Diazepam epilepsy

Table 32.1 describes 30 persons who have been observed to use one of four available therapeutic compounds for the treatment of one of three possible disorders. The four compounds in this measurement table are the benzodiazepine tranquillizers Clonazepam (C), Diazepam (D), Lorazepam (L) and Triazolam (T). The three disorders are anxiety (A), epilepsy (E) and sleep disturbance (S). In this example, both measurements (compounds and disorders) are defined on nominal scales. Measurements can also be defined on ordinal scales, or on interval and ratio scales in which case they need to be subdivided in discrete and non-overlapping categories. 

In Table 32.7 we observe a contrast (in the sense of difference) along the first row-singular vector u, between Clonazepam (0.750) and Lorazepam (-0.619). Similarly we observe a contrast along the first column-singular vector v, between epilepsy (0.762) and anxiety (-0.644). If we combine these two observations then we find that the first singular vector (expressed by both u, and v,) is dominated by the positive correspondence between Clonazepam and epilepsy and between Lorazepam and anxiety. Equivalently, the observations lead to a negative correspondence between Clonazepam and anxiety, and between Lorazepam and epilepsy. In a similar way we can interpret the second singular vector (expressed by both U2 and V2) in terms of positive correspondences between Triazolam and sleep and between Diazepam and anxiety. 

The two plots can be superimposed into a biplot as shown in Fig. 32.7. Such a biplot reveals the correspondences between the rows and columns of the contingency table. The compound Triazolam is specific for the treatment of sleep disturbances. Anxiety is treated preferentially by both Lorazepam and Diazepam. The latter is also used for treating epilepsy. Clonazepam is specifically used with epilepsy. Note that distances between compounds and disorders are not to be considered. This would be a serious error of interpretation. A positive correspondence between a compound and a disorder is evidenced by relatively large distances from the origin and a common orientation (e.g. sleep disturbance and Triazolam). A negative correspondence is manifest in the case of relatively large distances from the origin and opposite orientations (e.g. sleep disturbance and Diazepam). 

Benzodiazepines are primarily used in medicine as tranquilizers. However, they also have been snccessfully used for epilepsy in controlling long-lasting convnlsions. The most widely nsed is diazepam (5.1.2) and chlordiazepoxide (5.1.22). The synthesis of these was described in Chapter 5. 

Diazepam Status epilepticus-Epilepsy, all forms- 97 to 99 Liver, active metabolites... 

Nearly all central nervous system depressants have some capacity to suppress seizures by virtue of their depressant activity on the brain and spinal cord. Clonazepam and diazepam are two benzodiazepines that depress epileptiform activity and are used in the treatment of epilepsy and seizure disorders (see Chapter 32). 

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

It is a benzodiazepine useful in the treatment of petitmal epilepsy, myoclonic seizures and infantile spasms. It is used in the treatment of petitmal epilepsy not responding to ethosuximide and sodium valproate. Clonazepam and diazepam act by increasing the effectiveness of the inhibitory neurotransmitter GABA, within the central nervous system. 

It is 1,5 benzodiazepine with a chemical structure slightly different from that of diazepam and clonazepam. This change in structure results in less sedative and psychomotor retardation. Though introduced as an anxiolytic it has been found to be useful in treatment of patients with refractory epilepsy. 

Six benzodiazepines play prominent roles in the therapy of epilepsy (see also Chapter 22). Although many benzodiazepines are similar chemically, subtle structural alterations result in differences in activity. They have two mechanisms of antiseizure action, which are shown to different degrees by the six compounds. This is evident from the fact that diazepam is relatively more potent against electroshock and clonazepam against pentylenetetrazol (the latter effect correlating with an action at the GABA-benzodiazepine allosteric receptor sites). Possible mechanisms of action are discussed in Chapter 22. 

Among the various other types of epilepsy are partial seizures which involve some involuntary muscle spasm or sensual disturbance without loss of consciousness. Phenobarbital, diazepam, phenytoin and carbamazepine are the most commonly used medications for this condition. As... 

Several members of the benzodiazepine group are effective in treating epilepsy, but most are limited because of problems with sedation and tolerance. Some agents such as diazepam (Valium) and lorazepam (Ativan) are used in the acute treatment of status epilepti-cus (see Treatment of Status Epilepticus ), but only a few are used in the long-term treatment of epilepsy. Clonazepam (Klonopin) is recommended in specific forms of absence seizures (e.g., the Lennox-Gastaut variant) and may also be useful in minor generalized seizures such as akinetic spells and myoclonic jerks. Clorazepate (Tranxene) is another benzodiazepine that is occasionally used as an adjunct in certain partial seizures. 

