Benzodiazepines status epilepticus

Drugs used in the treatment of status epilepticus Benzodiazepines, e.g., diazepam... 

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... 

The first-line treatment for status epilepticus is intravenous benzodiazepines. Diazepam, lorazepam, or midazolam may be used to rapidly control clinical signs of seizures. Lorazepam is currently considered the first-line agent by most clinicians. 

Refractory status epilepticus is seizure activity that is not controlled by first-fine and second-line therapies, including benzodiazepines and antiepileptic drugs. 

All benzodiazepines are indicated in obsessive compulsive disorders. Diazepam and lorazepam are effective in status epilepticus, whereas chlordiazepoxide is indicated in alcohol withdrawal. 

Lorazepam is a short-acting benzodiazepine indicated for use in relieving anxiety and insomnia. Lorazepam may also be administered perioperatively to alleviate pain and in status epilepticus. Imipramine is a tricyclic antidepressant, paroxetine is a selective serotonin re-uptake inhibitor, venlafaxine is a serotonin and adrenaline re-uptake inhibitor and moclobemide is a reversible monoamine oxidase inhibitor. Imipramine, paroxetine, venlafaxine and moclobemide are all classified as antidepressants. 

The brief duration of a single epileptic fit makes acute drug treatment unfeasible. Instead, antiepileptics are used to prevent seizures and therefore need to be given chronically. Only in the case of status epilepticus (a succession of several tonic-clonic seizures) is acute anticonvulsant therapy indicated — usually with benzodiazepines given i.v. or, if needed, rectally. 

Benzodiazepines are the drugs of choice for status epilepticus (see above) however, development of tolerance renders them less suitable for long-term therapy. Clonazepam is used for myoclonic and atonic seizures. Clobazam, a 1,5-benzodiazepine exhibiting an increased anticonvulsant/seda-tive activity ratio, has a similar range of clinical uses. Personality changes and paradoxical excitement are potential side effects. 

Diazepam (Valium, Diastat) [C-IVj [Anxiolytic, Skeletal Muscle Relaxant, Anticonvulsant, Sedative/Hypnotic/ Benzodiazepine] Uses Anxiety, EtOH withdrawal, muscle spasm, status epilepticus, panic disorders, amnesia, preprocedure sedation Action Benzodiazepine Dose Adults. Status epilepticus 5-10 mg IV/IM Anxiety 2-5 mg IM/IV Preprocedure 5-10 mg IV just prior to procedure Peds. Status epilepticus 0.5-2 mg IV/IM Sedation 0.2-0.5 mg/kg IV (onset w/in 5IV and 30 min IM duration about 1 h IV and IM) Caution [D, / -] Contra Coma, CNS depression, resp d es-sion, NAG, severe uncontrolled pain, PRG Disp Tabs 2, 5, 10 mg soln 1, 5 mg/mL inj 5 mg/mL rectal gel 2.5, 5, 10, 20 mg/mL SE Sedation, amnesia, bradycardia, i BP, rash, X resp rate Interactions T Effects W/ antihistamines, azole antifungals, BBs, CNS depressants, cimetidine, ciprofloxin, disulfiram, INH, OCP, omeprazole, phenytoin, valproic acid, verapamil, EtOH, kava kava, valman T effects OF digoxin, diuretics X effects w/ barbiturates, carbamazepine. 

Refractory status epilepticus that has failed to respond to one of these treatments, and has continued for more than 20-30 min, requires urgent action. The accepted strategy is to paralyze and ventilate the patient and administer an antiepileptic drug in sufficient dosage to suppress EEG evidence of seizure activity. The barbiturate anaesthetic thiopental (thiopentone), the benzodiazepine midazolam, and the anaesthetic propofol have all been used. What little comparative evidence there is remains inconclusive. Such treatment can only be carried out with facilities for artificial ventilation and intensive care, and effects can only be monitored by EEG recording. 

The primary action of the benzodiazepines as anticonvulsants is to enhance inhibition through their interaction with the GABAa receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of status epilepticus (discussed later). 

