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  • CLASSES

    Low Ceiling Diuretics, excluding Thiazides

    DEA CLASS

    Rx

    DESCRIPTION

    Oral quinazoline diuretic; used for edema and HTN; sulfonamide derivative; may produce diuresis in patients with impaired renal function; Zaroxolyn® is a formulation with relatively slow and incomplete absorption. Mykrox®, a more rapidly absorbed product with enhanced bioavailability, is no longer available in the US.

    COMMON BRAND NAMES

    Zaroxolyn

    HOW SUPPLIED

    Metolazone/Zaroxolyn Oral Tab: 2.5mg, 5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage (Zaroxolyn or generic equivalent)
    Adults

    2.5 to 5 mg PO once daily.

    Geriatric

    See adult dosage. Geriatric patients may be more sensitive to the effects of the usual adult dosage.

    Children

    0.2 to 0.4 mg/kg/day PO, given in divided doses every 12 to 24 hours.

    Oral dosage (Mykrox formulation)

    NOTE: This product formulation is no longer available in the US.

    Adults

    Initially, 0.5 mg PO once daily. Titrate dosage up to 1 mg PO once daily.

    Geriatric

    See adult dosage. Geriatric patients may be more sensitive to the effects of the usual adult dosage.

    For the treatment of edema associated with congestive heart failure or renal diseases (e.g., nephrotic syndrome).
    Oral dosage (Zaroxolyn or generic equivalent)
    Adults

    5 to 20 mg PO once daily. Heart failure guidelines recommend metolazone in combination with a loop diuretic for reduced ejection fraction heart failure (HFrEF) patients experiencing diuretic resistance.

    Children†

    One source recommends 0.2 to 0.4 mg/kg/day PO in 1 to 2 divided doses. The manufacturer reports limited experience with metolazone in doses ranging from 0.05 to 0.1 mg/kg PO once daily in children with heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome, and nephrogenic diabetes insipidus. According to the manufacturer, prolonged use (beyond a few days) is generally not associated with further benefit and is not recommended.

    Infants†

    One small study reports the use of 0.2 mg/kg metolazone given enterally with or without furosemide to infants with bronchopulmonary dysplasia. Urinary flow rate and urinary excretion of sodium, chloride, and potassium were greater with the combination of metolazone and furosemide than with administration of furosemide alone.

    MAXIMUM DOSAGE

    Adults

    5 mg/day PO Zaroxolyn or generic equivalent for hypertension; 20 mg/day PO Zaroxolyn for edema; higher single doses such as 150 mg PO of Zaroxolyn have been used in the treatment of patients with chronic renal failure.

    Elderly

    5 mg/day PO Zaroxolyn for hypertension; 20 mg/day PO Zaroxolyn for edema; higher single doses such as 150 mg PO of Zaroxolyn have been used in the treatment of patients with chronic renal failure.

    Adolescents

    No maximum dosage information is available.

    Children

    0.4 mg/kg/day PO Zaroxolyn or generic equivalent.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No specific dosage adjustment is specified by the manufacturer due to limited data. Use with caution in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

    Renal Impairment

    No dosage adjustment is needed; however, higher doses may be needed to achieve clinical goals in some patients with end-stage renal disease.
     
    Intermittent hemodialysis
    No dosage adjustment is needed.

    ADMINISTRATION

    NOTE: Metolazone is a potent diuretic. When used in combination with a loop diuretic, electrolyte loss can be severe. The smallest effective dose of metolazone should be determined.
     

    Oral Administration

    Metolazone is available as an oral formulation with rapid and complete absorption (Mykrox) and as a formulation with relatively slow and incomplete bioavailability (Zaroxolyn). Formulations bioequivalent to Mykrox should not be substituted for formulations bioequivalent to Zaroxolyn. NOTE: The Mykrox product formulation is no longer available in the US.
    Due to the prolonged duration of action of Zaroxolyn, administer upon waking.

    STORAGE

    Zaroxolyn:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Thiazide diuretics, like metolazone, have been associated with a slight increase in serum cholesterol and triglyceride concentrations. Data from long-term studies, however, suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk.

    Sulfonamide hypersensitivity

    Metolazone is contraindicated in patients with metolazone hypersensitivity. Metolazone is considered a thiazide-like diuretic; it has a similar site of action. Although thiazide-like diuretics such as metolazone are sulfonamide derivatives, sulfonamide cross-sensitivity has been rarely documented. Until further data are available, thiazide diuretics should be used with caution in patients with sulfonamide hypersensitivity. Thiazide diuretics do not contain the N4-aromatic amine or the N1-substituent which are present in sulfonamide antibiotics. Non-arylamine sulfonamide derivatives, such as thiazide diuretics, have been proposed to have a lower risk of allergic reactions in patients with sulfonamide allergy, presumably due to lack of an arylamine group at the N4 position (a proposed structural site of action for sulfonamide allergy). One large retrospective cohort study has reported that in patients with the presence of an allergic reaction after exposure to a sulfonamide antibiotic, 9.9% had an allergic reaction after receiving a non-antibiotic sulfonamide derivative, while in patients who lacked an allergic reaction after sulfonamide antibiotic exposure, 1.6% had an allergic reaction after administration of a non-antibiotic sulfonamide derivative (adjusted odds ratio 2.8; 95% CI, 2.1—3.7). A causal relationship between sulfonamide hypersensitivity and allergic reactions with non-arylamine sulfonamide derivatives has not been definitively established and remains controversial. In general, patients with a documented sulfonamide allergy are considered to be predisposed for development of allergic drug reactions.

