Diuretic Ap-Es Side Effects

Generic Name: hydralazine / hydrochlorothiazide / reserpine

Note: This page contains information about the side effects of hydralazine / hydrochlorothiazide / reserpine. Some of the dosage forms included on this document may not apply to the brand name Diuretic Ap-Es.

Not all side effects for Diuretic Ap-Es may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to hydralazine / hydrochlorothiazide / reserpine: oral tablet

Suggestions that rauwolfia alkaloids may increase the risk of breast cancer occurring later have not been proven. However, rats and mice given 100 to 300 times the human dose had an increased number of tumors.

In addition to its needed effects, some unwanted effects may be caused by hydralazine / hydrochlorothiazide / reserpine. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking hydralazine / hydrochlorothiazide / reserpine:

More common
  • General feeling of discomfort or illness or weakness
Less common
  • Drowsiness or faintness
  • impotence or decreased sexual interest
  • lack of energy or weakness
  • mental depression or inability to concentrate
  • nervousness or anxiety
  • vivid dreams or nightmares or early-morning sleeplessness

If any of the following side effects occur while taking hydralazine / hydrochlorothiazide / reserpine, check with your doctor or nurse as soon as possible:

Signs and symptoms of too much potassium loss
  • Dryness of mouth
  • increased thirst
  • irregular heartbeat
  • mood or mental changes
  • muscle cramps or pain
  • weak pulse
Signs and symptoms of too much sodium loss
  • Confusion
  • convulsions
  • decreased mental activity
  • irritability
  • muscle cramps
  • unusual tiredness or weakness
Less common
  • Black, tarry stools
  • blisters on skin
  • bloody vomit
  • chest pain
  • fever and sore throat
  • headache
  • irregular heartbeat
  • joint pain
  • numbness, tingling, pain, or weakness in hands or feet
  • shortness of breath
  • skin rash or itching
  • slow heartbeat
  • stomach cramps or pain
  • swelling of lymph glands
Rare
  • Lower back or side pain
  • painful or difficult urination
  • stiffness
  • stomach pain (severe) with nausea and vomiting
  • trembling and shaking of hands and fingers
  • unusual bleeding or bruising
  • yellow eyes or skin
Signs and symptoms of overdose
  • Dizziness or drowsiness (severe)
  • dryness of mouth
  • flushing of skin
  • increased thirst
  • muscle cramps or pain
  • nausea or vomiting (severe)
  • pinpoint pupils of eyes
  • slow pulse

Some of the side effects that can occur with hydralazine / hydrochlorothiazide / reserpine may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Diarrhea
  • dizziness, especially when getting up from a lying or sitting position
  • loss of appetite
  • nausea or vomiting
  • stuffy nose
Less common
  • Constipation
  • flushing or redness of skin
  • increased sensitivity of skin to sunlight
  • swelling of feet and lower legs
  • watering or irritated eyes

After you stop taking this drug, it is possible that you may still experience side effects that need medical attention. If you notice any of the following side effects check with your doctor immediately:

  • Drowsiness or faintness
  • general feeling of discomfort or illness or weakness
  • impotence or decreased sexual interest
  • irregular heartbeat
  • mental depression or inability to concentrate
  • nervousness or anxiety
  • vivid dreams or nightmares or early-morning sleeplessness

For Healthcare Professionals

Applies to hydralazine / hydrochlorothiazide / reserpine: oral tablet

Immunologic

Because up to 20% of patients who receive 400 mg of hydralazine per day or more develop a systemic lupus erythematosus syndrome, some experts recommend checking a patient's acetylator status before giving higher doses. Up to 70% of "resistant" patients are fast acetylators, in whom the dose can be relatively safely increased.

Data suggest that hydralazine lupus may represent a unique hypersensitivity reaction in which antibodies to native DNA occur. These antibodies are believed to account for the clinical similarities between hydralazine-induced lupus and systemic lupus erythematosus.[Ref]

Immunologic side effects including a lupus-like syndrome have been reported. The lupus syndrome is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome.

The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea. It may also be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus.

Alternative therapy is recommended for patients who develop the clinical appearance of a lupus syndrome, sustained rises in the antinuclear antibody titer, or the presence of LE cells. The syndrome is reversible, but may take months to years to resolve.

