Primidone Chemical Properties

Melting point:

281-282°C

Boiling point:

358.94°C (rough estimate)

Density 

1.1402 (rough estimate)

refractive index 

1.6660 (estimate)

Flash point:

9℃

storage temp. 

Sealed in dry,Room Temperature

solubility 

Very slightly soluble in water, slightly soluble in ethanol (96 per cent). It dissolves in alkaline solutions.

pka

12.26±0.40(Predicted)

form 

Solid

color 

White to Off-White

Water Solubility 

<0.1 g/100 mL at 19 ºC

Merck 

14,7746

BCS Class

2

InChIKey

DQMZLTXERSFNPB-UHFFFAOYSA-N

CAS DataBase Reference

125-33-7(CAS DataBase Reference)

NIST Chemistry Reference

Primidone(125-33-7)

IARC

2B (Vol. 108) 2016

EPA Substance Registry System

Primidone (125-33-7)

Safety Information

Hazard Codes 

Xn,T,F

Risk Statements 

22-40-39/23/24/25-23/24/25-11

Safety Statements 

22-36-45-36/37-16-7

RIDADR 

3249

WGK Germany 

3

RTECS 

UV9100000

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29335990

Hazardous Substances Data

125-33-7(Hazardous Substances Data)

Toxicity

child,TDLo,oral,625mg/kg (625mg/kg),BEHAVIORAL: SLEEPBEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY)BEHAVIORAL: GENERAL ANESTHETIC,British Medical Journal. Vol. 1, Pg. 90, 1957.

MSDS

• Language:English Provider:Primidone
• Language:English Provider:SigmaAldrich

Primidone Usage And Synthesis

Description

Primidone is chemically and structurally similar to phenobarbital with the exception that the carbonyl group on C2 is replaced by a methylene group. This modification leads to the production of a drug with strong anticonvulsant properties without expressed soporific effects.

Description

Primidone (Item No. 19277) is an analytical reference material categorized as a barbiturate that can be detected in urine. The physiological and toxicological properties of this compound are not known; however, it is presumed to be a modulator of GABA_A receptors. This product is intended for research and forensic applications.

Chemical Properties

Crystalline Solid

Uses

Primidone is an Anticonvulsant.

Uses

Primidone is mainly used for major attacks.

Definition

ChEBI: A pyrimidone that is dihydropyrimidine-4,6(1H,5H)-dione substituted by an ethyl and a phenyl group at position 5. It is used as an anticonvulsant for treatment of various types of seizures.

brand name

Mysoline (Valeant); Mysoline (Xcel).

General Description

Odorless white crystalline powder. Slightly bitter taste. No acidic properties.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Primidone is an amide. May react with azo and diazo compounds to generate toxic gases. May react with strong reducing agents to form flammable gases. A very weak base. The Combustion generates toxic mixed oxides of nitrogen (NOx).

Fire Hazard

Flash point data for Primidone are not available; however, Primidone is probably combustible.

Biological Activity

Anticonvulsant.

Pharmacokinetics

Approximately 60 to 80% of an oral dose of primidone is absorbed and slowly metabolized by the liver to phenobarbital and phenylethylmalonamide (PEMA). All three molecules have antiseizure effects, but PEMA appears to be weaker and to be the more toxic metabolite. During chronic therapy, approximately 15 to 25% of an oral dose of primidone is excreted in the urine unchanged, 15 to 25% metabolized to phenobarbital, and 50 to 70% excreted as PEMA (half-life, 24–48 hours). The phenobarbital metabolite may be excreted in the urine unchanged, as its p-hydroxy metabolite, and as glucuronide or sulfate conjugates. Following an oral dose, the peak plasma levels for primidone are reached in approximately 4 hours, with a reported half-life of 10 to 12 hours. Plasma concentrations in the range of 8 to 12 μg/mL control seizures and minimize adverse effects. Primidone shows antiseizure activity before the phenobarbital levels reach therapeutic range. Only after chronic dosing of primidone are the levels of phenobarbital significant, suggesting autoinduction. Serum levels of chronically administered primidone exceed those of its metabolite, phenobarbital, thus demonstrating that it has antiseizure activity independent of phenobarbital. When primidone is coadministered with enzyme-inducing AEDs, the levels of its phenobarbital metabolite may be two- to threefold higher than those in the noninduced state. Protein binding of primidone and PEMA is negligible, and the phenobarbital metabolite is approximately 50% protein bound.
Primidone use is associated with decreases in CBZ, lamotrigine, valproate, tiagabine, and zonisamide serum levels. Primidone levels are increased by nicotinamide and isoniazid. Hydantoins increase the plasma concentrations of primidone, phenobarbital, and PEMA. CBZ increases levels of phenobarbital derived from primidone. Primidone levels are decreased by succinimides, CBZ, and acetazolamide.

Clinical Use

Primidone is the 2-deoxy derivative of phenobarbital and is approved by the U.S. FDA for initial or adjunctive treatment of simple partial, complex partial, and tonic-clonic seizures. It is less effective against these types of seizures than is phenytoin or CBZ, and it shares the antiseizure and sedative actions of phenobarbital. Although not approved for the purpose, it often is used to treat benign familial tremor (essential tremor).

