Primidone

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Primidone
Systematic (IUPAC) name
5-ethyl-5-phenyl-hexahydropyrimidine-4,6-dione
Identifiers
CAS number	125-33-7
ATC code	N03AA03
PubChem	4909
DrugBank	APRD00549
Chemical data
Formula	C12H14N2O2
Mol. mass	218.252 g/mol
Pharmacokinetic data
Bioavailability	~100%[1]
Protein binding	25%[1]
Metabolism	Hepatic
Half life	Primidone: 5-18 hours, Phenobarbital: 75-120 hours,[1] PEMA: 16 hours[2] Time to reach steady state: Primidone: 2-3 days, Phenobarbital&PEMA 1-4weeks[3]
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D(US)
Legal status	POM(UK) ℞-only(US)
Routes	oral

Primidone is an anticonvulsant of the pyrimidinedione^[4] class whose active metabolites, phenobarbital (minor) and phenylethylmalonamide (PEMA) (major), are also anticonvulsants. Like many anticonvulsants, it is regarded as a GABA receptor agonist (i.e., it simulates the action of GABA in the central nervous system).^[1]

Along with carbamazepine, phenobarbital, and phenytoin, primidone is an inducer of metabolic enzymes in the liver, which means that it accelerates the metabolism of many other pharmaceuticals. Like other anticonvulsants that entered the market before 1989, primidone has been associated with hyperhomocysteinemia, folate deficiency and its various symptoms (birth defects, depression, and megaloblastic anemia), reduced calcium absorption, and various bone diseases. It also shares with most other anticonvulsants the tendency to cause sedation.

Primidone was once regarded as a mainstay anticonvulsant in the treatment of partial and generalized seizures, and was the treatment of choice for secondarily generalized seizures originating in the temporal lobes, especially when combined with phenytoin, but by the mid-1970s, carbamazepine had surpassed it in popularity due to the latter's lower incidence of sedation. Since that time, it has largely fallen into disuse as more and more anticonvulsants entered the market and has been withdrawn from markets all over the world.

Since the 1980s, it has been a valuable alternative to propanolol in the treatment of essential tremor. Its efficacy is similar to propanolol. Unlike other anticonvulsants such as carbamazepine and valproic acid, primidone is rarely used in the treatment of bipolar disorder or any other psychiatric problem. Nor is it widely used in treatment of neuropathic pain.

Contents 1 History 2 Indications 2.1 Epilepsy 2.2 Essential tremor 2.3 Long QT syndrome 2.4 Psychiatric disorders 2.5 Trigeminal neuralgia 2.6 Veterinary 3 Adverse Effects 4 Interactions 5 Metabolism 6 Available forms 7 References 8 End Notes 9 External links

[edit] History

Primidone was introduced in 1954 under the brandname Mysoline® by Wyeth.^[5]

Fifteen years later, it was still considered to be a "sheet-anchor" anticonvulsant in the United Kingdom, along with phenobarbital and phenytoin, for the treatment of pediatric epilepsy^[6] and one of two drugs (the other being sultiame) that were tried in adult patients if a combination of phenytoin and phenobarbital failed to control seizures.^[7] It was most effective for partial onset seizures.^[8] Carbamazepine, which had been approved in Europe seven years earlier,^[9] was said not to live up to the claims of those who advocated its use in epilepsy.^[7]

By the late 1970s, however, this had changed. Primidone was no longer seen as the drug of choice for psychomotor epilepsy. While carbamazepine and primidone are of roughly equal effectiveness, the former is less likely to cause sedation and cognitive impairment. Also, primidone has a relatively greater tendency to cause undesirable psychiatric side effects compared with carbamazepine, which was noted to lessen pre-existing depressive symptoms.^[8]

In 1990, it, along with phenobarbital, was a second-line agent in partial epilepsy with or without secondarily generalized tonic-clonic seizures and was one of four agents (the others being carbamazepine, phenytoin and phenobarbital) that was used, along with ethosuximide or a benzodiazepine for any absence or myoclonic seizures, when valproate failed to control tonic-clonics (at least in the United States).^[10]

On February 28, 1998, Élan Corporation, plc, bought the trademark and exclusive product distribution rights for Mysoline from Wyeth in Canada and the United States at a cost of $46 million and a royalty on future sales.^[11] The actual manufacture and distribution was done by Athena Neurosciences; their name appeared on a Mysoline® package information sheet dated June 1998.^[12]