    Electrolyte imbalance, hypercalcemia, hypochloremia, hypokalemia, hypomagnesemia, hyponatremia, metabolic alkalosis

    Electrolyte imbalance should be corrected prior to initiation of metolazone therapy. Thiazide diuretics may induce metabolic alkalosis associated with hypokalemia and hypochloremia; this acid/base imbalance is effectively treated with potassium chloride replacement. Patients receiving metolazone should be monitored closely for signs of electrolyte imbalance including hyponatremia, hypomagnesemia, hypokalemia, and hypochloremia. Patients should be aware of the symptoms of these disturbances, (e.g., lassitude, mental confusion, fatigue, faintness, dizziness, muscle cramps, headache, paresthesia, thirst, anorexia, nausea, or vomiting), and report these signs immediately. Dosages should be reduced or withdrawn until homeostasis is achieved; electrolyte imbalances require correction by appropriate measures. Hot weather, a low-sodium diet, protracted vomiting, severe diarrhea, or administration of parenteral fluids all can increase the risk of electrolyte imbalance in patients receiving metolazone. Hyponatremia can occur at any time during metolazone therapy. Metolazone can cause increase in serum calcium concentrations and should be used with caution in patients with hypercalcemia.

    Coma, hepatic disease, hepatic encephalopathy

    Metolazone is contraindicated in patients with hepatic coma or pre-coma (hepatic encephalopathy). Metolazone-induced fluctuations in serum electrolyte concentrations can occur rapidly and precipitate hepatic coma in susceptible patients. Therefore, the drug should be used with caution in patients with impaired hepatic function or severe hepatic disease such as cirrhosis with ascites.

    Hypotension, hypovolemia, orthostatic hypotension, sympathectomy, syncope

    Patients with pre-existing hypovolemia or hypotension should have their condition corrected before diuretics, like metolazone, are initiated. Orthostatic hypotension may occur during treatment with thiazide diuretics. Orthostatic hypotension can be exacerbated by concurrent use of alcohol, narcotics, or antihypertensive drugs. Excessive hypotension during thiazide diuretic therapy can result in syncope. An increased risk of falls has been reported for older adult patients receiving thiazide and similarly-acting diuretics. In addition, the antihypertensive effects of thiazides may be enhanced in other patients predisposed for orthostatic hypotension, including the post-sympathectomy patient.

    Diabetes mellitus, hyperglycemia

    Hyperglycemia, reduced glucose tolerance, and glycosuria can occur during metolazone therapy, and blood and/or urine glucose levels should be assessed closely in patients with diabetes mellitus who are receiving metolazone therapy. Although hyperglycemia did occur, chlorthalidone, a related thiazide diuretic, has been shown to reduce cardiovascular disease events in elderly diabetic patients with isolated systolic hypertension. Greater sensitivity to the hypotensive and diuretic effects of metolazone is possible in elderly patients.

    Anuria, renal disease, renal failure, renal impairment

    Metolazone should be used cautiously in patients with severe renal disease including severe renal impairment or renal failure. Hypovolemia can precipitate azotemia in these patients. Therapy should be interrupted or discontinued if renal impairment or azotemia worsens. Unlike the other thiazide diuretics (e.g., hydrochlorothiazide), metolazone can be used in patients with renal impairment (e.g., CrCl < 30 ml/min). However, metolazone is excreted by the kidneys and can accumulate if renal function is very impaired. Metolazone is contraindicated in patients with anuria.

    Gout, hyperuricemia

    Caution should be used when metolazone is administered to patients with gout or hyperuricemia since thiazide diuretics have been reported to reduce the clearance of uric acid. Metolazone can cause hyperuricemia even in patients with no history of gout. Serum uric acid should be monitored in patients receiving metolazone.

    Systemic lupus erythematosus (SLE)

    Thiazide diuretics, like metolazone, have been reported to activate or exacerbate systemic lupus erythematosus (SLE).

    Jaundice, neonates

    Thiazides, like metolazone, should be avoided in neonates with jaundice. Thiazide-induced hyperbilirubinemia is greater in this patient population.

    Pancreatitis

    Thiazide diuretics have been reported to cause pancreatitis. Metolazone should be used with caution in patients with a history of pancreatitis.

    Pregnancy

    Metolazone is classified in FDA pregnancy risk category B. Animal studies have revealed no evidence of harm due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human fetal risk. Many experts reserve the use of diuretics for pregnant patients with cardiac disease or essential hypertension, due to the fact that diuretic use may decrease placental perfusion and the data do not indicate a positive benefit of diuretic use on the outcome of preeclampsia during pregnancy. The pregnancy risk factor for thiazide diuretics increases to category D for those pregnant patients with reduced uteroplacental perfusion (e.g., preeclampsia or intrauterine growth retardation (IUGR). In general, the bulk of the evidence does not indicate that thiazide diuretics are teratogenic in the 1st trimester, although, many experts limit their use to the 2nd and 3rd trimesters. Neonatal thrombocytopenia has been reported following maternal use of thiazide diuretics near term; at term, thiazide diuretics have been reported to cross the placenta. Potential risks from thiazide use include electrolyte imbalances in the newborn, pancreatitis, jaundice, or neonatal complications resulting from such maternal complications such as hyperglycemia, electrolyte imbalance, or hypotension.

    Breast-feeding

    According to the manufacturer, metolazone is excreted in breast milk, and because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In general, the use of bendroflumethiazide, chlorthalidone, chlorothiazide, and hydrochlorothiazide is considered usually compatible with breast-feeding by the American Academy of Pediatrics due to lack of noted adverse effects on the nursing infant [27500]; one of these diuretics may be a reasonable alternative for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Sunlight (UV) exposure

    Photosensitivity has been reported with thiazide diuretics. Patients should avoid excessive sunlight (UV) exposure and metolazone should be discontinued if phototoxicity occurs.

    Geriatric

    Excessive hypotension during metolazone therapy can result in syncope. An increased risk of falls has been reported for geriatric patients receiving thiazide and related diuretics. According to the Beers Criteria, diuretics are considered potentially inappropriate medications (PIMs) in geriatric patients and should be used with caution due to the potential for causing or exacerbating SIADH or hyponatremia; sodium levels should be closely monitored when starting or changing dosages of diuretics in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. In addition, diuretics may cause fluid and electrolyte imbalances and may precipitate or exacerbate urinary incontinence. There are many drug interactions that can potentiate the effects of antihypertensives.

