1.HYDROCHLOROTHIAZIDE HISTORY
How was Hydrochlorothiazide discovered?

Hydrochlorothiazide was discovered in 1955 by Dr.George DeStevens.

Hydrochlorothiazide is available under the brand names of Esidrix, Ezide, Hydrodiuril, Microzide and Oretic.

Note: World-drugs.net sells generic Hydrochlorothiazide

2.HYDROCHLOROTHIAZIDE FACTS
Hydrochlorothiazide belongs to the thiazide class of diuretics, acting on the kidney to reduce sodium (Na) reabsorption in the distal convoluted tubule. This reduces the osmotic pressure in the kidney, causing less water to be reabsorbed by the collecting ducts.  

3.ABOUT HYDROCHLOROTHIAZIDE MEDICATION

What are diuretics?

A diuretics helps reduce the amount of excess fluid in the body by increasing the amount of urine produced.

Diuretics prevent, treat or improve symptoms in a variety of conditions, such as:

• High blood pressure
• Congestive heart failure
• Edema
• Polycystic ovary syndrome
• Certain kidney disorders, such as kidney stones
• Diabetes insipidus
• Female hirsutism
• Osteoporosis

The potency of a diuretic is determined by its ability to result in sodium loss in the urine. This ability is measured as fractional sodium excretion. Fractional sodium excretion is the percentage of filtered sodium which is excreted in the urine. The more potent the diuretic, the greater the ability to interfere with the reabsorption of sodium from the renal tubules resulting in a larger amount of sodium remaining in the excreted urine. The greater the amount of sodium in the urine, the greater the volume of urine.

Potent diuretics include

• Furosemide (25% fractional sodium excretion)
• Ethacrynic acid (25% fractional sodium excretion)
• Moderately potent diuretics include the thiazides (10% fractional sodium excretion)

Weak diuretics include

• osmotic diuretics
• carbonic anhydrase inhibitors (5% fractional sodium excretion)
• aldosterone antagonists (2% fractional sodium excretion)

Classification of Diuretics

Diuretics are classified by their mechanism of action. Diuretics work at different locations within the nephron. The classes of Diuretics include:

• osmotics
• inhibitors of urinary acidification
• thiazides
• loop diuretics
• aldosterone antagonists
• xanthines

 

STRUCTURE OF NEPHRON

(Each human kidney consists of about one million nephrons, together with a maze of blood vessels and some connective tissue.)

Osmotic Diuretics

Osmotic diuretics include any low molecular weight substance that is freely filtered by the glomeruli but poorly reabsorbed from tubular fluid. Examples include:

• urea which is increased in blood in azotemic states acts as an endogenous diuretic
• glucose which is increased in diabetes mellitus or by exogenous administration
• mannitol which is most commonly used to reduce neuronal edema in patients with CNS signs and less commonly is used in the oliguric ARF patient.

Osmotic diuretics cause expansion of the extracellular fluid volume by relocating intracellular fluid to the extracellular space, specifically to the plasma.

Inhibitors of Urinary Acidification

Carbon dioxide is produced in renal tubular epithelial cells or is brought to the kidneys in the blood. (1) Carbon dioxide reacts with water in the presence of carbonic anhydrase (CA) to form carbonic acid.(2) Carbonic acid spontaneously breaks down to hydrogen ion and bicarbonate.(3) This bicarbonate is reabsorbed. (3) Water in the cell ionizes to hydrogen and hydroxyl ions. Hydrogen ions from the above 2 sources exchange for sodium in the tubular fluid. The secreted hydrogen ion (4) combines with bicarbonate (5) in the tubular fluid to form carbonic acid (6) that disassociates into water and carbon dioxide (7). The carbon dioxide equilibrates across the renal tubular epithelium. The end result is that for each bicarbonate filtered into tubular fluid one bicarbonate is reabsorbed. The blue numbers on the diagram correlate with the blue numbers in the text above.

Diuretics which inhibit the enzyme carbonic anhydrase impair the reabsorption of bicarbonate from tubular fluid. Sodium and water are eliminated in urine in conjunction with the lost bicarbonate.

Acetazolamide is an example of this class of Diuretics. The bicarbonate in the tubular fluid is negatively charged and will draw positively charged ions such as potassium into the urine, enhancing the loss of potassium. Some of the sodium which normally would have been reabsorbed from tubular fluid paired with bicarbonate will be reabsorbed with chloride instead. (for each negatively charged ion reabsorbed, one positively charged ion will be reabsorbed as well.) The increased reabsorption of chloride and increased loss of potassium coupled with impaired ability to reabsorb bicarbonate can lead to hyperchloremic acidosis and hypokalemia.

Carbonic anhydrase is also found in the eye where it is involved in the production of aqueous humour. Carbonic anhydrase inhibiting Diuretics are most often used to reduce the production aqueous humour in patients with glaucoma. The diuretic effects occur in conjunction with the effects on fluid production in the eye. Therefore the side effects of acidosis, hyperchloridemia, hypokalemia and dehydration may occur in treated patients.

