Ephedrine/phenobarbital/theophylline Disease Interactions

The use of barbiturates is contraindicated in patients with acute alcohol intoxication exhibiting depressed vital signs. The central nervous system depressant effects of barbiturates may be additive with those of alcohol. Severe respiratory depression and death may occur. Therapy with barbiturates should be administered cautiously in patients who might be prone to acute alcohol intake.

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Barbiturates have the potential to cause dependence and abuse. Tolerance as well as physical and psychological dependence can develop, particularly after prolonged use of excessive dosages. Abrupt cessation and/or a reduction in dosage may precipitate withdrawal symptoms. In patients who have developed tolerance to a barbiturate, overdosage can still produce respiratory depression and death, and cross-tolerance usually will occur with other agents in the class. Addiction-prone individuals, such as those with a history of alcohol or substance abuse, should be under careful surveillance or medical supervision when treated with barbiturates. It may be prudent to refrain from dispensing large quantities of medication to these patients. After prolonged use or if dependency is suspected, withdrawal of barbiturates should be undertaken gradually using a dosage-tapering schedule.

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Barbiturates are extensively metabolized by the liver. The plasma clearance of barbiturates may be decreased and the half-lives prolonged in patients with impaired hepatic function. Therapy with barbiturates should be administered cautiously and initiated at reduced dosages in patients with liver disease. Barbiturates are not recommended for use in patients with cirrhosis, hepatic failure, hepatic coma, or other severe hepatic impairment.

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The use of barbiturates is contraindicated in patients with a history of porphyria. Barbiturates may exacerbate acute intermittent porphyria or porphyria variegata by inducing the enzymes responsible for porphyrin synthesis.

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Skin eruptions may precede rare but potentially fatal barbiturate-induced reactions such as systemic lupus erythematosus and exfoliative dermatitis, the latter of which may be accompanied by hepatitis and jaundice. Therapy with barbiturates should be administered cautiously in patients with preexisting drug-induced dermatitis, since it may delay the recognition of a potential reaction to barbiturates. Barbiturate therapy should be withdrawn promptly at the first sign of a dermatologic adverse effect. However, cutaneous reactions may proceed to an irreversible stage even after cessation of medication due to the slow rate of metabolism and excretion of barbiturates. Patients should be advised to promptly report signs that may indicate impending development of barbiturate-related cutaneous lesions, including high fever, severe headache, stomatitis, conjunctivitis, rhinitis, urethritis, and balanitis. Rashes may be more likely to occur with phenobarbital and mephobarbital.

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Barbiturates may produce severe respiratory depression, apnea, laryngospasm, bronchospasm and cough, particularly during rapid intravenous administration. In usual hypnotic dosages, the degree of respiratory depression produced is similar to that which occurs during physiologic sleep, while at higher dosages, the rate, depth and volume of respiration may be markedly decreased. However, some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency or other respiratory disorders. Therapy with barbiturates should be administered cautiously in these patients. Appropriate monitoring and individualization of dosage are particularly important, and equipment for resuscitation should be immediately available if the parenteral route is used. Barbiturates, especially injectable formulations, should generally be avoided in patients with sleep apnea, hypoxia, or severe pulmonary diseases in which dyspnea or obstruction is evident.

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The intravenous administration of barbiturates may produce severe cardiovascular reactions such as bradycardia, hypertension, or vasodilation with fall in blood pressure, particularly during rapid infusion. Parenteral therapy with barbiturates should be administered cautiously in patients with hypertension, hypotension, or cardiac disease. The intravenous administration of barbiturates should be reserved for emergency treatment of acute seizures or for anesthesia.

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Barbiturates should not be administered by injection to patients in shock or coma or who have recently received another respiratory depressant. The hypnotic and hypotensive effects of these agents may be prolonged and intensified in such patients.