Immunologic side effects associated with reserpine are rare. A single case of angioimmunoblastic lymphadenopathy has been associated with reserpine. In one study of 231 patients, only one case of a lupus-like syndrome was recorded. The patient had previously received hydralazine.[Ref]

Metabolic

Since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, VLDL lipoprotein cholesterol levels by 50%, and may reduce insulin secretion, it should be used with caution in diabetic patients and in those with hypercholesterolemia.

Hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may occur, but are usually clinically insignificant except in malnourished patients.[Ref]

Metabolic side effects are commonly associated with HCTZ, especially when doses greater than 50 mg per day are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50%, and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, and elevated serum uric acid levels are also relatively common. HCTZ may increase serum cholesterol.[Ref]

Nervous system

Nervous system side effects commonly associated with reserpine have included sedation, lethargy (different from the psychiatric syndrome of depression), drowsiness, weakness, vertigo, insomnia, or headache in approximately 1% to 5% of patients. Peripheral neuropathy has been associated with hydralazine. This problem is dose-related and is more common in slow acetylators. Headache or dizziness is reported in approximately 5% of patients who are taking hydralazine alone. Rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.[Ref]

Hydralazine-associated peripheral neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine.

While reserpine is used to treat tardive dyskinesia, extrapyramidal movements may worsen upon withdrawal of therapy. A case of CNS hypertension, believed to be due to cerebral edema, has been associated with reserpine. Increased parkinsonian movements upon reserpine withdrawal (as with neuroleptics) may be due to supersensitivity to dopamine as a result of increased dopamine receptors that developed during reserpine therapy.[Ref]

Hypersensitivity

Hypersensitivity reactions to HCTZ, manifest as nausea, vomiting, diarrhea, and rash, are reported in less than 1% of patients. Cases of acute pulmonary edema, interstitial cystitis, interstitial nephritis, and anaphylaxis have been associated with HCTZ or other thiazide diuretics. Hypersensitivity reactions to hydralazine are rare, presenting as hepatitis, retroperitoneal fibrosis, or occupational asthma.[Ref]

A 44-year-old woman with hypertension and acute sinusitis developed acute renal failure, edema, and a generalized maculopapular erythematous rash during therapy with ampicillin, HCTZ, and hydralazine. A complete evaluation revealed bilateral hydronephrosis and hydroureters secondary to ureteral obstruction due to retroperitoneal fibrosis. Renal function returned to baseline after oral prednisone therapy. It is unclear whether this problem was due to one or more of her medications.

A 68-year-old man with a history of myocardial infarction (MI) developed dyspnea, chest tightness, a low grade fever, dizziness, sweating, and vomiting associated with cyanosis, a mild leukocytosis, radiographic evidence of pulmonary edema, clinical evidence of hypovolemia, and respiratory acidosis.

MI and infection were ruled out; the patient recovered after restoration of his intravascular volume with saline and albumin. The only precipitating factor per history was the ingestion of HCTZ, which the patient had taken without incident for two years. Rechallenge resulted in recurrent acute pulmonary edema. Other signs of hypersensitivity, such as rash or eosinophilia, were absent.[Ref]

Cardiovascular

Cardiovascular side effects can occur as a result of all three drugs in this combination product, which makes it a poor choice for the treatment of hypertension in the elderly or in patients with angina pectoris. By causing peripheral vasodilation and reflex tachycardia, palpitations, flushing, edema, or chest pain have been reported in up to 5% of patients who are taking hydralazine alone. The risk of hypotension or orthostatic changes is increased with the addition of reserpine and HCTZ. Reflexive tachycardia may be blunted by reserpine, which can cause bradycardia (and rare cases of syncope with bradycardia) in 3% of patients. The use of hydralazine in patients with severe chronic heart failure has rarely been associated with ischemia, including episodes of myocardial infarction.

In patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), hydralazine may increase pulmonary artery hypertension, especially during periods of hypoxia. The use of hydralazine in these patients may, on rare occasions, result in profound hypotension, tachycardia, and even death.

Rare cases of bradycardia or cardiac tamponade have been associated with hydralazine-induced lupus.

Cardiac arrhythmias, including ventricular ectopy and complete AV heart block, have been associated with HCTZ-induced hypokalemia and hyponatremia.[Ref]

Provocation of ischemia in patients with compromised left ventricular systolic function may be due to the inability of hydralazine to decrease preload or left ventricular filling pressures. Thus, in heart failure patients, hydralazine is often administered with a venous vasodilator such a nitrate.

