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.

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.

References

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