Chlordiazepoxide/clidinium Disease Interactions

Patients with tachycardia should be supervised closely during treatment with anticholinergic agents. Tachycardia is produced by blocking normal vagal inhibition of the SA node. Paradoxically, bradycardia may occur due to central vagal stimulation which may occur prior to peripheral cholinergic blockade.

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.

Anticholinergic agents and agents with secondary anticholinergic activity may aggravate tardive dyskinesia or induce previously suppressed symptoms. Therapy with these agents should be avoided, if possible, or administered cautiously in patients with preexisting tardive dyskinesia, particularly in the elderly. If tardive dyskinesia symptoms develop or worsen during treatment with an anticholinergic agent, prompt withdrawal of therapy will provide better chances of improving the condition.

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 benzodiazepines with alcohol is not recommended. Patients with acute alcohol intoxication exhibit depressed vital signs. The central nervous system depressant effects of benzodiazepines may be additive with those of alcohol, and severe respiratory depression and death may occur. Therapy with benzodiazepines should be administered cautiously in patients who might be prone to acute alcohol intake.

The manufacturers consider the use of benzodiazepines to be contraindicated in patients with acute angle-closure glaucoma or untreated open-angle glaucoma. These agents do not possess anticholinergic activity but have very rarely been associated with increased intraocular pressure.

Benzodiazepines have the potential to cause dependence and abuse. Tolerance as well as physical and psychological dependence can develop, particularly after prolonged use and/or excessive dosages. However, abrupt cessation following continual use of as few as 6 weeks at therapeutic levels has occasionally precipitated withdrawal symptoms. Addiction- prone individuals, such as those with a history of alcohol or substance abuse, should be under careful surveillance when treated with benzodiazepines. 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 benzodiazepine therapy should be undertaken gradually using a dosage- tapering schedule. If withdrawal symptoms occur, temporary reinstitution of benzodiazepines may be necessary.

Benzodiazepines are metabolized by the liver, and the metabolites are excreted in the urine. Chlordiazepoxide, clorazepate, diazepam, flurazepam and quazepam undergo oxidative N-dealkylation to active metabolites that are substantially longer-acting than the parent compound. These metabolites then undergo further biotransformation to pharmacologically inactive products before excretion by the kidney. Therapy with benzodiazepines should be administered cautiously at lower initial dosages in patients with impaired renal and/or hepatic function. Agents that are converted to weakly active, short-acting, or inactive metabolites may be preferable in hepatic impairment. Lorazepam, oxazepam and temazepam are conjugated to inactive metabolites, while alprazolam, estazolam and triazolam undergo hydroxylation to weakly active or inactive metabolites.

Benzodiazepines may cause respiratory depression and apnea, usually when given in high dosages and/or by intravenous administration. 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 benzodiazepines 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. Benzodiazepines, especially injectable formulations, should generally be avoided in patients with sleep apnea, severe respiratory insufficiency, or hypoxia.

The use of benzodiazepines in patients with seizure disorders may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). Appropriate anticonvulsant medication might need to be initiated or the dosage increased. Abrupt cessation of benzodiazepine therapy may precipitate seizures and other withdrawal symptoms, particularly after prolonged use and/or excessive dosages. Status epilepticus may occur in patients with a history of seizures withdrawn rapidly from benzodiazepine therapy. Following chronic administration, cessation of benzodiazepine therapy should occur gradually with incrementally reduced dosages. Patients should be advised not to discontinue medication without first consulting with the physician.

Benzodiazepines should not be administered by injection to patients in shock or coma. The hypnotic and hypotensive effects of these agents may be prolonged and intensified in such patients.

Toxic psychosis manifested as confusion, disorientation, agitation, excitation, memory impairment, delusions and hallucinations may develop at toxic and therapeutic dosages of antimuscarinic agents. Therapy with these agents should be administered cautiously in patients with mental disorders receiving antimuscarinic agents for control of drug-induced extrapyramidal effects, especially at the beginning of therapy or during dosage adjustment. Psychiatric deterioration and psychotic flare-ups have also been reported following withdrawal of therapy. Symptoms include delusions, hallucinations, aggression or violent behavior, and suicidal tendencies. In high dosages, antimuscarinic agents may sometimes produce euphorigenic effects. For this reason, it can be a drug of abuse.

Benzodiazepines depress the central nervous system and may cause or exacerbate mental depression and cause suicidal behavior and ideation. Episodes of mania and hypomania have also been reported in depressed patients treated with some of these agents. Therapy with benzodiazepines should be administered cautiously in patients with a history of depression or other psychiatric disorders. Patients should be monitored for any changes in mood or behavior. It may be prudent to refrain from dispensing large quantities of medication to these patients.

The plasma half-lives of benzodiazepines may be prolonged in obese patients, presumably due to increased distribution into fat. Marked increases in distribution (> 100%) have been reported for diazepam and midazolam, and moderate increases (25% to 100%) for alprazolam, lorazepam, and oxazepam. Therapy with benzodiazepines should be administered cautiously in obese patients, with careful monitoring of CNS status. Longer dosing intervals may be appropriate. When dosing by weight, loading doses should be based on actual body weight, while maintenance dose should be based on ideal body weight to avoid toxicity.

Paradoxical reactions, including excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams, have been reported with the use of benzodiazepines in psychiatric patients and pediatric patients with hyperactive aggressive disorders. Such patients should be monitored for signs of paradoxical stimulation during therapy with benzodiazepines. The manufacturers do not recommend the use of benzodiazepines for the treatment of psychosis.

There have been isolated reports associating the use of chlordiazepoxide with exacerbation of porphyria. Therapy with chlordiazepoxide should be administered cautiously in patients with porphyria.

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

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.