    ADVERSE REACTIONS

    Severe

    agranulocytosis / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    thrombosis / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    pancreatitis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    hyperuricemia / Delayed / 10.0
    orthostatic hypotension / Delayed / 1.0
    hypokalemia / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    metabolic alkalosis / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    hypochloremia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known
    gout / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypovolemia / Early / Incidence not known
    palpitations / Early / Incidence not known
    depression / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    sialadenitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    syncope / Early / Incidence not known
    vertigo / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    restlessness / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    xerostomia / Early / Incidence not known
    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    nausea / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    purpura / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    rash / Early / Incidence not known
    polyuria / Early / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Codeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Acetaminophen; Hydrocodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Oxycodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Acetaminophen; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Acetazolamide: (Moderate) Acetazolamide promotes electrolyte excretion including hydrogen ions, sodium, and potassium. It can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Acetohexamide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Acrivastine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Albiglutide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Albuterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Albuterol; Ipratropium: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Aldesleukin, IL-2: (Moderate) Thiazide diuretics may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alendronate; Cholecalciferol: (Major) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Alfentanil: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Allopurinol: (Moderate) The occurrence of certain hypersensitivity reactions may be increased in patients with renal impairment who receive allopurinol and thiazide diuretics in combination. The precise mechanism for such events is unclear but likely immune-mediated and may be related to an effect of oxypurinol; elevated oxypurinol concentrations appear to be associated with hypersensitivity reactions; decreased clearance of this metabolite may occur with renal impairment and with the concurrent use of thiazide diuretics. Severe skin reactions include exfoliative dermatitis, toxic epidermal necrolysis and Steven's Johnson syndrome; some reactions have been fatal. In addition, thiazide diuretics, like hydrochlorothiazide, can cause hyperuricemia. Since thiazides reduce the clearance of uric acid, patients with gout or hyperuricemia may have exacerbations of their disease.
    Alogliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Alogliptin; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Alogliptin; Pioglitazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Alpha-glucosidase Inhibitors: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as thiazide diuretics, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
    Amiodarone: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Amlodipine; Benazepril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Thiazides may increase blood levels and therefore potentiate the actions of amphetamines. Thiazide diuretics may increase urinary pH, acting as a urinary alkalinizer, thus reducing urinary excretion and increasing blood concentrations of the amphetamine. Co-administration of amphetamines and urinary alkalinizing agents should be avoided if possible. If needed, monitor for common amphetamine side effects, including decreased appetite, anxiety, dizziness, dry mouth, irritability, insomnia, nausea, increased blood pressure or increased heart rate. Amphetamines increase both systolic and diastolic blood pressure. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amphotericin B lipid complex (ABLC): (Moderate) The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amphotericin B liposomal (LAmB): (Moderate) The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amphotericin B: (Moderate) The risk of developing severe hypokalemia can be increased when amphotericin B is coadministered with thiazide diuretics. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Angiotensin-converting enzyme inhibitors: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Anticholinergics: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Arformoterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with thiazide diuretics. Electrolyte abnormalities, such as hypokalemia and hypomagnesemia, may increase the risk for QT prolongation and torsade de pointes. Monitor electrocardiograms and serum electrolytes more frequently if concurrent use cannot be avoided.
    Articaine; Epinephrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aspirin, ASA; Omeprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Aspirin, ASA; Oxycodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Atracurium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Atropine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Difenoxin: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Diphenoxylate: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Edrophonium: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Barbiturates: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Belladonna; Opium: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Benazepril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Benzhydrocodone; Acetaminophen: (Moderate) Benzhydrocodone may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Benzphetamine: (Moderate) Thiazides may increase blood levels and therefore potentiate the actions of amphetamines. Thiazide diuretics may increase urinary pH, acting as a urinary alkalinizer, thus reducing urinary excretion and increasing blood concentrations of the amphetamine. Co-administration of amphetamines and urinary alkalinizing agents should be avoided if possible. If needed, monitor for common amphetamine side effects, including decreased appetite, anxiety, dizziness, dry mouth, irritability, insomnia, nausea, increased blood pressure or increased heart rate. Amphetamines increase both systolic and diastolic blood pressure. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Benztropine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Beta-agonists: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with diuretics.
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Brompheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Budesonide; Formoterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Buprenorphine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Buprenorphine; Naloxone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Cabergoline: (Minor) Cabergoline has minimal affinity for adrenergic receptors; however, it has been associated with hypotension in some instances. Cabergoline should be used cautiously in those receiving antihypertensive agents.
    Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as diuretics, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Calcium: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Calcium; Vitamin D: (Major) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Canagliflozin: (Moderate) When canagliflozin is initiated in patients already receiving diuretics, symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, thiazide diuretics, can also decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. Thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients receiving canagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Canagliflozin; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) When canagliflozin is initiated in patients already receiving diuretics, symptomatic hypotension can occur. Patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, thiazide diuretics, can also decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. Thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients receiving canagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Captopril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Carbamazepine: (Moderate) Both thiazide diuretics and carbamazepine are associated with hyponatremia. Coadministration may result in an additive risk of developing hyponatremia. When concurrent therapy with a thiazide diuretic and carbamazepine is necessary, monitor patients for hyponatremia.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbetapentane; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Carbinoxamine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbinoxamine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Cardiac glycosides: (Moderate) Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Celecoxib: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Cetirizine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlordiazepoxide; Clidinium: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Codeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlorpheniramine; Hydrocodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlorpropamide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Cholestyramine: (Moderate) Cholestyramine, an ion exchange resin, binds hydrochlorothiazide and reduces its absorption from the gastrointestinal tract by up to 85% when co-administered as single doses. Although the manufacturer for Questran recommends that other medicines be taken at least 1 hour before or 4-6 hours after cholestyramine, it has been recommended that thiazides be administered at least 4 hours before or after cholestyramine to minimize the reduction in absorption. By administering hydrochlorothiazide at least 4 hours before cholestyramine, the decrease in absorption of hydrochlorothiazide is approximately 30-35%.