By the year 2000, primidone was seen as something that "may...be useful" (again, along with phenobarbital) as an add-on to valproate, lamotrigine, or topiramate in the treatment of GTCS, provided that carbamazepine or phenytoin could not be used for some reason.^[13]

In April of 2001, Élan decided to concentrate its efforts towards Zanaflex, Zonegran, Skelaxin, Abelcet, Azactam, Maxipime, Myobloc, and Cutivate. Mysoline was rationalized along with many other products that did not meet "certain commercial criteria."^[14] Yamanouchi Pharma Technologies, a Palo Alto-based subsidiary of Yamanouchi Pharmaceutical Co., Ltd,^[15] manufactured the actual drug.^[16]

• July of 2004: Acorus Therapeutics Ltd. took over the manufacture and distribution of Mysoline® from AstraZeneca^[17]
• February 3, 2005: almost four years after acquiring it from Elan, Xcel was acquired by Valeant Pharmaceuticals International.^[18]
• April 1, 2005: Yamanouchi merges with Fujisawa Pharmaceutical Co., Ltd to form Astellas Pharma.^[19]

[edit] Indications

[edit] Epilepsy

According to the electronic Medicines Compendium, primidone is licensed for generalized tonic-clonic seizures and complex partial seizures.^[20] In the United States, primidone is approved for adjunctive (in combination with other drugs) monotherapy (by itself)) in generalized tonic-clonic seizures, nocturnal myoclonic seizures, simple partial seizures, and complex partial seizures.

In 2002, a team of scientists headed by Dr. Kagitani-Shimono Kuriko at the Osaka University Graduate School of Medicine reported that a regimen consisting of a low dose of primidone combined with zonisamide was effective at controlling seizures in Unverricht-Lundborg type progressive myoclonus epilepsy (PME) patients, and recommended it as a first line therapy.^[21]

In juvenile myoclonic epilepsy (JME), it is a second-line therapy, reserved for when the valproates and/or lamotrigine do not work and when other second-line therapies—acetazolamide, clonazepam, and phenobarbital—do not work either.^[22]

In October of 1984, Powell, Painter and Pippenger published on the use of primidone in neonatal seizures resistant to phenobarbital and phenytoin therapy.^[23]

[edit] Essential tremor

Primidone is considered to be a first-line therapy for essential tremor along with propranolol.^[24]

[edit] Long QT syndrome

There are three case reports in which the shortening of the QT interval by primidone was documented. In the first two, primidone was used in the treatment of congenital long QT syndrome. In the third one, the effects on the QT interval in an adolescent male who did not have that were documented.

The first case, published in the July 1980 issue of Annals of Internal Medicine, involved three patients, a 31-year-old white woman , her 15-year-old nephew, and his 16-year-old sister. who still had ventricular fibrillation, syncope, and seizures even after the removal of her left stellate ganglion and her thoracic chain dissected.

The woman had previously been tried on a combination of phenobarbital and phenytoin when she was thought to have only seizures, followed by phenobarbital combined phenytoin and procainamide. The procainamide was replaced with propanolol, which in turn replaced the propanolol when the latter brought the tachycardia back almost instantaneously upon the first dose). The phenobarbital and phenytoin were then combined with atropine and acetylstrophanthidin. When this failed, the atropine acetylstrophanthidin were replaced with lidocaine prior to the surgery. After the surgery, the QT-prolongation returned, so the phenytoin was doubled to 200 mg four times daily. A month later, she was admitted to the hospital for phenytoin toxicity, where it was found that she had slow spike and abortive wave activity in her left temporal lobe. It was after this that primidone was substituted for phenytoin. The primidone suppressed the fibrillations and lengthened the QT interval for two years and eight months in the patient.

Her 16-year-old niece was started on primidone after an unsuccessful trial of phenytoin. Following this, her 15-year-old nephew, the niece's brother, was started because of family history.^[25]

The other case report, published in the December 1986 issue of Zhonghua Xin Xue Guan Bing Za Zhi, describes four cases, men, women, adults and adolescents, who were put on primidone for LQTS.^[26] The 2002 case focuses on hypocalcemia stemming from such treatment in an adolescent male.^[27]

[edit] Psychiatric disorders

In March of 1993, S.G. Hayes of the University of Southern California School of Medicine reported that nine out of twenty-seven people (33%) with either treatment-resistant depression or treatment-resistant bipolar disorder had a permanent positive response to primidone. It should be noted that a plurality of subjects were also given methylphenobarbital in addition to or instead of primidone.^[28]

