Determination of diphenine concentration in the blood, used for dose adjustment and prevention of toxic effects of this drug.
Synonyms Russian
Phenytoin, diphentoin, epanutin, hydantoinal, sodantone, alepsin
English synonyms
Phenytoin, Dilantin
Research method
Gas chromatography-mass spectrometry (GC-MS)
Units
µg/ml (micrograms per milliliter)
What biomaterial can be used for research?
Venous blood
How to properly prepare for research?
- Children under 1 year of age should not eat for 30-40 minutes before the test.
- Do not eat for 2-3 hours before the test; you can drink clean still water.
- Do not smoke for 30 minutes before the test.
General information about the study
Diphenine is one of the most commonly used anticonvulsants. The features of this drug are:
- Established therapeutic range: 10-20 mg/l;
- narrow therapeutic range;
- nonlinear pharmacokinetics, which means that it is difficult to predict changes in the level of the drug in the blood when its dose changes (for example, a small change in dose can lead to a disproportionate change in the concentration of the drug in the blood);
- significant intra- and inter-individual variability of pharmacokinetics;
- insufficient concentration of diphenine can lead to serious health consequences (convulsions);
- excessive concentration can lead to serious health consequences (toxic hepatitis);
- the presence of drug interactions with other drugs, including anticonvulsants.
Considering these features, it is advisable to carry out drug monitoring when using diphenine. To correctly interpret the result of a diphenine test, you should remember some aspects of its metabolism:
- A blood test for diphenine allows you to measure the concentration of total diphenine. On the other hand, in the blood most of the diphenine is in a state bound to albumin, although only unbound (free) diphenine is active. The level of total albumin affects which part (fraction) of diphenin is active. This must be taken into account when assessing the outcome of the study. For example, at the same concentration of total diphenin (free and bound), in a patient with a low albumin level, the free diphenin fraction will be higher than in a patient with a normal albumin level. In this example, the first patient is at greater risk of diphenine toxicity when the drug dose is increased without regard to albumin levels.
- As with drug monitoring of other drugs, it is advisable to measure the concentration of diphenine after achieving an equilibrium (stationary, stable) concentration of the drug. For diphenin this period is 5-7 days. After reaching equilibrium concentration, blood sampling for testing can be done at any time, however, as a rule, it is done before the next dose of the drug is administered. Also, after reaching equilibrium concentration and in the absence of any factors that can change the level of diphenin in the blood, a single analysis is sufficient and repeated tests are not necessary. On the other hand, when exposed to factors that may affect the level of diphenin in the blood, it is necessary to repeat the analysis. As in the first case, a repeat analysis is performed after 5-7 days, that is, after reaching a new equilibrium concentration, with the exception of situations where clinically significant acute intoxication is suspected.
The following factors may affect the concentration of diphenine in the blood:
- prescribing or discontinuing additional medications (for example, carbamazepine or phenobarbital);
- changes in the functional state of the body (pregnancy, kidney and liver dysfunction);
- other factors: age, gender, belonging to certain ethnic groups, individual characteristics of diphenine metabolism.
Concentrations of diphenine in the blood within the range of 10-20 mg/l are considered therapeutic. The general approach is as follows: if the concentration of total diphenin is less than 5 mg/l, the dose of the drug can be increased to 100 mg/day; if the concentration is above 5 mg/l, the dose of the drug can be increased by no more than 30 mg/day. It should be understood, however, that the stated therapeutic range was determined experimentally using a relatively small group of patients. Given this, it is clear why for some patients lower concentrations will be sufficient, but for others concentrations within the established therapeutic range will lead to side effects. Therefore, it is so important to evaluate the result of the study in the context of a specific clinical situation.
Measurement of diphenin levels prescribed for the treatment of other diseases (eg, trigeminal neuralgia) has no clinical significance.
What is the research used for?
- For dose adjustment and prevention of toxic effects of diphenine.
When is the study scheduled?
- At the beginning of treatment with diphenin and after changing its dose;
- If there is no response to treatment with diphenin;
- If the patient is suspected of non-compliance with the treatment regimen;
- When prescribing or discontinuing a drug that may interact with diphenin (for example, carbamazepine);
- When the physiological state of the patient’s body changes (pregnancy, liver and kidney dysfunction);
- if diphenin intoxication is suspected.
