iazides have been shown to decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. thiazides have also been shown to increase the paralyzing effect of nondepolarizing muscle relaxants such as tubocurarine (an effect attributed to potassium loss); consequently caution should be observed in patients undergoing surgery other considerations concurrent use of hydrochlorothiazide with amphotericin b or corticosteroids or corticotropin (acth) may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effect. thiazides may add to or potentiate the action of other antihypertensive drugs. see indications and usage for concomitant use with other antihypertensive drugs. the effect of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; dosage adjustments may be necessary. triamterene and hydrochlorothiazide may raise the level of blood uric acid; dosage adjustments of antigout medication may be necessary to control hyperuricemia and gout. the following agents given together with triamterene may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 meq of potassium per liter of plasma or up to 65 meq per liter of whole blood when stored for more than 10 days); low-salt milk (may contain up to 60 meq of potassium per liter); potassium-containing medications (such as parenteral penicillin g potassium); salt substitutes (most contain substantial amounts of potassium). exchange resins, such as sodium polystyrene sulfonate, whether administered orally or rectally, reduce serum potassium levels by sodium replacement of the potassium; fluid retention may occur in some patients because of the increased sodium intake. chronic or overuse of laxatives may reduce serum potassium levels by promoting excessive potassium loss from the intestinal tract; laxatives may interfere with the potassium-retaining effects of triamterene. the effectiveness of methenamine may be decreased when used concurrently with hydrochlorothiazide because of alkalinization of the urine.

opment of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. there is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. if this edema produces discomfort, increased recumbency will often provide relief. in rare instances this edema may cause extreme discomfort which is not relieved by rest. in these cases a short course of diuretics may provide relief and may be appropriate.

have been shown to cause the following additional adverse reactions: central nervous system: paresthesias, vertigo. ophthalmic: xanthopsia, transient blurred vision. respiratory: allergic pneumonitis, pulmonary edema, respiratory distress. other: necrotizing vasculitis, exacerbation of lupus. hematologic: aplastic anemia, agranulocytosis, hemolytic anemia. neonate and infancy: thrombocytopenia and pancreatitis–rarely, in newborns whose mothers have received thiazides during pregnancy. skin: erythema multiforme including stevens-johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

iazides have been shown to decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. thiazides have also been shown to increase the paralyzing effect of nondepolarizing muscle relaxants such as tubocurarine (an effect attributed to potassium loss); consequently caution should be observed in patients undergoing surgery other considerations concurrent use of hydrochlorothiazide with amphotericin b or corticosteroids or corticotropin (acth) may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effect. thiazides may add to or potentiate the action of other antihypertensive drugs. see indications and usage for concomitant use with other antihypertensive drugs. the effect of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; dosage adjustments may be necessary. triamterene and hydrochlorothiazide may raise the level of blood uric acid; dosage adjustments of antigout medication may be necessary to control hyperuricemia and gout. the following agents given together with triamterene may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 meq of potassium per liter of plasma or up to 65 meq per liter of whole blood when stored for more than 10 days); low-salt milk (may contain up to 60 meq of potassium per liter); potassium-containing medications (such as parenteral penicillin g potassium); salt substitutes (most contain substantial amounts of potassium). exchange resins, such as sodium polystyrene sulfonate, whether administered orally or rectally, reduce serum potassium levels by sodium replacement of the potassium; fluid retention may occur in some patients because of the increased sodium intake. chronic or overuse of laxatives may reduce serum potassium levels by promoting excessive potassium loss from the intestinal tract; laxatives may interfere with the potassium-retaining effects of triamterene. the effectiveness of methenamine may be decreased when used concurrently with hydrochlorothiazide because of alkalinization of the urine.

reproduction studies have been performed in rats at doses as high as 20 times the mrhd on the basis of body-weight, and 6 times the human dose on the basis of body-surface area without evidence of harm to the fetus due to triamterene. because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. hydrochlorothiazide: hydrochlorothiazide was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up to 3,000 and 1,000 mg/kg/day, respectively. at these doses, which are multiples of the mrhd equal to 3,000 for mice and 1,000 for rats, based on body-weight, and equal to 282 for mice and 206 for rats, based on body-surface area, there was 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. nonteratogenic effects thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. the use of thiazides and triamterene in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. these hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possible other adverse reactions which have occurred in the adult.