Side effects

As with phenobarbital, serious toxicity for primidone is rare, although it may cause disabling sedation, irritability, and decreased mental functioning in a number of persons. Ataxia, dysphoria, idiosyncratic rash, leukopenia, agranulocytosis, lymphadenopathy, hepatitis, and a systemic lupus erythematosus–like syndrome have been reported adverse effects for primidone. Deficiencies of folic acid and of vitamins D and K are possible with long-term therapy of primidone, as is a folateresponsive megaloblastic anemia. Measurement of the complete blood cell count should be performed at 6-month intervals.

Safety Profile

Poison by ingestion and intraperitoneal routes. Human teratogenic effects include developmental abnormalities of the craniofacial area, skin and skin appendages, and cardlovascular system. Human reproductive effects: effects on newborn, including unusual growth statistics, drug dependence, physical and other neonatal changes. Experimental teratogenic and reproductive effects. Human mutation data reported. An addictive drug. When heated to decomposition it emits toxic fumes of NOx. See also BARBITURATES.

Synthesis

Primidone, 5-ethyl-5-phenylhexahydropyrimidinedione-4,6 (9.2.1) is synthesized by reacting ethylphenylmalonic acid diamide with formamide [5,6]. An alternative method is the electrolytic reduction of phenobarbital or the catalytic reduction of the appropriate 2-thiobarbituric acid [7].

Veterinary Drugs and Treatments

Primidone is indicated for seizure control (idiopathic epilepsy, epileptiform convulsions) in the dog. Because it is rapidly converted into phenobarbital in this species (see Pharmacokinetics below), and has a greater incidence of hepatotoxicity and behavioral effects, most neurologists do not recommend its use. However, some clinicians feel that some animals not responding to phenobarbital do benefit from primidone therapy, perhaps as a result that PEMA has been demonstrated to potentiate the anticonvulsant activity of phenobarbital in animals. When compared with phenobarbital, increased incidence of hepatotoxicity associated with primidone is considered the major limitation to long-term therapy with this agent. Primidone is considered more toxic in rabbits and cats than in humans or dogs.

Drug interactions

Potentially hazardous interactions with other drugs
Aminophylline and theophylline: metabolism of aminophylline and theophylline increased, reduced effect.
Anthelmintics: concentration of albendazole and praziquantel reduced.
Anti-arrhythmics: reduced concentration of disopyramide and possibly propafenone; possibly reduced concentration of dronedarone - avoid.
Antibacterials: reduced concentration of chloramphenicol, doxycycline, metronidazole, telithromycin and rifampicin - avoid with telithromycin.
Anticoagulants: increased metabolism of coumarins (reduced effect); possibly reduced concentration of apixaban and edoxaban and possibly rivaroxaban.
Antidepressants: antagonise anticonvulsant effect; reduces concentration of paroxetine, reboxetine, mianserin and tricyclics; concentration reduced by St John’s wort - avoid.
Antiepileptics: concentration increased by fosphenytoin, oxcarbazepine, phenytoin, stripentol and valproate and possibly carbamazepine, also active metabolite of oxcarbazepine reduced and valproate concentration reduced, concentration of fosphenytoin and phenytoin usually reduced but can also be increased; concentration of ethosuximide, rufinamide and topiramate possibly reduced; concentration of lamotrigine, tiagabine and zonisamide reduced.
Antifungals: possibly reduced concentration of isavuconazole, itraconazole, posaconazole and voriconazole - avoid concomitant use with voriconazole; reduced absorption of griseofulvin (reduced effect).
Antimalarials: avoid with piperaquine with artenimol; anticonvulsant effect antagonised by mefloquine
Antipsychotics: antagonise anticonvulsant effect; metabolism of haloperidol increased; possibly reduces aripiprazole concentration - increase aripiprazole dose; concentration of both drugs reduced with chlorpromazine; possibly reduces clozapine concentration; possibly reduces lurasidone concentration - avoid.
Antivirals: concentration of abacavir, boceprevir, darunavir, dolutegravir, fosamprenavir, indinavir, lopinavir, rilpivirine and saquinavir possibly reduced; avoid with boceprevir and rilpivirine; concentration of daclatasvir, dasabuvir, ombitasvir, paritaprevir and simeprevir possibly reduced - avoid; avoid with elvitegravir, etravirine, ledipasvir, sofosbuvir and telaprevir.
Calcium-channel blockers: effects of calcium-channel blockers probably reduced - avoid with isradipine and nimodipine.
Cannabis extract: concentration possibly reduced by primidone - avoid.
Ciclosporin: reduced ciclosporin levels.
Cobicistat: concentration of cobicistat possibly reduced.
Corticosteroids: metabolism of corticosteroids accelerated, reduced effect.
Cytotoxics: possibly reduced concentration of axitinib, increase axitinib dose; possibly reduced concentration of bortezomib, bosutinib, cabozantinib, ceritinib, crizotinib, dasatinib, ponatinib and vandetanib - avoid; avoid with cabazitaxel, dabrafenib, gefitinib and panobinostat; concentration of irinotecan and its active metabolite and possibly etoposide reduced; possible increased hypersensitivity reactions with procarbazine.
Diuretics: concentration of eplerenone reduced - avoid; increased risk of osteomalacia with carbonic anhydrase inhibitors.
Guanfacine: concentration of guanfacine possibly reduced - increase dose of guanfacine.
Hormone antagonists: possibly reduced concentration of abiraterone - avoid; metabolism of toremifene accelerated.

Metabolism

Partially metabolised to phenobarbital and phenylethylmalonamide in the liver, both of which are active and have longer half-lives compared to primidone (metabolites may accumulate in renal impairment). It is excreted in urine as unchanged drug and metabolites.

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