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The long-acting barbiturate, phenobarbital, is partially eliminated by the kidney. The plasma clearance of phenobarbital may be decreased and the half-life prolonged in patients with impaired renal function. Therapy with phenobarbital should be administered cautiously and initiated at reduced dosages in patients with renal impairment. Since approximately 75% of a mephobarbital dose is metabolized to phenobarbital, the same precaution should be observed with mephobarbital. The remaining barbiturates, which are short- and intermediate-acting, are all negligibly excreted in the urine and may be appropriate alternatives in these patients.

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Methylxanthines are known to stimulate peptic acid secretion. Therapy with products containing methylxanthines should be administered with extreme caution in patients with active peptic ulcer disease. Some manufacturers consider their use to be contraindicated under such circumstance.

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The metabolites of theophylline, which are generally undetectable in patients with normal renal function, may accumulate in patients with renal impairment and contribute to the toxicity of theophylline. In addition, the plasma protein binding of theophylline may be significantly decreased in renal impairment, resulting in elevated free drug concentrations and further increasing the risk of toxicity. Therapy with theophyllines should be administered cautiously in patients with impaired renal function. Dosage adjustments and more intensive monitoring of serum theophylline concentrations may be required.

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The use of theophyllines is considered by some manufacturers to be contraindicated in patients with underlying seizure disorders unless they are receiving adequate anticonvulsant therapy. Theophyllines may cause seizures, which have generally been associated with toxic drug levels but have also been reported at therapeutic concentrations in patients with head trauma or cerebral infarct. If theophylline therapy is administered in patients with these or other risk factors for seizures, serum drug levels should be monitored closely and maintained in the low therapeutic range. Intractable seizures and death have been reported during acute theophylline toxicity.

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Sympathomimetic agents may cause adverse cardiovascular effects, particularly when used in high dosages and/or in susceptible patients. In cardiac tissues, these agents may produce positive chronotropic and inotropic effects via stimulation of beta- 1 adrenergic receptors. Cardiac output, oxygen consumption, and the work of the heart may be increased. In the peripheral vasculature, vasoconstriction may occur via stimulation of alpha-1 adrenergic receptors. Palpitations, tachycardia, arrhythmia, hypertension, reflex bradycardia, coronary occlusion, cerebral vasculitis, myocardial infarction, cardiac arrest, and death have been reported. Some of these agents, particularly ephedra alkaloids (ephedrine, ma huang, phenylpropanolamine), may also predispose patients to hemorrhagic and ischemic stroke. Therapy with sympathomimetic agents should generally be avoided or administered cautiously in patients with sensitivity to sympathomimetic amines, hyperthyroidism, or underlying cardiovascular or cerebrovascular disorders. These agents should not be used in patients with severe coronary artery disease or severe/uncontrolled hypertension.

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Antiepileptic drugs (AEDs) have been associated with an increased risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies involving the use of 11 different AEDs showed that patients receiving AEDs had approximately twice the risk of suicidal thinking or behavior compared to patients receiving placebo. AEDs should be administered cautiously in patients with depression or other psychiatric disorders; phentermine-topiramate should be avoided in patients with history of suicidal attempts or active suicidal ideation. The risk of suicidal thoughts and behavior should be carefully assessed against the risk of untreated illness, bearing in mind that epilepsy and many other conditions for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, caregivers, and families should be alert to the emergence or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior. If patients have symptoms of suicidal ideation or behavior, a dosage reduction or treatment discontinuation should be considered.

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Barbiturates, especially phenobarbital, secobarbital and butabarbital, may diminish the systemic effects of exogenous and endogenous corticosteroids via induction of hepatic microsomal enzymes, thereby accelerating the metabolism of corticosteroids. In addition, barbiturates may interfere with pituitary corticotropin production. Therapy with barbiturates should be administered cautiously in patients with adrenal insufficiency. Patients with borderline hypoadrenalism should be monitored closely, and patients receiving steroid supplementation may require an adjustment in dosage when barbiturates are added to or withdrawn from their medication regimen.

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Barbiturates depress the central nervous system and may cause or exacerbate mental depression. Therapy with barbiturates should be administered cautiously in patients with a history of depression or suicidal tendencies. It may be prudent to refrain from dispensing large quantities of medication to these patients.

