Primidone

Mechanism of Action

Primidone appears as a white crystalline powder; it is practically insoluble in water (1/2000), slightly soluble in alcohol (1/200), and soluble in alkaline solutions. The basic skeleton of primidone comprises pyrimidinedione, which after metabolism, converts into phenobarbital and phenylethylmalonamide (PEMA). The chemical structure of primidone differs from phenobarbital due to the substitution in the C2 position of the carbonyl group with the methylene bridge. This chemical modification of the molecule led to a product with a strong anti-convulsive effect and less sedation.

The mechanism of action is not well-demarcated, but it appears to bind centrally with voltage-gated sodium channels and inhibits the monotonous firing of action potentials.[9] Also, it activates gamma-aminobutyric acid (GABA)-A receptor complex with chloride ionophore, which extends the frequency of opening of the chloride channel, causing hyperpolarization by altered the electrical activity of the nerve cell membrane.[10] The effect of primidone in treating essential tremor is not mediated by the active metabolite PEMA.[11] Interestingly, because in vivo investigations proved that primidone inhibits TRPM3 and attenuates thermal nociception, this drug could have a role in pain medicine.[12]

Pharmacokinetic Factors

Absorption

Primidone is rapidly and completely absorbed from the gastrointestinal tract with a blood peak reached in about 3 hours; it shows a half-life of approximately 10 to 15 hours, shorter than that of the two metabolites while reaching steady-state within 1 to 2 days.[13] The half-life in elderly subjects over 75 years probably increases due to metabolic deficits. The half-life in neonates is longer than that in children/adults, probably due to a larger apparent volume of distribution and a lower metabolic capacity of these subjects.

Distribution 

The volume of distribution (Vd) is 0.8 L/Kg, while the plasma concentrations of primidone are between 5 and 12 mcg/mL; it is rapidly distributed in the tissues and shows a partial serum protein binding (about 35%); the therapeutic range is between 23 to 55 mg/mL. Primidone crosses the blood-brain barrier and the placental barrier and is also distributed in breast milk.

Metabolism

In addition to the two primary active metabolites (PEMA and phenobarbital), the drug has a minor metabolite, p-hydroxyprimidone. However, primidone cannot be considered a prodrug because it has intrinsic pharmacological activity. It is subject to two main metabolisms:

• Oxidation in C2 with the formation of phenobarbital
• Cleavage of the ring in C2 with the formation of PEMA.: It is not yet known which isoform of cytochrome P 450 is involved in its metabolism.

The percentage of primidone metabolized to phenobarbital fluctuates between 15% and 25%.

Elimination

It is excreted in the urine, in unmodified form, for 40%.

Administration

Primidone is available in 50 and 250 mg tablets in different generic formulations and under different brand names. This drug should start at the lowest possible dose, with dosing increases in a stepwise manner to minimize adverse effects.

Grand Mal and Psychomotor Seizure

Clinicians have sued primidone for the control of grand mal and psychomotor seizure. It may be used alone or in combination with other anticonvulsants. In adults and children over eight years, 250 mg at bedtime is initiated during the first week, which is increased to 250 mg twice daily in the second week, 250 mg thrice daily in the third week, and 250 mg four times a day in the fourth week. The clinical efficacy of a dosage regimen takes several days before it can be tested.

• Continue similar weekly increments are necessary until seizures are under control. 
• It is not recommended to dosage greater than 2 g daily. 

In patients who are already on other anticonvulsants, the usual dosage range of primidone in adults and children eight years and older is between 125 mg and 1500 mg daily in divided doses.

Essential Tremor

Primidone has also been used effectively in the treatment of essential tremor.  The recommended initial dose for adults is 100 to 125 mg each day, with slow increments to a maintenance dose of 250 mg three times each day.[10]

Adverse Effects

The most common side effect of primidone therapy is sedation and drowsiness. Ataxia, diplopia, and nystagmus occur at the initiation of treatment. Other adverse reactions include dizziness, vertigo, epigastric pain, megaloblastic anemia, respiratory depression, polyuria, skin rash, facial edema. Hypersensitivity reactions tend to occur more frequently in patients with a history of asthma, urticaria, or angioedema. Agranulocytosis and thrombocytopenia are rare.

Long term use of barbiturates is associated with:

• Connective tissue disorder.
• There is a higher risk of decreased bone mineral density that may lead to weakened or brittle bones. In such cases, the prescriber should consider discontinuation of primidone.
• An increased risk of rickets and osteomalacia (phenobarbital) due to increased metabolism of vitamin D.[14]
• There can also be folate deficiency leading to megaloblastic anemia.
• There have been instances of hyperhomocysteinemia secondary to reduced folate level, with elevated cholesterol and apoprotein A and B levels.[15]
• Newborns of mothers on primidone therapy have demonstrated a coagulation defect that is similar to vitamin K deficiency.[16] Primidone is an FDA pregnancy category D drug.

