Belladonna/caffeine/ergotamine/pentobarbital Disease Interactions

The amine ergot alkaloids, ergonovine and methylergonovine, can cause serious cardiovascular complications because of their vasospastic effects. Hypertension (more often with ergonovine) has been most commonly reported, particularly when administered IV undiluted or at an excessive rate or when used in conjunction with regional anesthesia or vasoconstrictors. Headaches, seizures, cerebrovascular accidents and death have been associated with the hypertensive episodes. Other, less common adverse effects include acute myocardial infarction, transient chest pains, thrombophlebitis, tachycardia and palpitations. Therapy with ergot alkaloids should generally be avoided, except under special circumstances, in patients with chronic hypertension, preeclampsia or eclampsia, cardiovascular disease, cerebrovascular disease, or peripheral vascular disease. Caution is advised when these agents are administered to patients with venoatrial shunts, mitral valve stenosis, or sepsis. Close monitoring of cardiovascular status is highly recommended during therapy.

Agents with anticholinergic activity can exacerbate many of the manifestations of autonomic neuropathy, including tachycardia, anhidrosis, bladder atony, obstipation, dry mouth and eyes, cycloplegia and blurring of vision, and sexual impotence in males. Therapy with antimuscarinic agents and higher dosages of antispasmodic agents (e.g., dicyclomine or oxybutynin) should be administered cautiously in patients with autonomic neuropathy.

Anticholinergics are contraindicated in patients with obstructive diseases such as achalasia, esophageal stricture or stenosis, pyloroduodenal stenosis, stenosing peptic ulcer, pyloric obstruction, and paralytic ileus. Anticholinergics may further suppress intestinal motility with resultant precipitation or aggravation of toxic megacolon.

Anticholinergic agents are contraindicated in patients with primary glaucoma, a tendency toward glaucoma (narrow anterior chamber angle), or adhesions (synechiae) between the iris and lens, as well as for the elderly and others in whom undiagnosed glaucoma or excessive pressure in the eye may be present. Because anticholinergics cause mydriasis, they may exacerbate these conditions.

In general, the use of anticholinergic agents is contraindicated in patients with urinary retention and bladder neck obstruction caused by prostatic hypertrophy. Dysuria may occur and may require catheterization. Also, anticholinergic drugs may aggravate partial obstructive uropathy. Caution is advised even when using agents with mild to moderate anticholinergic activity, particularly in elderly patients.

The use of systemic anticholinergics is contraindicated in the treatment of lower respiratory tract symptoms including asthma. Muscarinic receptor antagonists reduce bronchial secretions, which can result in decreased fluidity and increased thickening of secretions. However, ipratropium does not produce these effects and can be used safely in treating asthma.

Because antimuscarinic agents have anticholinergic effects, they are contraindicated in patients with myasthenia gravis. Their use may be appropriate to reduce adverse muscarinic effects caused by an anticholinesterase agent.

The use of drugs with antiperistaltic activity (primarily antidiarrheal and antimuscarinic agents, but also antispasmodic agents such as dicyclomine or oxybutynin at high dosages) is contraindicated in patients with diarrhea due to pseudomembranous enterocolitis or enterotoxin-producing bacteria. These drugs may prolong and/or worsen diarrhea associated with organisms that invade the intestinal mucosa, such as toxigenic E. coli, Salmonella and Shigella, and pseudomembranous colitis due to broad-spectrum antibiotics. Other symptoms and complications such as fever, shedding of organisms and extraintestinal illness may also be increased or prolonged. In general, because antiperistaltic agents decrease gastrointestinal motility, they may delay the excretion of infective gastroenteric organisms or toxins and should be used cautiously in patients with any infectious diarrhea, particularly if accompanied by high fever or pus or blood in the stool. Some cough and cold and other combination products may occasionally include antimuscarinic agents for their drying effects and may, therefore, require careful selection when necessary.

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.

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.

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.

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.

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.

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.

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.

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.

Many CNS stimulants are contraindicated in patients with significant cardiovascular impairment such as uncompensated heart failure, severe coronary disease, severe hypertension (including that associated with hyperthyroidism or pheochromocytoma), cardiac structural abnormalities, serious arrhythmias, etc. Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended dosages for attention deficit hyperactivity disorder; use of these agents should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. Additionally, stroke, myocardial infarction, chest pain, syncope, arrhythmias, and other symptoms have been reported in adults under treatment. A careful assessment of the cardiovascular status should be done in patients being considered for treatment. This includes family history, physical exam, and further cardiac evaluation (EKG and echocardiogram). Patients who develop symptoms should have a detailed cardiac evaluation and if needed, treatment should be suspended.

CNS stimulants increase blood pressure and heart rate; the use of some agents may be contraindicated in patients with severe/uncontrolled hypertension. Caution should be used when administering to patients with preexisting high blood pressure (even mild hypertension) and other cardiovascular conditions. All patients under treatment should be regularly monitored for potential tachycardia and hypertension.