What do the results mean?
Reference values: 10 - 20 µg/ml. Reasons for the increase:
- diphenin intoxication.
Reasons for the downgrade:
- insufficient therapeutic dose of diphenine.
What can influence the result?
- Individual characteristics of diphenine metabolism;
- age;
- floor;
- combined use of several drugs;
- functional state of the body (pregnancy, decreased liver and kidney function).
Difenin, 0.117 g, tablets, 20 pcs.
When used simultaneously with drugs that have a depressant effect on the central nervous system, the depressant effect on the central nervous system may be enhanced.
With the simultaneous use of amiodarone, antifungals (including amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole), metronidazole, chloramphenicol, chlordiazepoxide, diazepam, dicumarol, histamine H1 receptor blockers, halothane, isoniazid, methylphenidate, omeprazole, fluoxet ina , estrogens, salicylates, succinimides, sulfinpyrazone, sulfonamides, tolbutamide, trazodone, it is possible to increase the concentration of phenytoin in the blood plasma, which leads to an increase in its therapeutic effect and increases the risk of side effects.
The therapeutic effect of antifungals, clozapine, GCS, dicumarol, digitoxin, doxycycline, furosemide, estrogens, oral contraceptives, quinidine, rifampicin, vitamin D changes with the simultaneous use of phenytoin.
When used simultaneously with phenothiazine derivatives (including chlorpromazine, prochlorperazine, thioridazine), phenobarbital, and antitumor agents, an increase or decrease in the concentration of phenytoin in the blood plasma is possible. The effect of phenytoin on plasma concentrations of phenobarbital is unpredictable.
When used simultaneously with acetazolamide, osteomalacia and rickets are possible.
When used simultaneously with acyclovir, it is possible to reduce the concentration of phenytoin in the blood plasma and reduce its effectiveness.
With simultaneous use of valproic acid during the first few weeks, the total concentration of phenytoin in the blood plasma may decrease due to its displacement from sites of binding to plasma proteins by sodium valproate, induction of microsomal liver enzymes and acceleration of phenytoin metabolism. Next, the metabolism of phenytoin is inhibited by valproate and, as a result, the concentration of phenytoin in the blood plasma increases. Phenytoin reduces plasma concentrations of valproate, probably by increasing its metabolism in the liver. It is believed that phenytoin, as an inducer of liver enzymes, also increases the formation of a minor but hepatotoxic metabolite of valproic acid.
With simultaneous use, the plasma concentrations of verapamil, nimodipine, and felodipine decrease.
A case has been described of an increase in the concentration of phenytoin in the blood plasma and the development of toxic effects when used simultaneously with gabapentin.
With simultaneous use, a decrease in the concentration of desipramine in the blood plasma is possible.
When used simultaneously with diltiazem and nifedipine, it is possible to increase the concentration of phenytoin in the blood plasma and create a risk of developing toxic effects.
When used simultaneously with disulfiram, it is possible to increase the concentration of phenytoin in the blood plasma with the development of toxic reactions; with imipramine, clarithromycin - it is possible to increase the concentration of phenytoin in the blood plasma.
When used simultaneously with carbamazepine, folic acid, reserpine, sucralfate, vigabatrin, the concentration of phenytoin in the blood plasma may decrease and its therapeutic effect may decrease.
In patients receiving phenytoin, the effectiveness of paracetamol may be reduced.
When taking pyridoxine at a dose of 200 mg/day, a decrease in the concentration of phenytoin in the blood plasma is possible.
When used simultaneously with ritonavir, there are reports of increased plasma concentrations of phenytoin. It is believed that interaction is possible, but its nature has not been definitively established.
When used simultaneously with sucralfate, the absorption of phenytoin is reduced.
When used simultaneously with theophylline, it is possible to reduce the plasma concentrations of phenytoin and theophylline and reduce their effectiveness.
When used simultaneously with felbamate, it is possible to increase the concentration of phenytoin in the blood plasma.
When used simultaneously with phenylbutazone, cases of increased concentrations of phenytoin in the blood plasma with the development of toxic reactions have been described.
When treating folic acid deficiency, the use of folic acid preparations reduces the effectiveness of phenytoin.
