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Primidone
 

Primidone, is an anticonvulsant of the pyrimidinedione class whose active metabolites, phenobarbital (minor) and phenylethylmalonamide (PEMA) (major), are also anticonvulsants. Like many anticonvulsants, it is a GABA receptor agonist (i.e., it simulates the action of GABA in the central nervous system). Primidone, especially when combined with phenytoin, was once considered the treatment of choice for temporal lobe epilepsy with tonic-clonic seizures.}} 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).}}

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 can't be used for some reason. | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=11096777&dopt=ExternalLink}}

It has been available as a generic drug from Lannett since 1978.

Metabolism

Primidone converts to phenobarbital and PEMA via the CYP2C19 and CYP2C9 hepatic enzymes. The phenobarbital, in turn, is metabolized to p-hydroxyphenobarbital. | url = http://torpedo.nrl.navy.mil/tu/ps/openurl.html?issn=0021-9673&volume=182&issue=1&spage=71}} 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.}} In 1983, a new minor metabolite, p-hydroxyprimidone, was discovered. | url = http://dmd.aspetjournals.org/cgi/reprint/11/6/607}}

Uses

Primidone is used to treat, but not cure, the following conditions in the following countries:

Approved Uses

United Kingdom
According to the electronic Medicines Compendium, primidone is licensed for generalized tonic-clonic seizures and complex partial seizures.

United States
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.

Unapproved/Investigational/Off-Label Uses

Primidone is considered to be a first-line therapy for essential tremor along with propranolol and was first used for it in 1981.}} Serrano-Duenas found in 2003 that 250 mg/day was at least as effective for this as 750 mg/day and with fewer side effects. | url = http://linkinghub.elsevier.com/retrieve/pii/S1353802003000701}}

There are three case reports, one from 1980, one from 1986, and another from 2002, where primidone was specifically mentioned as being used in the treatment of congenital long QT syndrome. The first case involves three patients, the first a 31-year-old white woman who still had ventricular fibrillation, syncope, and seizures even after left stellate ganglionectomy and thoracic chain dissection; the primidone suppressed the fibrillations and lengthened the QT interval for two years and eight months in the patient. | url = http://openurl.epnet.com/linksvc/linking.aspx?genre=article&sid=PubMed&issn=0003-4819&title=Ann%20Intern%20Med&volume=93&issue=1&spage=53&atitle=Primidone%20in%20the%20treatment%20of%20the%20long%20QT%20syndrome:%20QT%20shortening%20and%20ventricular%20arrhythmia%20suppression.&aulast=DeSilvey&date=1980}} She had previously been tried on phenobarbital-phenytoin (when she was thought to have only seizures), phenobarbital-phenytoin-procainamide, phenobarbital-phenytoin-propanolol, phenobarbital-phenytoin-procainamide (when propanolol brought the tachycardia back almost instantaneously upon the first dose), phenobarbital-phenytoin-atropine-acetylstrophanthidin, and phenobarbital-phenytoin-lidocaine prior to the surgery. After the surgery, the QT-prolongation returned, so the phenytoin was doubled to 200 mg qid. 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 other two patients are the first one's 16-year-old niece and 15-year-old nephew, both brother and sister. The niece was started on primidone after an unsuccessful trial of phenytoin and the nephew was started because of family history.

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.}} The 2002 case focuses on hypocalcemia stemming from such treatment in an adolescent male.}}

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.

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

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, because the study was more about whether barbiturates in general could be effective for mood disorders, not just primidone).}} 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. | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8105181&query_hl=229&itool=pubmed_ExternalLink}} Lithium treatment was started two years later, but it only eliminated the mania, leaving her depressions unaffected. She would have between six and ten of them per year, lasting between eleven and twenty-four days that made her anergic, anxious, weepy, hypersomniac, and unable to meet any demands. Her depression, which was refractory to all antidepressants tried, gradually remitted during primidone therapy for essential tremor started in mid-1990. In 1999, 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%). | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=10440522&dopt=ExternalLink}}

In 1965, Monroe and Wise reported using primidone along with a phenothiazine derivative antipsychotic and chlordiazepoxide in treatment-resistant psychosis.}} 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.}}

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. | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=11814737&dopt=ExternalLink}}

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.}} 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.}}

Adverse Effects

Central nervous system

The common central nervous system side effects of primidone include vertigo, ataxia, impaired motor skills, sedation/drowsiness, cognitive impairment, hyperactivity, usually in children}} and the elderly; irritability, insomnia.

Less common side effects
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. | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WDT-4FPYWP8-5&_user=10&_coverDate=05%2F31%2F2005&_alid=301001088&_rdoc=1&_fmt=full&_orig=search&_qd=1&_cdi=6775&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=89357c80278ec360b1a64c6998eab8cf}} 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.

