Phenytoin an antiepileptic medication

1. PHENYTOIN
By,
Aleena Georgekutty
PharmD Intern
Department of Clinical Pharmacy

2. PHENYTOIN(DILANTIN)
• Class : AntiConvulsant
• Indications : Treatment For Status Seizures
• Contraindications : Hypersensitive, bradycardia, Heart Blocks,Hypoglycemia
• Common dose : 10-15 mg/kg infused under 50mg/min
HOW DOES IT WORK? (MECHANISM OF ACTION)
BLOCKS VOLTAGE-DEPENDANT SODIUM CHANNEL OF NEURONS
SHORTENS REFRACTORY PERIOD, SHORTENS QT INTERVAL, SHORTENS
DURATION OF ACTION POTENTIAL
BY BLOCKING SODIUM CHANNELS IT MAKES ACTION POTENTIAL
MORE DIFFICULT TO OCCUR

3. Phenytoin
• Phenytoin (PHT), sold under the brand
name Dilantin among others,is an anti-seizure
medication. It is useful for the prevention of tonic-
clonic seizures and partial seizures, but not absence
seizures. The intravenous form is used for status
epilepticus that does not improve
with benzodiazepines. It may also be used for
certain heart arrhythmias or neuropathic pain. It can
be taken intravenously or by mouth.The intravenous
form generally begins working within 30 minutes and
is effective for 24 hours. Blood levels can be
measured to determine the proper dose.

4. • Common side effects include nausea, stomach pain,
loss of appetite, poor coordination, increased hair
growth, and enlargement of the gums.Potentially
serious side effects include sleepiness, self harm, liver
problems, bone marrow suppression, low blood
pressure, and toxic epidermal necrolysis. There is
evidence that use during pregnancy results in
abnormalities in the baby.It appears to be safe to use
when breastfeeding.Alcohol may interfere with the
medication's effects.

7. Medical uses
Seizures
• Tonic-clonic seizures: Mainly used in the prophylactic
management of tonic-clonic seizures with complex
symptomatology (psychomotor seizures). A period of 5–10
days may be required to achieve anticonvulsant effects.
• Focal seizures: Mainly used to protect against the development
of focal seizures with complex symptomatology (psychomotor
and temporal lobe seizures). Also effective in controlling
partial seizures with autonomic symptoms.
• Absence seizures: Not used in treatment of pure absence
seizures due to risk for increasing frequency of seizures.
However, can be used in combination with other
anticonvulsants during combined absence and tonic-clonic
seizures.
• Seizures during surgery: Used as prevention and treatment of
seizures occurring during and after neurosurgery.
• Status epilepticus: Considered after failed treatment using
a benzodiazepine due to slow onset of action.

8. Other
• Abnormal heart rhythms: may be used in the treatment
of ventricular tachycardia and sudden episodes of atrial
tachycardia after other antiarrhythmic medications or
cardioversion has failed. It is a class 1b antiarrhythmic.
• Digoxin toxicity: IV formulation is drug of choice for
arrhythmias caused by cardiac glycoside toxicity.
• Trigeminal neuralgia: Second choice drug to
carbamazepine.
Special considerations
• Monitoring plasma concentrations: Narrow therapeutic
index. Anticonvulsant effect: 10–20 µg/mL; Antiarrhythmic
effect: 10–20 µg/mL
• Avoid giving intramuscular formulation unless necessary
due to skin cell death and local tissue destruction.
• Elderly: May show earlier signs of toxicity.

9. • Obese: Use ideal body weight for dosing calculations.
• Pregnancy: Pregnancy Category D due to risk of fetal hydantoin
syndrome and fetal bleeding. However, optimal seizure control is
very important during pregnancy so drug may be continued if
benefits outweigh the risks. Due to decreased drug concentrations
during pregnancy, dose of phenytoin may need to be increased if
only option for seizure control.
• Breast feeding: The manufacturer does not recommend breast
feeding because low concentrations of phenytoin are excreted in
breast milk.
• Liver disease: Do not use oral loading dose. Consider using
decreased maintenance dose.
• Kidney disease: Do not use oral loading dose. Can begin with
standard maintenance dose and adjust as needed.
• IV use is contraindicated in patients with sinus bradycardia, SA
block, second- or third-degree AV block, Stokes-Adams syndrome,
or have known hypersensitivity to phenytoin or any ingredient in the
respective formulation or to other hydantoins.

10. Side effects
• Common side effects include nausea, stomach pain, loss of
appetite, poor coordination, increased hair growth, and
enlargement of the gums. Potentially serious side effects
include sleepiness, self harm, liver problems, bone marrow
suppression, low blood pressure, and toxic epidermal
necrolysis. There is evidence that use during pregnancy results
in abnormalities in the baby. It appears to be okay
during breastfeeding. Alcohol may interfere with the
medication's effects.

11. P H E N Y T O I N
(1) Peripheral
Neuropathy
(3) Vertical
Nystagmus
(2) Hyperplasia
of gums
(4) Osteopenia
of bones
Folate
defeciency
(5) Teratogenic
NEURAL TUBE DEFECTS
(6) Fosphenytoin - IV

12. Heart and blood vessels
• Severe low blood pressure and abnormal heart
rhythms can be seen with rapid infusion of IV
phenytoin. IV infusion should not exceed
50 mg/min in adults or 1–3 mg/kg/min (or
50 mg/min, whichever is slower) in children.
Heart monitoring should occur during and
after IV infusion. Due to these risks, oral
phenytoin should be used if possible.
Neurological
• At therapeutic doses, phenytoin may
produce nystagmus on lateral gaze. At toxic
doses, patients experience vertical
nystagmus, double vision, sedation, slurred
speech, cerebellar ataxia, and tremor.] If
phenytoin is stopped abruptly, this may result
in increased seizure frequency,
including status epilepticus.
Nystagmus

13. • Phenytoin may accumulate in the cerebral cortex over long periods
of time which can cause atrophy of the cerebellum. The degree of
atrophy is related to the duration of phenytoin treatment and is not
related to dosage of the medication.
• Abrupt discontinuation of phenytoin can precipitate status
epilepticus.
• Phenytoin is known to be a causal factor in the development
of peripheral neuropathy.
Blood
• It has been suggested that phenytoin causes a reduction in folic
acid levels, predisposing patients to megaloblastic anemia. Folate is
presented in foods as polyglutamate, which is then converted into
monoglutamates by intestinal conjugase. Phenytoin acts by
inhibiting this enzyme, thereby causing folate deficiency. Other side
effects may include: agranulocytosis,aplastic anemia, decreased
white blood cell count, and a low platelet count.

14. Pregnancy
• Phenytoin is a known teratogen. The
syndrome consists of craniofacial
anomalies (broad nasal bridge, cleft lip
and palate, smaller than normal head)
and a mild form of mental retardation
(average IQ=71). This syndrome
resembles the well-described Fetal
Alcohol Syndromeand has also been
called the "fetal hydantoin syndrome".
Some recommend avoiding polytherapy
and maintaining the minimal dose
possible during pregnancy, but
acknowledge that current data do not
provide clear answers.Data now being
collected by the Epilepsy and
Antiepileptic Drug Pregnancy Registry
may one day answer this question
definitively.

16. Cancer
• There is no good evidence that phenytoin is a
human carcinogen.
Mouth
• Phenytoin has been associated with drug-induced gingival
enlargement (overgrowth of the gums), probably due to
above-mentioned folate deficiency; indeed, evidence from
a randomized controlled trial suggests that folic acid
supplementation can prevent gingival enlargement in
children who take phenytoin.Plasma concentrations
needed to induce gingival lesions have not been clearly
defined. Effects consist of the following: bleeding upon
probing, increased gingival exudate, pronounced gingival
inflammatory response to plaque levels, associated in
some instances with bone loss but without tooth
detachment.

17. Skin
• Hypertrichosis, Stevens-Johnson syndrome, purple glove
syndrome, rash, exfoliative dermatitis, itching, excessive
hairiness, and coarsening of facial features can be seen in
those taking phenytoin.
• Phenytoin therapy has been linked to the life-threatening
skin reactions Stevens–Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN). These conditions are
significantly more common in patients with a
particular HLA-B allele, HLA-B*1502. This allele occurs
almost exclusively in patients with ancestry across broad
areas of Asia, including South Asian Indians.

18. • Phenytoin is primarily metabolized to its inactive form by the
enzyme CYP2C9. Variations within the CYP2C9 gene that
result in decreased enzymatic activity have been associated
with increased phenytoin concentrations, as well as reports of
drug toxicities due to these increased concentrations. The U.S.
Food and Drug Administration (FDA) notes on the phenytoin
drug label that since strong evidence exists linking HLA-
B*1502 with the risk of developing SJS or TEN in patients
taking carbamazepine, consideration should be given to
avoiding phenytoin as an alternative to carbamazepine in
patients carrying this allele.

19. Immune system
• Phenytoin has been known to cause drug-induced lupus.
• Phenytoin is also associated with induction of reversible IgA
deficiency.
Psychological
• Phenytoin may increase risk of suicidal thoughts or behavior.
People on phenytoin should be monitored for any changes in
mood, the development or worsening depression, and/or any
thoughts or behavior of suicide

20. Bones
• Chronic phenytoin use has been associated with decreased
bone density and increased bone fractures. Phenytoin induces
metabolizing enzymes in the liver. This leads to increased
metabolism of vitamin D, thus decreased vitamin D
levels. Vitamin D deficiency, as well as low
calcium and phosphate in the blood cause decreased bone
mineral density.

21. Mechanism of action
Action of phenytoin on Na
channel
(A)Resting state in which Na
channel activation gate (A) is
closed
(B) Arrival of an action potential
causes depolarization and
opening of activation gate (A)
and Na flows into the cell.
(C) When depolarization
continues,an inactivation gate
(B) moves into the cell.
Phenytoin prolongs the
inactivated gate of the Na
channel by preventing the
reopening of inactivation
gate(B).

22. PHENYTOIN
Tonic clonic seizures
Blocks Na
Channels
Class 1A
antiarrhythmic
Zero-order (P E A)
Induces P450

23. • Phenytoin is believed to protect against seizures by
causing voltage-dependent block of voltage gated sodium
channels. This blocks sustained high frequency repetitive
firing of action potentials. This is accomplished by
reducing the amplitude of sodium-dependent action
potentials through enhancing steady state inactivation.
Sodium channels exist in three main conformations: the
resting state, the open state, and the inactive state.
• Phenytoin binds preferentially to the inactive form of the
sodium channel. Because it takes time for the bound drug
to dissociate from the inactive channel, there is a time
dependent block of the channel.

24. • Since the fraction of inactive channels is increased by
membrane depolarization as well as by repetitive firing, the
binding to the inactive state by phenytoin sodium can
produce voltage-dependent, use-dependent and time-
dependent block of sodium-dependent action potentials.
• The primary site of action appears to be the motor cortex
where spread of seizure activity is inhibited. Possibly by
promoting sodium efflux from neurons, phenytoin tends to
stabilize the threshold against hyperexcitability caused by
excessive stimulation or environmental changes capable of
reducing membrane sodium gradient. This includes the
reduction of post-tetanic potentiation at synapses which
prevents cortical seizure foci from detonating adjacent
cortical areas. Phenytoin reduces the maximal activity of
brain stem centers responsible for the tonic phase of
generalized tonic-clonic seizures.

25. Pharmacokinetics
• Phenytoin elimination kinetics show mixed-order behaviour at
therapeutic concentrations. A small increase in dose may lead
to a large increase in drug concentration as elimination
becomes saturated. The time to reach steady state is often
longer than 2 weeks.

26. Anticonvulsant used for
many seizure disorders.
Administered po or iv.
Exhibits nonlinear or
Michaelis-Menten
kinetics.
90% protein bound, only
unbound fraction is active
Therapeutic range:
Total = 10-20 μg/ml
Free = 1-2 μg/ml

27. Phenytoin:
Nonlinear (Michaelis-Menten)
elimination
CKm
VmaxC
ratenEliminatio




28. How to use Phenytoin Suspension, (Final Dose
Form)
• Shake this medication well before each dose. Take this
medication by mouth usually 2 or 3 times a day, or as
directed by your doctor. This product is not recommended
for use once a day. You may take it with food
if stomach upset occurs.
• Carefully measure the dose using a special measuring
device/spoon/syringe. Do not use a household spoon
because you may not get the correct dose.
• Use this medication regularly in order to get the most
benefit from it. It is important to take all doses on time to
keep the amount of medicine in your body at a constant
level. Remember to use it at the same times each day.
Dosage is based on your medical condition and response to
therapy.

29. • Products that contain calcium (e.g., antacids, calcium
supplements) and nutritional tube-feeding (enteral)
products may decrease the absorption of phenytoin.
Do not take these products at the same time as your
phenytoin dose. Separate liquid nutritional products
at least 1 hour before and 1 hour after your phenytoin
dose, or as directed by your doctor.
• Do not stop taking this medication without consulting
your doctor. Seizures may become worse when the
drug is suddenly stopped. Your dose may need to be
gradually decreased.
• Inform your doctor if your condition does not
improve or worsens.

30. PHENYTOIN TOXICITY
• Phenytoin is a commonly prescribed anticonvulsant used to
treat most types of seizure disorders and status epilepticus,
with the exception of absence seizures.
• Historically, phenytoin was used as an antidysrhythmic agent,
especially in the treatment of dysrhythmias due to digoxin
toxicity. It has fallen out of favor for that use because of the
advent of digoxin antibody fragments. Phenytoin is no longer
considered appropriate for the management of toxin-induced
or alcohol withdrawal seizures.
• Signs and symptoms of phenytoin toxicity typically
correspond to the serum level, and progress from occasional
mild nystagmus at 10-20 mcg/mL (the therapeutic range) to
coma and seizures at levels above 50 mcg/mL (see
Presentation and Workup). Treatment is supportive (see
Treatment and Medications).

31. PHENYTOIN TOXICITIESLIGHTAND
Lymphadenopathy
Induction of P450
Gingival Hyperplasia
Hirsutism
Teratogenic
(Fetal Hydantoin Syndrome)
Ataxia
Nystagmus
Diplopia
MMᴓPSS
Megaloblastic Anaemia
Malignant
Hyperthermia
Peripheral
Neuropathy
Systemic Lupus
Erythromatous
Sedation

32. PATHOPHYSIOLOGY
• Phenytoin blocks voltage-sensitive sodium channels in
neurons. This action leads to a delay in neuronal
electrical recovery from inactivation. Phenytoin's
inhibitory effect is dependent on the voltage and
frequency of neural cell firing by selectively blocking
the neurons that are firing at high frequency. Phenytoin
prevents the electrical spread of a focus of irritable
tissue from entering normal tissue.
• Phenytoin administration has been associated with toxic
effects. Phenytoin toxicity depends on the route of
administration, duration, exposure, and dosage. The
route of administration is the most important
determinant of toxicity. Phenytoin may be administered
orally or intravenously. In addition, fosphenytoin
(water-soluble phenytoin prodrug) may be administered
intramuscularly.

33. PHARMACOKINETICS
• Phenytoin is a weak acid and has erratic GI absorption. Following
ingestion, phenytoin precipitates in the stomach's acid environment;
this characteristic is particularly important in the setting of an
intentional overdose. Peak blood levels occur 3-12 hours following
single dose ingestion, but absorption can be extended up to 2 weeks,
especially in massive overdose. Oral exposures are associated
predominantly with CNS symptoms.
• The parenteral form of phenytoin is dissolved in 40% propylene
glycol and 10% ethanol and adjusted to a pH of 12; sodium
hydroxide is added to maintain solubility. Extravasation of the
solution may cause skin irritation or phlebitis. Phenytoin
administered intravenously at a rate higher than 50 mg/min may
cause hypotension and arrhythmias. These complications are
believed to be secondary to the diluent, propylene glycol. However,
cardiac toxicity was reported even after rapid administration of
fosphenytoin that does not contain propylene glycol, suggesting
intrinsic phenytoin cardiac toxicity. Orally administered phenytoin is
rarely, if ever, associated with cardiac toxicity.

34. • Phenytoin has a small volume of distribution of 0.6
L/kg and is extensively bound to plasma proteins
(90%). Blood levels of phenytoin reflect only total
serum concentration of the drug. Only the free unbound
phenytoin has biological activity. Because CNS tissue
levels are higher than in serum, levels may
underestimate CNS concentrations of phenytoin.
• Population groups that are predisposed to elevated free
phenytoin levels include neonates, elderly persons, and
individuals with uremia, hypoalbuminemia (due to
pregnancy, nephrotic syndrome, malignancy,
malnutrition), or hyperbilirubinemia. These patients
may exhibit signs of toxicity when drug levels are
within the therapeutic range (see Lab Studies). Certain
medications can interfere with phenytoin levels.

35. • Hepatic microsomal enzymes primarily metabolize
phenytoin. Much of the drug is excreted in the bile as an
inactive metabolite, which is then reabsorbed from the
intestinal tract and ultimately excreted in the urine. Less
than 5% of phenytoin is excreted unchanged in the urine.
Individuals with impaired metabolic or excretory pathways
may exhibit early signs of toxicity. Genetic polymorphism
in the cytochrome enzymes that metabolize phenytoin may
be responsible for variable rates of metabolism and thus
susceptibility to toxicity, even in individuals taking
appropriate doses.
• Phenytoin metabolism is dose dependent. Elimination
follows first-order kinetics (fixed percentage of drug
metabolized during a per unit time) at the low drug
concentrations and zero-order kinetics (fixed amount of
drug metabolized per unit time) at higher drug
concentrations. This change in kinetics reflects the
saturation of metabolic pathways. Thus, very small
increments in dosage may result in adverse effects.