Benzodiazepines are well absorbed, and the oral route is preferred in most situations. In the treatment of status epilepticus, the preferred route is usually intravenous. Benzodiazepines are extensively metabolized by the microsomal drug-metabohzing system frequently an active compound is broken down to another agent that is also active pharmacologically. This is the reason for the long duration of action of several benzodiazepines. 

The benzodiazepines have many clinical indications and are discussed in Chapters 25, 30, 35, and 40. As AEDs, they have their major usefulness in the treatment of absence, myoclonic, and atonic seizures and in the emergency treatment of status epilepticus. 

Lorazepam is the benzodiazepine of choice for emergency treatment of status epilepticus, serial seizures,... 

Contraindications Anticholinergic signs (such as mydriasis, dry mucosa, and hypo-peristalsis), arrhythmias, cardiovascular collapse, history of hypersensitivity to benzodiazepines, patients with signs of serious cyclic antidepressant overdose (such as motor abnormalities), patients who have been given a benzodiazepine for control of a potentially life-threatening condition (such as control of status epilepticus or increased intracranial pressure ICP )... 

Gatzonis SD, Angelopoulos EK, Daskalopoulou EG, et al. Convulsive status epilepticus following abrupt high-dose benzodiazepine discontinuation. Drug Alcohol Depenc 2000 59 95-97. 

Two prominent aspects of benzodiazepines limit their usefulness. The first is their pronounced sedative effect, which is unfortunate both in the treatment of status epilepticus and in chronic therapy. Children may manifest a paradoxical hyperactivity, as with barbiturates. The second problem is tolerance, in which seizures may respond initially but recur within a few months. The remarkable antiseizure potency of these compounds often cannot be realized because of these limiting factors. 

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. 

Lorazepam is less lipophilic than diazepam and there is evidence that it has a longer duration of anticonvulsant action than diazepam after intravenous administration. This could be due to the fact that diazepam is more rapidly removed from the brain compartment than lorazepam, which limits its duration of antiepileptic activity. In practice, when diazepam is used to control status epilepticus it is often necessary to continue treatment with diphenylhydantoin, which has a longer duration of action in the brain. The principal hazards of benzodiazepines when given intravenously include respiratory depression and hypotension. Diazepam may be administered rectally, its ease of absorption leading to peak plasma levels within about 10 minutes. 

Barbiturates may also be used to treat a life-threatening seizure condition called Status Epilepticus. Most epileptic seizures last for several seconds and then resolve on their own, but occasionally a patient will continue seizing for several minutes or even hours. This can be very dangerous because the seizure may cause serious damage to the patient s muscles and internal organs. Patients with this condition must be admitted to a hospital, and injectable medicines must be used to try to stop the seizure. The first drugs that are tried are benzodiazepines and some newer anti-epileptic medications, but if these fail to break the seizure, barbiturates like pentobarbital or secobarbital are used. 

The use of intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus has been evaluated in a double-blind, randomized trial in 205 adults (54). The patients presented either with seizures lasting 5 minutes or more or with repetitive generalized convulsive seizures, and were randomized to receive intravenous diazepam 5 mg, loraze-pam 2 mg, or placebo. Status epilepticus was controlled on arrival at the hospital in significantly more patients taking benzodiazepines than placebo (lorazepam 59%, diazepam 43%, placebo 21%). The rates of respiratory or circulatory complications related to drug treatment were 11% with lorazepam, 10% with diazepam, and 23% with placebo, but these differences were not significant. 

Benzodiazepines can provoke seizures and occasionally precipitate status epilepticus. 

Diazepam is often the first choice benzodiazepine to treat status epilepticus, and is administered either intravenously or rectally... 

If benzodiazepine was prescribed to control a life-threatening condition (e.g., status epilepticus, intracranial pressure)... 

Clonazepam (Rivotiil) (tV 25 h) is a benzodiazepine used as a second line drug for treatment of primary generalised epilepsy and for status epilepticus (see Table 20.1). 

Although it has been suggested that worsening of seizures after withdrawal of non-benzodiazepine anticonvulsants may reflect loss of efficacy rather than an abstinence phenomenon (143), rapid drug withdrawal can still result in dangerous loss of seizure control and status epilepticus. 

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