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 much more common with the valproates than with barbiturates. | url = http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WHP-457MDPK-N-1&_cdi=6856&_user=10&_orig=search&_coverDate=01%2F31%2F2002&_qd=1&_sk=999909998&view=c&wchp=dGLbVzz-zSkWA&md5=187493fdfe9a11cf9414ba1997a80a15&ie=/sdarticle.pdf}}

Autonomic Nervous System

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.}}

Cardiovascular

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. | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=15871863&dopt=ExternalLink}}

In 1985, both drugs were also reported to increase serum levels of high density lipoprotein (HDL) cholesterol, total cholesterol, and apolipoproteins A and B.}}

Connective Tissue System

In 1976, Critcheley et al reported an unusually high rate of Dupuytren's contracture in chronic epilepsy patients being studied and 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.}} As primidone metabolizes to phenobarbital, there could be a problem with that.

Dermatologic

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

Gastrointestinal

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

Hematopoietic

Primidone was first associated with megaloblastic anemia in 1957.}} 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 hypersegmentation neutrophils; regardless of etiology, all of the megaloblastic anemias involve impaired DNA synthesis.

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

Rousso reported in the February 1967 issue of Praxis that folic acid supplementation was successful in treating the megaloblastic anemia of one of his patients.}}

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.}} 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 was precipated by a dietary defiency of folate.}}

Hepatic

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

Immunologic

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. | url = http://gateway.ut.ovid.com/gw1/ovidweb.cgi?T=JS&PAGE=fulltext&D=ovft&AN=00003606-199800007-00002&NEWS=N&CSC=Y&CHANNEL=PubMed}}

Primidone is also known to cause drug-induced systemic lupus erythematosus.}}

Musculoskeletal

Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most heavily associated with osteoporosis, osteopenia, osteomalacia and fractures. | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=11524035&dopt=ExternalLink}}

Pregnancy

Primidone is a folic acid antagonist but is not a dihydrofolate reductase inhibitor, which means that not only does it increase the risk of neural tube, cardiovascular, oral cleft, and urinary tract defects, but also that vitamin supplementation will not prevent these defects. | url = http://content.nejm.org/cgi/content/full/343/22/1608}}

A coagulation defect resembling Vitamin K deficiency has been observed in newborns of mothers taking primidone. | url = http://www.treatment-options.com/no_entry.cfm?Access=Subs&KeyWords=&PubID=NE04-1-1-04&HitNum=&thePage=FullText}}

Effects of Age, Gender and Ethnicity on the Metabolism and Elimination of Primidone

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 oldsest patients (the maximum age being 55).

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.}} The clinical significance is unknown.

Drug Interactions

Primdone interferes with the metabolism of dexamethasone to the point where its withdrawal from the regimen of a 14-year-old living in the United Kingdom made her hypercortisolemic.

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.}}

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.}}

Like many anticonvulsants, primidone interacts with other anticonvulsants. Clobazam decreases clearance of primidone, | url = http://openurl.proquest.com/in?service=pq&issn=0883-0738&volume=12&issue=3&spage=208&pid=ipauto}} 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.

Availability

Australia

At some point in time, there was an ICI Australia Pty Ltd producing Mysoline® but current (post-1999) availability is unknown. What is known is that ICI Australia Pty Ltd changed its name to Orica Australia Pty Ltd on February 2, 1998, almost a year after its parent company, ICI plc, divested its 62.4% shareholding in it. And that a search for documents containing "orica" and "primidone" turned up nothing.

Canada

Apo-Primidone®, Mysoline®, PMS Primidone®, Sertan®. (Mysoline is no longer available in the Toronto area)

Germany

Liskantin® (Desitin), Resimatil® (Sanofi-Synthélabo GmbH), and Mylepsinum® (AWD.pharma GmbH & Co. KG)

Ireland

Mysoline®, as currently manufactured by Acorus Therapeutics Ltd.

Israel

Prysoline®, Rekah Pharmaceutical Products, Ltd.

Italy

Mysoline®, manufacturer unknown.

Japan

Mysoline® (マイソリン Maisorin), manufactured by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical Co.).

Sweden

There is one abstract of a Swedish study mentioning a Mylepsin published in 1955,}} but whether or not primidone is currently available there in any form is unknown.

Switzerland

Mysoline®, manufacturer unknown.

United Kingdom

Mysoline®, also manufactured by Acorus Therapeutics Ltd.

United States

Myidone® (current and former manufacturers unknown) and Mysoline®, which is currently manufactured by Valeant Pharmaceuticals International.

History of primidone

See also

References

End Notes

External links

Anticonvulsants

Primidon | Гексамидин | Primidone | プリミドン

 

This article is licensed under the GNU Free Documentation License. It uses material from the "Primidone".

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