The mechanism of increased pulmonary hypertension (PH) associated with hydralazine in patients with PH or COPD is a decrease of systemic vascular resistance accompanied by an increase in cardiac output without a fall in the pulmonary vascular resistance. Hydralazine-induced ventilation/perfusion mismatching with associated hypoxemia may also contribute to increased PH.

In case reports and small series of patients, the use of hydralazine in such patients resulted in palpitations, chest tightness, unchanged pulmonary vascular resistance, increased pulmonary artery pressure, decreased systemic vascular resistance, and increased heart rate and cardiac output. For this reason, if hydralazine must be used, many experts recommend hemodynamic monitoring during hydralazine therapy in such patients.

Rare cases of sinus pauses and profound hypotension during reserpine therapy have been reported. Reserpine is known to increase vagal tone and to deplete cardiac catecholamines.[Ref]

Psychiatric

The depressive syndrome associated with reserpine usually consists of melancholy, loss of self confidence, early morning awakening, loss of libido, and reduced appetite.

A case of reserpine withdrawal psychosis has been reported. This uncommon condition may be due to dopamine receptor supersensitivity, which may develop during reserpine therapy.[Ref]

Psychiatric problems related to reserpine therapy can be serious. Depression occurs in 2% to 28% of patients, is more likely when daily doses exceed 0.5 mg, and can present at any time during therapy. Suicidal ideation has been reported. Reserpine-induced depression is quickly reversible if therapy is withdrawn as soon as the syndrome is recognized, but can persist for several months after drug discontinuation if the syndrome fully develops. Reserpine withdrawal psychosis has been reported.[Ref]

Dermatologic

A 65-year-old man with ischemic cardiomyopathy developed a pruritic, erythematous, generalized rash within two months after beginning hydralazine (200 mg per day) therapy. There were no clinical or laboratory signs of lupus. The rash persisted upon gradual withdrawal of the patient's other medications, but cleared only after discontinuation of hydralazine. Rechallenge resulted in a recurrent pruritic rash.

A 67-year-old white woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion, personality changes, and positive ANA and anti-nRNP titers while taking HCTZ, levothyroxine, and amitriptyline. A skin biopsy was consistent with lupus erythematosus. Her rash resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.[Ref]

Dermatologic reactions to HCTZ are rare, and include erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus has been associated with HCTZ. The hydralazine-induced lupus-like syndrome can include cutaneous vasculitis. A generalized, pruritic rash without evidence of lupus has also been associated with hydralazine. Two cases of Sweet's syndrome (neutrophilic dermatosis) have been associated with hydralazine.[Ref]

Respiratory

A 48-year-old woman with hypertension developed dyspnea, hemoptysis, pleurisy, proteinuria, and hematuria one year after beginning hydralazine (150 mg per day), polythiazide, and atenolol therapy. Other associated findings included an elevated ESR, antinuclear factor, anti-DNA titer, a positive LE test, and radiographic findings of diffuse interstitial lung disease. Two weeks after stopping hydralazine, the signs and symptoms of lupus with pulmonary involvement disappeared.

Rare reports of reserpine-induced bronchospasm are believed to be due to inactivation of beta-adrenergic receptors, which can result in a marked potentiation of the bronchoconstrictive effect of histamine.[Ref]

Respiratory system side effect have included nasal congestion, occurring in 3% to 8% of patients who are taking either reserpine or hydralazine. Rare cases of bronchospasm (reserpine), "hydralazine lung" (hydralazine-induced lupus), and acute noncardiogenic pulmonary edema (HCTZ) have been reported.[Ref]

Gastrointestinal

Gastrointestinal side effects due to unopposed parasympathetic activity produced by catecholamine depletion may result in increased gastrointestinal motility and secretory activity. Because of this, new diarrhea or worsening of existing diarrhea or increased salivation have been reported in 2% of patients who were taking reserpine alone. Rare gastrointestinal complaints include increased appetite, abdominal pain, or vomiting. Rare cases of acute pancreatitis and acute cholecystitis have been associated with thiazide diuretics.[Ref]

Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in increased risk of cholesterol gallstone formation. Reports of bowel strictures associated with thiazide ingestion have been reported in the 1960's, although these patients were on a combination HCTZ-potassium product.[Ref]

Renal

Renal side effects including new or worsened renal insufficiency may occur due to HCTZ-induced intravascular volume depletion. Rare cases of interstitial nephritis have been associated with HCTZ. While renal side effects are common in idiopathic systemic lupus erythematosus, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome have often been accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.[Ref]

In one study, rapidly progressive glomerulonephritis (RPGN) was described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily hydralazine doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN have been reported. It appears to be far more common in patients who are slow acetylators.

