Benzodiazepin intoxication

The most important fluorinated benzodiazepine, flurazepam (21) has found considerable use (and abuse) as a hypnotic [I4 Flumazenil (22) is a fast-acting antidote in the treatment of benzodiazepine intoxication and m the reversal of the CNS effects of benzodiazepines dunng anesthesia [f<5,19]... 

With any hypnotic, the risk of suicidal overdosage cannot be ignored. Since benzodiazepine intoxication may become life-threatening only when other central nervous depressants (ethanol) are taken simultaneously and can, moreover, be treated with specific benzodiazepine antagonists, the benzodiazepines should be given preference as sleep remedies over the all but obsolete barbiturates. 

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). 

However, adverse effects also include dependence and thus drug abuse. Tolerance develops within 3 months for anxiety. However considerable interindividual variability exists for the development of this tolerance. Benzodiazepines have very little effect on respiration which is not seen with sedative doses. In cases involving benzodiazepine intoxication, respiratory assistance has only been needed in patients who had also taken another CNS depressants. 

Stahl MM, Saldeen P, Vinge E. Reversal of fetal benzodiazepine intoxication using flumazenil. BrJ Obstet Gynaecol 1993 100 185-188. 

FIGURE 13-33. Acute withdrawal of benzodiazepines in a benzodiazepine-dependent individual. If benzodiazepines are suddenly stopped in a patient who is tolerant to them and dependent on them, benzodiazepine receptors will experience this as an acute deficiency at their binding sites. Thus, the presence of desensitized benzodiazepine receptors actually worsens the impact of benzodiazepine discontinuation. The brain, which is used to too much benzodiazepine at its receptors, is suddenly starved for benzodiazepine. Therefore, the brain experiences the reverse of benzodiazepine intoxication, namely, dysphoria and depression instead of euphoria anxiety and agitation instead of tranquility and lack of anxiety insomnia instead of sedation and sleep muscle tension instead of muscle relaxation and at worst, seizures instead of anticonvulsant effects. These actions continue either until benzodiazepine is replaced or until the receptors readapt to the sensitivity they had prior to excessive benzodiazepine use. Alternatively, one can reinstitute benzodiazepines but taper them slowly, so that the receptors have time to readapt during dosage reduction, and withdrawal symptoms are prevented. 

Flumazenil (Romazicon) is a benzodiazepine antagonist that can reverse the CNS depressant effects of these agents. It should be used with caution in acute intentional benzodiazepine overdoses. Because acute benzodiazepine overdoses generally result in only mild toxicity, it has limited clinical utility in this setting. Flumazenil s use in the acute benzodiazepine intoxicated patient may lead to an unnecessarily long observation period after fumazenil s infusion. This observation is necessary to be certain that reoccurrence of benzodiazepine toxic effects do not occur... 

Despite their widespread use, abuse of benzodiazepines is relatively low and is more likely to occur in individuals who abuse other drugs or alcohol. However, as a result of their widespread use, benzodiazepine intoxication is not uncommon. Benzodiazepine CNS toxicity is generally mild to moderate and may be manifest as drowsiness, slurred speech, ataxia, and occasionally coma. More serious toxic effects causing respiratory depression or cardiovascular compromise are infrequent. Indeed, few well-documented deaths have been attributed to benzodiazepine intoxication alone. 

Flumazenil [78755-81-4], benzodiazepine antagonist, treatment of benzodiazepine intoxication, 121. Phosgene is used to prepare the key intermediate 6-fluoroisatoic anhydride 118 [90-93]. 

Benzodiazepines produce few pathognomonic signs of intoxication. Sedation, behavioral disinhibition, and occasional paradoxical excitation may all be... 

Low K, Crestani F, Keist R, et al Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134, 2000 Luddens H, Pritchett DB, Kohler M, et al Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346 648—651, 1990 LupoloverY, Safran AB, Desangles D, etal Evaluation ofvisual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol 27 505-507, 1984 Maher JF, Schreiner GE, Westervelt FB Jr Acute glutethimide intoxication 1. clinical experience (twenty-two patients) compared to acute barbiturate intoxication (sixty-three patients). Am J Med 33 70-82, 1962 Marks J The Benzodiazepines Use, Overuse, Misuse, Abuse. Baltimore, MD, University Park Press, 1978... 

Seizure history ° Chronic benzodiazepine use ° Concomitant TCA intoxication... 

Cocaine or stimulant intoxication may require administration of a small dose of a short-acting benzodiazepine (e.g., lorazepam 1 to 2 mg) for agitation or severe anxiety. Antipsychotics (e.g., haloperidol 2 to 5 mg) should be used only if psychosis is present. If hyperthermia is present, initiate cooling measures. 

Secobarbital exhibits the same pharmacologic properties as other members of the barbiturate class. Most nonmedical use is with short-acting barbiturates, such as secobarbital. Although there may be considerable tolerance to the sedative and intoxicating effects of the drug, the lethal dose is not much greater in addicted than in normal persons. Tolerance does not develop to the respiratory effect. The combination of alcohol and barbiturates may lead to fatalities because of their combined respiratory depressive effects. Similar outcomes may occur with the benzodiazepines. Severe withdrawal symptoms in epileptic patients may include grand mal seizures and delirium. 

Benzodiazepine (BZ) intoxication is manifested as slurred speech, poor coordination, swaying, drowsiness, hypotension, nystagmus, and confusion. 

Benzodiazepines should be used with caution in dementia patients. Used improperly, they can disinhibit patients and worsen behavior, or they can accumulate and lead to a state of intoxication. To minimize the risk of accumulation, benzodiazepines that are easily metabolized are preferred for elderly patients. Specifically, lorazepam (Ativan) and oxazepam (Serax) are easier for elderly patients to tolerate than other benzodiazepines. 

Drugs used to counteract drug overdosage are considered under the appropriate headings, e.g., physostigmine with atropine naloxone with opioids flu-mazenil with benzodiazepines antibody (Fab fragments) with digitalis and N-acetyl-cysteine with acetaminophen intoxication. 

---