Benzodiazepines administration

Miller LG, Greenblatt DJ, Barnhill JG, et al Chronic benzodiazepine administration, I tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. J Pharmacol Exp Ther 246 170-176, 1988a... 

Hypoventilation Monitor patients who have received flumazenil for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) for resedation, respiratory depression or other residual benzodiazepine effects for an appropriate period (120 minutes or less) based on the dose and duration of effect of the benzodiazepine employed, because flumazenil has not been established as an effective treatment for hypoventilation due to benzodiazepine administration. Flumazenil may not fully reverse postoperative airway problems or ventilatory insufficiency induced by benzodiazepines. In addition, even if flumazenil is initially effective, such problems may recur because the effects of flumazenil wear off before the effects of many benzodiazepines. 

The popularity of the benzodiazepines as an anesthetic supplement in cardiac surgery is related to their amnesic potential. They can ensure unawareness during the initial period, when the anesthetics are being diluted in the fluid of the bypass circuit. Lorazepam is often chosen for this purpose because it is longer acting and more potent than either midazolam or diazepam. Benzodiazepine administration may cause amnesia even when used in doses that do not produce unconsciousness. Antegrade amnesia may occur with the doses that are used to relieve preoperative anxiety. 

Since most of the benzodiazepines do undergo biotransformation, it is possible that changes in liver function may alter the duration of the therapeutic effect produced by these drugs. Despite the fact that few clinical studies have demonstrated serious toxicities associated with benzodiazepine administration in individuals with compromised liver function, prudence in the use of... 

Less common adverse effects include blurred vision, hallucinations, and paradoxical reactions consisting of excitement, stimulation, and hyperactivity. Also, a variety of gastrointestinal complaints occur, and blood dyscrasias have been reported, but these are rare. Benzodiazepine administration during pregnancy, delivery, or lactation has the potential to have adverse effects on the fetus or newborn. 

Ross J, Darke S Hall W (1997). Transitions between routes of benzodiazepine administration among heroin users in Sydney. Addiction, 92, 697-705... 

Miller LG, Greenblatt DJ, Roy RB, et al. Chronic benzodiazepine administration II. Discontinuation syndrome is associated with upregulation of aminobutyric acid receptor complex binding and function. J Pharmacol Exp Ther 1987 246 177-182. 

Consistent with their depressant and sedative effects, benzodiazepines administered acutely typically decrease CFF threshold.119 120 Specifically, significant decreases have been reported for 1 mg alprazolam, 10 mg diazepam, and 15 mg quazepam 121 4 to 11 mg midazolam 122 7.5 to 50 mg oxazepam 123 1 and 2 mg lorazepam 124 and 0.5 mg triazolam and 1 mg flunitrazepam.120 As is evident, this effect on CFF threshold was observed at therapeutic doses of each drug, and when multiple doses were tested, the effect was dose-related. However, there are reports of acute, therapeutic doses of diazepam (5 mg)125 and lorazepam (1 and 2 mg)125,126 having no effect on CFF threshold. One study investigating numerous benzodiazepines120 reported next-day impairment after acute doses of triazolam (0.5 mg) and lormetazepam (1 to 2 mg). No studies were found that examined the effect of chronic benzodiazepine administration on CFF threshold. 

When benzodiazepines are used or abused chronically, they may cause adaptive changes in benzodiazepine receptors such that their power to modulate GABA-A receptors in response to a benzodiazepine decreases with time (Fig. 13—32). These patients may become irritable or anxious or even experience panic attacks if they suddenly stop taking the drugs (Fig. 13—33). This shift in benzodiazepine abusers to a desensitized receptor (Fig. 13—32) may manifest itself as the need to take higher doses of benzodiazepines to get high. This receptor desensitization is most likely to be uncovered once chronic abusive benzodiazepine administration is discontinued, particularly if discontinuation is sudden (Fig. 13-33). This desensitized receptor worsens the impact of benzodiazepine discontinuation because the brain, which is... 

Flumazenll [floo MAZ eh nill] is a GABA receptor antagonist that can rapidly reverse the effects of benzodiazepines. The drug is available by IV administration only. Onset is rapid but duration is short, with a half-life of about one hour. Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine. Administration of flumazenil may precipitate withdrawal in dependent patients or may cause seizures if a benzodiazepine is used to control seizure activity. Dizziness, nausea, vomiting, and agitation are the most common side effects. 

Buchsbaum, M.S., Hazlett, E., Sicotte, N., Stein, M., Wu, J. and Zetin, M. (1985) Topographic EEG changes with benzodiazepine administration in generalized anxiety disorder. Biological Psychiatry, 20, 832—842. 

