Benzodiazepine cardiovascular effects

Benzodiazepines are used as hypnotics because they have the ability to increase total sleep time. They demonstrate minimal cardiovascular effects, but do have the ability to increase heart rate and decrease cardiac output. Most CNS depressants, including the benzodiazepines, exhibit the ability to relax skeletal muscles. Clozapine, a dibenzodiazepine, is used in the treatment of schizophrenia. It has both sedative and antipsychotic actions, and is the only FDA-approved medication indicated for treatment-resistant schizophrenia, and for reducing the risk of suicidal behavior in patients with schizophrenia. This drug can have potentially life-threatening side effects, but appears to have no abuse potential and will not be considered further. 

CARDIOVASCULAR SYSTEM The cardiovascular effects of benzodiazepines are minor in normal subjects except in severe intoxication. In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate. 

Other adverse cardiovascular and respiratory effects Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, start treatment with 12.5 mg once or twice daily (see Warnings). Because collapse, respiratory arrest, and cardiac arrest during initial treatment have occurred in patients receiving benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug. 

Recovery is sufficiently rapid with most intravenous drugs to permit their use for short ambulatory (outpatient) surgical procedures. In the case of propofol, recovery times are similar to those seen with sevoflurane and desflurane. Although most intravenous anesthetics lack antinociceptive (analgesic) properties, their potency is adequate for short superficial surgical procedures when combined with nitrous oxide or local anesthetics, or both. Adjunctive use of potent opioids (eg, fentanyl, sufentanil or remifentanil see Chapter 31) contributes to improved cardiovascular stability, enhanced sedation, and perioperative analgesia. However, opioid compounds also enhance the ventilatory depressant effects of the intravenous agents and increase postoperative emesis. Benzodiazepines (eg, midazolam, diazepam) have a slower onset and slower recovery than the barbiturates or propofol and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines (eg, midazolam) can be used to provide anxiolysis, sedation, and amnesia when used as part of an inhalational, intravenous, or balanced anesthetic technique. 

Trazodone Hydrochloride Trazodone overdose causes severe toxic effects. These effects are severe if taken along with benzodiazepines or alcohol. Trazodone interacts with MAOIs, cardiovascular drugs, CNS depressants, and antiepileptics. 

If undesired effects are noted in time, seizure activity can be treated with benzodiazepines or thiobarbiturates (see Ch. 9) and cardiovascular collapse can be treated symptomatically (volume expansion, adrenergic agonists, oxygen, sodium bicarbonate see Ch. 12). 

The toxic effects of an overdosage result from profound central depression and may include coma, respiratory and cardiovascular depression with hypertension, and shock leading to renal failure. Withdrawal of the drug is more frequently a problem with barbiturates than with benzodiazepines. Withdrawal of barbiturates leads to rapid eye movement (REM) sleep rebound and rebound insomnia. 

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. 

The pharmacology of benzodiazepine derivatives differs significantly from that of the neuroleptics, in that the benzodiazepines have no psychoplegic (antipsychotic) activity and cause no extrapyramidal, autonomic, or endocrine side effects. In addition, unlike the neuroleptics, which lower the seizure threshold, these substances are anticonvulsants. In addition, they are anxiolytics, muscle relaxants, and mild sedatives. Although the benzodiazepine derivatives do not produce pronounced autonomic or CV side effects, they can reduce or block the emotionally induced changes in cardiovascular functions, probably through actions on the limbic system. 

The barbiturates are derivatives of 2,4,6-trioxohexahydropyrimidine (Table 16-3) that reversibly depress the activity of all excitable tissues. The CNS is exquisitely sensitive, and even when barbiturates are given in anesthetic concentrations, direct effects on peripheral excitable tissues are weak. However, serious deficits in cardiovascular and other peripheral functions occur in acute barbiturate intoxication. Except for a few specialized uses, barbiturates have been replaced by the much safer benzodiazepines. 

The combined regimen is safe and effective, although severe cardiovascular or respiratory adverse effects may occur with high doses of clozapine when combined with diazepam and lorazepam. There are no reports of pharmacokinetic interactions between olanzapine and benzodiazepines (studied mainly with diazepam). 

Overdosage Overdosage causes severe respiratory and cardiovascular depression these potentially lethal effects are more likely to occur with alcohols, barbiturates, and carbamates than with benzodiazepines. Management of intoxication requires maintenance of a patent airway and ventilatory support. Flumazenil may reverse CNS depressant effects of benzodiazepines, zolpidem, and zaleplon but has no beneficial actions in overdosage with other sedative-hypnotics. 

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