Benzodiazepines used to treat epilepsy include diazepam, clonazepam, clobazam and lorazepam. Of these, diazepam and lorazepam have been most widely used to control status epilepticus, while use of clonazepam is usually restricted to the chronic treatment of severe mixed types of seizures (e.g. Lennox-Gastaut syndrome and infantile spasm). The major problem with most of the benzodiazepines, with the possible exception of clobazam, is sedation. 

Seizures Clonazepam [kloe NA ze pam] is useful in the chronic treatment of epilepsy, whereas diazepam is the drug of choice in terminating grand mal epileptic seizures and status epilepticus (see p. 149). Chlordiazepoxide [klor di az e POX ide], clorazepate [klor AZ e pate], diazepam, and oxazepam [ox A ze pam] are useful in the acute treatment of alcohol withdrawal. 

This fivefold clinical activity is possessed, to a greater or lesser extent, by all benzodiazepines in current clinical use. The properties of benzodiazepines make them ideally useful for managing anxiety (e.g. diazepam, chlordiazepoxide, lorazepam) insomnia (e.g. diazepam, temazepam, nitrazepam, loprazolam, flurazepam, lormetazepam) epilepsy (e.g. clobazam, diazepam, lorazepam) sports injuries where muscle relaxation is required (e.g. diazepam) and as premedications prior to surgery (e.g. midazolam, lorazepam). The benzodiazepines have a number of other uses, including management of alcohol withdrawal syndrome (chlordiazepoxide, diazepam) and restless legs (clonazepam). Short... 

Brodtkorb E, Aamo T, Henriksen O, Lossius R. Rectal diazepam pitfalls of excessive use in refractory epilepsy. Epilepsy Res 1999 35(2) 123—33. 

Mahmoudian T, Zadeh MM. Comparison intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav 2004 5(2) 253-5. 

FIGURE 63.4. Experimental design revealing anticonvulsant effects of diazepam and pentobarbital in epilepsy research (A). Anticonvulsant effects achieved by triple regimen when administered 30-40 min after onset of seizures (B). 

It turned out that the nearly discarded substance had a novel structure, 5, a chlordiazepoxide. It was developed further and became known under the trade name Librium , which was the first antianxiety agent. Librium became the lead compound for the development of many other compounds with related structures. The best known is the diazepam Vh/ium , 6, a tranquilizer used to treat anxiety, muscle spasm, and symptoms of epilepsy. Today, about 40 diazepines are in the market. Nearly forgotten on the laboratory shelf, Librium and Valium became blockbuster drugs that fueled the growth of the Roche company. (Drugs are called blockbusters when sales are much higher than US 1 billion per year.)... 

When a child has febrile convulsions the decision to embark on continuous prophylaxis is serious for the child, and depends on an assessment of risk factors, e.g. age, nature and duration of the fits. Most children who have febrile convulsions do not develop epilepsy. Prolonged drug therapy, e.g. with phenytoin or phenobarbitone, has been shown to interfere with cognitive development, the effect persisting for months after the drug is withdrawn. Parents may be supplied with a specially formulated solution of diazepam for rectal administration (absorption from a suppository is too slow) for easy and early administration, and advised on managing fever, e.g. use paracetamol at the first hint of fever, and tepid sponging. 

Visual field defects associated with various antiepUeptic drugs (carbamazepine, diazepam, gabapentin, pheny-toin, tiagabine, and vigabatrin) have been reviewed (19). The true frequency is unknown, but in a retrospective study in 158 patients with partial epilepsy visual field defects were detected in 21 (13%) 13 patients had concentric visual field constriction without subjective spontaneous manifestations. Of these 13 patients, 9 were taking vigabatrin. 

ANTICONVULSANTS are drugs used to treat convulsions of various types, for instance, in drug or chemical poisoning, e.g. chlorpromazine, diazepam. However, these anticonvulsants are not necessarily effective or suitable for epilepsy. 

For a one-compartment elimination, the visualization and quantification of elimination is straightforward. However, for a multicompartment system consisting of distribution followed by elimination, two (or more) half lives can be calculated. Usually, the first and most rapid t1/2 relates to drug distribution, while the second (slower) t relates to elimination (and therefore is of more clinical relevance see Figure 9.20). However, as was seen in Figure 9.17A, if the distribution relates to a therapeutically relevant compartment, such as the brain for diazepam treatment of epilepsy, then the first t1/2 may also be therapeutically relevant. 

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