adult cases were reported to the dutch national poison control center. out of these, one person taking it with phenytoin and phenobarbital died, twelve became drowsy and four were comatose. treatments for primidone overdose have included hemoperfusion with forced diuresis, a combination of bemegride and amiphenazole; and a combination of bemegride, spironolactone, caffeine, pentylenetetrazol, strophanthin, penicillin and streptomycin. in the three adults who are reported to have succumbed, the doses were 20–30 g. however, two adult survivors ingested 30 g 25 g, and 22.5 g. one woman experienced symptoms of primidone intoxication after ingesting 750 mg of her roommate's primidone. interactions taking primidone with monoamine oxidase inhibitors (maois) such as isocarboxazid (marplan), phenelzine (nardil), procarbazine (matulane), selegiline (eldepryl), tranylcypromine (parnate) or within two weeks of stopping any one of them may potentiate the effects of primidone or change one's seizure patterns. isoniazid, an antitubercular agent with maoi properties, has been known to strongly inhibit the metabolism of primidone. like many anticonvulsants, primidone interacts with other anticonvulsants. clobazam decreases clearance of primidone, mesuximide increases plasma levels of phenobarbital in primidone users, both primidone and phenobarbital accelerate the metabolism of carbamazepine via cyp3a4, and lamotrigine's apparent clearance is increased by primidone. in addition to being an inducer of cyp3a4, it is also an inducer of cyp1a2, which causes it to interact with substrates such as fluvoxamine, clozapine, olanzapine, and tricyclic antidepressants. it also interacts with cyp2b6 substrates such as bupropion, efavirenz, promethazine, selegiline, and sertraline; cyp2c8 substrates such as amiodarone, paclitaxel, pioglitazone, repaglinide, and rosiglitazone; and cyp2c9 substrates such as bosentan, celecoxib, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, sulfonamides, trimethoprim, warfarin, and zafirlukast. it also interacts with estrogens. primidone and the other enzyme-inducing anticonvulsants can cut the half-life of antipyrine roughly in half (6.2 ± 1.9 h vs. 11.2 ± 4.2 h), and increases the clearance rate by almost 70%. phenobarbital reduces the half-life to 4.8 ± 1.3 and increases the clearance by almost 109%. it also interferes with the metabolism of dexamethasone, a synthetic steroid hormone, to the point where its withdrawal from the regimen of a 14-year-old living in the united kingdom made her hypercortisolemic. tempelhoff and colleagues at the washington university school of medicine's department of anesthesiology reported in 1990 that primidone and other anticonvulsant drugs increase the amount of fentanyl needed during craniotomy based on the patient's heart rate. mechanism of action the exact mechanism of primidone's anticonvulsant action is still unknown after over fifty years. it is believed to work via interactions with voltage-gated sodium channels which inhibit high-frequency repetitive firing of action potentials. the effect of primidone in essential tremor is not mediated by pema. the major metabolite, phenobarbital, is also a potent anticonvulsant in its own right and likely contributes to primidone's effects in many forms of epilepsy. according to brenner's pharmacology textbook, primidone also increases gaba-mediated chloride flux: thereby hyperpolarizing the membrane potential. primidone was recently shown to directly inhibit the trpm3 ion channel; whether this effect contributes to its anticonvulsant effect is not known, but gain of function mutations in trpm3 were recently shown to be associated with epilepsy and intellectual disability. pharmacokinetics primidone converts to phenobarbital and pema; it is still unknown which exact cytochrome p450 enzymes are responsible. the phenobarbital, in turn, is metabolized to p-hydroxyphenobarbital. the rate of primidone metabolism was greatly accelerated by phenobarbital pretreatment, moderately accelerated by primidone pretreatment, and reduced by pema pretreatment. in 1983, a new minor metabolite, p-hydroxyprimidone, was discovered. primidone, carbamazepine, phenobarbital and phenytoin are among the most potent hepatic enzyme inducing drugs in existence. this enzyme induction occurs at therapeutic doses. in fact, people taking these drugs have displayed the highest degree of hepatic enzyme induction on record. in addition to being an inducer of cyp3a4, it is also an inducer of cyp1a2, which causes it to interact with substrates such as fluvoxamine, clozapine, olanzapine, and tricyclic antidepressants, as well as potentially increasing the toxicity of tobacco products. its metabolite, phenobarbital, is a substrate of