User talk:Fuzzform/ProjectBenzo

Links (not currently used) for diazepam:
 * General information
 * BehaveNet.com - Includes: DEA number, worldwide brand names, FDA approved uses.
 * Aesnet.org - American Epilepsy Foundation
 * nlm.nih.gov - NLM/NIH: MedlinePlus monograph page.
 * rch.org.au - Chlidren's Epilepsy Program
 * Kpemsc.org - EMS House of DeFrance
 * Volusia.org - Volusia County EMS Protocols


 * Veterinary usage
 * Diazepam For Veterinary Use - by Barbara Forney, VMD
 * PetEducation.com
 * FDA.gov - FOI page for Hoffman-La Roche's animal studies


 * Specific products
 * Intekom.com - Calmpose Injection (South African Electronic Package Inserts)
 * Visn21.med.va.gov - Diazepam rectal gel
 * Rxmed.com - Diazemuls®
 * Epilepsy.com - Diastat
 * Firstpharm.co.za - Micro diazepam injection


 * Other information
 * PslGroup.com - Diastat (Diazepam Rectal Gel) Does Not Produce Respiratory Depression In Epileptics, by Jill Stein
 * American Society of Health-System Pharmacists - Drug shortage news
 * OxfordJournals.org - Comparison of lorazepam/diazepam as initial treatment for status epilepticus
 * Inchem.org - Antidotes for Poisoning by Organophosphorus Pesticides: Diazepam

Side Effects

 * Inchem
 * Main adverse effects
 * The primary adverse effects are secondary to the pharmacologic action of enhanced CNS GABA activity. Cognitive and psychomotor abilities may be impaired at therapeutic doses. Additional adverse effects include dizziness and prolonged reaction time, motor incoordination, ataxia, mental confusion, dysarthria, anterograde amnesia, somnolence, vertigo, and fatigue. Dysarthria and dystonia occur much less frequently.
 * Paradoxical reactions of CNS hyperactivity occur rarely and manifest primarily as aggressive behaviour, irritability, and anxiety. Intravenous injection can produce local phlebitis and thrombophlebitis. Intra-articular injection may produce arterial necrosis.  Diazepam and other benzodiazepines can cause physical and psychological dependence when administered at high doses for prolonged periods of time.


 * Drugs.com
 * Side effects most commonly reported were drowsiness, fatigue and ataxia. Infrequently encountered were confusion, constipation, depression, diplopia, dysarthria, headache, hypotension, incontinence, jaundice, changes in libido, nausea, changes in salivation, skin rash, slurred speech, tremor, urinary retention, vertigo and blurred vision. Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported; should these occur, use of the drug should be discontinued.
 * Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy. Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after Valium therapy and are of no known significance.


 * RxList - Needs to be referenced if any info is used.
 * Side effects most commonly reported were drowsiness, fatigue and ataxia; venous thrombosis and phlebitis at the site of injection. Other adverse reactions less frequently reported include: CNS: confusion, depression, dysarthria, headache, hypoactivity, slurred speech, syncope, tremor, vertigo. GI: constipation, nausea. GU: incontinence, changes in libido, urinary retention. Cardiovascular: bradycardia, cardiovascular collapse, hypotension. EENT: blurred vision, diplopia, nystagmus. Skin: urticaria, skin rash. Other: hiccups, changes in salivation, neutropenia, jaundice. Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported; should these occur, use of the drug should be discontinued. Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after Valium therapy and are of no known significance.
 * In peroral endoscopic procedures, coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm and pain in throat or chest have been reported.
 * Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy.

Contraindications

 * Inchem
 * The primary absolute contraindication is an allergy to diazepam or other benzodiazepines, or the constituents of the parenteral formulation.
 * There are relative contraindications, which require more careful monitoring of patients after receiving diazepam, and stronger consideration of alternative drug therapy.
 * In these patients, the initial dose should be decreased:
 * Chronic obstructive respiratory disease
 * Myasthenia gravis
 * Close angle glaucoma
 * Poisoning by other CNS depressants
 * Geriatric/seriously ill patients
 * Liver failure
 * Kidney failure
 * Pregnancy
 * Breast feeding
 * Neonates and infants up to 6 months of age


 * Drugs.com
 * Diazepam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.


