(From Dr. Tweeddale’s path lecture, 9 Nov 2000, by Brian Buschman)
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Usually these drugs are lipid soluble so they are rapidly and easily absorbed. Action is also shortened because they are able to spread throughout the entire body. Thiopental, a barbiturate, is the fastest to be redistributed.
Most sedative-hypnotics are metabolized to active metabolites before being excreted. All barbs and benzadiazopenes form active metabolites except for:
1) Benzadiazopene exceptions include lorazepam and oxazepam.
2) Barbs include phenobarbital.
Benzadiazopenes bind the BZ receptor on GABAA receptors and increase the rate of opening of the Cl- channels. This causes CNS depression. Flumazenil is the BZ antagonist.
Zolpidem is not a benzadiazopene but it functions on the BZ1 receptor and is antagonized by flumazenil.
Barbiturates work primarily on the midbrain reticular formation increasing the duration of action of the Cl- channels associated with the GABA receptors.
Buspirone works as a partial agonist of the 5-HT1A receptor.
Usually the depressant effects are addative with the stepness of the response curve varying from drug to drug. The difference is that the dose-response for barbiturates continues up to the point of coma and death while the curve for benzadiazopenes plateaus at the point of severe depression. The principles that cause this cause benzadiazopenes to have a larger therapeutic range then barbiturates. This also makes also makes benzadiazopenes and buspirone the most useful for anxiolytics.
When using these drugs for hypnosis they usually bring increased sleep and decreased REM sleep. Therefore withdrawal/termination of use leads to REM rebound.
Benzadiazopenes like midazolam or barbiturates like thiopental can be used in anesthesia.
Anticonvulsant effects are caused by most barbiturates but only after a few drugs can work as anticonvulsants without extreme sedation. This is done with the barbiturate phenobarbital and the benzadiazopene clonazepam.
Status epilepticus is treated with high doses of diazepam, lorazepam or phenobarbital where both anticonvulsant and sedative effects are desired.
Muscle relaxation is achieved but again at the cost of sedation. Diazepam is a benzadiazopene used at sedative doses. Meprobamate is a carbamates that can function selectively as a muscle relaxant.
Tolerance can occur and dependence is common. There are usually withdrawal symptoms of anxiety and such associated symptoms. Buspirone and zolpidem don’t develop dependence.
Anxiolytics are usually long acting benzadiazopenes. Buspirone is the DOC for GAD. Alprazolam and clonazepam are used with panic/phobic disorders.
Zolpidem is the best because it has less daytime effects. Usually benzadiazopenes like flurazepam and triazolam are used for sleep disorders.
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