Hydrochlorothiazide (Microzide) is a thiazide diuretic that is used in patients with fluid overload and hypertension as monotherapy or in combination with other drugs.

Hydrochlorothiazide (Microzide) Uses:

• Edema:

  • It is used in the treatment of edema due to heart failure, hepatic cirrhosis, various forms of renal dysfunction like nephrotic syndrome, acute glomerulosclerosis, and chronic renal failure.
  • It is also used in treatment for edema caused by corticosteroid and estrogen therapy
  • However, it is important to note that the use of hydrochlorothiazide in the treatment of edema for hepatic cirrhosis has largely been replaced by spironolactone.
  • The use of hydrochlorothiazide in the management of edema in patients with renal dysfunction has largely been replaced by the use of loop diuretics like furosemide.

• Hypertension:

  • Management of mild to moderate hypertension
  • Guideline recommendations:
    • The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults recommends if monotherapy is warranted, in the absence of comorbidities (eg, cerebrovascular disease, chronic kidney disease, diabetes, heart failure, ischemic heart disease, etc), that thiazide-like diuretics or dihydropyridine calcium channel blockers are preferred options due to improved cardiovascular endpoints (eg, prevention of heart failure and stroke).
    • ACE inhibitors and ARBs are also acceptable for monotherapy.
    • Combination therapy might be required to achieve blood pressure goals and is initially recommended in patients at high risk (stage 2 hypertension or atherosclerotic cardiovascular disease.

• Off Label Use of Hydrochlorothiazide in Adults:

  • Calcium nephrolithiasis.
  • Lithium-induced diabetes insipidus.

Hydrochlorothiazide (Microzide) Dose in Adults

Hydrochlorothiazide (Microzide) Dose in the treatment of Calcium nephrolithiasis (off-label):

• It is given as 50 mg daily in 1 or 2 divided doses.

Hydrochlorothiazide (Microzide) Dose in the treatment of Edema:

• Orally it is given as 25 to 100 mg daily in 1 to 2 divided doses. One may administer intermittently on alternate days or on 3 to 5 days each week.

Hydrochlorothiazide (Microzide) Dose in the treatment of mild fluid retention in heart failure:

• Initially, it is given as 25 mg once or twice a day. The maximum daily dose is 200 mg.

Hydrochlorothiazide (Microzide) Dose in the treatment of Hypertension:

• Initially, it is given orally as 12.5 to 25 mg once a day.
• Titrate up as needed based on patient response up to 50 mg daily in 1 or 2 divided doses; The maximum dosage is 50 mg/day.

Hydrochlorothiazide (Microzide) Dose in Childrens

Hydrochlorothiazide (Microzide) Dose in the treatment of Bronchopulmonary dysplasia:

• Infants:

  • Oral: it is given as 3 to 4 mg/kg/day in 2 divided doses.

Hydrochlorothiazide (Microzide) Dose in the treatment of Edema (diuresis):

• Infants <6 months:

  • Oral: it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses. However, some infants do require 3 mg/kg/day in 2 divided doses. The maximum daily dose is 37.5 mg/day

• Infants ≥6 months and Children <2 years:

  • • Orally it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses. The maximum daily dose is 37.5 mg/day.

• Children ≥2 years:

  • Orally it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses. The maximum daily dose is 100 mg/day.

• Adolescents:

  • Orally it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses; The maximum adult daily dose is 200 mg/day is recommended for heart failure-related edema.

Hydrochlorothiazide (Microzide) Dose in the treatment of Hypertension:

• Manufacturer's labeling:

  • Infants <6 months:

    • Oral: it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses. However, some infants might require 3 mg/kg/day in 2 divided doses. The maximum daily dose is  37.5 mg/day.

  • Infants ≥6 months and Children <2 years:

    • Orally it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses. The maximum daily dose is 37.5 mg/day

  • Children ≥2 years:

    • Oral: it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses. The maximum daily dose is 100 mg/day.

• Alternate dosing:

  • Infants, Children, and Adolescents:

    • Oral: Initially it is given as  1 mg/kg/day once a day.
    • It might be increased to a maximum daily dose is 3 mg/kg/day or 50 mg/day, whichever is lower.