Although HCTZ has been used to treat nephrogenic diabetes insipidus, a case in which the drug was believed to have caused this condition has been reported.[Ref]

Hematologic

Hematologic abnormalities have been associated with the hydralazine-induced lupus-like syndrome. Anemia may be caused by one of at least four hydralazine-associated problems: hemolysis, the formation of a circulating anticoagulant, thrombocytopenia, and vasculitis. Rare cases of leukopenia and agranulocytosis have been associated with hydralazine, and rare cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with HCTZ.[Ref]

There are rare case reports of HCTZ-induced immune hemolytic anemia. The following illustrates a fatal case:

A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, and hemoglobinuria, and elevated lactic dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg per dl. Direct and indirect Coombs' tests were positive. The patient died suddenly; autopsy revealed left ventricular hypertrophy and mild coronary atherosclerosis, but no obvious cause of death.

A 71-year-old man with hypertension developed anorexia, weight loss, petechiae, and a microcytic anemia during therapy with hydralazine and oxprenolol. Evaluation for iron deficiency, hemolysis, or marrow depression was negative. The patient was found to have fecal blood loss, anti-DNA antibodies, decreased complement levels, a normal upper GI series, and biopsy-proven vasculitis. The syndrome resolved within two weeks after discontinuation of hydralazine.[Ref]

Genitourinary

At least two cases of male impotence associated with hydralazine have been reported. The mechanism is unclear. There was no evidence of a neuropathy in either case.[Ref]

Genitourinary complaints have been limited to impotence, reported in approximately 5% of male patients.[Ref]

Endocrine

A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed an increased mean fasting blood glucose level after treatment. Withdrawal of thiazide therapy for 7 months in 10 of the patients resulted in mean reductions of 10% in fasting blood glucose and 25% in the 2-hour glucose tolerance test values. A control group was not reported.[Ref]

Endocrinologic problems associated with thiazide diuretics include glucose intolerance and a potentially deleterious effect on the lipid profile. This may be important in some patients with or who are at risk for diabetes or coronary artery disease. Reserpine can cause elevation of serum prolactin levels. This can result in gynecomastia in men or breast engorgement or pseudolactation in women.[Ref]

Hepatic

A 59-year-old woman with hypertension and cholecystic gallbladder disease developed abdominal pain, nausea, vomiting, and painful hepatomegaly associated with elevated serum transaminases, direct hyperbilirubinemia, and liver biopsy findings of subacute hepatitis (with bridging necrosis) within two days after hydralazine was added to her medical regimen. The signs and symptoms of hepatitis resolved after all medications were withheld, but returned upon rechallenge with hydralazine.[Ref]

Hepatic reactions are rare. Less than ten cases of hepatitis have been associated with hydralazine, many of which are believed to be due to hypersensitivity. Histologic findings include hepatocellular, cholestatic, mixed hepatocellular-cholestatic, and granulomatous patterns.[Ref]

Musculoskeletal

Musculoskeletal cramps have occasionally been reported during HCTZ-induced diuresis.[Ref]

Oncologic

Oncologic concerns were raised after a large drug surveillance center in Boston reported an association between reserpine, a stimulator of prolactin, and breast cancer in 1974. These data were partially, but not completely, confirmed in two similar centers in Europe. A critical review of the these studies elucidated several design flaws. Subsequent, controlled studies failed to show an association between reserpine and an increased incidence of breast carcinoma.[Ref]

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71. Dilsaver SC, Greden JF "Possible cholinergic mechanism in reserpine and tardive dyskinesia." Am J Psychiatry 141 (1984): 151-2

72. Tsujimoto G, Horai Y, Ishizaki T, Itoh K "Hydralazine-induced peripheral neuropathy seen in a Japanese slow acetylator patient." Br J Clin Pharmacol 11 (1981): 622-5

73. Reus VI "Behavioral side effects of medical drugs." Prim Care 6 (1979): 283-94

74. Murayama M, Yasuda K, Minamori Y, Mercado-Asis LB, Yamakita N, Miura K "Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation." J Clin Endocrinol Metab 75 (1992): 935-42