    Cidofovir: (Severe) The administration of cidofovir with another potentially nephrotoxic agent, such as diuretics, is contraindicated. Diuretics should be discontinued at least 7 days prior to beginning cidofovir.
    Cisapride: (Major) Cisapride should be used with great caution in patients receiving thiazide diuretics. Drugs that are associated with depletion of electrolytes may cause cisapride-induced cardiac arrhythmias. Serum electrolytes and creatinine should be assessed prior to administration of cisapride and whenever conditions develop that may affect electrolyte imbalance or renal function.
    Cisatracurium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Citalopram: (Moderate) Citalopram causes dose-dependent QT interval prolongation. Concurrent use of citalopram and medications known to cause electrolyte imbalance may increase the risk of developing QT prolongation. Therefore, caution is advisable during concurrent use of citalopram and diuretics. In addition, patients receiving a diuretic during treatment with citalopram may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of citalopram should be considered in patients who develop symptomatic hyponatremia.
    Clindamycin; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Clozapine: (Major) Caution is advisable during concurrent use of clozapine and thiazide diuretics. Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Concurrent use of clozapine and medications known to cause electrolyte imbalance may increase the risk of QT prolongation.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Cod Liver Oil: (Major) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine. (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in systolic or diastolic blood pressure in untreated hypertensive patients. Relatively high doses of fish oil are required to produce any blood pressure lowering effect. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Codeine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Codeine; Guaifenesin: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Codeine; Phenylephrine; Promethazine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Codeine; Promethazine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Colestipol: (Moderate) Although to a lesser extent than cholestyramine, colestipol also has been shown to inhibit the GI absorption and therapeutic response of thiazide diuretics. Single doses of colestipol resins reduce the absorption of HCTZ by up to 43%. Administering thiazide diuretics at least 2 hours before colestipol has been suggested to minimize the interaction.
    Conivaptan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Corticosteroids: (Moderate) Additive hypokalemia may occur when non-potassium sparing diuretics, including thiazide diuretics, are coadministered with other drugs with a significant risk of hypokalemia, such as corticosteroids. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.
    Cosyntropin: (Moderate) Use cosyntropin cautiously in patients receiving diuretics. Cosyntropin may accentuate the electrolyte loss associated with diuretic therapy.
    Cyclophosphamide: (Moderate) Coadministration of thiazide diuretics and antineoplastic agents such as cyclophosphamide may result in reduced renal excretion of the antineoplastic agent and therefore increased myelosuppressive effects.
    Dapagliflozin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Dapagliflozin; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Dapagliflozin; Saxagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Desloratadine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Desvenlafaxine: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Dexlansoprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Dexmethylphenidate: (Moderate) Dexmethylphenidate can reduce the hypotensive effect of antihypertensive agents, including thiazide diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of dexmethylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazoxide: (Moderate) Enhanced hyperglycemia is possible during concurrent use of diazoxide and thiazide diuretics. Additive hypotensive effects can also occur with the concomitant administration of diazoxide with thiazide diuretics.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and diuretics together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including loop diuretics and thiazide diuretics. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Diclofenac; Misoprostol: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Dicyclomine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Diethylpropion: (Major) Diethylpropion has vasopressor effects and may limit the benefit of thiazide diuretics. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Diflunisal: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Digitoxin: (Moderate) Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Digoxin: (Moderate) Thiazide diuretics can cause hypokalemia, hypomagnesemia, or hypercalcemia which may increase digoxin's pharmacologic effect. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. It is also recommended that serum potassium, magnesium, and calcium be monitored regularly in patients receiving digoxin.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Diphenhydramine; Ibuprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Diphenhydramine; Naproxen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Dobutamine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Dofetilide: (Severe) Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for dofetilide-induced torsade de pointes. Additionally, in patients treated with either hydrochlorothiazide 50 mg or hydrochlorothiazide/triamterene 50 mg/100 mg daily in combination with dofetilide 500 mcg twice daily for 5 days, dofetilide AUC and Cmax concentrations increased by 27% and 21%, respectively, for the hydrochlorothiazide alone group and by 30% and 16%, respectively, for the hydrochlorothiazide/triamterene group. Furthermore, a 197% and 190% QTc increase over time was seen in the hydrochlorothiazide and hydrochlorothiazide/triamterene groups, respectively. Based on these findings, the manufacturer of dofetilide contraindicates the concomitant use of hydrochlorothiazide (alone or in combination with other drugs such as triamterene); these findings can be explained both by an increase in the plasma concentration of dofetilide and a reduction in the serum potassium concentration. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean dofetilide clearance of dofetilide was 16% lower in patients on thiazide diuretics. It is prudent to avoid the use of any thiazide diuretic in combination with dofetilide.
    Dolasetron: (Major) The manufacturer warns that the coadministration of dolasetron with diuretics associated with hypokalemia could increase the risk of QT prolongation. Patients taking certain diuretics may develop an electrolyte abnormality that may lead to cardiac dysrhythmias and/or QT prolongation. Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as thiazide diuretics, increasing the potential for cardiac arrhythmias. Potassium levels should be within the normal range prior to and during therapy with dolasetron.
    Dopamine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Doxacurium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Droperidol: (Moderate) Caution is advised when using droperidol in combination with thiazide diuretics which may lead to electrolyte abnormalities, especially hypokalemia or hypomagnesemia, as such abnormalities may increase the risk for QT prolongation or cardiac arrhythmias.
    Dulaglutide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Duloxetine: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Empagliflozin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Empagliflozin; Linagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Empagliflozin; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Enalapril, Enalaprilat: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Enalapril; Felodipine: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Ephedrine: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by thiazide diuretics. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epinephrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Ergocalciferol, Vitamin D2: (Major) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Ertugliflozin; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients.
    Ertugliflozin; Sitagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Escitalopram: (Moderate) Patients receiving a diuretic during treatment with escitalopram may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of escitalopram should be considered in patients who develop symptomatic hyponatremia.
    Esomeprazole: (Moderate) Proton pump inhibitors, such as esomeprazole, have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Esomeprazole; Naproxen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. (Moderate) Proton pump inhibitors, such as esomeprazole, have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ethanol: (Moderate) Patients should be cautioned that ingesting alcohol can increase the chance of low blood pressure and dizziness when taking a thiazide diuretic or the related drug, metolazone. Patients may wish to limit alcohol ingestion while taking one of these diuretics and should be monitored for signs or symptoms of hypotension, including postural hypotension and dizziness.