Five months later, Brown, Stone, and Rathbone published a case report titled, "Primidone and rapid cycling affective disorders" describing a 62-year-old woman who had rapid-cycling bipolar disorder starting in 1978. Lithium treatment was started two years later, but it only eliminated the manic swings, leaving her depressions unaffected. Between 1980 and 1989, the patient had six to ten episodes a year, each lasting between eleven and twenty-four days that left her with little energy, made tasks seem more arduous than they actually were, a smaller appetite, a tendency to sleep too much, anxious, and weepy. No antidepressant eliminated all her symptoms.^[29]

At the age of fifty-eight, she was started on 125 mg/day of primidone for hand tremor. Her depression, which was resistant to all the antidepressants she tried, gradually remitted during primidone therapy; the expected depressive episode lasted three days instead of 13-17. Eight weeks later, she had an episode lasting twenty-eight days. Her last two episodes were nineteen weeks apart, lasting twenty-five and twenty-seven days, respectively. It was during the final episode, in the middle of 1990, that her dose of primidone was stabilized at 500 mg/day. She had been free of depression for two and a half years before the case report was written up.^[29]

In 1999, Drs. Linda C. Schaffer, Charles B. Schaffer, and J. Caretto conducted a follow-up study on those earlier reports, as no one else had done so in the six years following their publication, and found it to be roughly as (permanently) effective for refractory bipolar disorder as Hayes had reported it to be (31% vs. Hayes's 33%).^[30]

In 1965, Monroe and Wise reported using primidone along with a phenothiazine derivative antipsychotic and chlordiazepoxide in treatment-resistant psychosis.^[31] What is known is that ten years later, Monroe went on to publish the results of a meta-analysis of two controlled clinical trials on people displaying out-of-character and situationally inappropriate aggression, who had abnormal EEG readings, and who responded poorly to antipsychotics; one of the studies was specifically mentioned as involving psychosis patients. When they were given various anticonvulsants they were administered not only did their EEGs improve, but so did the aggression.^[32]

[edit] Trigeminal neuralgia

Unlike carbamazepine, there are few case reports mentioning the use of primidone in the treatment of trigeminal neuralgia. The first, published in the October 10, 1957 issue of Gazette Médicale de France, has no abstract.^[33] The second one was a case report of a woman taking primidone and prednisolone for trigeminal neuralgia; she developed toxic epidermal necrolysis, as well as endocarditis and gastrointestinal hemorrhage.^[34]

[edit] Veterinary

Mysoline has veterinary uses, including the prevention of aggressive behavior and cannibalism in gilt pigs, and treatment of nervous disorders in dogs and other animals.^[35][36]

[edit] Adverse Effects

The common central nervous system side effects of primidone include vertigo, ataxia, impaired motor skills, sedation/drowsiness, and cognitive impairment.^[37] It also causes hyperactivity, usually in children^[38] as well as irritability and insomnia.

It was realized by 1973 that primidone's sedative properties were not solely due to phenobarbital.^[39]

In May of 2005, Dr. M. Lopez-Gomez's team reported an association between the use of primidone and depression in epilepsy patients; this same study reported that inadequate seizure control was also a factor. They had been looking for factors associated with depression in epilepsy patients.^[40] Schaffer et al 1999 reported that one of their treatment failures, a 45-year-old woman taking 50 mg a day along with lithium 600 mg/day, clozapine 12.5 mg/day, trazadone 50 mg/day, and alprazolam 4 mg/day for three and a half months experienced auditory hallucinations that led to discontinuation of primidone.^[30]

Hyperammonemic encephalopathy was reported by Katano Hiroyuki of the Nagoya City Higashi General Hospital in early 2002 in a patient who had been stable on primidone monotherapy for five years before undergoing surgery for astrocytoma, a type of brain tumor. Additionally, her phenobarbital levels were inexplicably elevated post-surgery. This is much more common with the valproates than with any of the barbiturates.^[41]

A randomized controlled trial whose results were published in the July 1985 issue of The New England Journal of Medicine found that primidone was more likely to cause impotence than phenytoin, carbamazepine, or phenobarbital.^[42]