When used simultaneously with cimetidine, the concentration of phenytoin in the blood plasma increases, and there is a risk of developing toxic effects.
When used simultaneously with ciprofloxacin, a decrease or increase in the concentration of phenytoin in the blood plasma is possible. The interaction is ambiguous.
Description of the drug DIFENIN
When used simultaneously with drugs that have a depressant effect on the central nervous system, the depressant effect on the central nervous system may be enhanced.
With the simultaneous use of amiodarone, antifungals (including amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole), metronidazole, chloramphenicol, chlordiazepoxide, diazepam, dicumarol, histamine H1 receptor blockers, halothane, isoniazid, methylphenidate, omeprazole, fluoxet ina , estrogens, salicylates, succinimides, sulfinpyrazone, sulfonamides, tolbutamide, trazodone, it is possible to increase the concentration of phenytoin in the blood plasma, which leads to an increase in its therapeutic effect and increases the risk of side effects.
The therapeutic effect of antifungals, clozapine, GCS, dicumarol, digitoxin, doxycycline, furosemide, estrogens, oral contraceptives, quinidine, rifampicin, vitamin D changes with the simultaneous use of phenytoin.
When used simultaneously with phenothiazine derivatives (including chlorpromazine, prochlorperazine, thioridazine), phenobarbital, and antitumor agents, an increase or decrease in the concentration of phenytoin in the blood plasma is possible. The effect of phenytoin on plasma concentrations of phenobarbital is unpredictable.
When used simultaneously with acetazolamide, osteomalacia and rickets are possible.
When used simultaneously with acyclovir, it is possible to reduce the concentration of phenytoin in the blood plasma and reduce its effectiveness.
With simultaneous use of valproic acid during the first few weeks, the total concentration of phenytoin in the blood plasma may decrease due to its displacement from sites of binding to plasma proteins by sodium valproate, induction of microsomal liver enzymes and acceleration of phenytoin metabolism. Next, the metabolism of phenytoin is inhibited by valproate and, as a result, the concentration of phenytoin in the blood plasma increases. Phenytoin reduces plasma concentrations of valproate, probably by increasing its metabolism in the liver. It is believed that phenytoin, as an inducer of liver enzymes, also increases the formation of a minor but hepatotoxic metabolite of valproic acid.
With simultaneous use, the plasma concentrations of verapamil, nimodipine, and felodipine decrease.
A case has been described of an increase in the concentration of phenytoin in the blood plasma and the development of toxic effects when used simultaneously with gabapentin.
With simultaneous use, a decrease in the concentration of desipramine in the blood plasma is possible.
When used simultaneously with diltiazem and nifedipine, it is possible to increase the concentration of phenytoin in the blood plasma and create a risk of developing toxic effects.
When used simultaneously with disulfiram, it is possible to increase the concentration of phenytoin in the blood plasma with the development of toxic reactions; with imipramine, clarithromycin - it is possible to increase the concentration of phenytoin in the blood plasma.
When used simultaneously with carbamazepine, folic acid, reserpine, sucralfate, vigabatrin, the concentration of phenytoin in the blood plasma may decrease and its therapeutic effect may decrease.
In patients receiving phenytoin, the effectiveness of paracetamol may be reduced.
When taking pyridoxine at a dose of 200 mg/day, a decrease in the concentration of phenytoin in the blood plasma is possible.
When used simultaneously with ritonavir, there are reports of increased plasma concentrations of phenytoin. It is believed that interaction is possible, but its nature has not been definitively established.
When used simultaneously with sucralfate, the absorption of phenytoin is reduced.
When used simultaneously with theophylline, it is possible to reduce the plasma concentrations of phenytoin and theophylline and reduce their effectiveness.
When used simultaneously with felbamate, it is possible to increase the concentration of phenytoin in the blood plasma.
When used simultaneously with phenylbutazone, cases of increased concentrations of phenytoin in the blood plasma with the development of toxic reactions have been described.
When treating folic acid deficiency, the use of folic acid preparations reduces the effectiveness of phenytoin.
When used simultaneously with cimetidine, the concentration of phenytoin in the blood plasma increases, and there is a risk of developing toxic effects.
When used simultaneously with ciprofloxacin, a decrease or increase in the concentration of phenytoin in the blood plasma is possible. The interaction is ambiguous.
