Difference between revisions of "Primidone"

Latest revision as of 17:27, 18 July 2012

Introduction

The structure of primidone. Source: Wikimedia Commons; Author: Jesse (2006)

Primidone is a barbiturate derivative that is closely related to phenobarbital. It is a colourless, tasteless substance that forms crystals and is metabolised to the active metabolites phenobarbital and phenylethylmalonamide (PEMA). Primidone is widely used in veterinary medicine for the control of epileptiform seizures, but does not appear to have an advantage over phenobarbital despite its greater potential to cause hepatotoxicity. However, it appears that certain individuals may respond more favourably to primidone than phenobarbital.

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 dissociation and thereby increase chloride conductance. This results in hyperpolarisation of the membrane and reduced neuronal excitability, giving a sedative effect. However, as the concentration of barbituate increases, it starts to have a direct effect on the chloride conductance and this is thought to bring about anaesthetic effects. Barbiturates depress the motor centres, conferring anticonvulsant activity, and the sensory centres, inducing anaesthesia.

Pharmacologic Considerations

In man, 60-90% of an oral dose of primidone is absorbed from the gastointestinal tract, with serum levels peaking about three hours after administration. Absorption is thought to be similar in animals, but primidone is metabolised once absorbed. Oxidation at carbon 2 results in the formation of phenobarbital, and cleavage at the same site gives PEMA. Primidone, phenobarbital and PEMA all possess anticonvulsant activity, but 85% of primidone's activity in dogs is due to the phenobarbital it forms. This is because the potency of primidone and PEMA is one-thirtieth that of phenobarbital, and phenobarbital has the longest half-life and so accumulates to the highest concentrations.

Some vets use primidone in patients which are refractory to phenobarbital at maximum doses. The efficacy of primidone in this capacity has not been proven, and may simply be due to animals receiving primidone metabolising the drug to greater concentrations of phenobarbital than those generated from administration of straight phenobarbital. In most dogs, however, there is no advantage in using primidone over phenobarbital for seizure control, and there are added side effects. Primidone is also more expensive than phenobarbital, but in some countries may be subject to lesser degrees of control and record keeping.

Cats metabolise primidone to phenobarbital to a lesser extent than dogs, so it follows that the drug may be less effective and more toxic. Primidone is not recommended for use in cats.

Side Effects and Contraindications

Since a large proportion of primidone is converted to phenobarbital, most adverse effects are the same as for this drug. These may include polyphagia, polyuria and polydipsia, which are usually transient and disappear with time. A sedative effect may also be seen. Additional side effects of primidone are nausea, drowsiness, ataxia, nystagmus and, rarely, dermatitis. In man, megaloblastic anaemia may develop from primidone use, and so the drug should be stored securely out of the reach of children.

Primidone is associated with a higher incidence of hepatotoxicity than phenobarbital: hepatic necrosis, fibrosis and cirrhosis have all been associated with chronic use of primidone. One study reported that up to 14 in 20 dogs develop liver toxicity following primidone administration. It is therefore important that liver enzyme assays and tests of liver function are regularly performed to monitor toxicity when primidone is prescribed to veterinary patients.

Primidone should not be used in combination with chloramphenicol, as chloramphenicol is a potent inhibitor of microsomal enzymes and so may lead to primidone toxicity. Signs include severe central nervous system depression and inappetance. Primidone has also been reported to cause intrahepatic cholestasis when used in combination with phenytoin.

Manufacturers do not recommend the use of primidone in cats, although studies have suggested that primidone is probably safe in this species.

Primidone Learning Resources
Literature Search Search for recent publications via CAB Abstract (CABI log in required)	Primidone publications

Links

References

Riviere, J E and Papich, M G (2009) Veterinary Pharmacology and Therapeutics, Wiley.
Adams, R H (2001) Veterinary pharmacology and therapeutics, Wiley-Blackwell.
NOAH (2010) Compendium of Data Sheets for Animal Medicines.
Merck & Co (2008) The Merck Veterinary Manual (Eighth Edition), Merial.