    Etodolac: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Exenatide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Famotidine; Ibuprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Fenoprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Fentanyl: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Fexofenadine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Major) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine. (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flavoxate: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Fluocinolone; Hydroquinone; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Fluoxetine: (Moderate) Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Moderate) Patients receiving a diuretic during treatment with fluoxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Flurbiprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Fluticasone; Salmeterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Fluticasone; Vilanterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Fluvoxamine: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
    Formoterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Formoterol; Mometasone: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Fosinopril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Gallium Ga 68 Dotatate: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Glimepiride: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glimepiride; Pioglitazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glipizide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glipizide; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glyburide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glyburide; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Glycopyrrolate: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Glycopyrrolate; Formoterol: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms. (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Granisetron: (Moderate) According to the manufacturer, caution is warranted when administering granisetron to patients with preexisting electrolyte abnormalities. Patients taking certain diuretics may develop an electrolyte abnormality that may lead to cardiac dysrhythmias and/or QT prolongation. Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for cardiac arrhythmias.
    Guaifenesin; Hydrocodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Halofantrine: (Major) Due to the risks of cardiac toxicity of halofantrine in patients with hypokalemia and/or hypomagnesemia, the use of halofantrine should be avoided when feasible in those patients receiving thiazide diuretics. Electrolyte imbalances may occur while on these diuretics, which may in turn predispose patients to the cardiac effects of halofantrine.
    Haloperidol: (Major) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension. The risk of QT prolongation may also be increased during use of haloperidol and medications known to cause electrolyte imbalance such as thiazide diuretics.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata may lower peripheral vascular resistance. Hawthorn use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients receiving hawthorn concurrently with antihypertensive medications should receive periodic blood pressure monitoring.
    Homatropine; Hydrocodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Hydrocodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrocodone; Ibuprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrocodone; Phenylephrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrocodone; Pseudoephedrine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydromorphone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hyoscyamine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Ibuprofen lysine: (Moderate) Ibuprofen lysine may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients. During coadministration of NSAIDs and diuretic therapy, patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.
    Ibuprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Ibuprofen; Oxycodone: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Ibuprofen; Pseudoephedrine: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Icosapent ethyl: (Moderate) Thiazide diuretics may exacerbate hypertriglyceridemia and should be discontinued or changed to alternate therapy, if possible, prior to initiation of icosapent ethyl.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Inamrinone: (Moderate) Hypokalemia may occur due to excessive diuresis during inamrinone therapy. Fluid and electrolyte changes and renal function should be carefully monitored during inamrinone therapy.
    Incretin Mimetics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Indacaterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Indacaterol; Glycopyrrolate: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms. (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Indomethacin: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
    Insulin Degludec; Liraglutide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Insulin Glargine; Lixisenatide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Ketoprofen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Ketorolac: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Lansoprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Lansoprazole; Naproxen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Lesinurad; Allopurinol: (Moderate) The occurrence of certain hypersensitivity reactions may be increased in patients with renal impairment who receive allopurinol and thiazide diuretics in combination. The precise mechanism for such events is unclear but likely immune-mediated and may be related to an effect of oxypurinol; elevated oxypurinol concentrations appear to be associated with hypersensitivity reactions; decreased clearance of this metabolite may occur with renal impairment and with the concurrent use of thiazide diuretics. Severe skin reactions include exfoliative dermatitis, toxic epidermal necrolysis and Steven's Johnson syndrome; some reactions have been fatal. In addition, thiazide diuretics, like hydrochlorothiazide, can cause hyperuricemia. Since thiazides reduce the clearance of uric acid, patients with gout or hyperuricemia may have exacerbations of their disease.
    Levalbuterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomethadyl: (Moderate) Caution is advised when using levomethadyl in combination with other agents that may lead to electrolyte abnormalities, especially hypokalemia or hypomagnesemia. Agents that require monitoring for potential hypokalemia include thiazide diuretics.
    Levomilnacipran: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Linagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Linagliptin; Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Liraglutide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Lisdexamfetamine: (Moderate) Thiazides may increase blood levels and therefore potentiate the actions of amphetamines. Thiazide diuretics may increase urinary pH, acting as a urinary alkalinizer, thus reducing urinary excretion and increasing blood concentrations of the amphetamine. Co-administration of amphetamines and urinary alkalinizing agents should be avoided if possible. If needed, monitor for common amphetamine side effects, including decreased appetite, anxiety, dizziness, dry mouth, irritability, insomnia, nausea, increased blood pressure or increased heart rate. Amphetamines increase both systolic and diastolic blood pressure. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Lisinopril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Lithium: (Major) Concurrent use of lithium and thiazide diuretics may result in lithium toxicity. Therapeutic doses of thiazide diuretics can result in an approximate 25% to 40% decrease in lithium clearance, potentially leading to significant toxicity. Lithium is primarily re-absorbed from the proximal tubules, and thiazide diuretics block sodium reabsorption at the distal tubule, which results in sodium depletion and subsequent compensatory reabsorption of sodium and lithium at the proximal tubules. If treatment with lithium and a thiazide diuretic cannot be avoided, patients should have their serum lithium concentrations closely monitored, and the lithium dosage adjusted if necessary. Monitoring for changes in lithium effectiveness as well as careful assessment of lithium concentrations is advisable, particularly during initial co-administration and after dose changes or discontinuation of the diuretic. In some cases, thiazide diuretics may be used to counteract lithium-induced polyuria, although close monitoring is necessary if such treatment is initiated. There is a lack of evidence to evaluate the safety of lithium and metolazone, a thiazide-like diuretic. The manufacturer of metolazone recommends general avoidance of diuretics and lithium due to the potential for lithium toxicity.
    Lixisenatide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Loop diuretics: (Moderate) Concomitant use of a thiazide diuretiic, or the related drug metolazone, with a loop diuretic can cause additive electrolyte and fluid loss. In patients with creatinine clearances > 30 ml/min, the combinations may also lead to profound fluid and electrolyte loss in some patients. Thus, use cautiously and with monitoring of renal function, blood pressure, cardiac status, electrolytes (especially potassium), and monitor the clinical response for the condition treated.