Primidone has other cardiovascular effects in addition to shortening the QT interval. Both it and phenobarbital are associated with elevated serum levels (both fasting and six hours after methionine loading) of homocysteine, an amino acid derived from methionine. This is almost certainly related to the low folate levels reported in primidone users. Elevated levels of homocysteine have been linked to coronary heart disease. In 1985, both drugs were also reported to increase serum levels of high density lipoprotein (HDL) cholesterol, total cholesterol, and apolipoproteins A and B.^[43]

Dupuytren's contracture, a disease of the fasciae in the palm and fingers that permanently bends the fingers (usually the little and ring fingers) toward the palm, was first noted to be highly prevalent in epileptic people in 1941 by a Dr. Lund, fourteen years before primidone was on the market. Lund also noted that it was equally prevalent in individuals with idiopathic and symptomatic epilepsy and that the severity of the epilepsy did not matter. However, only one quarter of the women were affected vs. half of the men.^[44] Thirty-five years later, Critcheley et al reported a correlation between how long a patient had had epilepsy and his or her chance of getting Dupuytren's contracture. They suspected that this was due to phenobarbital therapy, and that the phenobarbital was stimulating peripheral tissue growth factors.^[45]

Dupuytren's contracture is almost exclusively found in Caucasians, especially those of Viking descent, and highest rates are reported in Northern Scotland, Norway, Iceland, and Australia. It has also been associated with alcoholism, heavy smoking, diabetes mellitus, physical trauma (either penetrating in nature or due to manual labor), tuberculosis, and HIV. People with rheumatoid arthritis are less likely to get this, and Drs. Hart and Hooper speculate that this is also true of gout due to the use of allopurinol This is the only susceptibility factor that is generally agreed upon. Anticonvulsants do not seem to increase the incidence of Dupuytren's contracture in non-whites.^[44]

Primidone was first linked to toxic epidermal necrolysis in a 1973 case report of a woman taking it, along with phenobarbital, for trigeminal neuralgia.^[34]

Nausea and vomiting are not unheard of side effects that are usually transient.

Primidone was first reported to exacerbate hepatic porphyria in August of 1979,^[46] and by 1981, it was listed as an unsafe agent in patients with known hepatic porphyria.^[47]

According to a tutorial created by Schlienger and Shear in 1998, primidone is one of the anticonvulsants associated with anticonvulsant hypersensitivity syndrome, others being carbamazepine, phenytoin, and phenobarbital.^[48]

Primidone is also known to cause drug-induced systemic lupus erythematosus.^[49]

Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most heavily associated with bone diseases such as osteoporosis, osteopenia (which can precede osteoporosis), osteomalacia and fractures. The populations most at risk are institutionalized people, postmenopausal women, older men, people taking more than one anticonvulsant, and children, who are also at risk of rickets.^[50]

Drs. Pack and Morrell stated in 2001 that institutionalized patients are at risk of bone disease whether they take anticonvulsants or not, due to their limited exposure to sunlight and relative lack of access to exercise.^[50] However, a 1987 study of elderly institutionalized people conducted at the University College Hospital's Department of Geriatric Medicine in London found that the rate of osteomalacia in the ones taking anticonvulsants—one out of nineteen individuals taking an anticonvulsant (vs. none among the thirty-seven people taking none) —was similar to that expected in elderly people. They speculated that this was due to improvements in diet, sun exposure and exercise in response to earlier findings, and/or that this was because it was sunnier in London than in the Northern European countries which had earlier reported this.^[51]

The same is true of postmenopausal women. However, the use of more than one anticonvulsant has been associated with an increased prevalence of bone disease in institutionalized epilepsy patients versus institutionalized people who did not have epilepsy. Likewise, postmenopausal women taking anticonvulsants have a greater risk of fracture than their drug-naive counterparts.^[50]

Granulocytopenia, agranulocytosis, and red-cell hypoplasia and aplasia, and megaloblastic anemia are rarely associated with the use of primidone.^[52] Megaloblastic anemia is actually a group of related disorders with different causes that share morphological characteristics—enlarged erythrocytes with abnormally high nuclear-to-cytoplasmic ratios resulting from delayed maturation of nuclei combined with normal maturation of cytoplasm, in to abnormal megakaryocytes and sometimes hypersegmented neutrophils; regardless of etiology, all of the megaloblastic anemias involve impaired DNA synthesis.^[53]

The first report associating it with megaloblastic anemia came the same year it went to market from Drs. Chalmers and Boheimer. They reported a case of a 32-year-old woman who was treated with phenobarbital for fourteen years, then with phenytoin (the first anticonvulsant reported to cause this) for five years, and then primidone with phenobarbital for two months before anemia was detected and she was given folic acid, leading to full recovery.^[54]

