Benzodiazepines tolerance development

Tolerance to many of the effects of the depressants develops. Unlike opioids, barbiturate and benzodiazepine tolerance develops slowly. Also, tolerance is incomplete in some instances or does not influence some pharmacological effects. One such exception is the lack of tolerance to barbiturate lethality. The lethal dose in a tolerant individual is not much different from that of the general population. Cross-tolerance develops to some degree between the depressant classes of drugs. 

Clonazepam, a typical 1 4 benzodiazepine, is effective in absence seizures, myoclonic jerks and tonic-clonic seizures and given intravenously it attenuates status epilepticus. It is less sedative than phenobarbitone but tolerance develops and its withdrawal, as... 

Motor effects Harmaline produces a motor tremor (8-14 Hz) through activation of cells in the inferior olive, which is blocked by noncompetitive NMDA antagonists (Du et al. 1997 Stanford and Fowler 1998). Harmaline tremor is also reversed by benzodiazepine agonists (Robertson 1980). The tremor is initiated by synchronous rhythms in the olivocere-bellar system and red nucleus (Lorden et al. 1988 Gogolak et al. 1977 Batini et al. 1980). The tremor is associated with increased cGMP in the cerebellum, and tolerance with a relative normalization of cGMP (Lutes et al. 1988). Rapid tolerance develops to this effect with repeated doses. 

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. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Sherman GT, Miksic S, Lai H (1979) Lack of tolerance development to benzodiazepines in antagonism of the pentylenetetrazol discriminative stimulus. Pharmacol Biochem Behav 10 795-797... 

Although tolerance develops to the sedative, muscle relaxant, and anticonvulsant activities, the benzodiazepines do not appear to lose anxiolytic or antipanic efficacy. The anxiolytic efficacy of benzodiazepines in long-term clinical trials (>6 to 8 months of chronic use) has not been reported. ... 

Tolerance develops to the sleep effects of benzodiazepines but not the antianxiety effects. 

Three of the drugs listed are effective in absence seizures. Ethosuximide and valproic acid are not sedating, and tolerance does not develop to their antiseizure activity. Clonazepam is effective but exerts troublesome CNS depressant effects, and tolerance develops with chronic use. At high doses, the drug has a dependence liability like most benzodiazepines. The answer is (A). 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

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. 

The clinical consequences of the currently used benzodiazepines range from sedation, muscle relaxation, seizure reduction, anxiolysis, and hypnosis. Clearly, it would be highly desirable to be able to separate some of these effects. In addition, it would be useful to reduce other undesirable consequences such as development of tolerance and dependence, abuse, synergistic interaction with ethanol, and memory impairment (for a comprehensive review see [22]). Animal models for some of the aforementioned conditions, in combination with transgenic mouse technology, have recently led to a deeper understanding of the contribution some of the individual a subunits make to these behaviors. 

---