The use of CNS stimulants can cause psychotic symptoms, suicidal ideation, and aggression, and can exacerbate symptoms of behavior disturbance and thought disorder; CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Psychiatric symptoms have been reported in patients with and without history of psychiatric disorders. All patients (particularly those with psychotic or bipolar disorders) should be monitored closely, especially during treatment initiation and at times of dose changes. Extreme caution should be exercised when CNS stimulants are given to patients with a history of psychosis, depression, mania, or bipolar disorder. Prior to initiating therapy, all patients should be screened for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disease, or depression). If any psychiatric symptoms emerge or are exacerbated, treatment suspension should be considered. Some CNS stimulants are contraindicated in patients with marked agitation or anxiety.

The use of ergot alkaloids is contraindicated in patients with conditions predisposing them to vasospastic reactions, including, ischemic heart disease (angina, history of myocardial infarction, silent ischemia), peripheral vascular disease, sepsis, shock, vascular surgery, uncontrolled hypertension, and severely impaired hepatic or renal function. The vasoconstriction produced be ergot alkaloids may exacerbate these conditions. Ergot alkaloids may cause vasospastic reactions other than coronary artery vasospasm such as peripheral vascular reactions, and colonic ischemia, causing muscle pains, numbness, coldness, pallor, and cyanosis of the digits. In patients with compromised circulation, persistent vasospasm may result in gangrene or death. Nitroprusside and heparin have been used to treat ergotamine- induced severe vasoconstriction.

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.

Anticholinergics block vagal inhibition of the SA nodal pacemaker. Therapy with anticholinergics should be administered cautiously to patients with tachycardia, congestive heart failure, or coronary artery disease. Premature ventricular depolarization, ventricular tachycardia, and fibrillation associated with anticholinergics are rare.

Anticholinergics block vagal inhibition of the SA nodal pacemaker. Therapy with anticholinergics should be administered cautiously in patients with tachycardia, congestive heart failure, or coronary artery disease. Premature ventricular depolarization or ventricular tachycardia or fibrillation associated with anticholinergics is rare.

Antimuscarinic agents block vagal inhibition of the SA nodal pacemaker. These agents should be administered cautiously in patients with tachycardia, congestive heart failure, or coronary artery disease. Premature ventricular depolarization or ventricular tachycardia or fibrillation associated with antimuscarinic drugs is rare.

Antimuscarinic agents may cause a delay in gastric emptying and possibly antral stasis in patients with gastric ulcer. Therapy with antimuscarinic agents should be administered cautiously to patients with gastric ulcer.

Antimuscarinic agents decrease gastric motility and relax the lower esophageal sphincter which promotes gastric retention and can aggravate reflux. These drugs should be administered cautiously in patients with gastroesophageal reflux or hiatal hernia associated with reflux esophagitis.

Antimuscarinic agents may suppress intestinal motility and produce paralytic ileus with resultant precipitation of toxic megacolon. These drugs should be administered cautiously to patients with ulcerative colitis.

Atropine-like agents undergo significant hepatic metabolism. Therapy with atropine-like agents should be administered cautiously to patients with liver disease.

Atropine-like agents are primarily eliminated by the kidney. Therapy with atropine-like agents should be administered cautiously to patients with renal disease.

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.

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.

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.

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.

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.

Like other methylxanthines, caffeine at high dosages may be associated with positive inotropic and chronotropic effects on the heart. Caffeine may also produce an increase in systemic vascular resistance, resulting in elevation of blood pressure. Therapy with products containing caffeine should be administered cautiously in patients with severe cardiac disease, hypertension, hyperthyroidism, or acute myocardial injury. Some clinicians recommend avoiding caffeine in patients with symptomatic cardiac arrhythmias and/or palpitations and during the first several days to weeks after an acute myocardial infarction.

In general, CNS stimulants are extensively metabolized by the liver. Their plasma clearance may be decreased and their half-life prolonged in patients with impaired hepatic function. Therapy with CNS stimulants should be administered cautiously in patients with moderate to severe liver disease, and the dosage should be adjusted accordingly in certain agents. Additionally, postmarketing reports have shown that atomoxetine can cause severe liver injury; laboratory testing should be done at the first sign/symptom of liver dysfunction (jaundice, dark urine, upper quadrant tenderness) and treatment should be discontinued in patients with evidence of liver injury.

Overall CNS stimulants should be administered with caution in patients with significantly impaired renal function as the reduction in the rate of elimination may alter the therapeutic response. The dosage should be adjusted accordingly in certain agents.

Due to general central nervous system stimulation, therapy with CNS stimulant drugs may cause seizures. These drugs may lower the convulsive threshold in patients with history of seizures, with prior electroencephalogram (EEG) abnormalities without seizures, and very rarely, without history of seizures and no prior EEG evidence of seizures. Therapy with CNS stimulants should be used with caution in patients with or predisposed to seizures. If seizures occur, therapy should be discontinued.

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.

Cardiovascular effects of anticholinergics may exacerbate hypertension. Therapy with anticholinergic agents should be administered cautiously in patients with hypertension.

In general, agents with anticholinergic activity may exacerbate hyperthyroidism. Therapy with anticholinergics should be administered cautiously in patients with hyperthyroidism. Thyroid levels should be monitored if usage is prolonged.

Diarrhea may be a symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. Antimuscarinic agents may further aggravate the diarrhea. Therefore, these drugs should be administered cautiously in patients with diarrhea.

Atropine-like agents may increase the risk of hyperthermia in patients with fever by producing anhidrosis. Therapy with atropine-like agents should be administered cautiously in febrile patients.