Contraindications

Several clinical conditions contraindicate the use of primidone.

• Primidone is contraindicated in patients who are known to be hypersensitive to barbituric acid derivatives.
• Contraindications to primidone include patients with a history of porphyria. By inducing the enzymes responsible for porphyrin synthesis, barbiturates may worsen acute porphyria.
• This drug is also contraindicated in patients with severe respiratory depression or pulmonary insufficiency, hepatic impairment, alcoholism, renal impairment, sleep apnea, suicidal potential, drug dependence, or in the presence of uncontrolled pain.[17]

Monitoring

The therapeutic range for primidone is between 5 and 10 mg/L. Suicidal ideation and activity have occurred in many cases of patients treated with antiepileptic agents. All patients treated with antiepileptic medications, regardless of indication, should be monitored for signs of suicidal ideation and behavior, and consideration should be given to appropriate treatment. Patients (and patient caregivers) should be encouraged to seek medical advice should there be signs of suicidal ideation or behavior.

The deficiency of folic acid is known to occur during pregnancy and can lead to an increased occurrence of congenital disabilities in the offspring of women with treated epilepsy. As with many other antiepileptic medications, primidone may lead to or aggravate the deficiency of folic acid. Supplementation with folic acid is advisable before and during pregnancy.

Metabolism of primidone occurs slowly within the liver to produce phenobarbital and PEMA. Phenobarbital induces UGT enzymes CYP2C and CYP3A; therefore, the efficacy of some drugs such as anticoagulants, adrenal steroids, antibiotics, oral contraceptives, and anticonvulsants such as phenytoin can be reduced by the metabolic acceleration. Immediate withdrawal of the drug may cause status epilepticus; reduce dosage slowly. Again, barbiturates hinder the ability to perform mental-conscious activities such as driving.

Finally, a complete blood count and liver function test are necessary every six months, and primidone therapy can be monitored by phenobarbital concentration if required.[1]

Toxicity

Primidone toxicity has been studied in numerous animal species and was found to be exceptionally low. Nevertheless, hepatotoxicity and behavioral problems with primidone are more common than phenobarbital. For patients undergoing chronic primidone therapy, the ALT and ALP serum levels are more elevated than for any other widely used anticonvulsant. Additionally, there is documentation that hepatic cirrhosis secondary to chronic primidone use may also occur. Idiosyncratic reactions to primidone may also occur, which include hepatotoxicity and megaloblastic anemia. In patients with renal impairment, dosing adjustments should be according to clinical response and biological monitoring.

Moreover, several studies demonstrated that primidone could have significant toxicity, including:

• Genotoxicity. While the antiepileptic agent showed mutagenic proprieties in one strain of Salmonella typhimurium strain and genotoxicity during in vivo experiments, the real risk of genotoxicity to humans is unclear.[18][19] 
• Carcinogenicity. Studies demonstrated an increased incidence of hepatocellular neoplasms in mice, thyroid neoplasms in both mice and rats, and an increased incidence of renal carcinomas in male rats at clinical doses. Nevertheless, the risk of carcinogenicity to humans is unknown.[20]
• Teratogenicity. Teratogenic effects in rodents included palatal defects, enlargement of cerebral ventricles, club foot, open eyes, and subarachnoid hemorrhage. The drug also showed memory impairment and effects on fertility in animals.[21] 

Primidone Overdose

Patients who have had a primidone overdose may present with hypotension, coma, CNS depression, suppressed response to pain, suppressed reflexes, respiratory depression, and decreased urine output. Overdose requires management with symptomatic and supportive treatment, including the removal of any unabsorbed drug. Urine alkalinization and forced diuresis may enhance excretion. Hemodialysis may be necessary.[10]

Enhancing Healthcare Team Outcomes

Management of primidone therapy and especially possible overdose requires an interprofessional team of healthcare professionals, including nurses, pharmacists, laboratory technologists, and several clinicians (MDs, DOs, NPs, PAs) in various specialties. Without proper treatment, the morbidity and mortality from primidone overdose are high. Patients who have consumed primidone in excess often require hemodynamic and respiratory support; this could include ventilation, intubation, boluses of isotonic IV fluids, and inotropic infusions. Once the airway of a patient is protected, activated charcoal should be administered to minimize the absorption of orally administered primidone; multiple doses of activated charcoal improve phenobarbital clearance, although no evidence exists that it actually improves clinical outcomes. Urinary alkalinization also enhances phenobarbital clearance in patients with normal cardiac and renal function. Urinary alkalinization has not been shown to improve clinical outcomes, either.

A consult with a mental health professional to evaluate the patient to determine if it was an intentional act and if the patient may be at continued risk for self-harm may be appropriate. The pharmacist should make sure that there are no drug interactions, and the risk of possible drug overdose requires monitoring, open communication, and coordinated action from the clinical team.[22]