Inderide LA Side Effects

Please note - some side effects for Inderide LA may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects by Body System

Cardiovascular

Cardiovascular side effects are the most common, and include hypotension, bradycardia, syncope, and exacerbation of Raynaud's phenomenon, atrioventricular block, and/or congestive heart failure (CHF). Hydrochlorothiazide (HCTZ)-induced hypokalemia or hyponatremia may predispose some patients to cardiac arrhythmias including ventricular ectopy and complete AV heart block. Rare cases of hypotension have been associated with HCTZ-induced acute pulmonary edema (probably due to hypersensitivity).

Use of a nonselective beta-blocker like propranolol may at least blunt cardiac output in some patients, especially those with preexisting left ventricular systolic dysfunction and during exertion. Data have shown that cardiac conditioning can delay or attenuate this side effect of propranolol.

Abrupt cessation of propranolol therapy may result in hypertension, myocardial infarction, and angina pectoris in some patients.

Paradoxical hypertension may occur in patients with pheochromocytoma unless alpha-adrenergic blockade is already instituted.

At least two cases of electrical alternans associated with propranolol have been reported from pediatric cases. In one case, electrical alternans was clearly not rate-related (since it occurred during propranolol therapy at a slower rate than the patient's "native" ventricular tachycardia) and was associated with echocardiographically-demonstrated mechanical alternans.

Metabolic

Metabolic side effects associated with HCTZ are more likely with daily doses of 50 mg or more. 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. Use of HCTZ may increase serum cholesterol levels.

Since HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and 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. Propranolol may also adversely affect the lipid profile.

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.

Hypersensitivity

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 and eosinophilia, were absent.

Hypersensitivity reactions are rare. They often present as nausea, vomiting, diarrhea, or rash and occur in less than 1% of patients. Cases of acute pulmonary edema, interstitial cystitis, interstitial nephritis, and anaphylaxis have been associated with the use of this combination drug.

Nervous system

Nervous system side effects may be related to the dose of propranolol. Fatigue, dizziness, impaired sleep, and dreams occur in approximately 2% to 5% of patients. Rare cases of cerebrovascular insufficiency have been associated with HCTZ-induced plasma volume contraction.

Rare cases of paresthesias associated with propranolol have been reported.

Renal

Renal side effects including new or worsened renal insufficiency, related to lowering of systemic blood pressure and intravascular volume depletion, has occurred in less than 1% of patients. Rare cases of interstitial nephritis have been reported.

There are reports of patients with renal insufficiency who experienced a reversible decline in renal function without a decline in systemic blood pressure during propranolol therapy. Although HCTZ has been used to treat nephrogenic diabetes insipidus, a case report in which the drug was believed to have caused this condition has been reported.

Respiratory

Respiratory side effects include potential worsening of reactive airways diseases. Some large studies have shown that many patients, regardless of a history of lung disease, complain of dyspnea during propranolol monotherapy. Approximately 30 case reports of acute noncardiogenic pulmonary edema have been associated with HCTZ. The mechanism is unknown, but some evidence points towards hypersensitivity.

Limited data have shown a mean fall in maximal midexpiratory flow rate (MMFR) during propranolol therapy relative to placebo in nine of ten patients. Interestingly, the fall was not related to smoking or to atopic status, suggestive of resting beta-adrenergic bronchodilator activity in non-asthmatic subjects.

Non-selective beta-blockers, such as propranolol, are used with caution in patients with asthma and chronic obstructive pulmonary disease due to inhibition of bronchodilation.

Endocrine

Endocrine side effects have been reported. Both drugs are associated with endocrinologic problems that may be important in some patients with or who are at risk for diabetes or coronary artery disease. Each may cause hyperglycemia (glucose intolerance) and have a potentially deleterious effect on the serum lipid profile. Propranolol, like other nonselective beta-blockers, can mask some signs of hypoglycemia, such as sweating and tachycardia.

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 value. A control group was not reported.

Gastrointestinal

Gastrointestinal side effects, such as diarrhea, nausea, constipation, and vomiting, are usually transient. Rare cases of elevated liver function tests have been associated with propranolol and rare cases of pancreatitis and acute cholecystitis have been associated with HCTZ.

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

Dermatologic

A 67-year-old white woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion, and personality changes associated with a new positive ANA and anti-nRNP and a skin biopsy consistent with lupus erythematosus while taking HCTZ, levothyroxine, and amitriptyline. The eruption 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.

Dermatologic reactions associated with the use of HCTZ include erythema annular centrifugum, acute eczematous dermatitis, and morbilliform or 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. Rare cases of psoriatic flares have been associated with propranolol. Other cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been associated with use of propranolol.

Psychiatric

Psychiatric depression has been associated with the use of beta-blockers, particularly the more lipophilic, nonselective beta-blockers like propranolol. Well-described cases of major depressive episodes after initiation of propranolol therapy, which were dose-dependent and remittent upon drug discontinuation, have been reported.

One study of 34 hypertensive patients who were taking propranolol found an incidence of depressive symptoms ranging from 50% to 74% (depending on the criteria used). Propranolol-induced depression may be more likely in patients with a personal or family history of depression. Of the 34 patients, 12 had a history of depression and 8 had a history of substance abuse, alcoholism, or a family history of psychiatric disorders. Since none of the 12 patients with a history of depression were clinically depressed at the start of propranolol therapy and were similar in age, diagnosis, and propranolol dosage to the other 22 patients, a comparison was made. Patients with a personal or family history of depression had significantly higher scores on depression scales than those without such histories.

Rare cases of psychoses associated with propranolol have been reported.

Musculoskeletal

Musculoskeletal pains, sometimes associated with chills, have been associated with HCTZ-induced diuresis.

Hematologic

Hematologic side effects associated with either drug are rare. Rare cases of purpura with and without normal platelet counts and cases of agranulocytosis have been associated with the use of propranolol, and rare cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with the use of HCTZ.

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, hemoglobinuria, and elevated serum lactate dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg/dL. Direct and indirect Coombs tests were positive. The patient died suddenly; autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.

Immunologic

Propranolol can enhance the immune system by causing an increase in the number of circulating T cells, increased interleukin-2 (IL-2) secretion, increased expression of IL-2 receptors, and increased lymphocyte production in response to the T cell mitogen Con A. Interestingly, NK cell activity may be decreased during propranolol therapy, although the number of circulating NK cells may remain unchanged. These results are consistent with previous data showing decreased immunologic function during periods of elevated sympathetic activity, such as congestive heart failure, uremia, or life-threatening events.

Immunologic side effects have not been reported. Limited data have shown that propranolol can enhance the immune system. The clinical significance of this is unknown.

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