Sedative-hypnotics toxicity

Uni 1ke other drugs of abuse, the diagnosis of PCP intoxication is often difficult because of the wide spectrum of clinical findings that occurs with this drug. PCP toxicity sometimes can be mistaken for delirium tremens, acute psychiatric illness, sedative/ hypnotic overdosage, amphetamine intoxication, or sedative/ hypnotic withdrawal syndromes. 

Patients with the lethargy pattern of PCP toxicity may be clinically indistinguishable from patient with mild sedative/hypnotic intoxication, although hypertension and grand mal seizures which may occur with PCP intoxication, are not expected with sedative/ hypnotic overdose. The remaining minor patterns are differentiated as follows. 

Since GABA-ergic synapses are confined to neural tissues, specific inhibition of central nervous functions can be achieved for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a specific antidote (see below). 

The sedative hypnotic ethchlorvynol has approximately the same activity and toxicity as phenobarbital however, its hypnotic effect develops and dissipates qnicker. It is nsed mnch less than benzodiazepines in treating insomnia for a nnmber of reasons. 

Exposure to toxicants can vary, producing what is known as acute or chronic poisoning. Poisoning can also be classified according to the intent of use. Poisoning can either be suicidal (non-accidental) or accidental in nature. Recreational poisoning, such as substance abuse, can be a source of harmful intoxication and, in some cases, can lead to addiction and withdrawal symptoms. Intentional harm is observed when there is criminal doping with sedative-hypnotic medicines, often associated with robberies. 

Anxiolytics and Sedative-Hypnotics. Because of their large therapeutic index, measurement of anxiolytic or sedative-hypnotic serum concentrations is not usually necessary in clinical practice, unless abuse, overdose, or inadvertent toxicity are suspected. Some data indicate that plasma alprazolam levels of 40 ng/mL may be required to manage panic disorder ( 51) (see the sections Adverse Effects of Anxiolytics and Adverse Effects of Sedative-Hypnotics in Chapter 12). 

At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. 

CLINICAL TOXICOLOGY OF SEDATIVE-HYPNOTICS Direct Toxic Actions... 

Buspirone Mechanism uncertain Partial agonist at 5-HT receptors but affinity for D2 receptors also possible Slow onset (1-2 weeks) of anxiolytic effects t minimal psychomotor impairment—no additive CNS depression with sedative-hypnotic drugs Generalized anxiety states Oral activity forms active metabolite short half-life Toxicity Tachycardia paresthesias t gastrointestinal distress Interactions CYP3A4 inducers and inhibitors... 

Corydalis yanhusuo W. T. Wang ex Z. Y. Su et C. Y. Wu China d-corydaline, corydalis, dl-tetrahydropalmatine, crybulbine, alpha-allocryptopine, tetrahydrocoptisine, corydalamine, tetrahydrocolumbamine, protopine, coptisine, dehydrocorydaline, columbamine, dehydrocorydalmine.33 Overdosage is toxic. Analgesic, sedative, hypnotic, synergistic, increase coronary flow. 

The first sedative-hypnotic, or minor tranquilizer, bromide, originated in the 1860s. Bromides are long-acting sedatives that were rarely used past the turn of the nineteenth century however, bromide can still be found in Bromo Seltzer. The bromides are gastric irritants with a narrow safety margin and may cause a chronic toxicity known as bromism. 

At high doses, both the major and minor tranquilizers are severely toxic and may cause coma, respiratory arrest, convulsions, acute renal failure, speech impairment, or death. However, at therapeutic doses, the neuroleptics have been associated with more severe, longterm side effects than the sedative-hypnotics. 

When insomnia is not caused by, or fails to respond to treatment for, another medical or psychiatric condition in dementia, pharmacological treatment with sedating agents may be considered as symptomatic therapy. Controversies regarding the use of sedating medications in demented patients revolve around issues of efficacy and issues of potential toxicity, neither of which have been resolved by appropriately comprehensive empirical study. There is evidence, however, that sedative-hypnotics as a class may be inappropriately prescribed or overprescribed for demented patients. 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

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