    Loratadine; Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium Salts: (Moderate) Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of thiazide diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia. In addition, use caution when prescribing sulfate salt bowel preps in patients taking medications that may affect renal function such as diuretics.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as diuretics.
    Mannitol: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Meclofenamate Sodium: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Mefenamic Acid: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Meglitinides: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Meloxicam: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Mepenzolate: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Meperidine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Meperidine; Promethazine: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Mequinol; Tretinoin: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metaproterenol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Metformin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients.
    Metformin; Pioglitazone: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Metformin; Repaglinide: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Metformin; Rosiglitazone: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Metformin; Saxagliptin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Metformin; Sitagliptin: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Methadone: (Moderate) Diuretics can cause electrolyte disturbances such as hypomagnesemia and hypokalemia, which may prolong the QT interval. As methadone may also prolong the QT interval, cautious coadministration with diuretics is needed. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Methamphetamine: (Moderate) Thiazides may increase blood levels and therefore potentiate the actions of amphetamines. Thiazide diuretics may increase urinary pH, acting as a urinary alkalinizer, thus reducing urinary excretion and increasing blood concentrations of the amphetamine. Co-administration of amphetamines and urinary alkalinizing agents should be avoided if possible. If needed, monitor for common amphetamine side effects, including decreased appetite, anxiety, dizziness, dry mouth, irritability, insomnia, nausea, increased blood pressure or increased heart rate. Amphetamines increase both systolic and diastolic blood pressure. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Methazolamide: (Moderate) Thiazide diuretics may increase the risk of hypokalemia if used concurrently with methazolamide. Monitor serum potassium levels to determine the need for potassium supplementation and/or alteration in drug therapy. There may also be an additive diuretic or hyperuricemic effect.
    Methenamine: (Major) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.
    Methenamine; Sodium Acid Phosphate: (Major) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Thiazide diuretics may cause the urine to become alkaline. This may reduce the effectiveness of methenamine by inhibiting its conversion to formaldehyde. (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Methotrexate: (Moderate) Coadministration of thiazide diuretics and antineoplastic agents such as methotrexate may result in reduced renal excretion of the antineoplastic agent and therefore increased myelosuppressive effects.
    Methoxsalen: (Moderate) Concomitant administration of methoxsalen and other photosensitizing agents, such as thiazide diuretics, can increase the incidence or severity of photsensitization from either compound.
    Methscopolamine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Methylphenidate: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as thiazide diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Metoclopramide: (Minor) Coadministration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Midodrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Miglitol: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Milnacipran: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mirtazapine: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Mivacurium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Moexipril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Morphine: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Morphine; Naltrexone: (Moderate) Morphine may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Morphine may also cause acute urinary retention by causing a spasm of the bladder sphincter; men with enlarged prostates may have a higher risk of this reaction. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Nabumetone: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Naproxen: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Naproxen; Pseudoephedrine: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Naproxen; Sumatriptan: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Nateglinide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nesiritide, BNP: (Moderate) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Neuromuscular blockers: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Nonsteroidal antiinflammatory drugs: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Norepinephrine: (Moderate) Thiazide diuretics can cause decreased arterial responsiveness to norepinephrine, but the effect is not sufficient to preclude their coadministration.
    Octreotide: (Moderate) Patients receiving diuretics or other agents to control fluid and electrolyte balance may require dosage adjustments while receiving octreotide due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olodaterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Omeprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Omeprazole; Sodium Bicarbonate: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Ondansetron: (Moderate) The coadministration of ondansetron with diuretics associated with hypokalemia could increase the risk of QT prolongation. Potassium levels should be within the normal range prior to and during therapy with ondansetron.
    Oprelvekin, rh-IL-11: (Major) Patients receiving thiazide diuretics during oprelvekin, rh-IL-11 therapy are at increased risk for developing severe hypokalemia; close monitoring of fluid and electrolyte status is warranted during concurrent diuretic and oprelvekin therapy.
    Oxaprozin: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Oxybutynin: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Oxycodone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by diuretics. If these drugs are used together, closely monitor for changes in blood pressure.
    Oxymorphone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and thiazide diuretics who are susceptible to hypotension.
    Pancuronium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Pantoprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Paroxetine: (Moderate) Patients receiving a diuretic during treatment with paroxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of paroxetine should be considered in patients who develop symptomatic hyponatremia.
    Pasireotide: (Major) Cautious use of pasireotide and medicines that can affect potassium or magnesium concentrations such as diuretics is advised. Pasireotide may prolong the QT interval, and hypokalemia and/or hypomagnesemia are risk factors for QT prolongation. Assess the patient's potassium and magnesium concentration before and periodically during pasireotide receipt. Correct hypokalemia and hypomagnesemia before pasireotide receipt.
    Pentamidine: (Moderate) Drugs that are associated with hypokalemia and/or hypomagnesemia such as thiazide diuretics should be used with caution in patients also receiving pentamidine. Since pentamidine may cause QT prolongation independently of electrolyte imbalances, the risk for cardiac arrhythmias is potentiated by the concomitant use of agents associated with electrolyte loss. Closely monitor serum electrolytes during pentamidine therapy.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perindopril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Perindopril; Amlodipine: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Phendimetrazine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenothiazines: (Moderate) Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) may occur with administration of thiazide diuretics, and electrolyte disturbances may increase the potential for proarrhythmic effects (e.g., QT prolongation, torsade de pointes), particularly with mesoridazine, thioridazine, or chlorpromazine. In the absence of electrolyte imbalances, these agents can be used together safely with appropriate monitoring; clinicians should monitor for evidence of electrolyte disturbances or cardiac-related patient complaints. Thiazide diuretics may potentiate the orthostatic hypotension that can be seen with the use of the phenothiazine antipsychotics.
    Phentermine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Phentermine; Topiramate: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Phenylephrine; Promethazine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Photosensitizing agents: (Moderate) Thiazide diuretics may cause photosensitivity and may increase the photosensitization effects of photosensitizing agents used in photodynamic therapy. Prevention of photosensitivity includes adequate protection from sources of UV radiation (e.g., avoiding sun exposure and tanning booths) and the use of protective clothing and sunscreens on exposed skin.