 * RxList
 * When used intravenously, the following procedures should be undertaken to reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, and, rarely, vascular impairment: the solution should be injected slowly, taking at least 1 minute for each 5 mg (1 mL) given; do not use small veins, such as those on the dorsum of the hand or wrist; extreme care should be taken to avoid intra-arterial administration or extravasation.
 * Do not mix or dilute Valium with other solutions or drugs in syringe or infusion flask. If it is not feasible to administer Valium directly IV, it may be injected slowly through the infusion tubing as close as possible to the vein insertion.
 * Extreme care must be used in administering Valium Injection, particularly by the IV route, to the elderly, to very ill patients and to those with limited pulmonary reserve because of the possibility that apnea and/or cardiac arrest may occur. Concomitant use of barbiturates, alcohol or other central nervous system depressants increases depression with increased risk of apnea. Resuscitative equipment including that necessary to support respiration should be readily available.
 * When Valium is used with a narcotic analgesic, the dosage of the narcotic should be reduced by at least one-third and administered in small increments. In some cases the use of a narcotic may not be necessary.
 * Valium Injection should not be administered to patients in shock, coma or in acute alcoholic intoxication with depression of vital signs. As is true of most CNS-acting drugs, patients receiving Valium should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.
 * Tonic status epilepticus has been precipitated in patients treated with IV Valium for petit mal status or petit mal variant status.
 * Usage in Pregnancy: An increased risk of congenital malformations associated with the use of minor tranquilizers (diazepam, meprobamate and chlordiazepoxide) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.
 * In humans, measurable amounts of diazepam were found in maternal and cord blood, indicating placental transfer of the drug. Until additional information is available, Valium Injection is not recommended for obstetrical use.
 * Although seizures may be brought under control promptly, a significant proportion of patients experience a return to seizure activity, presumably due to the short-lived effect of Valium after IV administration. The physician should be prepared to readminister the drug. However, Valium is not recommended for maintenance, and once seizures are brought under control, consideration should be given to the administration of agents useful in longer term control of seizures.
 * In highly anxious patients with evidence of accompanying depression, particularly those who may have suicidal tendencies, protective measures may be necessary. The usual precautions in treating patients with impaired hepatic function should be observed. Metabolites of Valium are excreted by the kidney; to avoid their excess accumulation, caution should be exercised in the administration to patients with compromised kidney function.
 * Since an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent and the availability of necessary countermeasures are recommended.


 * ElephantCare
 * Diazepam may cause significant thrombophlebitis. Too rapid of an injection of intravenous diazepam in small animals or neonates may cause cardiotoxicity secondary to the propylene glycol in the formulation. Intra-carotid artery injections must be avoided. Diazepam should be administered to patients in coma, shock or with significant respiratory depression very cautiously.
 * Diazepam has been implicated in causing congenital abnormalities in humans if administered during the first trimester of pregnancy. Infants born of mothers receiving large doses of benzodiazepines shortly before delivery have been reported to suffer from apnea, impaired metabolic response to cold stress, difficulty in feeding, hyperbilirubinemia, hypotonia, etc. Withdrawal symptoms have occurred in infants whose mothers chronically took benzodiazepines during preg­nancy. The veterinary significance of these effects is unclear, but the use of these agents during the first trimester of pregnancy should only occur when the benefits clearly outweigh the risks associated with their use. Benzodiazepines and their metabolites are distributed into milk and may cause CNS effects in nursing neonates.(ElephantCare)

Routes of administration
(Inchem) Clinically Used
 * Oral
 * This is the most frequent route of diazepam administration for therapeutic use as well as accidental poisonings, intentional overdoses, and abuse.
 * Parenteral
 * The preferred route of parenteral administration is intravenous. Indications include severe anxiety, excitation, alcohol and drug withdrawal syndrome, and seizures. The intramuscular route of diazepam administration should be avoided because absorption is erratic, and may be significantly delayed. The benzodiazepine lorazepam is more consistently absorbed from muscle, and should be used if intramuscular administration is required.
 * The intraosseous infusion of diazepam has been described as efficacious in the critically ill child, however, this route of administration is not commonly used.
 * Parenteral diazepam is irritating, and intravenous administration should be into a large peripheral vein. The rate of administration should be no faster than 5 mg per minute, and be followed by a saline flush to decrease local venous irritation.
 * Significant adverse effects of intravenous diazepam include coma, hypotension, bradycardia, and respiratory failure. Such effects usually occur in the setting of rapid administration, administration of excessive doses, or administration to high-risk patients (the elderly, infants, patients with chronic respiratory disease).
 * Other
 * Administration of diazepam rectally as either suppositories or solution results in good absorption. This route of administration is primarily used in convulsing children with no route of parenteral access.

Not Clinically Used
 * Inhalation
 * The administration of diazepam solution into the lungs via an endotracheal tube has been demonstrated to produce therapeutic serum diazepam concentrations in animal models.
 * Histologic examination of the lung demonstrated pneumonitis. These results suggest adequate absorption, however, the increased pulmonary toxicity indicates that this route should not be used in clinical practice.
 * Dermal
 * Diazepam is absorbed through the skin, however, this route of administration is not used clinically.

Pharmacology
The toxic and therapeutic effects of diazepam are a result of its effect on CNS GABA activity. GABA (gamma-aminobutyric acid) is an important inhibitory neurotransmitter which mediates pre- and post-synaptic inhibition in all regions of the central nervous system.(Inchem.org)

Diazepam and the other benzodiazepines appear to either enhance or facilitate GABA activity by binding to the benzodiazepine receptor, which is part of a complex including an aminobutyric acid receptor, benzodiazepine receptor, and barbiturate receptor. Binding at the complex results in increased CNS inhibition by GABA. The anticonvulsant and other effects of diazepam are believed to be produced by a similar mechanism, possibly involving various subtypes of the receptor.(Inchem.org)

The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNS are depressed by diazepam and other benzodiazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action is unknown, but postulated mechanisms include: antagonism of serotonin, increased release of and/or facilitation of gamma-aminobutyric acid (GABA) activity, and diminished release or turnover of acetylcholine in the CNS. Benzodiazepine specific receptors have been located in the mammalian brain, kidney, liver, lung, and heart. In all species studied, receptors are lacking in the white matter.(ElephantCare)

Pharmacodynamics
(Inchem) The pharmacodynamic effects of diazepam are also produced primarily by its actions with the result being enhancement of the inhibitory effects of GABA on the CNS. Two different zones have been described for the benzodiazepine binding at receptor sites and they have been classified as type I (chloride independent) and type II (chloride dependent. Type I receptor stimulation is believed to be responsible for anxiolysis, and Type II receptors responsible for sedation and ataxia.

Skeletal muscle relaxation is most likely secondary to the CNS effects of diazepam, and may also involve inhibition of a presynaptic neural conduction at GABA mediated sites in the spinal chord. It is unclear how diazepam produces amnesia. Similar to other sedative hypnotic drugs, preanesthetic doses of diazepam produce anterograde amnesia in the presence of therapeutic concentrations of diazepam, probably by impairing the establishment of the memory trace in the CNS. It has been suggested that diazepam may have some anticholinergic effects, however, these are not clearly defined, and not generally of clinical importance. Grade IV come has, however, been reversed by physostigmine in a case of severe nitrazepam poisoning, confirmed by drug screening. The serum nitrazepam concentration was 6 µmol/L.

Pharmacokinetics
(Inchem)
 * Absorption by route of administration
 * Oral - Diazepam is absorbed rapidly following oral administration; with peak plasma concentrations generally being achieved within 1.0 hour (range 0.08 to 2.5 hours). The absorption rate is slowed by food and antacids. Absorption is almost complete with bioavailability close to 1.0.
 * Parenteral
 * Intramuscular - Absorption is poor and erratic after intramuscular injection; plasma levels attained are equal to 60% of those reached after the same oral dose. The use of intramuscular diazepam has been described, however, this route should only be considered when other routes of administration or benzodiazepines are not available.
 * Intravenous - Blood concentrations of 400 ng/mL and 1,200 ng/mL were measured 15 minutes after intravenous bolus doses of 10 and 20 mg, respectively (Hillestead et al., 1974). Chronic administration of daily doses ranging from 2 mg to 30 mg result in plasma diazepam concentrations of 20ng/mL to 1,010ng/mL, and concentrations of desmethyldiazepam, an active metabolite, of 55 ng/mL to 1,765 ng/mL.

The volume of distribution has been calculated to range from 0.7 to 2.6 L/kg. In humans, the plasma protein binding of diazepam is greater than 95%. The concentration in the CSF appears to approximately correlate with the plasma free fraction. Patients with low serum albumin concentrations may have greater CNS effects secondary to an increased free fraction of diazepam.
 * Distribution by route of exposure

Following intravenous administration, diazepam concentrations can be described by a 2 compartment kinetic model. An initial rapid decline in serum concentrations associated with distribution into tissue, is followed by a slower decline reflecting the terminal elimination half-life.

The terminal elimination half-life of diazepam ranges from approximately 24 hours to more than two days. With chronic dosing, steady state concentrations of diazepam are achieved between 5 days to 2 weeks. The half-life is prolonged in the elderly and in patients with cirrhosis or hepatitis. It is shortened in patients taking drugs which induce hepatic enzymes, included anticonvulsants. The active metabolite desmethyldiazepam has a longer half-life than diazepam, and takes longer to reach steady state concentrations.
 * Biological half-life by route of exposure

A sample of 48 healthy male volunteers ranging in age from 18 to 44 years demonstrated variable pharmacokinetic parameters. This demonstrates the need for further understanding of the variables which determine diazepam absorption, distribution, metabolism, and elimination.

The hepatic cytochrome enzyme isozyme responsible for S- mephenytoin hydroxylation polymorphism is most likely the hepatic enzyme species responsible for diazepam metabolism. Hepatic n-demthylation results in the formation of the active metabolite desmethyldiazepam (also known as nordiazepam). This metabolite is hydroxylated to form oxazepam, which is conjugated to oxazepam glucuronide. A minor active metabolite is temazepam. The main active substances found in blood are diazepam and desmethyldiazepam, because oxazepam and temazepam are conjugated and excreted at almost the same rate as they are generated.
 * Metabolism

A two-compartment open model is usually used to describe elimination kinetics of diazepam and plasma clearance of 26 to 35 mL/min after a single intravenous dose has been reported. Urinary excretion of diazepam is primarily in the form of sulphate and glucuronide conjugates, and accounts for the majority of the ingested dose. There is some evidence that the disposition of diazepam is slowed by chronic dosing and by plasma desmethyldiazepam levels.
 * Elimination and excretion

There is some evidence for species differences in biliary excretion. However, studies suggest that biliary excretion of diazepam is probably clinically unimportant in man.

Toxicity

 * Human data
 * Adults - There is no specific dose associated with death. In the few documented fatal cases doses have not been known with certainty and other factors complicated the clinical presentation. In a survey of 914 benzodiazepine related deaths in North America, only 2 cases were associated with diazepam alone, in the remainder other drugs were present which either contributed to or caused death. After the intentional ingestion of doses of 450 to 500 mg, and 2000 mg in two cases, patients recovered without specific therapy within 24 to 48 hours. Toxicity associated with rapid intravenous injection is not dose related, and may occur at therapeutic doses.(Inchem)
 * Children - As with adults, no specific diazepam dose is associated with severe toxicity. A range of 4 to 5 mg/kg has been described as producing clinical toxicity. Cases involving the ingestion of 20mg to 150mg have resulted in complete recovery.
 * The neonate is very sensitive to the effects of benzodiazepines.(Inchem)


 * Animal data
 * LD50 (oral) rat  1200 mg/kg (ElephantCare)
 * LD50 (oral) dog  1000 mg/kg
 * LD50 (oral) mice 700  mg/kg

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.(Inchem)

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 apnoea.(Inchem)

When administered alone, diazepam overdoses are generally limited to significant CNS depression (confusion, coma, decreased reflexes, etc). Hypotension, respiratory depression, and cardiac arrest have been reported in human patients, but apparently are quite rare.(ElephantCare)

Treatment of acute toxicity consists of standard protocols for removing and/or binding the drug in the gut if taken orally, and supportive systemic measures. The use of analeptic agents (CNS stimulants such as caffeine) are generally not recommended.(ElephantCare)