Primidone

primidone is a close congener of phenobarbital. The drug is a white, crystlalling tastless substance. Orimidone is approved by the FDA for use in the dog for control ov convulsions associated with "true" (rimary" epilepsy, epileptform seizures, virus encephalitis, distemper and "hardpad" disease. It may be the most commonly used antiepileptic agent in veterinary medicine. Although primidone does not appear to have an advantage over phenobarbital therapy in control of seizure disorders, this does not exclude the possibility that a single animal may respond more favourable to one or the other. Primidone is less well tolerated that phenobarbital because of its potential for inducing hepatotoxicity. Primidone is a barbiturate derivative metabolised to phenobarbital (major) and phenylethylmalonamide, or PEMA (minor). Primidone and its two major metabolites hace anticonvulsant activity, but at leas 85% od the pharmacologic activity is derived from phenobarbital.

Although seizures can be controlled with primidone in dogs, primidone has little advantage over phenobarbital in dogs. Control of seizures ion dogs is correlated with the plasma concentration of phenobarbital rather than primidone. In a comparison between primidone and phenobarbital. there was no significant difference between phenobarbital and primidone with respect to seizure control, and primidone appeared more likely to induce liver injury than phenobarbital. The authors conluded that phenobarbital, rather than primidone, should be the drug of first choice for treatment of canine epilepsy. However, there may be rare cases that respons to primodone when phenobarbital alone has not been effective (1 out f 15). primodone is more expensive than phenobarbital but is not classifies as a controlled drug in the US and therefore does not require the same degree of record keeping.

Initial dosages in dogs are 3-5mg/kg q8-12h but have been increased up to 12mg/kg q8h. If one is converting a patient from primidone to phenobarbital or vice versa, the conversion is 65mg phenobarbital to 250mg primidone.

Mechanism of Action

Barbituates act by depressing the central nervous system (CNS) by acting at the Gamma Aminobutyric Acid A receptors (GABAa). They mimic and enhance GABA, which is the principle inhibitory neurotransmitter in the CNS. Once bound to the GABAa receptor they reduce the rate of GABA dissocation and thereby increase chloride conductance is maintained resulting in hyperpolarisation of the membrane and reduced neuronal excitability. However, as the concentration of barbituate increases, it starts to have a direct effect on the chloride conductance and it is this that is thought to bring about the anaesthetic effects, while the GABA related increases causes a sedative effect. They act to depress the motor centres allowing there use as an anticonvulsant agent, as well as depressing the sensory centres and inducing an anesthetised state.

Pharmacologic Activity

In humans, approximately 60-90% of an oral does of primidone is rapidly absorbed from the GI tract, with a peak serum level being obtained in about 3 hours. in animals, primidone is oxidised to phenobarbital and cleaved to PEMA (C2). Although all three compounds have anticonvulsant activity, most of primidone's anticonvulsant activity in dogs results from phenobarbital: as the compounf with the longest half-life, it accumulates to the highest concentrations. The potency of primidone and PEMA is 1/30 that of phenobarbital. The efficacy of primidone generally is equal to or less that that or phenobarbital, and anticonvulsant acitivity can be correlated to serum phenobarbital levels. Because of this relationship. serum phenobarbital concentrats can and should be used to guide design of primidone dosing regimens. Target therapetic ranges are teh same as for phenobarbital. Primidone continues to be used in patients which have proven refractory to phenobarbital at the maximum therapeutic drug concentration. Note that its efficacy in the scenario has not been proven. efficacy may simply reflect improced conversion to phenobarbital (i.e. animals that are induced may metabolise the drug to greater concentrations of phenobarbital that those generated from administration of phenobarbital alone). There is no advantage in useing primisone rather than phenobarbital for control of epilepsy in most dogs. Primidone is more toxin in cats and rabis. cats metabolise primidone to phenobarbital to a lesser extent than dogs - less effective, more toxic.

Side Effects and Contraindications

Most adverse effects and side effects are the same as those listed for phenobarbital; however, primidone administration may be associated with a higher incidence of hepatotoxicity. Hepatic necrosis, fibrosis and cirrhosis have been associated with chronic use of primidone. Intrahepatic cholestasis has occured in dogs in which primisone was combined with phenytoin. manufacturers do nor recommed its used in cats; in fact it is stated on the package inerst that its use should be cautioned in cats. However, studies in cats have demonstrated that primidone is probably safe.

identical sedative side effects are seen in the dog after treatment with phenobarbital and after treatment with primidone. Primidone will cause all of the side effects noted for phenobarbital. primidone may induce nystagmus, nausea, drowsiness and ataxia. PD is more common in dogs treated with primisone. In man, megaloblastic anaemia is a side effect of primidone. In the dog, primidone induces progressive hepatic injury as manifested by increases in liver enzyme values. In a clinica study, signs of lover toxicity were repoerted in 14 of 20 dofs. Hepatic cirrhosis associated wth primidone and phenobarbital after 7 years of use has been reported in a dog. Dermatitis is a rarely reported side effect.

Should not be used with chloramphenicol - potent inhibotr of the microsomal enzyme system: sever CNS deression and inappetance.

References

1. Riviere, J E and Papich, M G (2009) Veterinary Pharmacology and Therapeutics, Wiley.