General tonic

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

Generalized seizures include absence, myoclonic, and tonic-clonic. Manifestations of a generalized tonic-clonic seizure include alternate contraction (tonic phase) and relaxation (clonic phase) of muscles, a loss of consciousness, and abnormal behavior. Myoclonic seizures involve sudden, forceful contractions involving the musculature of the trunk, neck, and extremities. Absence seizures, previously referred to as petit mal seizures, are seizures characterized by a brief loss of consciousness during which physical activity ceases. The seizures typically last a few seconds, occur many times a day, and may go unnoticed by others. 

Myoclonic Single and very brief jerks of all major muscle groups. Patients with these may not lose consciousness, due to the seizure lasting less than 3 to 4 seconds. Patients may describe these seizures as shoulder shrugs or spinal chills. Myoclonic seizures may cluster and build into a generalized tonic-clonic seizure. 

Juvenile absence epilepsy with generalized tonic-clonic seizure on awakening... 

AG, a 20-year-old male college student, is seen by his physician 4 days after an apparent seizure during finals week. According to his roommate, he suddenly fell to the floor and had a generalized tonic-clonic seizure. This seizure lasted for 1 to 2 minutes. The patient was incontinent for urine during the seizure. He was sleepy and confused when the paramedics arrived 1 0 minutes later. Due to final examinations he reports being sleep-deprived. His physical exam is completely normal and no focal neurologic deficits were observed. 

BC, a 22-year-old woman, was diagnosed 2 years ago with juvenile myoclonic epilepsy. She has been treated with valproate 1500 mg/day. Since starting valproate she has gained 45 pounds (20.5 kg), continues to have occasional myoclonic jerks, had a generalized tonic-clonic seizure 3 months ago, and is sexually active. Additionally, she complains of easily falling asleep during the day. Due to adverse effects, poor seizure control, and the risk of birth defects with valproate, the decision is made to switch to a different antiepileptic drug. 

Valproate Sodium Valproate sodium is an older AED that was released as an intravenous preparation (Depacon ) in 1996. Although it is not FDA-approved for SE, its use has been documented in various types of SE including generalized tonic-clonic, myoclonic, and non-convulsive SE.22,23 Reports indicate... 

A 38 year-old male with a 15-year history of grand mal seizures is brought to the ED with generalized tonic-clonic seizures that are unremittent... 

Large numbers of generalized tonic-clonic (GTC) seizures (more than 100) and multiple episodes of status epilepticus may be associated with neuronal damage. In particular, continued exposure to glutamate may contribute to neuronal damage. 

C. Secondarily generalized (partial onset evolving to generalized tonic-clonic seizures)... 

GTC seizures may be preceded by premonitory symptoms (i.e., an aura). A tonic-clonic seizure that is preceded by an aura is likely a partial seizure that is secondarily generalized. Tonic-clonic seizures begin with a short tonic contraction of muscles followed by a period of rigidity. The patient may lose sphincter control, bite the tongue, or become cyanotic. The episode may be followed by unconsciousness, and frequently the patient goes into a deep sleep. 

Primary generalized (tonic-clonic) U.S. guidelines Valproic acid Topiramate ... 

Anticonvulsant (mephobarbital, phenobarbital) Treatment of partial and generalized tonic-clonic and cortical focal seizures. 

Tonic-clonic seizures- Adjunctive therapy for primary generalized tonic-clonic seizures in adults and children 2 to 16 years of age. 

Adults (17 years of age and older) partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome-The recommended total daily dose as adjunctive therapy is 200 to 400 mg/day in 2 divided doses in adults with partial seizures, and 400 mg/day in 2 divided doses in adults with tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50... 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

Ethotoin has appeared to be of some value in the treatment of partial as well as generalized tonic-clonic seizures and to be relatively free of the typical adverse effects of phenytoin. Because of its low efficacy, it is rarely used and then only in combination with other agents. 

Carbamazepine is a tricyclic iminostilbene derivative and structurally related to the tricyclic antidepressants. It is used as a first-line agent for the management of generalized tonic-clonic epilepsy. It is also highly effective for partial seizures but has no efficacy in patients with absence seizures or atonic seizures. In epilepsy it supposedly has the same mechanism of action as phenytoin. An other well... 

Oxcarbazepine is a derivative of carbamazepine and although its precise mechanism of action is unknown it has similar properties as carbamazepine and is also used for the treatment of primary generalized tonic-clonic seizures and partial seizures. Also the adverse effects are similar to those of carbamazepine. However the drug interaction profile is different as oxcarbazepine has hardly any enzyme-inducing capacity. 

Valproic acid is a fatty acid derivative which is used for the management of absences and the control of generalized tonic-clonic seizures. Multiple mechanisms of action have been proposed. It prolongs Na+ inactivation which could explain its effectiveness against grand mal seizures. However also inhibition of T-Type Ca++ channels has been postulated. 

Carbamazepine is an effective agent for the treatment of partial seizures and generalized tonic-clonic seizures its use is contraindicated in absence epilepsy. Carbamazepine is also useful in the treatment of trigeminal neuralgia and is an effective agent for the treatment of bipolar disorders (see Chapter 33). 

Zonisamide has only recently been approved for use in the United States, although it has been available in Japan for several years. It is effective in partial complex and generalized tonic-clonic seizures and also appears to be beneficial in certain myoclonic seizures. It has a long half-life (about 60 hours) and requires about 2 weeks to achieve steady-state levels. It causes cerebellovestibular side effects similar to those of most other AEDs sharing its mechanism of action. In addition, it appears to cause an increased incidence of kidney stones. 

Valproic acid has become a major AED against several seizure types. It is highly effective against absence seizures and myoclonic seizures. In addition, valproic acid can be used either alone or in combination with other drugs for the treatment of generalized tonic-clonic epilepsy and for partial seizures with complex symptoms. 

At present, phenobarbital and primidone are considered as alternative drugs for the treatment of partial seizures and for generalized tonic-clonic epilepsy. They are judged to be less effective than carbamazepine and phenytoin. 

A 10-year-old boy with generalized tonic seizures is seen by his dentist at a routine checkup. The dentist observes that the patient has an overgrowth of gum tissue. The patient was most likely receiving which of the following agents ... 

Brazil. Hot water extract of the dried leaf and stem is taken orally by males as an aphrodisiac. Extract is taken orally as nerve and general tonics h Oleoresin powder, crushed with the fingertips, is used as a condiment . 

Mattson, R.H., Ctamer, J.A., and Collins, J.F. (1992) A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group [see comments]. N Engl J Med 327 765-771. 

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