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Hematologic toxicity, including agranulocytosis, thrombocytopenic purpura and megaloblastic anemia, has been reported rarely during use of barbiturates. Therapy with barbiturates should be administered cautiously in patients with preexisting blood dyscrasias or bone marrow suppression. Blood counts are recommended prior to and periodically during long-term therapy, and patients should be instructed to immediately report any signs or symptoms suggestive of blood dyscrasia such as fever, sore throat, local infection, easy bruising, petechiae, bleeding, pallor, dizziness, or jaundice. Barbiturate therapy should be discontinued if blood dyscrasias occur.

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Rickets and osteomalacia have rarely been reported following prolonged use of barbiturates, possibly due to increased metabolism of vitamin D as a result of enzyme induction by barbiturates. Long-term therapy with barbiturates should be administered cautiously in patients with vitamin D deficiency.

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Paradoxical reactions characterized by excitability and restlessness may occur in pediatric patients with hyperactive aggressive disorders. Such patients should be monitored for signs of paradoxical stimulation during therapy with barbiturates.

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Sympathomimetic agents such as ephedrine have the potential for producing clinically significant systemic effects, particularly during prolonged or indiscriminate use. In patients with prostate enlargement, urinary difficulty may develop or worsen due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with ephedrine should be administered cautiously in patients with difficulty for urination due to hypertrophy or neoplasm of the prostate. It is important that the recommended dosages are not exceeded.

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Ephedrine may produce slight increases in blood glucose concentrations. Therapy with ephedrine should be administered cautiously in patients with diabetes mellitus. Closer monitoring of blood glucose concentrations may be appropriate. It is important that the recommended dosages of ephedrine are not exceeded.

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Methylxanthines increase gastric acidity and may also relax lower esophageal sphincter, which can lead to gastric reflux into the esophagus. Therapy with products containing methylxanthines should be administered cautiously in patients with significant gastroesophageal reflux.

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Theophylline is removed by hemodialysis. Doses should either be scheduled for administration after dialysis or supplemental doses be given after dialysis.

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Certain conditions have been identified as causes of reduced theophylline clearance. They include age (neonates and infants < 1 year as well as elderly patients > 60 years) and the following concurrent diseases: acute pulmonary edema; decompensated heart failure; cor pulmonale; fever (>= 102 degrees for 24 hours or more, or lesser temperature elevations for longer periods); influenza; untreated or uncontrolled hypothyroidism; liver disease, cirrhosis or acute hepatitis; reduced renal function in infants < 3 months of age; sepsis with multi-organ failure; and shock. Therapy with theophyllines should be administered cautiously in patients presenting with one or more of these risk factors, and the dosage should be appropriately reduced to prevent toxicity. More intensive monitoring of serum theophylline concentrations may be required. Toxicity is most likely to occur when levels exceed 20 mcg/mL. Severe cases, sometimes without previous warning, have led to cardiac arrhythmias, intractable seizures, and death.

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The use of theophyllines is associated with an increase in heart rate which may progress to supraventricular tachycardia or ventricular arrhythmia at high serum drug concentrations. Appearance of cardiac adverse effects is generally an indication of theophylline toxicity, although patients with a history of tachyarrhythmias may be more susceptible to the chronotropic effect of these drugs. Therapy with theophyllines should be administered cautiously in such patients. Caution is also advised in patients with hypertension, hyperthyroidism, angina pectoris, or recent myocardial infarction, since high dosages of the drugs are associated with positive inotropic as well as chronotropic effects. Clinical monitoring of serum drug concentrations is recommended to prevent toxicity.

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Sympathomimetic agents may cause or worsen urinary difficulty in patients with prostate enlargement due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with sympathomimetic agents should be administered cautiously in patients with hypertrophy or neoplasm of the prostate.

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Sympathomimetic agents may cause increases in blood glucose concentrations. These effects are usually transient and slight but may be significant with dosages higher than those normally recommended. Therapy with sympathomimetic agents should be administered cautiously in patients with diabetes mellitus. Closer monitoring of blood glucose concentrations may be appropriate.

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