Clorazepate

Clorazepate, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from clorazepate is extremely rare. A few only partially convincing case reports of acute hepatocellular injury from clorazepate have been reported. Rare instances of drug induced liver injury have been reported with other benzodiazepines, such as chlordiazepoxide, diazepam, flurazepam, triazolam and alprazolam. In benzodiazepine related cases of acute liver injury, the latency has ranged from a few weeks to 6 months; the typical pattern of liver enzyme elevations has been cholestatic or mixed, but instances of hepatocellular patterns have also been reported. The injury is usually mild to moderate in severity and self-limited. Fever and rash have not been described nor has autoantibody formation.

IDENTIFICATION: Clorazepate dipotassium is classified as a psychloleptc, anxiolytic benzodiazepine derivative. White or light yellow solid crystals which are soluble in water, practically insoluble in acetone, in chloroform in dichloromethane and in ether. HUMAN EXPOSURE: Main risks and target organs: Central nervous system, causing depression of respiration and consciousness. Summary of clinical effects: Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and other manifestations of severe CNS depression are rare. Sedation, somnolence, diplopia, dysarthria, ataxia and intellectual impairment are the most common adverse effects of benzodiazepines. Overdose in adults frequently involves co-ingestion of other CNS depressants, which act synergistically to increase toxicity. Elderly and very young children are more susceptible to the CNS depressant action. Intravenous administration of even therapeutic doses of benzodiazepines may produce apnea and hypotension. Dependence may develop with regular use of benzodiazepines, even in therapeutic doses for short periods. If benzodiazepines are discontinued abruptly after regular use, withdrawal symptoms may develop. Acute poisoning: Ingestion: The onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma Grade I or Grade II (see below) following very large ingestions. Reed Classification of Coma: Coma Grade I: Depressed level of consciousness, response to painful stimuli. Deep tendon reflexes and vital signs intact. Coma Grade II: Depressed level of consciousness, no response to painful stimuli. Deep tendon reflexes and vital signs intact. Coma Grade III: Depressed level of consciousness, no response to painful stimuli. Deep tendon reflexes absent. Vital signs intact. Coma Grade IV: Coma grade III plus respiratory and circulatory collapse. Parenteral exposure: Overdose by the intravenous route results in symptoms similar to those associated with ingestion, but they appear immediately after the infusion, and the progression of central nervous system (CNS) depression is more rapid. Acute intentional poisoning by this route is uncommon and most cases are iatrogenic. Rapid intravenous infusion may cause hypotension, respiratory depression and apnea. Chronic poisoning: Ingestion: Toxic effects associated with chronic exposure are secondary to the presence of the drug and metabolites and include depressed mental status, ataxia, vertigo, dizziness, fatigue, impaired motor co-ordination, confusion, disorientation and anterograde amnesia. Paradoxical effects of psychomotor excitation, delirium and aggressiveness also occur. These chronic effects are more common in the elderly, children and patients with renal or hepatic disease. Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly. Parenteral exposure: The chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms. Systematic description of clinical effects: Cardiovascular: Hypotension, bradycardia and tachycardia have been reported with overdose. Hypotension is more frequent when benzodiazepines are ingested in association with other drugs. Rapid intravenous injection is also associated with hypotension. Respiratory: Respiratory depression may occur in benzodiazepine overdose and the severity depends on dose ingested, amount absorbed, type of benzodiazepine and co-ingestants. Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdoses. The dose-response for respiratory depression varies between individuals. Respiratory depression or respiratory arrest may rarely occur with therapeutic doses. Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnea or other sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure. Neurological: Central nervous system (CNS): CNS depression is less marked than that produced by other CNS depressant agents. Even in large overdoses, benzodiazepines usually produce only mild symptoms and this distinguishes them from other sedative-hypnotic agents. Sedation, somnolence, weakness, diplopia, dysarthria, ataxia and intellectual impairment are the most common neurological effects. The clinical effects of severe poisoning are sleepiness, ataxia and coma. Grade I to Grade II (Reed). The presence of more severe coma suggests the possibility of co-ingested drugs. The elderly and very young children are more susceptible to the CNS depressant action of benzodiazepines. The muscle relaxation caused by benzodiazepines is of CNS origin and manifests as dysarthria, incoordination and difficulty standing and walking. Gastrointestinal: Oral benzodiazepine poisoning will produce minimal effects on the gastrointestinal tract (GI) tract but can occasionally cause nausea or vomiting. Endocrine and reproductive systems: Galactorrhoea with normal serum prolactin concentrations has been noted in 4 women taking benzodiazepines. Allergic reactions: Hypersensitivity reactions including anaphylaxis are rare. Other clinical effects: Hypothermia was reported in 15% of cases in one series. Pregnancy: Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus. Adverse effects may persist in the neonate for several days after birth because of immature drug metabolizing enzymes. The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of benzodiazepines during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn. Breast feeding: Benzodiazepines are excreted in breast milk in significant amounts and may result in lethargy and poor feeding in neonates. Benzodiazepines should be avoided in nursing mothers. Other: Dependence and withdrawal: Benzodiazepines have a significant potential for abuse and can cause physical and psychological dependence. Abrupt cessation after prolonged use causes a withdrawal syndrome. The mechanism of dependence is probably related to functional deficiency of GABA activity. Withdrawal symptoms include anxiety, insomnia, headache, dizziness, tinnitus, anorexia, vomiting, nausea, tremor, weakness, perspiration, irritability, hypersensitivity to visual and auditory stimuli, palpitations, tachycardia and postural hypotension. In severe and rare cases of withdrawal from high doses, patients may develop affective disorders or motor dysfunction: seizures, psychosis, agitation, confusion, and hallucinations. The time of onset of the withdrawal syndrome depends on the half-life of the drug and its active metabolites; the symptoms occur earlier and may be more severe with short-acting benzodiazepines. Others risk factors for withdrawal syndrome include prolonged use of the drug, higher dosage and abrupt cessation of the drug. Abuse: Benzodiazepines, have been abused both orally and intravenously. /Clorazepate dipotassium/

Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA_A) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

DROWSINESS IS MOST COMMON ADVERSE EFFECT. LESS COMMON UNTOWARD REACTIONS INCL DIZZINESS, VARIOUS GI COMPLAINTS, NERVOUSNESS, BLURRED VISION, DRY MOUTH, HEADACHE, & MENTAL CONFUSION. /DIPOTASSIUM SALT/

OTHER ADVERSE REACTIONS INCL INSOMNIA, TRANSIENT SKIN RASHES, FATIGUE, ATAXIA, GENITOURINARY COMPLAINTS, IRRITABILITY, DIPLOPIA, DEPRESSION, & SLURRED SPEECH. HYPOTENSION & ABNORMAL LIVER & KIDNEY FUNCTION HAVE ALSO BEEN REPORTED. /DIPOTASSIUM SALT/

/ADVERSE EFFECTS INCL/ ... EUPHORIA, CONSTIPATION, HICCUPS, ... SEVERE DIARRHEA & VOMITING HAVE BEEN REPORTED AFTER INGESTION OF 187.5 MG, BUT ANOTHER PATIENT EXPERIENCED ONLY TRANSIENT MILD CONFUSION AFTER APPARENT INGESTION OF 750 MG. /DIPOTASSIUM SALT/

A PARADOXICAL EFFECT IS AN/INCR IN ANXIETY, BUT SUCH RESPONSE CAN OCCUR IN PATIENT WHOSE NEED FOR MASTERY OF THEIR SITUATION IS DULLED BY SEDATIVE EFFECTS OF ANTIANXIETY AGENTS. /BENZODIAZEPINES/

For more Human Toxicity Excerpts (Complete) data for CLORAZEPATE (17 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

clorazepate

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

The serum half-life of clorazepate is approximately 2 days. Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about 40 to 50 hours.