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-{{unfinished}}
+{{OpenPagesTop}}
+==Introduction==
+[[Image:Primidone.jpg|thumb|right|300px|The structure of primidone. Source: Wikimedia Commons; Author: Jesse (2006)]]
+Primidone is a barbiturate derivative that is closely related to phenobarbital. It is a colourless, tasteless substance that forms crystals and is metabolised to the active metabolites phenobarbital and phenylethylmalonamide (PEMA). Primidone is widely used in veterinary medicine for the control of epileptiform seizures, but does not appear to have an advantage over phenobarbital despite its greater potential to cause hepatotoxicity. However, it appears that certain individuals may respond more favourably to primidone than phenobarbital.
-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.
+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 dissociation and thereby increase chloride conductance. This results in hyperpolarisation of the membrane and reduced neuronal excitability, giving a sedative effect. However, as the concentration of barbituate increases, it starts to have a direct effect on the chloride conductance and this is thought to bring about anaesthetic effects. Barbiturates depress the motor centres, conferring anticonvulsant activity, and the sensory centres, inducing anaesthesia.
 ==Pharmacologic Considerations==
+In man, 60-90% of an oral dose of primidone is absorbed from the gastointestinal tract, with serum levels peaking about three hours after administration. Absorption is thought to be similar in animals, but primidone is metabolised once absorbed. Oxidation at carbon 2 results in the formation of phenobarbital, and cleavage at the same site gives PEMA. Primidone, phenobarbital and PEMA all possess anticonvulsant activity, but 85% of primidone's activity in dogs is due to the phenobarbital it forms. This is because the potency of primidone and PEMA is one-thirtieth that of phenobarbital, and phenobarbital has the longest half-life and so accumulates to the highest concentrations.
-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.
+Some vets use primidone in patients which are refractory to phenobarbital at maximum doses. The efficacy of primidone in this capacity has not been proven, and may simply be due to animals receiving primidone metabolising the drug to greater concentrations of phenobarbital than those generated from administration of straight phenobarbital. In most dogs, however, there is no advantage in using primidone over phenobarbital for seizure control, and there are added side effects. Primidone is also more expensive than phenobarbital, but in some countries may be subject to lesser degrees of control and record keeping.
-Primidone is more toxin in cats and rabis. cats metabolise primidone to phenobarbital to a lesser extent than dogs - less effective, more toxic.
+Cats metabolise primidone to phenobarbital to a lesser extent than dogs, so it follows that the drug may be less effective and more toxic. Primidone is not recommended for use in cats.
 ==Side Effects and Contraindications==
+Since a large proportion of primidone is converted to phenobarbital, most adverse effects are the same as for this drug. These may include polyphagia, polyuria and polydipsia, which are usually transient and disappear with time. A sedative effect may also be seen. Additional side effects of primidone are nausea, drowsiness, ataxia, nystagmus and, rarely, dermatitis. In man, megaloblastic anaemia may develop from primidone use, and so the drug should be stored securely out of the reach of children.
-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.
+Primidone is associated with a higher incidence of hepatotoxicity than phenobarbital: hepatic necrosis, fibrosis and cirrhosis have all been associated with chronic use of primidone. One study reported that up to 14 in 20 dogs develop liver toxicity following primidone administration. It is therefore important that liver enzyme assays and tests of liver function are regularly performed to monitor toxicity when primidone is prescribed to veterinary patients.
-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.
-Occasionally polyphagia, polyuria and polydipsia have been reported, but these effects are usually transitory and disappear with continued medication.
+Primidone should not be used in combination with chloramphenicol, as chloramphenicol is a potent inhibitor of microsomal enzymes and so may lead to primidone toxicity. Signs include severe central nervous system depression and inappetance. Primidone has also been reported to cause intrahepatic cholestasis when used in combination with phenytoin.
-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.
+Manufacturers do not recommend the use of primidone in cats, although studies have suggested that primidone is probably safe in this species.
-Should not be used with chloramphenicol - potent inhibotr of the microsomal enzyme system: sever CNS deression and inappetance.
+{{Learning
+|literature search = [http://www.cabdirect.org/search.html?it=any&q1=primidone&calendarInput=yyyy-mm-dd&occuring1=title&show=all&rowId=1&rowId=2&rowId=3&options1=AND&options2=AND&options3=AND&occuring3=freetext&occuring2=freetext&publishedend=yyyy&la=any&publishedstart=yyyy&fq=sc%3A%22ve%22&y=15&x=38 Primidone publications]
+}}
+==Links==
+*[[Barbiturates]]
+*[http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/190702.htm The Merck Veterinary Manual - Anticonvulsants].
 ==References==
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 #Adams, R H (2001) '''Veterinary pharmacology and therapeutics''', ''Wiley-Blackwell''.
 #NOAH (2010) '''Compendium of Data Sheets for Animal Medicines'''.
-[[Category:Hepatotoxicity, Drug induced]]
+#Merck & Co (2008) '''The Merck Veterinary Manual (Eighth Edition)''', ''Merial''.
-[[Category:To_Do_-_Lizzie]]
+{{review}}
+{{OpenPages}}
+[[Category:Hepatotoxicity, Drug induced]]
+[[Category:Expert_Review]]