Because benzodiazepines do not significantly induce the synthesis of hepatic CYPs, chronic benzodiazepine administration usually does not result in the accelerated metabolism of benzodiazepines or other substances. Cimetidine and oral contraceptives inhibit N-dealkylation and 3-hydroxylation of benzodiazepines, as do ethanol, isoniazid, and phenytoin to a lesser degree. These reactions usually are reduced to a greater extent in elderly patients and in patients with chronic liver disease than are those involving conjugation. 

A water-soluble phosphine derivative of diazepam allows for more convenient parenteral tranquilizer therapy and avoids some complications due to blood pressure lowering caused by the propylene glycol medium otherwise required for administration. Fosazepam (82) is prepared from benzodiazepine by sodium hydride-mediated alkylation with chioromethyldimethyl phosphine... 

Mice lacking the 8 subunit, which is mainly expressed in cerebellum and thalamus, display an attenuation of ssatrighting reflex time following the administration of the neurosteroids, alphaxalone and pregnanolone, while the responses to propofol, etomindate, ketamine and the benzodiazepine midazolam were unaffected. This demonstrates the role of GABAa receptors containing the 8 subunit for neurosteroid action. 

Salicylates antagonize probenecid s uricosuric action. Concurrent administration of probenecid increases die effects of acyclovir, barbiturates, benzodiazepines, dap-sone, mediotrexate, NSAIDs, rifampin, and the sulfonamides. 

Although rare, benzodiazepine toxicity may occur from an overdose of the drug. Benzodiazepine toxicity causes sedation, respiratory depression, and coma. Flumazenil (Romazicon) is an antidote (antagonist) for benzodiazepine toxicity and acts to reverse die sedation, respiratory depression, and coma within 6 to 10 minutes after intravenous administration. The dosage is individualized based on the patient s response, widi most patients responding to doses of 0.6 to 1 mg. However, die drug s action is short, and additional doses may be needed. Adverse reactions of flumazenil include agitation, confusion, seizures, and in some cases, symptoms of benzodiazepine withdrawal. Adverse reactions of flumazenil related to the symptoms of benzodiazepine withdrawal are relieved by die administration of die benzodiazepine. 

There is some evidence of a synergistic effect on reinforcement with concurrent administration of benzodiazepines and opioids (Walker and Ettenberg 2003). Cocaine abusers are less likely than opioid abusers to abuse benzodiazepines, preferring alcohol and opioids as secondary drugs of abuse. The most common pattern of benzodiazepine misuse in these individuals is intermittent use of therapeutic or supratherapeutic doses to counter unwanted effects of cocaine. 

Darragh A, Lambe R, Kenny M, et al Tolerance of healrhy volunteers to intravenous administration of the benzodiazepine antagonist Ro 15-1788. EurJ Clin Pharmacol 24 569-370, 1983... 

Greenblatt DJ, Shader RI Long-term administration of benzodiazepines pharmacokinetic versus pharmacodynamic tolerance. Psychopharmacol Bull 22 416 23, 1986... 

Griffiths RR, Wolf B Relative abuse liability of different benzodiazepines in drug abusers. J Clin Psychopharmacol 10 237-243, 1990 Griffiths RR, Weerts EM Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse. Psycho-pharmacology (Berl) 134 1-37, 1997... 

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... 

Inadequate activity of an endogenous ligand which is a benzodiazepine receptor agonist and suppresses anxiety. In this case, the administration of the antagonist, fiumazenil, should induce anxiety in normal subjects and exacerbate anxiety in anxious patients. 

These observations question the role of noradrenaline as an initiator of anxiety as does the finding that the anti-anxiety drug, buspirone (see Chapter 9), increases the concentration of noradrenaline in the extracellular fluid in the frontal cortex of freely-moving rats (Done and Sharp 1994). Whether this is because buspirone is metabolised to l-(2-pyrimidinyl)-piperazine (1-PP), which is an a2-adrenoceptor antagonist, is uncertain. Unfortunately, no studies have investigated the effects of chronic administration of this drug on noradrenergic transmission this could be important because, unlike benzodiazepines, buspirone is effective therapeutically only after several weeks of treatment. 

Evidence for the false transmitter theory as the cause of encephalopathy is demonstrated by the fact that administration of flumazenil (a benzodiazepine antagonist) has resulted in functional improvement. Unfortunately, long-term benefit has not been shown, and since flumazenil can only be administered par-enterally, it is not an appropriate choice for long-term therapy. 

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