75. Luxenberg J, Feigenbaum LZ "The use of reserpine for elderly hypertensive patients." J Am Geriatr Soc 31 (1983): 556-9

76. Lins L-E, Berglund J, Eliasson K, Wernersson B "Efficacy and tolerability of hydralazine, in conventional and slow-release preparations, during long-term treatment of primary hypertension." Clin Ther 5 (1983): 251-9

77. Pfeifer HJ, Greenblatt DK, Koch-Wester J "Clinical toxicity of reserpine in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program." Am J Med Sci 271 (1976): 269-76

78. Peters HA "Questioning reserpine's adverse effect on tardive dyskinesia." Am J Psychiatry 140 (1983): 1106

79. Fagan TC, Sternleib C, Vlachakis N, et al "Efficacy and safety comparison of nitrendipine and hydralazine as antihypertensive monotherapy." J Cardiovasc Pharmacol 6 (1984): s1109-13

80. Young EJ, Fainstein V, Musher DM "Drug-induced fever: cases seen in the evaluation of unexplained fever in a general hospital population." Rev Infect Dis 4 (1982): 69-77

81. Dorn MR, Walker BK "Noncardiogenic pulmonary edema associated with hydrochlorothiazide therapy." Chest 79 (1981): 482-3

82. Perrin B, Malo J-L, Cartier A, et al "Occupational asthma in a pharmaceutical worker exposed to hydralazine." Thorax 45 (1990): 980-1

83. Hoegholm A, Rasmussen SW, Kristensen KS "Pulmonary oedema with shock induced by hydrochlorothiazide: a rare side effect mimicking myocardial infarction." Br Heart J 63 (1990): 186

84. Beaudry C, Laplante L "Severe allergic pneumonitis from hydrochlorothiazide." Ann Intern Med 78 (1973): 251-3

85. Goette DK, Beatrice E "Erythema annulare centrifugum caused by hydrochlorothiazide-induced interstitial nephritis." Int J Dermatol 27 (1988): 129-30

86. Grace AA, Morgan AD, Strickland NH "Hydrochlorothiazide causing unexplained pulmonary oedema." Br J Clin Pract 43 (1989): 79-81

87. Biron P, Dessureault J, Napke E "Acute allergic interstitial pneumonitis induced by hydrochlorothiazide [published erratum appears in Can Med Assoc J 1991 Sep 1;145(5):391]." Can Med Assoc J 145 (1991): 28-34

88. Magil AB, Ballon HS, Cameron EC, Rae A "Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathologic observations in three cases." Am J Med 69 (1980): 939-43

89. Alted E, Navarro M, Cantalapiedra JA, Alvarez JA, Blasco MA, Nunez A "Non-cardiogenic pulmonary edema after oral ingestion of hydrochlorothiazide ." Intensive Care Med 13 (1987): 364-5

90. Grunwald MH, Halevy S, Livni E "Allergic vasculitis induced by hydrochlorothiazide: confirmation by mast cell degranulation test." Isr J Med Sci 25 (1989): 572-4

91. Schapel GJ "Skin rash and hydralazine." Med J Aust 141 (1984): 765-6

92. Hoss DM, Nierenberg DW "Severe shaking chills and fever following hydrochlorothiazide administration." Am J Med 85 (1988): 747

93. Klein MD "Noncardiogenic pulmonary edema following hydrochlorothiazide ingestion." Ann Emerg Med 16 (1987): 901-3

94. Magil AB "Drug-induced acute interstitial nephritis with granulomas." Hum Pathol 14 (1983): 36-41

95. Prupas HM, Brown D "Acute idiosyncratic reaction to hydrochlorothiazide ingestion." West J Med 138 (1983): 101-2

96. Waters VV "Hydralazine, hydrochlorothiazide and ampicillin associated with retroperitoneal fibrosis: case report." J Urol 141 (1989): 936-7

97. Levay ID "Hydrochlorothiazide-induced pulmonary edema." Drug Intell Clin Pharm 18 (1984): 238-9

98. Packer M, Meller J, Medina N, et al "Provocation of myocardial ischemic events during initiation of vasodilator therapy for severe chronic heart failure." Am J Cardiol 48 (1981): 939-46

99. Kronzon I, Cohen M, Winer HE "Adverse effect of hydralazine in patients with primary pulmonary hypertension." JAMA 247 (1982): 3112-4