Hydrochlorothiazide (Microzide) Dose in the treatment of Hypercalciuria:

• Infants, Children, and Adolescents:

  • Oral: Initially it is given as 1 to 2 mg/kg/day in 1 to 2 divided doses.
  • Titrate up until goal urinary calcium excretion goals reached and symptoms resolve.
  • The treatment usually continued for 1 year and the usual adult dose is 25 to 100 mg/day.

Hydrochlorothiazide (Microzide) Dose in the treatment of Congenital Nephrogenic diabetes insipidus:

• Infants, Children, and Adolescents:

  • Oral: it is given as 2 mg/kg/day in combination with amiloride.
  • Some patients do require 3 mg/kg/day in divided doses.
  • In adults, the usual dose range is 25 mg once or twice a day.

Pregnancy Risk Factor B

• Although hydrochlorothiazide can cross the placenta, adverse events are not seen in animal reproduction studies.
• Use of maternal contraceptives may cause neonatal or fetal jaundice, thrombocytopenia or other adverse reactions in adults.
• Thiazide diuretics are not recommended for treating edema in normal pregnancies. 
• If edema is caused by pathologic reasons (as in the patient not pregnant), it can be used. Pay attention.
• Chronic maternal hypertension, if not treated, can lead to adverse outcomes in the infant, mother, and fetus.
• Women who used thiazide diuretics to treat hypertension prior to pregnancy can continue their use.

Use of hydrochlorothiazide during breastfeeding

• Breast milk contains hydrochlorothiazide.
• Hydrochlorothiazide's relative infant dose (RID), is 0.6%-1.2% compared to a infant therapeutic dose of 1–2 mg/kg/day.
• When the RID is less than 10%, breastfeeding is generally acceptable.
• Hydrochlorothiazide's RID was calculated using a milk concentration of 80ng/mL, based on a single case report.
• This gives an estimated daily infant dose via breastmilk of 0.012 mg/day.
• This was achieved after maternal administration of oral chlorothiazide 50mg once daily for 3.5 years.
• The infant serum did not contain hydrochlorothiazide.
• The potential for serious adverse reactions in breastfeeding infants is a reason the guidelines suggest that you decide whether to stop nursing or discontinue using the drug.
• This decision should be made taking into consideration the importance of the mother's treatment.
• It is compatible with breastfeeding if hydrochlorothiazide has been taken. 
• Large doses of hydrochlorothiazide should be avoided, as they can cause lactation to be impeded.

Hydrochlorothiazide (Microzide) Dose in Kidney Disease:

• There are no dosage adjustments provided in the literature. Its use is contraindicated with anuria.

• The following adjustments have been recommended:

  • CrCl ≥10 mL/minute:
    • No dose adjustments are necessary.
    • Usually ineffective with CrCl <30 mL/minute unless in combination with a loop diuretic.
  • CrCl <10 mL/minute:
    • Its use is not recommended.

Dose in Liver disease:

There are no dosage adjustments provided in the literature. However, use with caution and observe for exacerbation of hepatic coma.

Side effects of Hydrochlorothiazide (Microzide):

• Cardiovascular:

  • Hypotension
  • Necrotizing Angiitis
  • Orthostatic Hypotension

• Central Nervous System:

  • Dizziness
  • Headache
  • Paresthesia
  • Restlessness
  • Vertigo

• Dermatologic:

  • Alopecia
  • Erythema Multiforme
  • Exfoliative Dermatitis
  • Skin Photosensitivity
  • Skin Rash
  • Stevens-Johnson Syndrome
  • Toxic Epidermal Necrolysis
  • Urticaria

• Endocrine & Metabolic:

  • Glycosuria
  • Hypercalcemia
  • Hyperglycemia
  • Hyperuricemia
  • Hypochloremic Alkalosis
  • Hypokalemia
  • Hypomagnesemia
  • Hyponatremia

• Gastrointestinal:

  • Abdominal Cramps
  • Anorexia
  • Constipation
  • Diarrhea
  • Gastric Irritation
  • Nausea
  • Pancreatitis
  • Sialadenitis
  • Vomiting

• Genitourinary:

  • Impotence

• Hematologic & Oncologic:

  • Agranulocytosis
  • Aplastic Anemia
  • Hemolytic Anemia
  • Leukopenia
  • Purpura
  • Thrombocytopenia

• Hepatic:

  • Jaundice

• Hypersensitivity:

  • Anaphylaxis

• Neuromuscular & Skeletal:

  • Muscle Spasm
  • Weakness

• Ophthalmic:

  • Transient Blurred Vision
  • Xanthopsia

• Renal:

  • Interstitial Nephritis
  • Renal Failure
  • Renal Insufficiency

• Respiratory:

  • Respiratory Distress
  • Pneumonitis
  • Pulmonary Edema

• Miscellaneous:

  • Fever

Contraindications to Hydrochlorothiazide (Microzide):

• Hypersensitivity to hydrochlorothiazide or any of its components, as well as sulfonamide-derived drugs, is an absolute contraindication.
• Anuria
• It is important to note that although some product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged.

Canadian labeling:Additional contraindications not listed in the US labeling:

• Treatment of severe progressive kidney disease may involve an increase in azotemia or oliguria.
• Breastfeeding
• Studies on allergenic cross-reactivity of thiazide-related diuretics to thiazides are very limited. Cross-sensitivity is possible due to similarities in pharmacologic reactions.

Warnings and precautions

• Electrolyte disturbances:

  • It can lead to low serum potassium, hypomagnesemia and hypochloremic acidosis.
  • Combining with other electrolyte sparing drugs (eg, ACE inhibitors and angiotensin receptor blocking agents) can reduce the risk of electrolyte disturbances.

• Gout

  • Hydrochlorothiazide can trigger gout in certain patients who have a history of gout or are at risk for chronic renal failure.
  • Doses exceeding 25 mg may increase the risk.

• Hypersensitivity reactions

  • Hydrochlorothiazide may cause hypersensitivity reactions.
  • Patients with a history bronchial or allergy disorder are at greater risk.

• Ocular effects

  • It can cause acute transient myopia or acute angle-closure blindness.
  • These symptoms usually appear within hours to weeks of initiation.
  • Patients suffering from severe visual impairment or ocular pain should stop taking the medication immediately. 
  • If intraocular pressure is not controlled, additional treatments may be necessary.
  • A history of penicillin allergy or sulfonamide allergy could be a risk factor.

• Photosensitivity

  • Photosensitization can occur.

• Allergy to sulfonamide ("sulfa")

  • FDA-approved product labels for medications that contain a sulfonamide chemical groups include a wide contraindication for patients who have had an allergic reaction to sulfonamides in the past.
  • Cross-reactivity is possible between members of one class (e.g., two antibiotics sulfonamides).
  • Crossreactivity concerns have been raised for all compounds with the sulfonamide structural.
  • Research has shown that allergies can be caused by cross-reactivity between nonantibiotic and antibiotic sulfonamides.
  • Nonantibiotic sulfonamides, in particular, are unlikely to cause cross-reactions due to antibody production such as anaphylaxis.
  • T-cell-mediated reactions i.e. type IV reactions (eg. maculopapular skin rash) are less well understood. It is impossible to exclude this possibility based on current knowledge.
  • Some doctors choose to avoid these classes in cases of severe reactions (Stevens Johnson syndrome/TEN).

• Insufficiency of the adrenal glands:

  • Patients with Addison’s disease should not be treated for high blood pressure by diuretics.
  • To treat hypertension, it is preferable to adjust glucocorticoid or mineralocorticoid therapy.

• Cirrhosis can cause ascites:

  • Hydrochlorothiazide is not recommended for the treatment of ascites caused by cirrhosis.
  • Extreme caution should be taken. Combining it with spironolactone or furosemide could lead to hyponatremia.

• Diabetes:

  • Patients with diabetes mellitus or prediabetes should exercise caution. It is possible to affect glucose control.

• Hepatic impairment

  • Patients with severe hepatic dysfunction should exercise caution. 
  • Avoid electrolyte imbalances and acid-base imbalances in patients with severe or progressive liver disease.

• Hypercalcemia:

  • Thiazide diuretics may decrease renal calcium excretion. Patients with hypercalcemia should avoid using it.

• Hypercholesterolemia:

  • Patients with high or moderate cholesterol levels should exercise caution. 
  • There have been reports of increased cholesterol and triglyceride levels.