One year later, Drs. Berlyne and colleagues reported another case occurring in a 28-year-old who had been treated with a combination of phenobarbital and phenytoin for four years and primidone combined with the first two for three months prior to being hospitalized for anemia. When there was no response to vitamin B₁₂ after three days, they administered folic acid, resulting in complete recovery.^[54]

In 1957, Drs. M. J. D Sumner and D. W. Newman two more cases of megaloblastic anemia associated with primidone. The patients were two housewives aged fifty-two and forty-nine. Both had been admitted to the hospital in 1955. They speculated that this was related to the slight similarities between folic acid and primidone and phenytoin.^[54]

In 1958, Chanarin, Elmes, and Mollin conducted folic acid studies on megaloblastic anemia patients who had been taking primidone.^[55] Eight years earlier, Daubenmerkl reported that folic acid was effective in a patient of his that was refractory to liver extract^[56] and by the early 1960s, it was established that folic acid deficiency could cause megaloblastic anemia.^[57] In 1962, primidone was reported to interfere with folic acid metabolism.^[58]

By the mid-1970s, it was obvious that this antagonistic effect was not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.^[59] By the late 1980s, it was recognized that not only was oral supplementation with folic acid an effective way to treat primidone-induced megaloblastic anemia, but also that the latter could only occur in the presence of a dietary deficiency of folate.^[60]

In addition to increasing the risk of megaloblastic anemia, this also increases the risk of neural tube, cardiovascular, oral cleft, and urinary tract defects, but also that vitamin supplementation will not prevent these defects.^[61]

Additionally, a coagulation defect resembling Vitamin K deficiency has been observed in newborns of mothers taking primidone.^[62][63]

Because of this, primidone is a Category D medication.^[62]

[edit] 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 since 1975.^[64]

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.^[65]

Like many anticonvulsants, primidone interacts with other anticonvulsants. Clobazam decreases clearance of primidone,^[66] mesuximide increases plasma levels of phenobarbital in primidone users,^[67] both primidone and phenobarbital accelerate the metabolism of carbamazepine via CYP3A4,^[68] and lamotrigine's apparent clearance is increased by primidone.^[69]

Like the other enzyme-inducing anticonvulsants, primidone 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%.^[70]

Primdone 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.^[71]

[edit] Metabolism

Primidone converts to phenobarbital and PEMA via the CYP2C19 and CYP2C9 hepatic enzymes.^[72] The phenobarbital, in turn, is metabolized to p-hydroxyphenobarbital.^[73] Alvin, Goh, and Bush reported in 1975 that the rate of primidone metabolism was greatly accelerated by phenobarbital pretreatment, moderately accelerated by primidone pretreatment, and reduced by PEMA pretreatment.^[74] In 1983, a new minor metabolite, p-hydroxyprimidone, was discovered.^[75]

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.^[70]

In 1983, Battino et al reported that 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).^[76] Martines et al reported in 1990 that, relative to the 18-26 group, subjects aged 70-81 had 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.^[77] The clinical significance is unknown.

[edit] Available forms

Primidone is available as a 250mg/5mL suspension, and in the form of 50 mg, 125 mg, and 250 tablets. It is also available in a chewable tablet formulation in Canada.^[78]

The available brands include Mysoline® (Canada,^[79] Ireland,^[80] Japan,^[81] the United Kingdom,^[82] and the United States^[79]), Prysoline® (Israel, Rekah Pharmaceutical Products, Ltd.),^[83] Apo-Primidone,^[78][84] Liskantin® (Germany, Desitin),^[85] Resimatil® (Germany, Sanofi-Synthélabo GmbH),^[86] and Mylepsinum® (Germany, AWD.pharma GmbH & Co., KG).^[87]

It has been available in the United States as a generic drug from Lannett since 1978.^[88]

[edit] References

• National Institutes of Health (2005). Primidone (Systemic). MedlinePlus. Retrieved on July 2, 2007.
• Apo-Primidone Drug Information. Retrieved on July 4, 2007.
• American Epilepsy Society. Primidone. Anti-Epileptic Drugs. Retrieved on July 2, 2007.
• TR-476 Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B₆C₃F₁ Mice (Feed Studies). Department of Health and Human Services National Toxicology Program. Retrieved on July 2, 2007.

[edit] End Notes

[edit] External links

• Official Website of Valeant Pharmaceuticals International