CPD ACCREDITED ARTICLE
Timing of sampling : Trough levels are defined as sampling 2 – 0 hrs before the dose of medication .
Levitski showed using 33 animals that there was no real difference in testing at 0 , 3 or 6 hrs post treatment in 91 % of dogs- which remained in the same serum concentration category . In the 9 % which showed a significant difference in drug concentrations between samples - the mean dose of PB was 8.6mg / kg / day ( 6.3 – 10.9mg / kg / d ) vs 5.6mg / kg / day in the “ consistent ” group .
So in the majority of cases on < 8mg / kg / day - sampling can occur at any time of the day .
However in some cases with higher / kg dosages - induction of hepatic metabolism may result in a significant decrease in serum levels and a shortening of elimination half-life . In these cases it may be preferable to collect a trough level .
Although the literature recommends trough samples for determining therapeutic ranges , the above studies show that it is only in a few cases , determined mainly by high daily dosage of PB , where trough sampling may be considered . However statistical significance is not always translated into clinical significance and the article concluded that consistency when collecting is in the end more important to allow proper comparison in the same patient with serial samples
Side effects :
• Polyuria , polydipsia , polyphagia , sedation and ataxia These signs are generally noted in the first month of therapy - but have generally decreased by 6 months . This is definitely true of the sedation and ataxia which generally resolves within the first week of therapy . Mean bodyweights increased significantly over time many of the trials .
• Induction of hepatic p450 cytochrome pathways : - Cytochrome-p450 , glucuronosyltransferases , glutathione-s-transferases .
• Idiosyncratic liver disease - no morphological or histological damage - Infrequent side effects - resulting in clinical liver disease and increased liver enzymes .
• Pancytopaenia - Infrequent
• Induction of liver enzyme ALP A reversible increase in liver enzymes occurs . Increases above pre-treatment values are seen from week 5 and were above the reference range by 2-3 months . Increases were up to 10 x baseline values . ALP is found in bone , liver , intestine and kidney . The very short t 1 / 2 of intestinal and renal iso-enzymes makes them undetectable . In the dog there is practically only the bone , liver and the unique corticosteroid induced ALP present in the blood . No single iso-enzyme is responsible for the increase in ALP , thus iso-enzyme analysis cannot help differentiate PB induced elevations .
Aitken showed that a high dose of PB and a long treatment period rather than a high serum concentration , were associated with increases in liver enzymes - a result consistent with enzyme induction rather than hepatotoxicity .
... Consensus recommendation continued
4 . Levetiracetum and zonisamide were graded as low recommendation and may not be effective . This was based on level 3 and 4 data ( case series type studies ) only as not much is published . 5 . Primidone was contraindicated
Monitoring Optimal comparison of successive drug concentrations is best achieved by evaluating samples collected at the same time after dosing .
Trough concentrations are indicated when the patient has shown a predilection to seizure just before the next dose is due . It is important to determine if treatment failure is due to pharmacological ( short half-life ), metabolic ( tolerance ) or poor client compliance before removing a drug from a regimen
Consensus recommendations regarding monitoring :
Phenobarbitone :
• 2 and 6 weeks after initiating the drug and thereafter every 6 months or 2 weeks after a dose change
• Range 15 – 35 ug / ml ( 65 – 150 umol / l )
Bromide :
• Measure 1 and 3 months after initiation of treatment and thereafter yearly or if > 3 seizures occur or if toxicity is suspected .
• Bromide concentrations between 810 – 2500 ug / ml with PB combination treatment are effective .
• Efficacy with monotherapy is seen in higher concentrations , up to 3000 ug / ml .
Imepitoin
• Imepitoin has a short half-life in dogs so no drug accumulation occurs during prolonged treatment . Inter-individual differences are also low and the therapeutic index is high - meaning toxicity is minimal and rapid dose adjustments are unlikely to cause side effects . Therapeutic monitoring is thus not needed .
Risk of Treatment Adverse effects can be divided into transient , persistent and life-threatening . Most transient effects are avoidable with dose titration and resolve within weeks . Persistent effects are generally CNS related ( sedation , ataxia , imbalance , cognitive impairment ). Life-threatening side effects are mainly associated with idiosyncratic bone marrow toxicity or predictable organ damage over time ( hepatotoxicity ).
Imepitoin scores the best in this category with only transient adverse effects listed . Safety studies showed a dose up to 3X the maximum dose for 26 weeks showed no observed adverse events / changes . In clinical studies mild adverse effects such as sleepiness , ataxia and transient polyphagia , polyuria , polydipsia , vomiting and diarrhoea were observed - all were less freqeunt than in the PB group . The hyperactivity scores were higher in the PB group .
Issue 06 | FEBRUARY 2017 | 7