Thiazide Diuretics
Thiazides such as hydrochlorothiazide are moderately potent Diuretics. They inhibit carbonic anhydrase to a minor degree and more importantly, impede the reabsorption of sodium and chloride in the distal convoluted tubule and loop of Henle. The end result is increased excretion of Na, Cl, K and water. Additionally thiazide diuretics decrease renal excretion of calcium and therefore should not be given to hypercalcemic patients. Potential side effects of thiazides include hypokalemia and metabolic alkalosis. Alkalosis occurs as the sodium that is reabsorbed is absorbed primarily with bicarbonate as the reabsorption of chloride is blocked. Thiazides are used in the treatment of arterial hypertension and may have some direct relaxing effect on vascular smooth muscle in addition to the diuretic effect. Thiaizide diuretics may decrease the severity of polyuria in patients with diabetes insipidus (decrease urine volume by 30-40%). It is not clear how a diuretic actually decreases urine volume in these patients

Loop diuretics include furosemide and ethacrynic acid. They have a rapid oral absorption. There is a diuretic effect within minutes, which persists for 1-3 hours. The action is to strongly inhibit Cl pump in ascending loop of Henle (and subsequently Na reabsorption). They can produce hypokalemia and metabolic alkalosis.

 

Aldosterone antagonists

Aldosterone antagonists like spironolactone compete with aldosterone for its physiologic binding site. Aldosterone antagonists are usually given with other, more potent, diuretics for their effect of potassium sparing. Hyperkalemia (increased levels of potassium) is a possible side effect

Xanthines

Xanthines include caffeine, theobromine, and theophylline, which is a bronchodilator. Xanthines act to increase cardiac output, which increases GFR (Glomerular filtration rate) resulting in a modest loss of Na, Cl, and water. Additionally a direct tubular action is suspected as their effect persists after GFR returns to normal.

Uses of Hydrochlorothiazide

Hydrochlorothiazide prevents, treats or improves symptoms in a variety of conditions, such as:

• High blood pressure

 

Hypertension is a disorder characterized by consistently high blood pressure. Generally, high blood pressure consists of systolic blood pressure (the "top" number, which represents the pressure generated when the heart beats) higher than 140, or diastolic blood pressure (the "bottom" number, which represents the pressure in the vessels when the heart is at rest) over 90.

• Congestive heart failure
• Edema

 

• Certain kidney disorders, such as kidney stones
• Diabetes insipidus
• Osteoporosis  

4.HYDROCHLOROTHIAZIDE EFFECTIVENESS
When is Hydrochlorothiazide best taken?

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 Hydrochlorothiazide dosing, and range from 70 to 490 ng/mL following oral doses of Hydrochlorothiazide 12.5 to 100 mg. Plasma concentrations are linearly related to the administered doses of Hydrochlorothiazide. 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. 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 urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. In patients with renal disease, plasma concentrations of Hydrochlorothiazide are increased and the elimination half-life is prolonged.

When Hydrochlorothiazide is administered with food, its bioavailability is reduced by 10%, the maximum plasma concentration is reduced by 20%, and the time to maximum concentration increases from 1.6 to 2.9 hours.

Pharmacodynamics: Acute antihypertensive effects of Hydrochlorothiazideare 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 toward normal, but peripheral vascular resistance is decreased. The exact mechanism of the antihypertensive effect of Hydrochlorothiazide is not known. 

Hydrochlorothiazide does not affect normal blood pressure. 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.

5.HYDROCHLOROTHIAZIDE EFFECTS ON SPECIAL POPULATION
How do different people react to Hydrochlorothiazide?

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, Hydrochlorothiazide should be used during pregnancy only if clearly needed. 

Non-teratogenic Effects:

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

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.

Elderly Use : A greater blood pressure reduction and an increase in side effects may be observed in the elderly (>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.

6.HYDROCHLOROTHIAZIDE EFFECTS ON MEDICAL CONDITIONS
(How does Hydrochlorothiazide affect your existing condition/ailment?

Hyperuricemia : Hyperuricemia or acute gout may be precipitated in certain patients receiving Hydrochlorothiazide.

Impaired Hepatic Function: Hydrochlorothiazide 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 Hydrochlorothiazide, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.

7.OTHER/ALTERNATE USES OF HYDROCHLOROTHIAZIDE
What else does Hydrochlorothiazide treat?

Hydrochlorothiazide is also being used for a condition known as "water diabetes" (diabetes insipidus) and to help prevent calcium kidney stones.

8.ADVERSE/SIDE EFFECTS of HYDROCHLOROTHIAZIDE
What are the side effects of Hydrochlorothiazide?

The adverse reactions associated with Hydrochlorothiazide have been shown to be dose related. In controlled clinical trials, the adverse events reported with doses of 12.5 mg Hydrochlorothiazide once daily were comparable to placebo.

The following adverse reactions have been reported for doses of Hydrochlorothiazide 25 mg and greater and, within each category, are listed in the order of decreasing severity.

Body as a whole: Weakness.

Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs).

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

Metabolic: Electrolyte imbalance hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal: Muscle spasm.

Nervous System/Psychiatric: Vertigo, paresthesia, dizziness, headache, restlessness.

Renal: Renal failure, renal dysfunction, interstitial nephritis

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

Special Senses: Transient blurred vision, xanthopsia.

Urogenital: Impotence.

Whenever adverse reactions are moderate or severe, doses of Hydrochlorothiazide should be reduced or therapy withdrawn.