Benzodiazepine epilepsy

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Benzodiazepines which can be possessed by those above and also others as long as they are a medicinal product (use for epilepsy, anxiety and sleeping pills)... 

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. 

Risa J, Risa A, Adsersen A, et al. Screening of plants used in southern Africa for epilepsy and convulsions in the GABAA-benzodiazepine receptor assay. J Ethnophar-macol 2004 93 177-182. 

Colonazepam belongs to the class of 1,4-benzodiazepines that has been found to be therapeutically effective in controlling minor motor seizures i.e., petitmal epilepsy in humans ... 

Benzodiazepines have a wide array of clinical uses. In addition to relieving anxiety, they can be used to treat epilepsy, alcohol withdrawal, insomnia, agitation, and perhaps impulsivity. They can also be used as muscle relaxants or to produce conscious sedation during certain medical procedures such as cardiac catheterization and colonoscopy. 

Benzodiazepines. Safer than the barbiturates but acting in a similar manner, the benzodiazepines have largely replaced barbiturates since their introduction in the 1960s. Other uses of benzodiazepines include treatment for epilepsy, alcohol withdrawal, several anxiety disorders, agitation, and impulsivity, as muscle relaxants, and as conscious sedation during certain medical procedures. 

Flumazenil is a benzodiazepine antagonist that is used in anaesthesia for the reversal of central sedative effects of benzodiazepines. It should not be administered rapidly so as to avoid patient wakening too rapidly, which can lead to agitation, anxiety, fear and convulsions, particularly in high-risk patients, e.g. those with a history of epilepsy or head injury. 

Various drugs including barbiturates and benzodiazepines, which are used for relieving the severe, convulsive conditions that originate as a result of conditions other than epilepsy, are used in treating epilepsy. It is believed that various mechanisms may be operating within the genesis of epilepsy, and it is possible to influence these mechanisms medicinally. 

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. 

The third drug of the benzodiazepine family used for epilepsy is called clonazepam. 

Tolerance may occur which means that the effect of some AEDs may wear off with time (benzodiazepines, barbiturates, vigabatrin). There are exceptional cases where refractory epilepsy escapes... 

Riban V, Bouilleret V, Pham-L BT, Fritschy JM, Marescaux C, Depaulis A (2002) Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience 112 101-111 Rudolph U, Crestani F, Benke D, Brunig I, Benson J, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific y-aminobutyric acid A receptor subtypes. Nature 401 796-800... 

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). 

Historically, alcohol has been used as an anxiety-reducing agent, both casually and in professional medical settings. In 1903, barbital was introduced as the first barbiturate to treat anxiety, and phenobarbital followed a few years later. Barbiturates have many side effects and addictive properties, and overdose can lead to coma and death. For these reasons, they are rarely used today, except to treat some forms of epilepsy. This class of drugs was eventually replaced by the benzodiazepines (see Chapter 4). 

The benzodiazepines are one of the most widely used (and abused) classes of drugs they are widely used in the treatment of epilepsy, insomnia, anxiety, movement disorders, and a variety of other neurological disorders. The discovery of the benzodiazepines is a good example of the importance of serendipity. 

The discovery of benzodiazepines is a story of serendipity and certainly one that is difficult to predictably reproduce as part of a drug discovery program. Regrettably (or fortuitously), this story of the benzodiazepines is not an isolated example. Valproic acid, an agent used to treat epilepsy, migraine, chronic pain, and bipolar affective disorder, was also discovered by accident. 

Benzodiazepines and barbiturates are used as anticonvulsant drugs in the treatment of epilepsy. Epilepsy, a medical disorder characterized by recurrent seizures, has many different forms. The four most common seizure types are generalized tonic-clonic seizures (old name grand mal seizures), generalized absence seizures (petit mal seizures), complex partial seizures (psychomotor or temporal lobe seizures), and simple partial seizures (focal seizures). 

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. 

Specific myoclonic syndromes are usually treated with valproate an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine valproate is the drug of choice followed by lamotrigine and topiramate. 

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