cyp2c9, cyp2b6, cyp2c8, cyp2c19, cyp2a6, cyp3a5, cyp1e1, and the cyp2e subfamily. the gene expression of these isoenzymes is regulated by human pregnane receptor x (pxr) and constitutive androstane receptor (car). phenobarbital induction of cyp2b6 is mediated by both. primidone does not activate pxr. the rate of metabolism of primidone into phenobarbital was inversely related to age; the highest rates were in the oldest patients (the maximum age being 55). people aged 70–81, relative to people aged 18–26, have decreased renal clearance of primidone, phenobarbital, and pema, in ascending order of significance, and that there was a greater proportion of pema in the urine. the clinical significance is unknown. the percentage of primidone converted to phenobarbital has been estimated to be 5% in dogs and 15% in humans. work done twelve years later found that the serum phenobarbital 0.111 mg/100 ml for every mg/kg of primidone ingested. authors publishing a year earlier estimated that 24.5% of primidone was metabolized to phenobarbital. however, the patient reported by kappy and buckley would have had a serum level of 44.4 mg/100 ml instead of 8.5 mg/100 ml if this were true for individuals who have ingested large dose. the patient reported by morley and wynne would have had serum barbiturate levels of 50 mg/100 ml, which would have been fatal. history primidone is a congener of phenobarbital where the carbonyl oxygen of the urea moiety is replaced by two hydrogen atoms. the effectiveness of primidone for epilepsy was first demonstrated in 1949 by yule bogue. he found it to have a similar anticonvulsant effect, but more specific, i.e. with fewer associated sedative effects. it was brought to market a year later by the imperial chemical industry (ici), now known as astrazeneca in the united kingdom and germany. in 1952, it was approved in the netherlands. also in 1952, drs. handley and stewart demonstrated its effectiveness in the treatment of patients who failed to respond to other therapies; it was noted to be more effective in people with idiopathic generalized epilepsy than in people whose epilepsy had a known cause. dr. whitty noted in 1953 that it benefitted patients with psychomotor epilepsy, who were often treatment-resistant. toxic effects were reported to be mild. that same year, it was approved in france. primidone was introduced in 1954 under the brandname mysoline by wyeth in the united states. association with megaloblastic anemia in 1954, chalmers and boheimer reported that the drug was associated with megaloblastic anemia. between 1954 and 1957, twenty-one cases of megaloblastic anemia associated with primidone and/or phenytoin were reported. in most of these cases the anemia was due to vitamin deficiencies: usually folic acid deficiency; in one case vitamin b12 deficiency and in one case vitamin c deficiency. some cases were associated with deficient diets: one patient ate mostly bread and butter, another ate bread, buns, and hard candy, and another could rarely be persuaded to eat in the hospital. the idea that folic acid deficiency could cause megaloblastic anemia was not new. what was new was the idea that drugs could cause this in well-nourished people with no intestinal abnormalities. in many cases, it was not clear which drug had caused it. it was speculated that this might be related to the structural similarity between folic acid, phenytoin, phenobarbital, and primidone. folic acid had been found to alleviate the symptoms of megaloblastic anemia in the 1940s, not long after it was discovered, but the typical patient only made a full recovery—cessation of cns and pns symptoms as well as anemia—on b12 therapy. five years earlier, folic acid deficiency was linked to birth defects in rats. primidone was seen by some as too valuable to withhold based on the slight possibility of this rare side effect and by others as dangerous enough to be withheld unless phenobarbital or some other barbiturate failed to work for this and other reasons (i.e., reports of permanent psychosis). available forms primidone is available as a 250 mg/5ml suspension, and in the form of 50 mg, 125 mg, and 250 mg tablets. it is also available in a chewable tablet formulation in canada. it is marketed as several different brands including mysoline (canada, ireland, japan, the united kingdom, and the united states), prysoline (israel, rekah pharmaceutical products, ltd.), apo-primidone, liskantin (germany, desitin), resimatil (germany, sanofi-synthélabo gmbh), mylepsinum (germany, awd.pharma gmbh & co., kg)., and sertan (hungary, 250 mg tablets, icn pharmaceuticals inc.) other animals primidone has veterinary uses, including the prevention of aggressive behavior and cannibalism in gilt pigs, and treatment of nervous disorders in dogs and other animals.