Hydrochlorothiazide

Hydrochlorothiazide is an antihypertensive agent belonging to Thiazide Diuretics.

Hydrochlorothiazide is a thiazide diuretic used to treat hypertension and edema in congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Hydrochlorothiazide is well absorbed (65% to 75%) following oral administration. Absorption of hydrochlorothiazide is decreased in patients with congestive heart failure.

Peak plasma concentrations are observed within 1-5 hours of dosing and range from 70 to 490 ng/mL following oral doses of 12.5 to 100 mg. Plasma concentrations are linearly related to the administered dose. Binding to the serum proteins has been reported to be approximately 40% to 68%. The plasma elimination half-life has been reported to be 6-15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Following oral doses of 12.5 to 100 mg, 55% to 77% of the administered dose appears in the urine and greater than 95% of the absorbed dose is excreted in urine as an unchanged drug.

Hydrochlorothiazide shows common side effects Nausea, vomiting, loss of appetite, diarrhea, constipation, muscle spasm, dizziness, headache, etc.

Hydrochlorothiazide is available in the dosage form of Oral tablets, Oral solutions, and Oral capsules.

Hydrochlorothiazide is available in India, China, the US, Europe, the UK, Italy, and Poland.

Hydrochlorothiazide belonging to the Thiazide Diuretics, acts as an antihypertensive agent.

Hydrochlorothiazide blocks the reabsorption of sodium and chloride ions, and it thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. A portion of the additional sodium presented to the distal tubule is exchanged there for potassium and hydrogen ions. With continued use of hydrochlorothiazide and depletion of sodium, compensatory mechanisms tend to increase this exchange and may produce excessive loss of potassium, hydrogen, and chloride ions. Hydrochlorothiazide also decreases the excretion of calcium and uric acid, may increase the excretion of iodide and may reduce the glomerular filtration rate. Metabolic toxicities associated with excessive electrolyte changes caused by hydrochlorothiazide have been shown to be dose-related.

The onset of action of Hydrochlorothiazide occurs within 2 hours of its administration.

The Duration of Action for Hydrochlorothiazide in the body is approximately 6-12 hours.

The Tmax was found within 1-5 hours and Cmax 70 to 490 ng/mL following the administration of Hydrochlorothiazide.

Hydrochlorothiazide comes as an Oral Tablet, Capsule, and Oral solution (liquid) to take by mouth. It is usually taken once or twice a day.

Hydrochlorothiazide is a thiazide diuretic used to treat hypertension and edema in congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Hydrochlorothiazide may also be used to treat patients with diabetes insipidus and to prevent kidney stones in patients with high levels of calcium in their blood.

Hydrochlorothiazide is an antihypertensive agent belonging to Thiazide Diuretics.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by sodium-chloride symporter, also known as the Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 decreases the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, decreasing the reabsorption of water. Hydrochlorothiazide is used to treat edema in people with congestive heart failure, cirrhosis of the liver, kidney disorders, or edema caused by taking steroids or estrogen and hypertension.

Hydrochlorothiazide is approved for use in the following clinical indications

• Edema

Hydrochlorothiazide is indicated alone or in combination for the management of edema associated with congestive heart failure, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and corticosteroid and estrogen therapy.

• Hypertension

Hydrochlorothiazide is also indicated alone or in combination for the management of hypertension.

• Edema

Adult- Some patients respond to intermittent therapy, (i.e., administration on alternate days or on 3-5 days each week). Excessive response and undesirable electrolyte imbalance are less likely to occur with intermittent dosing.

Usual dose: 25 mg to 100 mg orally once or twice daily.

Pediatric-

Less than 6 months: Up to 3 mg/kg/day (up to 1.5 mg/pound) orally in 2 divided doses

Less than 2 years: 1 to 2 mg/kg/day (0.5 to 1 mg/pound) orally daily as a single dose or in 2 divided doses. Maximum dose 37.5 mg per day

2 to 12 years: 1 to 2 mg/kg/day (0.5 to 1 mg/pound) orally daily as a single dose or in 2 divided doses. Maximum dose 100 mg per day

• Hypertension

Adult- Patients usually do not require doses in excess of 50 mg daily when used concomitantly with other antihypertensive agents.

Initial dose: 25 mg orally once daily

Maintenance dose: May increase to 50 mg orally daily, as a single or 2 divided doses

Pediatric

Less than 6 months: Up to 3 mg/kg/day (up to 1.5 mg/pound) orally in 2 divided doses

Less than 2 years: 1 to 2 mg/kg/day (0.5 to 1 mg/pound) orally daily as a single dose or in 2 divided doses. Maximum dose 37.5 mg per day

2 to 12 years: 1 to 2 mg/kg/day (0.5 to 1 mg/pound) orally daily as a single dose or in 2 divided doses. Maximum dose 100 mg per day.

Although not approved, there have been certain off-label indications. These include

• Nephrocalcinosis

Initial: 25 mg orally once daily

Maintenance dose: May increase to 50 mg twice daily

• Osteoporosis

Initial: 25 mg orally once daily

Maintenance dose: May increase to 50 mg daily.