PLASMA HALF-LIFE ... 53 HR ... .

PRIMARY METABOLITE, NORDIAZEPAM, ... PLASMA HALF-LIFE IS ABOUT 24 HR.

N-DIMETHYLDIAZEPAM, METABOLITE OF CHLORAZEPATE: MEAN HALF-LIFE 62 HR.

CLORAZEPATE ADMIN IM TO PREGNANT & NONPREGNANT WOMEN. ELIMINATION HALF-LIFE WERE 1.3 HR IN PREGNANT WOMEN & 2.0 HR IN NONPREGNANT WOMEN. ITS METABOLITE, NORDIAZEPAM, REACHED PEAK CONCN WITHIN 12 HR. HALF-LIFE OF ELIMINATION FOR METABOLITE WAS 180 IN PREGNANT & 60 HR IN NONPREGNANT WOMEN.

Elimination half-lives for metabolites: desmethyldiazepam (30-200 hr) and oxazepam (3-21 hr)

Clorazepate is metabolized in the liver and excreted mainly through urine. Following oral administration, clorazepate is decarboxylated by the gastric acid of the stomach before absorption. The primary metabolite, nordiazepam, is further metabolized by hydroxylation. The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p-hydroxynordiazepam and nordiazepam are also found in the urine.

CHLORAZEPATE IS PROBABLY CONVERTED TO N-DIMETHYL DIAZEPAM, WHICH IS THEN OXIDIZED TO OXAZEPAM. /CHLORAZEPATE/

PRIMARY METABOLITE /IS/ NORDIAZEPAM ... .

Following oral administration of clorazepate dipotassium, it appears that most of the drug is rapidly decarboxylated in the GI tract and is absorbed as desmethyldiazepam (nordiazepam). The rate of decarboxylation of clorazepate decreases as gastric pH increases. /Clorazepate dipotassium/

Clorazepate active metabolites in liver are desmethyldiazepam, and oxazepam; active substances in blood include desmethyldiazepam. /From table/

For more Metabolism/Metabolites (Complete) data for CLORAZEPATE (8 total), please visit the HSDB record page.

D51WO0G0L4

CLORAZEPIC ACID

Established Pharmacologic Class [EPC] - Benzodiazepine

Chemical Structure [CS] - Benzodiazepines

Clorazepic acid is a Benzodiazepine.

Drugs used to prevent SEIZURES or reduce their severity.

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here.

Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.

Clorazepate is a prodrug for nordiazepam, and this conversion occurs almost entirely before entering systemic circulation. Therefore, the pharmacokinetic parameters of clorazepate are based on nordiazepam concentrations. In healthy volunteers given a 20 mg oral dose of clorazepate, nordiazepam had a peak plasma level of 356 ng/mL, which was reached approximately 0.9 h after the administration of clorazepate. The plasma levels of nordiazepam increase proportionally with the clorazepate dose and show moderate accumulation with repeated administration. The oral bioavailability of clorazepate is 91%.

Clorazepate is mainly excreted through urine and feces. In two volunteers given 15 mg of [14C]-clorazepate, 62-67% of the radioactivity was excreted in the urine and 15-19% was eliminated in the feces within 10 days. On day 10, both subjects were still excreting about 1% of the [14C]-dose in the urine.

Following a single 20 mg intravenous dose, the volume of distribution of nordiazepam (active metabolite of clorazepate) was 1.24 L/kg.

Following a single 20 mg intravenous dose, nordiazepam (the active metabolite of clorazepate) had a total clearance of 0.24 mL/min/kg.

PRIMARY METABOLITE, NORDIAZEPAM, REACHES PEAK LEVELS IN PLASMA IN 1 HR; PLASMA HALF-LIFE IS ABOUT 24 HR.

PLASMA HALF-LIFE ELIMINATION COEF, CONCN, & APPARENT VOL OF DISTRIBUTION CALCULATED & MEAN VALUES WERE 53 HR, 0.0147 HR-1, 884 NG/ML, & 1.13 L/KG.