    Pimozide: (Major) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Use of pimozide and medications known to cause electrolyte imbalance may increase the risk of QT prolongation. Therefore, caution is advisable during concurrent use of pimozide and thiazide diuretics. According to the manufacturer, potassium deficiencies should be correctly prior to treatment with pimozide and normalized potassium levels should be maintained during treatment.
    Pioglitazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Pirbuterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Piroxicam: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Polycarbophil: (Moderate) Coadministration may lead to hypercalcemia because thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg). Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium polycarbophil is used concomitantly, monitoring of serum calcium may be prudent.
    Polyethylene Glycol; Electrolytes: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as diuretics.
    Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as diuretics.
    Porfimer: (Moderate) Thiazide diuretics may cause photosensitivity and may increase the photosensitization effects of photosensitizing agents used in photodynamic therapy. Prevention of photosensitivity includes adequate protection from sources of UV radiation (e.g., avoiding sun exposure and tanning booths) and the use of protective clothing and sunscreens on exposed skin.
    Pramlintide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
    Prilocaine; Epinephrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives such as metolazone when administered concomitantly.
    Probenecid: (Moderate) Thiazide diuretics can cause hyperuricemia. Although this effect represents a pharmacodynamic interaction and not a pharmacokinetic one, dosage adjustments of probenecid may be necessary if these agents are administered concurrently to patients being treated with probenecid.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propantheline: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Pseudoephedrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Quetiapine: (Major) QT prolongation has occurred during concurrent use of quetiapine and medications known to cause electrolyte imbalance. Therefore, caution is advisable during concurrent use of quetiapine and metolazone.
    Quinapril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Rabeprazole: (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Ramipril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Rapacuronium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Remifentanil: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Repaglinide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritodrine: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Rocuronium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Rofecoxib: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Rosiglitazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Salicylates: (Moderate) Salicylates can increase the risk of renal toxicity in patients receiving diuretics. Salicylates inhibit renal prostaglandin synthesis, which can lead to fluid retention and increased peripheral vascular resistance. Salicylates may decrease the hyperuricemic effect of hydrochlorothiazide.
    Salmeterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Saxagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Scopolamine: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Selegiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with diuretics. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Semaglutide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Sertraline: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
    Simvastatin; Sitagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Sitagliptin: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as diuretics, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as diuretics. In addition, use caution in patients receiving drugs where hypokalemia is a particular risk.
    Solifenacin: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms. Risk versus benefit should be addressed in patients receiving diuretics and solifenacin.
    Streptozocin: (Minor) Because streptozocin is nephrotoxic, concurrent or subsequent administration of other nephrotoxic agents (e.g,. aminoglycosides, amphotericin B, cisplatin, foscarnet, or diuretics) could exacerbate the renal insult.
    Succinylcholine: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Sufentanil: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Sulfacetamide: (Moderate) Sulfonamides may cause photosensitization and may increase the photosensitizing effects of thiazide diuretics.
    Sulfacetamide; Sulfur: (Moderate) Sulfonamides may cause photosensitization and may increase the photosensitizing effects of thiazide diuretics.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and thiazide diuretics. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients during coadministration.
    Sulfinpyrazone: (Moderate) Sulfinpyrazone facilitates urinary excretion of uric acid and thereby decreases plasma urate concentrations. Thiazide diuretics can cause hyperuricemia. Dosage adjustments of sulfinpyrazone may be necessary if thiazides are administered concurrently.
    Sulfonylureas: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Sulindac: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Tazarotene: (Moderate) The manufacturer states that tazarotene should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Tegaserod: (Minor) Coadminisitration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic.
    Terbutaline: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thiazolidinediones: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Tiotropium; Olodaterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tolazamide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Tolbutamide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Tolmetin: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Tolterodine: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Tolvaptan: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Toremifene: (Moderate) Monitor serum calcium levels in patients receiving concomitant treatment with toremifene and thiazide diuretics. Thiazide diuretics decrease renal calcium excretion and may increase the risk of hypercalcemia in patients receiving toremifene.
    Trandolapril: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Trandolapril; Verapamil: (Moderate) Patients with hyponatremia or hypovolemia are more susceptible to developing reversible renal insufficiency when given angiotensin converting enzyme (ACE) inhibitors and diuretics concomitantly.
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Treprostinil: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
    Tretinoin, ATRA: (Moderate) A manufacturer of topical tretinoin states that tretinoin, ATRA should be administered with caution in patients who are also taking drugs known to be photosensitizers, such as thiazide diuretics, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
    Trihexyphenidyl: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Trospium: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Tubocurarine: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Umeclidinium; Vilanterol: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
    Valdecoxib: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Vecuronium: (Moderate) Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers (e.g., tubocurarine) can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.
    Venlafaxine: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Verteporfin: (Moderate) Thiazide diuretics may cause photosensitivity and may increase the photosensitization effects of photosensitizing agents used in photodynamic therapy. Prevention of photosensitivity includes adequate protection from sources of UV radiation (e.g., avoiding sun exposure and tanning booths) and the use of protective clothing and sunscreens on exposed skin.
    Vilazodone: (Moderate) Patients receiving vilazodone with medications known to cause hyponatremia, such as diuretics, may be at increased risk of developing hyponatremia. Hyponatremia has occurred in association with the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of vilazodone, as well as implementation of the appropriate medical interventions.
    Vitamin D analogs: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Vitamin D: (Major) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Vorinostat: (Moderate) Use vorinostat and thiazide diuretics together with caution; the risk of QT prolongation and arrhythmias may be increased if electrolyte abnormalities occur. Thiazide diuretics may cause electrolyte imbalances including low potassium; hypomagnesemia, hypokalemia, or hypocalcemia may increase the risk of QT prolongation with vorinostat. Frequently monitor serum electrolytes if concomitant use of these drugs is necessary.
    Vortioxetine: (Moderate) Patients receiving a diuretic during treatment with vortioxetine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinically significant hyponatremia has been reported during therapy with vortioxetine. One case involving serum sodium levels lower than 110 mmol/l has occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of vortioxetine should be considered in patients who develop symptomatic hyponatremia.
    Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled blood pressure.
    Ziconotide: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
    Ziprasidone: (Minor) Monitor potassium and magnesium levels when thiazide diuretics are used during ziprasidone therapy. The risk of QT prolongation from ziprasidone is increased in the presence of hypokalemia or hypomagnesemia.

