

Serious Side Effects of Diuril

Tell your doctor immediately if you experience any of the following serious side effects:

• Confusion
• Decreased urination
• Gout
• Inflammation of the pancreas
• Muscle pain, weakness, or cramps
• Rapid or irregular heartbeat
• Inability to keep an erection (in men)
• Red, swollen, blistered, or peeling skin
• Seizures
• Restlessness
• Shortness of breath
• Severe dry mouth
• Severe diarrhea or vomiting
• Unusual tiredness, weakness, or drowsiness
• Severe thirst
• Fever
• Jaundice
• Signs of anaphylaxis, which may include rash, hives, difficulty breathing, chest tightness, or swelling of the face, mouth, lips, or tongue

DIURIL (Chlorothiazide) is a diuretic and antihypertensive. It is 6-chloro-2 H-1,2,4-benzothiadiazine­7-sulfonamide 1,1-dioxide. Its empirical formula is C7H6ClN3O4S2 and its structural formula is:

It is a white, or practically white, crystalline powder with a molecular weight of 295.72, which is very slightly soluble in water, but readily soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent of about 150 mg per 100 mL at pH 7.

DIURIL Oral Suspension contains 250 mg of chlorothiazide per 5 mL, alcohol 0.5 percent, with methylparaben 0.12 percent, propylparaben 0.02 percent, and benzoic acid 0.1 percent added as preservatives. The inactive ingredients are D&C Yellow 10, flavors, glycerin, purified water, sodium saccharin, sucrose and tragacanth.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment.

The degree to which chlorothiazide sodium is removed by hemodialysis has not been established.

The oral LD50 of chlorothiazide is 8.5 g/kg, greater than 10 g/kg, and greater than 1 g/kg, in the mouse, rat and dog respectively.

Chlorothiazide may be found in some form under the following brand names:

• Diupres-250

• Diuril

Oral/Injectable:

Common side effects include:

• headache
• dizziness
• nausea
• vomiting
• cramping
• constipation
• loss of appetite
• fatigue
• muscle weakness or spasm
• loss of energy
• blurred vision 
• nervousness or restlessness

This is not a complete list of chlorothiazide side effects. Ask your doctor or pharmacist for more information.

Serious side effects can occur. See "Drug Precautions" section.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Oral/Injectable:

Chlorothiazide can cause serious side effects including:

• electrolyte imbalance. This medication may affect electrolytes including sodium and potassium. Your doctor will check these levels using a blood test. Warning signs of electrolyte imbalance include:
  • dry mouth
  • thirst
  • weakness
  • lack of energy
  • drowsiness
  • restlessness
  • muscle pains or cramps
  • muscle fatigue
  • low blood pressure
  • decreased urination
  • fast heart rate
  • nausea and vomiting
• worsening of kidney disease
• worsening of gout
• sensitivity reactions. Patients with a history of asthma or allergy may experience sensitivity reactions.
• high blood glucose "sugar" concentrations in people with diabetes
• systemic lupus erythematosus (SLE or lupus) or worsening of lupus
• hepatic coma. Thiazide diuretics, like chlorothiazide, should be used with caution in people with liver disease.

This medication may cause drowsiness or dizziness. Do not drive or operate heavy machinery until you know how it affects you.

Do not take chlorothiazide if you:

• are allergic to chlorothiazide or any other ingredient in this medication
• are allergic to "sulfa" drugs
• are unable to produce urine

If you take too much chlorothiazide call your doctor or local Poison Control Center, or seek emergency medical attention right away.

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Drinking alcohol with this medicine can cause side effects.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Hypertension

Used alone or in combination with other antihypertensive agents for all stages of hypertension.b 110 500

Thiazide diuretics are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, angiotensin II receptor antagonists, and calcium-channel blockers.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.500 501 502 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Black hypertensive patients generally tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).109 500 501 504 However, diminished response to these other drug classes is largely eliminated when administered concomitantly with a thiazide diuretic or calcium-channel blocker.500 504

Thiazides may be preferred in hypertensive patients with osteoporosis. Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis due to effect on calcium homeostasis and bone mineralization.

Edema (General)

Management of edema resulting from various causes; diagnose etiology before use.b 110 111

Edema caused by renal disease or by corticosteroids or estrogens may be relatively resistant to treatment.b

Ineffective in patients with Scr or BUN concentrations greater than twice normal.b

May be ineffective in patients with GFR <15–25 mL/minute; even when GFR is 25–50 mL/minute, more potent (e.g., loop) diuretics may be indicated.b

No substantial difference in clinical effects or toxicity of comparable thiazide or thiazide-like diuretics except metolazone may be more effective in edema with renal impairment.b

Edema in Heart Failure

Management of edema associated with heart failure.b c

Most experts state that all patients with symptomatic heart failure who have evidence for, or history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.524

Loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are diuretics of choice for most patients with heart failure.524

Do not use diuretics as monotherapy in heart failure even if symptoms (e.g., peripheral edema, pulmonary congestion) are well controlled; diuretics alone do not prevent progression of heart failure.

