Primidone side effects

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. 

Special mention must be accorded to iatrogenic effects, where the usefulness of novel synthetic drugs is impaired by untoward side effects of obscure etiology. In some, if not many of them, these side effects may find their explanation in the inhibitory action of the drug upon a vitamin, as in the case of primidone vs. folic acid (B3a). These relationships appear to be fortuitous until the structural chemical kinship of drug and vitamin is recognized. 

Toxic side effects in association with primidone levels of 10 /tg/ml or more have been reported (B17). 

The major untoward effect of phenobarbital and primidone, when used as anticonvulsants, is sedation. Another side effect of considerable importance, particularly in children, is a possible disturbance in cognitive function. Even when the serum concentration is within the therapeutic range, apparently the ability to concentrate and perform simple tasks is decreased. 

Herranz, J.L., Armijo, J.A., and Arteaga, R. (1988) Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia 29 794-804. 

With chronic exposure, side effects may include rash, thrombocytopenia, leukopenia, and a lupus-like disorder. Chronic therapy is likely to result in tolerance, and withdrawal symptoms if primidone therapy is abruptly stopped. Doses in excess of 1500 mg (twice the maximum recommended daily dose) should be considered toxic. Less common side effects are hypotension, hypothermia, and dermal bullae. Encephalopathy has been observed in an epileptic patient with high plasma levels and poor renal function. With plasma concentrations exceeding 80pgml primidone may precipitate and cause crystalluria. Plasma levels >10 rgpml are associated with toxic effects. The therapeutic range is reportedly 5-10pgml , but clinical effects correlate more closely with phenobarbital blood levels. 

An anticonvulsant, primidone is given at an initial dose of 100 to 125 mg/day at bedtime, increasing gradually to a maintenance dose of 125 to 250 mg three times daily. The most frequent side effect of primidone is heavy sedation, which seems to be due to primidone itself and not to its metabolite phenobarbital. Tolerance develops to this sedation within a few days or weeks of continuous administration. 

Phenobarbital is probably as effective as carbamazepine and phenytoin in the treatment of tonic-clonic and partial seizures, but it i,s much more sedative. Tolerance occurs with prolonged use and sudden withdrawal may precipitate status epilcpticus. Side-effects include cerebellar symptoms (e.g, sedation, iitaxia. nystagmus), drowsiness in adults and liyperkinc.sia in children. Primidone is metabolized to active anticonvulsant metabolites, one of which is phenobarbital. 

---