iamterene and hydrochlorothiazide capsules exerts its diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium in exchange for potassium and hydrogen ions. its natriuretic activity is limited by the amount of sodium reaching its site of action. although it blocks the increase in this exchange that is stimulated by mineralocorticoids (chiefly aldosterone), it is not a competitive antagonist of aldosterone and its activity can be demonstrated in adrenalectomized rats and patients with addison's disease. as a result, the dose of triamterene required is not proportionally related to the level of mineralocorticoid activity, but is dictated by the response of the individual patients, and the kaliuretic effect of concomitantly administered drugs. by inhibiting the distal tubular exchange mechanism, triamterene maintains or increases the sodium excretion and reduces the excess loss of potassium, hydrogen and chloride ions induced by hydrochlorothiazide. as with hydrochlorothiazide, triamterene may reduce glomerular filtration and renal plasma flow. via this mechanism it may reduce uric acid excretion although it has no tubular effect on uric acid reabsorption or secretion. triamterene does not affect calcium excretion. no predictable antihypertensive effect has been demonstrated for triamterene. duration of diuretic activity and effective dosage range of the hydrochlorothiazide and triamterene components of triamterene and hydrochlorothiazide capsules are similar. onset of diuresis with triamterene and hydrochlorothiazide takes place within 1 hour, peaks at 2 to 3 hours and tapers off during the subsequent 7 to 9 hours. triamterene and hydrochlorothiazide capsules are well absorbed. upon administration of a single oral dose to fasted normal male volunteers, the following mean pharmacokinetic parameters were determined. auc ( 0 - 4 8 ) ng * hrs / ml (± sd ) c m a x ng / ml (± sd ) median t m a x hrs ae mg (± sd ) triamterene 148.7 (87.9) 46.4 (29.4) 1.1 2.7 (1.4) hydroxytriamterene sulfate 1,865 (471) 720 (364) 1.3 19.7 (6.1) hydrochlorothiazide 834 (177) 135.1 (35.7) 2 14.3 (3.8) where auc (0-48) , c max , t max and ae represent area under the plasma concentration versus time plot, maximum plasma concentration, time to reach c max , and amount excreted in urine over 48 hours. a capsule of triamterene and hydrochlorothiazide is bioequivalent to a single-entity 25 mg hydrochlorothiazide tablet and 37.5 mg triamterene capsule used in the double-blind clinical trial below ( see clinical trials ). in a limited study involving 12 subjects, coadministration of triamterene and hydrochlorothiazide capsules with a high-fat meal resulted in: (1) an increase in the mean bioavailability of triamterene by about 67% (90% confidence interval = 0.99, 1.90), p-hydroxytriamterene sulfate by about 50% (90% confidence interval = 1.06, 1.77), hydrochlorothiazide by about 17% (90% confidence interval = 0.90, 1.34); (2) increases in the peak concentrations of triamterene and p-hydroxytriamterene; and (3) a delay of up to 2 hours in the absorption of the active constituents.

centrations at baseline (mean systolic blood pressure range: 137±14 mmhg to 140±16 mmhg; mean diastolic blood pressure range: ±9 mmhg to ±8 mmhg; mean serum potassium range: 2.3 to 3.4 meq/l with the majority of patients having values between 3.1 and 3.4 meq/l). while all triamterene regimens reversed hypokalemia, at week 4 the 37.5 mg regimen proved optimal compared with the other tested regimens. on this regimen, 81% of the patients had a significant (p<0.05) reversal of hypokalemia vs.59% of patients on the placebo/hydrochlorothiazide regimen. the mean serum potassium concentration on 37.5 mg triamterene went from 3.2±0.2 meq/l at baseline to 3.7±0.3 meq/l at week 4, a significantly greater (p<0.05) improvement than that achieved with placebo/hydrochlorothiazide (i.e., 3.2±0.2 meq/l at baseline and 3.5±0.4 meq/l at week 4). also, 51% of patients in the 37.5 mg triamterene group had an increase in serum potassium of ≥0.5 meq/l at week 4 vs. 33% in the placebo group. the 37.5 mg triamterene/25 mg hydrochlorothiazide regimen also maintained control of blood pressure; mean supine systolic blood pressure at week 4 was 138±21 mmhg while mean supine diastolic blood pressure was 87±13 mmhg.