Diuretics produce rapid symptomatic benefits, relieving pulmonary and peripheral edema more rapidly (within hours or days) than cardiac glycosides, ACE inhibitors, or β-blockers (in weeks or months).

Diuretics should be continued in heart failure and comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs are indicated.500

Edema Secondary to Nephrotic Syndrome

May be useful if the patient fails to respond to corticosteroid therapy.b

More likely to become refractory to thiazides than edema associated with congestive heart failure, and more potent diuretics may be required.b

Edema in Pregnancy

Generally responds well to thiazides except when caused by renal disease.b

Thiazides should not be used for routine therapy in pregnant women with mild edema who are otherwise healthy.b

• Exact mechanism of diuretic action is unclear; may act by altering metabolism of the tubular cells.b

• Enhances excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium.b

• Primary site of diuretic action appears to be the cortical diluting segment of the nephron.b

• GFR decreases, but unclear whether secondary to a direct effect on renal vasculature or to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption.b The fall in GFR is not important in the mechanism of action.b

• Enhances urinary excretion of potassium secondary to increased amount of sodium at distal tubular site of sodium-potassium exchange.b

• Increases urinary bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal; diuretic efficacy is not affected by the acid-base balance of the patient.b

• Hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased; also, slight or intermittent elevations in serum calcium concentration.b

• Rate of uric acid excretion is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption.b

• Hypotensive activity in hypertensive patients; also augments the action of other hypotensive agents.b Precise mechanism of hypotensive action has not been determined, but postulated that part of this effect is caused by direct arteriolar dilation.b

In addition to the use of chlorothiazide, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium or potassium. Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many patients feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

chlorothiazide will not cure your high blood pressure, but it does help control it. You must continue to receive it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems, such as heart failure, blood vessel disease, stroke, or kidney disease.

Dosing

The dose of chlorothiazide will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of chlorothiazide. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For fluid retention (edema):
  • For oral dosage forms (suspension):
    • Adults—The usual dose is 10 to 20 milliliters (mL) once or twice a day. Your doctor may adjust how often you take your dose.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage forms (tablets):
    • Adults—The usual dose is 500 to 1000 milligrams (mg) once or twice a day. Your doctor may adjust how often you take your dose.
    • Children—Dose is based on body weight and must be determined by your doctor.
• For high blood pressure:
  • For oral dosage forms (suspension):
    • Adults—The usual dose is 10 to 20 milliliters (mL) once a day as a single dose or in divided doses. Your doctor may adjust your dose if needed.
    • Children—Dose is based on body weight and must be determined by your doctor.
  • For oral dosage forms (tablets):
    • Adults—The usual dose is 500 to 1000 milligrams (mg) once a day as a single dose or in divided doses. Your doctor may adjust your dose if needed.
    • Children—Dose is based on body weight and must be determined by your doctor.

Missed Dose

If you miss a dose of chlorothiazide, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

The mechanism of the antihypertensive effect of thiazides is unknown. Chlorothiazide does not usually affect normal blood pressure.

Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy.

Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.

Pharmacokinetics and Metabolism

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life of Chlorothiazide is 45 to 120 minutes. After oral doses, 10 to 15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Diuresis: Oral: Within 2 hours; IV: 15 minutes; Peak effect: Oral: ~4 hours; IV: 30 minutes

Diuretic action: Oral: ~6 to 12 hours; IV: 2 hours

Half-Life Elimination

45 to 120 minutes

Note: The manufacturer states that IV and oral dosing are equivalent. Some clinicians may use lower IV doses; however, because of chlorothiazide's poor oral absorption.

Hypertension: Oral: 500 to 2000 mg daily divided in 1 to 2 doses

Edema: Oral, IV: 500 to 1000 mg once or twice daily; intermittent treatment (eg, therapy on alternative days) may be appropriate for some patients

ACCF/AHA 2013 heart failure guidelines:

Oral: 250 to 500 mg once or twice daily (maximum daily dose: 1000 mg)

IV: 500 to 1000 mg once daily in combination with a loop diuretic for sequential nephron blockade

Chlorothiazide is not recommended in patients with severe renal insufficiency since it is not expected to be filtered into the renal tubule (its site of action) when the glomerular filtration rate is less than 25 mL/min.