100. Williams LL, Lopez LM, Thorman AD, et al "Plasma lipid profiles and antihypertensive agents: effects of lisinopril, enalapril, nitrendipine, hydralazine, and hydrochlorothiazide." Drug Intell Clin Pharm 22 (1988): 546-50

101. Combs RM "Unusual response to reserpine in paroxysmal atrial tachycardia with block unassociated with digitalis." South Med J 60 (1967): 839-42

102. Laslett LJ, DeMaria AN, Amsterdam EA, Mason DT "Hydralazine-induced tachycardia and sodium retention in heart failure: hemodynamic and symptomatic correlation by prazosin therapy." Arch Intern Med 138 (1978): 819-20

103. Tuxen DV, Powles AC, Mathur PN, et al "Detrimental effects of hydralazine in patients with chronic air-flow obstruction and pulmonary hypertension." Am Rev Respir Dis 129 (1984): 388-95

104. Keller CA, Shepard JW, Chun DS, et al "Effects of hydralazine on hemodynamics, ventilation, and gas exchange in patients with chronic obstructive pulmonary disease and pulmonary hypertension." Am Rev Respir Dis 129 (1984): 606-11

105. Aylward PE, Tonkin AM "Cardiac tamponade in hydrallazine-induced systemic lupus erythematosus." Aust N Z J Med 12 (1982): 546

106. Wehner RJ, Romanauskas VS "An adverse reaction with hydralazine: a case study." AANA J June (1981): 274-5

107. Hammond TG, Mosesson MW "Fatal small-bowel necrosis and pulmonary hypertension in sickle cell disease." Arch Intern Med 149 (1989): 447-8

108. Widmer RB "Reserpine: the maligned antihypertensive drug." J Fam Pract 20 (1985): 81-3

109. Miller AJ, Abrams DL, Kaplan BM "Persistent reversal of severe systemic hypertension after prolonged toxic reaction to hydralazine." Cardiology 60 (1975): 251-6

110. Lodeiro JG, Feinstein SJ, Lodeiro SB "Fetal premature atrial contractions associated with hydralazine." Am J Obstet Gynecol 160 (1989): 105-7

111. Sharon E, Paolino JS, Kaplan D "Hematemesis after reserpine for Raynaud's phenomenon." Ann Intern Med 77 (1972): 479-80

112. Packer M, Greenberg B, Massie B, Dash H "Deleterious effects of hydralazine in patients with pulmonary hypertension." N Engl J Med 306 (1982): 1326-31

113. Blumenthal M, Davis R, Doe RP "Carcinoid syndrome following reserpine therapy in thyrotoxicosis." Arch Intern Med 116 (1965): 819-23

114. Samuels AH, Taylor AJ "Reserpine withdrawal psychosis." Aust N Z J Psychiatry 23 (1989): 129-30

115. Fleishman M "Letter: Reserpine, ECT, and depression." Am J Psychiatry 132 (1975): 1088

116. Lewis WH "Iatrogenic psychotic depressive reaction in hypertensive patients." Am J Psychiatry 127 (1971): 1416-7

117. Freis ED "Reserpine in hypertension: present status." Am Fam Physician 11 (1975): 120-2

118. Ambrosino SV "Depressive reactions associated with reserpine." N Y State J Med 74 (1974): 860-4

119. Kent TA, Wilber RD "Reserpine withdrawal psychosis: the possible role of denervation supersensitivity of receptors." J Nerv Ment Dis 170 (1982): 502-4

120. Parodi A, Romagnoli M, Rebora A "Subacute cutaneous lupus erythematosus-like eruption caused by hydrochlorothiazide." Photodermatol 6 (1989): 100-2

121. Goodrich AL, Kohn SR "Hydrochlorothiazide-induced lupus erythematosus: a new variant?" J Am Acad Dermatol 28 (1993): 1001-2

122. Robinson HN, Morison WL, Hood AF "Thiazide diuretic therapy and chronic photosensitivity." Arch Dermatol 121 (1985): 522-4

123. Diffey BL, Langtry J "Phototoxic potential of thiazide diuretics in normal subjects." Arch Dermatol 125 (1989): 1355-8

