Hydrochlorothiazide¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ As a diuretic, hydrochlorothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like hydrochlorothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of hydrochlorothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. Spironolactone¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule.
Pharmacology
Hydrochlorothiazide¿¡ ´ëÇÑ Pharmacology Á¤º¸ Thiazides such as hydrochlorothiazide promote water loss from the body (diuretics). They inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. Spironolactone¿¡ ´ëÇÑ Pharmacology Á¤º¸ Spironolactone is a synthetic 17-lactone steroid which is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics. On its own, spironolactone is only a weak diuretic, but it can be combined with other diuretics. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgendered people. Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptor in the distal tubule cells. This increases the secretion of water and sodium, while decreasing the excretion of potassium. Spironolactone has a fairly slow onset of action, taking several days to develop and similarly the effect diminishes slowly.
Metabolism
Hydrochlorothiazide¿¡ ´ëÇÑ Metabolism Á¤º¸ # Phase_1_Metabolizing_Enzyme:Not Available Spironolactone¿¡ ´ëÇÑ Metabolism Á¤º¸ # Phase_1_Metabolizing_Enzyme:Not Available
Protein Binding
Hydrochlorothiazide¿¡ ´ëÇÑ ´Ü¹é°áÇÕ Á¤º¸ 67.9% Spironolactone¿¡ ´ëÇÑ ´Ü¹é°áÇÕ Á¤º¸ Spironolactone and its metabolites are more than 90% bound to plasma proteins.
Hydrochlorothiazide¿¡ ´ëÇÑ Absorption Á¤º¸ 50-60% Spironolactone¿¡ ´ëÇÑ Absorption Á¤º¸ Fairly rapidly absorbed from the gastrointestinal tract. Food increases the bioavailability of unmetabolized spironolactone by almost 100%.
Biotransformation
Hydrochlorothiazide¿¡ ´ëÇÑ Biotransformation Á¤º¸ Hydrochlorothiazide is not metabolized. Spironolactone¿¡ ´ëÇÑ Biotransformation Á¤º¸ Rapidly and extensively metabolized. The metabolic pathway of spironolactone is complex and can be divided into two main routes: those in which the sulfur moiety is retained and those in which the sulfur moiety is removed by dethioacetylation. Spironolactone is transformed to a reactive metabolite that can inactivate adrenal and testicular cytochrome P450 enzymes. It also has anti-androgenic activity.
Toxicity
Hydrochlorothiazide¿¡ ´ëÇÑ Toxicity Á¤º¸ 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. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat. Spironolactone¿¡ ´ëÇÑ Toxicity Á¤º¸ The oral LD50 of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits. Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats.
Drug Interactions
Hydrochlorothiazide¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Amantadine The diuretic increases the adverse effect of amantadineDeslanoside Possible electrolyte variations and arrhythmiasDigitoxin Possible electrolyte variations and arrhythmiasDigoxin Possible electrolyte variations and arrhythmiasLithium The thiazide diuretic increases serum levels of lithiumDofetilide Increased risk of cardiotoxicity and arrhythmiasDiazoxide Significant hyperglycemic effect Spironolactone¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Not Available
Hydrochlorothiazide¿¡ ´ëÇÑ Food Interaction Á¤º¸ Avoid alcohol.Avoid excess salt/sodium unless otherwise instructed by your physician.Take with food.Increase potassium intake; add a banana or orange juice; unless instructed otherwise.Avoid natural licorice.Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication. Spironolactone¿¡ ´ëÇÑ Food Interaction Á¤º¸ Avoid alcohol.Avoid salt substitutes containing potassium.Take with food.
Hydrochlorothiazide¿¡ ´ëÇÑ Description Á¤º¸ A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [PubChem] Spironolactone¿¡ ´ëÇÑ Description Á¤º¸ A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827)
The database contains the following fields: The generic name of each chemical For module A10 (liver enzyme composite module): Overall activity category for each compound (A for active, M for marginally active, or I for inactive) based on the number of active and marginally active scores for each compound at the five individual endpoints (see research article for full description of method) Number of endpoints at which each compound is marginally active (M) Number of endpoints at which each compound is active (A) For modules A11 to A15 (alkaline phosphatase increased, SGOT increased, SGPT increased, LDH increased, and GGT increased, respectively): Overall activity category for each compound (A for active, M for marginally active, or I for inactive) based on the RI and ADR values (see the research article for full description of method) Number of ADR reports for each compound, given as <4 or ¡Ã4 Reporting Index value for each compound, except where no shipping units were available (NSU) Group 1 comprises of compounds for which ADR data were available for the first five years of marketing, so when no ADR reports were listed during this period the compounds were evaluated as inactive. Group 2 comprises of compounds for which a 'steady state' period of ADR data were available (1992-1996). In cases where no ADR reports were filed during this period, the compounds were scored as 'NA' (data not available) since they may have had one or more ADR reports during their first five years of marketing which should not be negated by a lack of ADR reports during the steady-state period. SPIRONOLACTONE [GGT Increase] [Composite Activity] (Score) NA (Marginal) 0 (Active) 0
[Alkaline Phosphatase Increase] (Activity Score) NA (Number of Rpts) NA (Index value) NA
[SGOT Increase] (Activity Score) NA (Number of Rpts) NA (Index value) NA
[SGPT Increase] (Activity Score) NA (Number of Rpts) NA (Index value) NA
[LDH Increase] (Activity Score) NA (Number of Rpts) NA (Index value) NA
[GGT Increase] (Activity Score) NA (Number of Rpts) NA (Index value) NA