Sedative-hypnotic drugs barbiturates

The barbiturates were widely used as sedative-hypnotic drugs. Barbital was introduced as a drug in 1903. The method of synthesis for thousands of its analogs has undergone little change. Urea reacts with various derivatives of malonic acid, usually a diethyl ester of a dialkyl substituted malonic acid. This is a classic example of a nucleophilic acyl substitution. A derivative of ammonia reacts with esters to form an amide, only in this case a cyclization to a strainless six-membered ring results because of the proximity of the bifunctionality. 

Another chemical class of sedative-hypnotic drugs, the barbiturates, also binds to receptors associated with the GABA-chloride ionophore, but these drugs appear to prolong rather than intensify GABA s effects. Fig. 24.4 shows the presumed drug receptor-GABA-chloride ionophore relationship. 

Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic actions of sedative-hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions. In experimental animal models, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the... 

An understanding of common mechanisms of death due to poisoning can help prepare the care-giver to treat patients effectively. Many toxins depress the central nervous system (CNS), resulting in obtundation or coma. Comatose patients frequently lose their airway protective reflexes and their respiratory drive. Thus, they may die as a result of airway obstruction by the flaccid tongue, aspiration of gastric contents into the tracheobronchial tree, or respiratory arrest. These are the most common causes of death due to overdoses of narcotics and sedative-hypnotic drugs (eg, barbiturates and alcohol). 

Overdosage with ethanol and sedative-hypnotic drugs (eg, benzodiazepines, barbiturates, 7-hydroxybutyrate [GHB], carisoprodol [Soma] see Chapters 22 and 23) occurs frequently because of their common availability and use. 

Thiopental is a short-acting barbiturate commonly used for induction of anesthesia. The general pharmacology of the barbiturates is discussed in Chapter 22 Sedative-Hypnotic Drugs. 

Thiopental may reduce hepatic blood flow and glomerular filtration rate, but it produces no lasting effects on hepatic and renal function. Barbiturates may exacerbate acute intermittent porphyria by inducing the synthesis of hepatic ALA synthase (see Chapter 22 Sedative-Hypnotic Drugs). Thiopental has precipitated porphyric crisis when used as an induction agent in susceptible individuals. 

The researchers Joseph von Mering and Emil Fischer, a student of von Baeyer, developed the first barbiturate drug to be marketed. Fischer produced 5.5-diethylbarbituric acid, a hypnotic (medication to help patients sleep) and sedative (medication to relax people with constant nervousness and anxiety). This sedative/hypnotic drug was known by the trade names Barbital, Veronal, and Dorminal. Barbital proved to be a more effective sedative/hypnotic agent and replaced the class of drugs, sedative bromides, which were used at the time.14... 

Sedative-hypnotic drugs and anxiolytic drugs are CNS depressants that are used medically to reduce anxiety and/or induce sleep. They may also be used as anticonvulsants. Phenobarbital, for example, is often the maintenance drug of choice for seizure-prone individuals. In general, the sedative-hypnotic family of drugs includes alcohol, barbiturates, benzodiazepines, and such barbiturate-like drugs as chloral hydrate, glutethi-mide, meprobamate, and methaqualone. 

As noted, the barbiturates once were used extensively as sedative-hypnotic drugs, but except for certain specialized uses they now have been replaced by the safer benzodiazepines. Short-acting barbiturates still are used to produce anesthesia. Other current uses include emergency treatment of convulsions and prevention of seizures in persons with certain types of epilepsy (Perrine, 1996). 

S.2.2.2 Barbiturates. A major event in the field was the launching of barbital (6,5-dieth-ylbarbituric acid) in 1903 and phenobarbital (5-ethyl-5-phenylbarbituricacid)in 1912. The barbiturates dominated the field for nearly 50 years, until the launch of Librium (chlordiaz-epoxide) in 1960, the first of the benzodiazepine class drugs. Benzodiazepines completely overtook the barbiturates and had become The dominant class of sedative hypnotic drugs until the launch of retrocyclic sedative-hypnotics. 

Benzodiazepines show less tendency to tolerance and dependency than other older sedative-hypnotic drugs, especially barbiturates. Also, benzodiazepines produce less abuse potential. 

Explain why benzodiazepines have a much safer dose-response curve than other sedative hypnotic drugs (e.g., barbiturates). 

Drug interactions sedatives/hypnotics, opioids, barbiturates, antihistamines, alcohol, neuroleptics, anticonvulsants, and SSRIs can all enhance the sedative effects of BNZs. 

Other sedative-hypnotic medications, such as barbiturates, may play a useful role in severe withdrawal from this group of drugs. For example, in a case series of GBL withdrawal, use of intravenous pentobarbital in the range of 1-2 mg/kg/hour lowered the total requirement for intravenous lorazepam (Sivilotti et al. 2001). Antipsychotic medications are often used to reduce psychotic agitation. However, because antipsychotic medications lower the seizure threshold and may contribute to loss of central control of temperature leading to hyperthermia or neuroleptic malignant syndrome (NMS), they are not indicated as first-line medications for GHB withdrawal delirium (Dyer and Roth 2001 McDaniel and Miotto 2001 Sharma et al. 2001). If anti-... 

Barbiturate The family name for a group of drugs with anticonvulsant, anaesthetic and sedative-hypnotic properties. Examples include amylobarbitone and pheno-barbitone. The problem of dependence and the introduction of safer benzodiazepine alternatives has resulted in a marked reduction in their clinical use. 

---