• Diabetes Insipidus

Initial: 50 mg orally once daily

Maintenance dose: May increase to 100 mg orally daily.

Hydrochlorothiazide is available in various strengths 25 mg; 50 mg; 100 mg; 50 mg/5 mL; 12.5 mg.

Hydrochlorothiazide is available in the form of Oral Tablet, Oral solution Oral capsule, and Solution for Injection.

Avoid consumption of a high-salt or high-sodium diet while taking Hydrochlorothiazide 

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Hydrochlorothiazide is contraindicated in patients with

• Hydrochlorothiazide is contraindicated in patients with anuria.
• Hypersensitivity to this product or other sulfonamide-derived drugs is also contraindicated.

• Diabetes and Hypoglycemia

Latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose.

• Renal Disease

Cumulative effects of thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate azotemia.

• Electrolyte and Fluid Balance Status

Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroid or adrenocorticotropic hormone (ACTH), or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium-rich foods.

• Hyperuricemia

Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics.

• Impaired Hepatic Function

Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease.

• Parathyroid Disease

Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.

Consumption of alcohol is not recommended while taking this drug as it may increase the risk of orthostatic hypotension.

Thiazides are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes the mother and fetus to unnecessary hazards. Diuretics do not prevent the development of toxemia in pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Avoid consumption of a high-salt or high-sodium diet while taking Hydrochlorothiazide 

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• Common Adverse effects

Headache, Confusion, Vertigo, Vomiting, Dizziness, Epigastric distress, Disorder of hematopoietic structure, Fatigue.

• Rare Adverse effects

Anaphylaxis, Anorexia, Hepatotoxicity, Hypercalcemia, Hypercholesterolemia, Hyperglycemia, Hyperlipidemia, Hyperuricemia, Hypokalemia, Hypomagnesemia, Hypotension, Interstitial nephritis, Metabolic acidosis, Muscle weakness or cramps, Nausea, Necrotizing angiitis, Pancreatitis, Phototoxicity, Pneumonitis, Pulmonary edema, Purpura, Rash, Respiratory distress, Stevens-Johnson syndrome, Toxic epidermal necrolysis, Xanthopsia

• Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.
• Antidiabetic drugs: (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.
• Other antihypertensive drugs: additive effect or potentiation.
• Cholestyramine and colestipol resins: Cholestyramine and colestipol resins bind the hydrochlorothiazide and decrease its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.
• Corticosteroid, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
• Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.
• Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.
• Lithium: Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and greatly increase the risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Hydrochlorothiazide (hydrochlorothiazide capsule).
• Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can decrease the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. When Hydrochlorothiazide (hydrochlorothiazide capsule) and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.

The common side of Hydrochlorothiazide includes the following

• Common
  

Nausea, vomiting, loss of appetite, diarrhea, constipation, muscle spasm, dizziness, and headache.

• Rare

Lightheadedness, eye pain, vision problems, yellowing of the skin or eyes (jaundice), pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), shortness of breath, wheezing, cough with foamy mucus, chest pain, dry mouth, thirst, Drowsiness.

Pregnancy

Teratogenic Effects

• Pregnancy Category B: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

Thiazides are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

A greater blood pressure reduction and an increase in side effects may be observed in the elderly (i.e. > 65 years) with hydrochlorothiazide. Starting treatment with the lowest available dose of hydrochlorothiazide (12.5 mg) is therefore recommended. If further titration is required, 12.5 mg increments should be utilized.

• 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 hydrochlorothiazide is removed by hemodialysis has not been established.
• The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rats.

Pharmacodynamic

Acute antihypertensive effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns to normal, but peripheral vascular resistance is decreased. The exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known. Thiazides do not affect normal blood pressure. The onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and activity persists for up to 24 hours.

Pharmacokinetics

• Absorption

Hydrochlorothiazide is well absorbed (65% to 75%) following oral administration. Absorption of hydrochlorothiazide is reduced in patients with congestive heart failure.

Peak plasma concentrations are observed within 1 to 5 hours of dosing, and range from 70 to 490 ng/mL following oral doses of 12.5 to 100 mg.

• Distribution

Plasma concentrations are linearly related to the administered dose. Concentrations of hydrochlorothiazide are 1.6 to 1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%. The plasma elimination half-life has been reported to be 6 to 15 hours.

• Metabolism and Excretion

Hydrochlorothiazide is eliminated primarily by renal pathways. Following oral doses of 12.5 to 100 mg, 55% to 77% of the administered dose appears in the urine and greater than 95% of the absorbed dose is excreted in urine as an unchanged drug.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/040735s004,040770s003lbl.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020504s026lbl.pdf
• https://www.rxlist.com/microzide-drug.htm#clinpharm
• https://reference.medscape.com/drug/microzide-hydrodiuril-hydrochlorothiazide-342412#4
• https://www.drugs.com/hydrochlorothiazide.html
• https://go.drugbank.com/drugs/DB00999