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Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.[4] Diazepam is used to treat a wide range of conditions and is one of the most frequently prescribed benzodiazepines.
BenzodiazepineDiazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the endogenous GABA molecule.[5][6]The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity. Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.[5][7]
HistoryDiazepam was the second benzodiazepine to be invented by Leo Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is five times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.[8] The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).[9] Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills.[8] In 1966, The Rolling Stones released the song "Mother's Little Helper," which is about a mother needing the "little yellow pill" to get through the day.[10] While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.[11] Diazepam is also found in nature. Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.[12] PharmacokineticsDiazepam can be administered orally, intravenously, intramuscularly, or as a suppository.[13] When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1-5 minutes for IV administration and 15-30 minutes for IM administration. The duration of the diazepam's main pharmacological effects is 15 minutes to 1 hour for both routes of administration.[14] Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.[1][15] Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.[13][15] Diazepam is metabolised in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.[1][15] Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours.[15] Most of the drug is metabolised; very little diazepam is excreted unchanged.[13] In humans, the protein binding of diazepam is around 98.5%.[1] IndicationsDiazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia prior to certain medical procedures (e.g. endoscopy).[1] Diazepam is rarely used as a primary drug for the long-term treatment of epilepsy. This is due to the fact that tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose.[13] Diazepam has a broad spectrum of indications (most of which are off-label), including:
Veterinary uses
DosageDosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.[13] Typical dosages for healthy adults range from 2mg per dose to 30mg per dose, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.[7] AvailabilityDiazepam is supplied in the following forms:
Side effectsDiazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include:
Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence.[23][24][25] If these side effects are present, diazepam treatment should be immediately terminated. Up to 30% of individuals treated on a long-term basis develop a form of dependence known as "low-dose-dependence." These patients do not develop a tolerance, and do not need increasingly large doses to experience the euphoric side effects of the drug.[citation needed] Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.[7] During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[26] Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death. Organic changes such as leukopenia[27] and liver-damage of the cholostatic type with or without jaundice (icterus) have been observed in a few cases.[citation needed] InteractionsIf diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.[7] Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.[13] Agents which have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.[13]
ContraindicationsUse of diazepam should be avoided, when possible, in individuals with the following conditions:
Special caution needed
Patients at a high risk for abuse and dependenceDiazepam can lead to physiological tolerance, and psychological and/or physical dependence[citation needed]. At a particularly high risk for diazepam misuse, abuse, and dependence are:
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.[7][33] The American Society of Addiction Medicine has policy indicating that patients with addictive disease should not be prescribed benzodiazepines such as diazepam. OverdoseAn individual who has consumed too much diazepam will display one or more of the following symptoms[7][35]:
Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate®). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.[13][9][7][35] The oral LD50 (lethal dose in 50% of the population) of diazepam is 720mg/kg in mice and 1240mg/kg in rats.[7] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 2000 and 500 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced important complications in spite of having high concentrations of diazepam and its metabolites—desmethyldiazepam, oxazepam, and temazepam—according to samples taken in the hospital and as follow-up.[36] Overdoses of diazepam with alcohol and/or other depressants may be fatal.[9] Recreational useGenerally, diazepam is not used as a recreational drug as frequently as alprazolam or flunitrazepam. Diazepam is often found as an adulterant in heroin.[37] This may be because diazepam greatly amplifies the effects of opioids. Sometimes diazepam is used by stimulant abusers to 'come down' and sleep and to help control the urge to binge[38] and also by users of LSD and other hallucinogens to help ease their trip without unpleasant after-effects.[citation needed] Legal statusInternationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[39] Physical propertiesDiazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5°C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.[13] Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.[15] Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes. It can absorb into plastic bags and tubing used for intervenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.[15]
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