• Hypokalemia

  • It is important to monitor hypokalemia closely. Before starting therapy, it is important to correct low potassium levels.

• Parathyroid disease

  • Thiazide diuretics reduce calcium excretion;
  • Long-term use has been associated with pathologic changes in parathyroid glands that are hypercalcemia or hypophosphatemia.
  • Before testing for parathyroid function, it is important to stop the treatment.

• Renal impairment

  • Patients with impaired renal function can experience cumulative effects, including azotemia. In severe renal disease, it is not recommended.

• Systemic lupus erythematosus (SLE):

  • It can trigger activation or flare-ups.

Hydrochlorothiazide: Drug Interaction

Monitoring parameters:

• Blood pressure, dizziness, lightheadedness.
• Serum sodium, potassium, BUN, creatinine.
• Photosensitivity testing of the skin
• Skin cancer

Hypertension:The 2017 Guidelines for the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in Adults

• Confirmed hypertension, known cardiovascular disease, or 10-year ASCVD risk (>10%)
  • It is recommended to aim for a blood pressure of 130/80 mm Hg.
• Confirmed hypertension, but no signs of an increased ASCVD risk
  • A target blood pressure of 130/80 mm Hg is possible.

Diabetes and hypertensionGuidelines from the American Diabetes Association (ADA).

• Patients aged 18-65 years without ASCVD and a 10-year ASCVD chance 15%
  • Preferably, target blood pressure should be less than 140/90mm Hg.
• Patients aged 18-65 years old with known ASCVD or 10-year ASCVD risks >15%
  • If it is safe, a target blood pressure of 130/80 mm Hg may be possible.
• Patients over 65 years old (healthy, complex/intermediate):
  • Preferably, target blood pressure is less than 140/90mm Hg.
• Patients over 65 years old (very complex/poor):
  • It is advised to aim for a blood pressure of 150/90 mm Hg.

How to administer Hydrochlorothiazide (Microzide)?

Oral:

• Administer early in the day to avoid nocturia.
• Take the last dose of multiple doses no later than 6 PM unless instructed otherwise by the physician.

Mechanism of action of Hydrochlorothiazide (Microzide):

It inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions.

The onset of action:

• Diuresis: Infants: 2 to 6 hours.
• In Adults: ~2 hours

Peak effect:

• 4 to 6 hours

Duration:

• Infants: 8 hours.
• In Adults: 6 to 12 hours

Absorption:

• Well absorbed. Its absorption is reduced in patients with CHF.

Protein binding:

• ~40% to 68%

Metabolism:

• Not metabolized

Bioavailability:

• 65% to 75%

Half-life elimination:

• ~6 to 15 hours

Time to peak:

• ~1 to 5 hours

Excretion:

• Urine (≥61% as unchanged drug)

International Brand Names of Hydrochlorothiazide:

• Microzide
• APO-Hydro
• BIO-Hydrochlorothiazide
• MINT-Hydrochlorothiazide
• PMS-Hydrochlorothiazide
• TEVA-Hydrochlorothiazide
• Urozide
• Acortiz
• Acuren
• Apo-Hydro
• BPzide
• Chlothia
• Clorana
• Di-Ertride
• Di-Eudrin
• Dichlorzid
• Dichlotride
• Didralin
• Disalunil
• Disothiazide
• Dithiazide
• Diubiz
• Diurace
• Diures
• Diuret-P
• Diuretyk
• Diurex
• Diurix
• Diursan
• Diuzid
• Esidrex
• Esidrix
• C.T.
• HCT
• HCTZ 25
• Hidroronol
• Hidrosaluretil
• Hipotiazyd
• HTZ
• Hychlozide
• Hydrex
• Hydro-Saluric
• Hydrochlorothiazidum
• Hydrochlorzide
• Hydromed
• Hydrozide
• Hypezide
• Hypothiazid
• Hytaz
• Lonpra
• Maschitt
• Modiur
• Monozide
• Newtolide
• Pantemon
• Ridaq
• Rofucal
• Staplex
• Tandiur
• Tiazid
• Unazid
• Urilzid
• Varidrex

Hydrochlorothiazide Brand Names in Pakistan: