TDM Phenytoin Flashcards
What are the indications of Phenytoin?
Phenytoin, an anti-epileptic is indicated for the prophylaxis and treatment of the following sub-classes of seizures:
- Third line add on therapy for focal seizures
- Prevention of seizures during or following neurosurgery or following a severe head injury
- IV status epilepticus following insufficient response to benzodiazepines
- Also used for bipolar disorder
BNF indications include tonic-clonic and focal seizures however NICE states that if myoclonic or absent seizures are present they should not be used
What is the mechanism of action of Phenytoin?
Phenytoin binds to sodium channels in their inactivated state causing a voltage dependent block, preventing the repetitive firing of action potentials which occurs during a seizure and results in high neuronal discharge. The drug has a high selective inhibitory effect on the motor area of the cerebral cortex.
The drug is also thought to exert a post-synaptic effect by stabilising the function of brain cell membranes and increasing GABA and 5-HT concentrations in the brain also reducing excitatory transmission. The drug can also reduce calcium entry, blocking the release of other neurotransmitters.
Does Phenytoin affect seizure threshold?
Phenytoin stabilises rather than increases the threshold for a seizure it is indicated for. However there is growing evidence indicating that AEDs may worsen pre-existing seizures by increasing their frequency or inducing a new type of seizure. Carbamazepine, oxcarbazepine, and phenytoin can aggravate absence and myoclonic seizures; to a lesser extent, atonic seizures; and, more rarely, tonic seizures hence why the drug isn’t indicated in these seizure types.
Which patient groups are contra-indicated with Phenytoin therapy?
General therapy:
Acute porphyrias
IV therapy:
Second- and third-degree heart block; sino-atrial block; sinus bradycardia; Stokes-Adams syndrome
Which patient groups are cautioned with Phenytoin therapy?
- Enteral feeding
- Presence of HLA-B*1502 allele Han Chinese or Thai origin
- Absent or myoclonic seizures (can exacerbate)
- Heart failure
- Hypotension
- Respiratory depression
What are the main interactions of Phenytoin?
Drugs metabolised by CYP450 (decreasing exposure of the drugs) as Phenytoin is a CYP450 inducer
Drugs causing sedation
Amiodarone increases the exposure of Phenytoin
Carbamazepine affects the concentration of Phenytoin and Phenytoin decreases the concentration of Carbamazepine.
What is an important consideration to make regarding dose equivalence and conversion of Phenytoin?
Preparations containing phenytoin sodium are not bioequivalent to those containing phenytoin base (such as Epanutin Infatabs® and Epanutin® suspension); 100 mg of phenytoin sodium is approximately equivalent in therapeutic effect to 92 mg phenytoin base. The dose is the same for all phenytoin products when initiating therapy. However, if switching between these products the difference in phenytoin content may be clinically significant. Care is needed when making changes between formulations and plasma-phenytoin concentration monitoring is recommended.
Why is Phenytoin TDM required?
Phenytoin not only has a narrow therapeutic index but it also displays non-linear pharmacokinetics meaning that once metabolism becomes saturated, small changes in dose can result in significant increases in serum levels resulting in toxic side effects. Similarly, a few missed doses or a small change in drug absorption may result in a marked change in plasma-drug concentration.
Significance between bound and unbound Phenytoin?
Phenytoin drug is highly protein bound to albumin - roughly 90% of the total dose. The remaining 10% - unbound Phenytoin is the proportion that exerts its therapeutic effect.
Therefore changes to albumin levels or variations in protein binding of Phenytoin can change the concentration which is unbound and therefore have different therapeutic effects.
Is the unbound Phenytoin the portion which is monitored therapeutically?
Are unbound or bound Phenytoin reflected when a drug level is taken?
Taking a drug level of Phenytoin is the overall Phenytoin concentration including both bound and free drug. This is how toxicity can occur even within therapeutic levels as it is not reflective of the proportion which is free drug. Therefore actually taking albumin levels can give a greater insight into the proportion of drug which will be free if hypoalbuminaemia is suspected.
Outline the factors which reduce protein binding of Phenytoin.
Reduced Phenytoin binding causes the proportion of unbound Phenytoin to increase which can be caused by the following factors:
- Hypoalbuminaemia, often caused by renal or liver disease. Less albumin ultimately means there is less for the drug to bind to
- Hyperbilirubinaemia as bilirubin binds competitively to albumin, again displacing Phenytoin
- Uraemia as urea also binds competitively to albumin
- Acidic drugs such as salicylates, valproic acid can displace Phenytoin from protein binding site. However Phenytoin can increase metabolism of valproate from the liver, reducing the therapeutic effect
What is the therapeutic range for Phenytoin?
10-20 mg/L however some patients are controlled within 5-10 mg/L
When should drug levels of Phenytoin be taken?
Drug levels should be taken as trough levels (pre dose levels)
Outline all the monitoring required for Phenytoin therapy.
Pre-screening also required for HLA-B*1502 allele (like Carbamazepine)
Therapeutic monitoring of trough drug-plasma concentration:
Reference range of 10-20 mg/litre
Elderly, pregnancy and when counteracting medications are used, frequency of therapeutic monitoring may be increased as well as careful interpretation of the total plasma-phenytoin concentration is necessary; it may be more appropriate to measure free plasma-phenytoin concentration.
Ongoing monitoring:
FBC - blood dyscrasias
IV use both ECG and BP should be monitored
At which drug level would you expect signs of Phenytoin toxicity to occur?
Usually above 20mg/L however Nystagmus (repetitive movements of the eyes) can occur above 15mg/L.