124. Segal MS "Bronchospasm after reserpine." N Engl J Med 281 (1969): 1426-7

125. Atuk NO, Owen JA, Jr "Bronchospasm after reserpine." N Engl J Med 281 (1969): 908-9

126. Diamond L "Drug-induced bronchospasm." J Clin Pharmacol J New Drugs 10 (1970): 215-6

127. Smith BL, Tedeschi A, Lane CD "Pancreatitis with a twist." Hosp Pract (Off Ed) 23 (1988): 150,

128. Campbell JR, Knapp RW "Small bowel ulceration associated with thiazide and potassium therapy: review of 13 cases." Ann Surg 163 (1966): 291-6

129. Dillon PT, Babe J, Meloni CR, Canary JJ "Reserpine in thyrotoxic crisis." N Engl J Med 283 (1970): 1020-3

130. Wagner W, Longerbeam JK, Smith LL, Feikes HL "Drug-induced ulcers of the small bowel causing intestinal obstruction or perforation." Am Surg 33 (1967): 7-11

131. Holland GW "Stenosing ulcers of the small bowel associated with thiazide and potassium therapy." N Z Med J 64 (1965): 383-5

132. Dietz MW "Iatrogenic jejunal ulcer." Am J Roentgenol Radium Ther Nucl Med 99 (1967): 136-8

133. Reinus FZ, Weinberger HA, Fischer WW "Medication-induced ulceration of the small bowel." Am J Surg 112 (1966): 97-101

134. Delevett AF, Recalde M "Diuretic-induced renal colic." JAMA 225 (1973): 992

135. Widerlov E, Karlman I, Storsater J "Hydralazine-induced neonatal thrombocytopenia." N Engl J Med 303 (1980): 1235

136. Eisner EV, Crowell EB "Hydrochlorothiazide-dependent thrombocytopenia due to IgM antibody." JAMA 215 (1971): 480-2

137. Orenstein AA, Yakulis V, Eipe J, Costea N "Immune hemolysis due to hydralazine." Ann Intern Med 86 (1977): 450-1

138. Macleod WN "Anaemia in the hydrallazine-induced lupus syndrome." Scott Med J 28 (1983): 181-2

139. Garratty G, Houston M, Petz LD, Webb M "Acute immune intravascular hemolysis due to hydrochlorothiazide." Am J Clin Pathol 76 (1981): 73-8

140. Keidan H "Impotence during antihypertensive treatment." Can Med Assoc J 114 (1976): 874

141. Balizet L "Recurrent parathyroid adenoma. Association with prolonged thiazide administration." JAMA 225 (1973): 1238-9

142. Myers JL, Augur NA "Hydralazine-induced cholangitis." Gastroenterology 87 (1984): 1185-8

143. Bartoli E, Massarelli G, Solinas A, et al "Acute hepatitis with bridging necrosis due to hydralazine intake." Arch Intern Med 139 (1979): 698-9

144. Barnett DB, Hudson SA, Golightly PW "Hydralazine-induced hepatitis." Br Med J 05/10/80 (1980): 1165-6

145. Jori GP, Peschle C "Hydralazine disease associated with transient granulomas in the liver." Gastroenterology 64 (1973): 1163-7

146. Forster HS "Hepatitis from hydralazine." N Engl J Med 303 (1980): 1362

147. Rice D, Burdick CO "Granulomatous hepatitis from hydralazine therapy." Arch Intern Med 143 (1983): 1077

148. Stewart GW, Peart WS, Boylston AW "Obstructive jaundice, pancytopenia and hydralazine." Lancet 05/30/81 (1981): 1207

149. Itoh S, Yamaba Y, Ichinoe A, Tsukada Y "Hydralazine-induced liver injury." Dig Dis Sci 25 (1980): 884-7

150. Labarthe DR, O'Fallon WM "Reserpine and breast cancer. A community-based longitudinal study of 2,000 hypertensive women." JAMA 243 (1980): 2304-10

151. Mack TM, Henderson BE, Gerkins VR, et al "Reserpine and breast cancer in a retirement community." N Engl J Med 292 (1975): 1366-71

152. Curb JD, Hardy RJ, Labarthe DR, Borhani NO, Taylor JO "Reserpine and breast cancer in the Hypertension Detection and Follow- Up Program." Hypertension 4 (1982): 307-11

153. Jick H "Editorial: Reserpine and breast cancer: a perspective." JAMA 233 (1975): 896-7

154. Newball HH, Byar DP "Does reserpine increase prolactin and exacerbate cancer of prostate? Case control study." Urology 2 (1973): 525-9

155. Kodlin D, McCarthy N "Reserpine and breast cancer." Cancer 41 (1978): 761-8

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