    PREGNANCY AND LACTATION

    Pregnancy

    Metolazone is classified in FDA pregnancy risk category B. Animal studies have revealed no evidence of harm due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human fetal risk. Many experts reserve the use of diuretics for pregnant patients with cardiac disease or essential hypertension, due to the fact that diuretic use may decrease placental perfusion and the data do not indicate a positive benefit of diuretic use on the outcome of preeclampsia during pregnancy. The pregnancy risk factor for thiazide diuretics increases to category D for those pregnant patients with reduced uteroplacental perfusion (e.g., preeclampsia or intrauterine growth retardation (IUGR). In general, the bulk of the evidence does not indicate that thiazide diuretics are teratogenic in the 1st trimester, although, many experts limit their use to the 2nd and 3rd trimesters. Neonatal thrombocytopenia has been reported following maternal use of thiazide diuretics near term; at term, thiazide diuretics have been reported to cross the placenta. Potential risks from thiazide use include electrolyte imbalances in the newborn, pancreatitis, jaundice, or neonatal complications resulting from such maternal complications such as hyperglycemia, electrolyte imbalance, or hypotension.

    According to the manufacturer, metolazone is excreted in breast milk, and because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In general, the use of bendroflumethiazide, chlorthalidone, chlorothiazide, and hydrochlorothiazide is considered usually compatible with breast-feeding by the American Academy of Pediatrics due to lack of noted adverse effects on the nursing infant [27500]; one of these diuretics may be a reasonable alternative for some patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Metolazone has properties similar to the thiazide diuretics, acting to increase the excretion of sodium, chloride, and water by inhibiting sodium ion transport across the renal tubular epithelium. Metolazone exerts its effect primarily at the level of the cortical diluting segment of the nephron, although the increased excretion of phosphate and magnesium ions in patients with severely compromised renal function suggests proximal tubular activity as well. Thiazide diuretics decrease the glomerular filtration rate (GFR), contributing to the lower efficacy observed in patients with renal impairment. In contrast, metolazone does not decrease the GFR or the renal plasma flow, and is therefore able to produce diuresis in patients with a reduced GFR (i.e., less than 20 mL/min).
     
    In clinical practice, metolazone is frequently used in combination with furosemide or other loop diuretics in patients who are refractory to diuresis with the loop diuretic alone. This combination often leads to marked diuresis. The increased delivery of sodium to the distal tubule accelerates potassium excretion via the sodium-potassium exchange mechanism, and hypochloremia and hypokalemia can occur, leading to mild metabolic alkalosis. Urinary calcium excretion is significantly decreased during long-term administration of thiazide therapy due to the decrease in extracellular fluid (ECF) volume and the slight increase in calcium reabsorption. Uric acid excretion is also decreased due to both the diuretic-induced decrease in ECF volume and the competitive inhibition of uric acid secretion.
     
    Antihypertensive effects from diuretics initially are caused by hypovolemia, but after several weeks, other mechanisms are responsible. Plasma and ECF volumes eventually return to slightly less than normal, cardiac output returns to normal, and peripheral vascular resistance remains low. At this point, blood pressure is reduced by depletion of sodium within the smooth muscle cells of the arteriolar wall or loss of vascular autoregulatory feedback systems. Decreased plasma volume increases plasma renin activity, and aldosterone secretion is increased, contributing to the hypokalemia associated with thiazide diuretic therapy. In general, diuretics worsen glucose tolerance and exert detrimental effects on the lipid profile.

    PHARMACOKINETICS

    Metolazone is administered orally. Approximately 50—70% of circulating drug is bound to erythrocytes, and up to 33% is bound to plasma proteins. The drug crosses the placenta and is distributed into breast milk. A small portion of an oral dose is metabolized, while the majority (70%) of the drug is excreted unchanged in the urine by glomerular filtration and active tubular secretion. Clearance of the drug is proportional to creatinine clearance rates. The elimination half-life of metolazone has been reported to be roughly 14 hours.

    Oral Route

    Metolazone is available as an oral formulation with rapid and complete absorption (Mykrox) as well as an oral formulation with relatively slow and incomplete bioavailability (Zaroxolyn). Formulations bioequivalent to Mykrox and formulations bioequivalent to Zaroxolyn should not be substituted for one another. Metolazone is absorbed in varying degrees from the GI tract, depending on which formulation is used. Following oral administration of Mykrox, peak blood concentrations are attained within 2—4 hours. The Mykrox product formulation is no longer available in the US. After oral administration of Zaroxolyn, peak concentrations are observed about 8 hours after the dose. Healthy patients absorb approximately 65% of an oral dose of Zaroxolyn and other similar metolazone formulations, while patients with cardiac disease absorb about 40% of an oral dose.