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Sedative Hypnoticsphamacist

Sedative Hypnoticsphamacist

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Published by Han Hopper

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Published by: Han Hopper on Apr 04, 2012
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Page 1
Sedative-HypnoticsPharmacy 725: Principle of Drug Mechanisms
In terms of drugs,
 sedative
refers to a substance that moderates activity and excitementwhile inducing a calming effect, while
hypnotic 
refers to a substance that causes drowsinessand facilitates the onset and maintenance of natural sleep. The term
 anxiolytic 
is some-times applied to a sedative-hypnotic; however, be aware that many other drugs, especially the selective-serotonin reuptake inhibitors (SSRIs), are useful as chronic anxiolytics, asdemonstrated by their efficacy in certain psychiatric disorders like generalized anxiety dis-order.Due to their pharmacodynamic actions, especially the sedative effects, many of thesedative-hypnotics are considered 
 potential drugs of abuse
, and are therefore regulated ascontrolled substances. Along these lines, several sedative-hypnotic drugs have developed an interesting and alarming niche in the group of “club drugs” that have become popular in the past decade. One such example is the widespread use of 
 alprazolam (Xanax
®
 )
in com-bination with stimulant drugs of abuse, such as ecstasy or methamphetamine.In clinical therapeutics, sedative-hypnotics are useful for treatment of a variety of dis-eases related to the central nervous system, such as acute and chronic anxiety, anesthesia,seizure control, and insomnia. The sedative-hypnotics may be divided into three major groups: (1)
benzodiazepines 
, (2)
barbiturates 
, and (3) other drugs that do not fall into either of the first two groups.
Sedative-Hypnotic Drugs
Michael H. Nelson, Ph.D., R.Ph.
Pharmacy 725: Principles of Drug Mechanisms Wingate University School of Pharmacy Spring 2006 
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Page 2
Sedative-HypnoticsPharmacy 725: Principle of Drug Mechanisms
Page 2
Chemistry & Molecular Pharmacology 
Benzodiazepines
All of the
benzodiazepines have the same general chemical structure
, as shown below. Dif-ferent benzodiazepine drugs have been developed through the years based on chemicalsubstitutions at two major positions on the benzodiazepine structure. Therefore, allbenzodiazpines are simply variations on the same core chemical structure.The benzodiazepines are frequently classified into three groups: (1)
 short-acting 
, (2)
inter-mediate-acting 
, and (3)
long-acting 
. The
duration of action
for an individual benzodiazepineplays a major role in determining how that specific drug will be used clinically. The du-ration of action is dependent on two factors:(1)
the half-life
and (2)
the metabolic fate
of thebenzodiazepine.The first factor, the drug half-life, is the timeit takes for 50% of the drug be eliminated.
Thelonger the half-life, the longer the duration of action.
 The second factor that determines the du-ration of action is the metabolic fate of thebenzodiazepine after it enters the body. In many cases, a benzodiazepine will be metabolized by enzymes in the body to another benzodiazepinewith the same pharmacodynamic effects (i.e.,
BenzodiazepineClassificationHalf-Life
1
Midazolam
Short-Acting2-6 Triazolam
Short-Acting2-3Alprazolam
Intermediate-Acting12-15EstazolamIntermediate-Acting10-24Lorazepam
Intermediate-Acting10-20 TemazepamIntermediate-Acting10-40ClonazepamLong-Acting18-50ClorazepateLong-Acting40-50Diazepam
Long-Acting20-80FlurazepamLong-Acting40-100
1
Half-life includes parent drug and active metabolites
Know name and classification for exam
NNClON(C
2
H
5
)
2
F
Flurazepam
NNClOCH
3
Diazepam
NNClOClOHH
Lorazepam
NNClNNH
3
C
Alprazolam
NNORX
General Benzodiazepine Structure
Benzodiazepines
 
Page 3
Sedative-HypnoticsPharmacy 725: Principle of Drug Mechanisms
Page 3
an
 active metabolite
). In fact, several benzodiazepines are actually converted into other benzodiazepines that are also marketed drugs. For example,
diazepam (Valium
®
 )
is metabo-lized in two steps to
oxazepam (Serax
®
 )
.To summarize, the
duration of action of an individual benzodiazepine is a combination of thehalf-life of the parent drug and the half-life of any active metabolites 
generated by drug metabo-lism.Most of the benzodiazepines undergo both oxidative metabolism (phase 1 metabolism)and conjugation to glucuronic acid, or glucuronidation (phase 2 metabolism). Both typesof drug metabolism will be discussed in detail during Biopharmaceutics & Introductory Pharmacokinetics in the first semester of your second year of classes. For now, what is im-portant to know is that some benzodiazepines do
not 
undergo significant oxidative me-tabolism (
temazepam
,
oxazepam
,
lorazepam
); there may be some benefit to using these agentsin patients with liver disease or compromised hepatic function, as the majority of oxidativemetabolism occurs in the liver. The
outlines the general meta-bolic pathway of most currently marketed benzodiazepines.The molecular site of action for the benzodiazepines is at the
GABA
 A
receptors 
in theCNS. GABA, or 
 gamma-aminobutyric acid 
, is an amino acid neurotransmitter that has aninhibitory effect on neurotransmission in the CNS. Therefore, an increase in the effect of GABA results in general suppression of the CNS. When GABA binds to GABA
A
receptors,
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