PHENYTOIN

Dr/Saleh Abd El Rasoul

Faculty of clinical pharmacy
Al Baha University

1
 INTRODUCTION
• Phenytoin is a hydantoin derivative related to
the barbiturates with anticonvulsant and
antiarrhythmic properties.

‫الفينيتوين هو مشتق من الهيدانتوين مرتبط بالباربيتورات بخصائص مضادة لالختالج ومضادة‬

.‫الضطراب النظم‬

2
 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
• Phenytoin follows Michaelis-
Menten or saturable
pharmacokinetics.
• This is the type of nonlinear
pharmacokinetics that occurs
when the number of drug
molecules overwhelms or
saturates the enzyme’s ability to
metabolize the drug.
• When this occurs, steady-state
drug serum concentrations
increase in a disproportionate
manner after a dosage increase .
‫هذا هو نوع الحرائك الدوائية غير الخطية الذي يحدث عندما يغمر عدد جزيئات الدواء أو‬
.‫يشبع قدرة اإلنزيم على استقالب الدواء‬
‫ تزداد تركيزات مصل الدواء ذات الحالة املستقرة بطريقة غير‬، ‫عندما يحدث هذا‬
.‫ متناسبة بعد زيادة الجرعة‬3
In this case the rate of drug removal is described by the classic
Michaelis-Menten relationship that is used for all enzyme
systems:
Vmax . C
rate of metabolism =
Km + C

Vmax : is the maximum rate of metabolism in mg/d,

C : is the phenytoin concentration in mg/L
Km : (Michaelis- Menten constant) is the concentration
at which the rate of metabolism is half the maximum
rate Vmax & i.e. = Vmax /2.
Michaelis- ‫ يتم وصف معدل إزالة الدواء من خالل عالقة‬، ‫في هذه الحالة‬
:‫ الكالسيكية املستخدمة لجميع أنظمة اإلنزيمات‬Menten

Vmax & ie = ‫هو التركيز الذي يكون فيه معدل التمثيل الغذائي نصف املعدل األقصى‬
.Vmax / 2
4
 Vmax

-dC/dt

Km Concentration
 ‫ هو أن تخليص الفينيتوين ليس ثابتًا كما هو الحال مع الحرائك‬Michaelis-Menten ‫التضمني السريري للحرائك الدوائية لـ‬
.‫ ولكنه يعتمد على التركيز أو الجرعة‬، ‫الدوائية الخطية‬

• The clinical implication of Michaelis-Menten

pharmacokinetics is that the clearance of phenytoin is
not a constant as it is with linear pharmacokinetics,
but is concentration- or dose-dependent.
• As the dose or concentration of phenytoin increases,
the clearance rate (Cl) decreases as the enzyme
approaches saturable conditions:
‫( مع‬Cl) ‫ ينخفض معدل التصفية‬، ‫مع زيادة جرعة أو تركيز الفينيتوين‬
:‫اقتراب اإلنزيم من ظروف التشبع‬
Cl = Vmax / (Km + C)

• This is the reason concentrations increase

disproportionately after a phenytoin dosage increase.
‫هذا هو السبب في زيادة التركيزات بشكل غير متناسب بعد زيادة‬
.‫جرعة الفينيتوين‬
6
For example,
• phenytoin follows saturable pharmacokinetics with average
Michaelis-Menten constants of Vmax = 500 mg/d and Km = 4
mg/L.
• The therapeutic range of phenytoin is 10–20 μg/mL.
• As the steady-state concentration of phenytoin increases from
10 μg/mL to 20 μg/mL, clearance decreases from 36 L/d to 21
L/d:
The answer
• Cl = Vmax/(Km + C);
• Cl = (500 mg/d) / (4 mg/L + 10 mg/L) = 36 L/d
• Cl = (500 mg/d) / (4 mg/L+ 20 mg/L) = 21 L/d.

7
 ‫( مرتبطًا بالتخليص وحجم التوزيع باستخدام نفس املعادلة‬t1 / 2) ‫ال يزال نصف العمر‬
:‫الخاصة بالحرائك الدوائية الخطية‬

• half-life (t1/2) is still related to clearance and volume of

distribution using the same equation as for linear
pharmacokinetics:
t1/2 = (0.693 ⋅ V)/Cl.
• However, since clearance is dose- or concentration-
dependent, half-life also changes with phenytoin dosage or
concentration changes. ‫ فإن عمر النصف يتغير‬، ‫ نظرًا ألن التصفية تعتمد على الجرعة أو التركيز‬، ‫ومع ذلك‬
.‫أيضًا مع تغير جرعة الفينيتوين أو تغيرات التركيز‬
:
• As doses or concentrations increase for a drug that follows
Michaelis- Menten pharmacokinetics, clearance decreases
and half-life becomes longer for the drug:
‫• مع زيادة الجرعات أو التركيزات لعقار يتبع الحرائك الدوائية‬
• ↑t1/2 = (0.693 ⋅ V) / ↓Cl. ‫ يتناقص التصفية ويصبح عمر النصف أطول‬، ‫ مينتني‬-‫للميكايليس‬
‫للعقار‬

8
 .‫( أطول مع زيادة جرعة أو تركيز الفينيتوين‬t1 / 2 5-4) ‫املعنى السريري لهذه النتيجة هو أن الوقت املستقر للحالة‬

• The clinical implication of this finding is that the

time to steady state (4–5 t1/2) is longer as the dose
or concentration is increased for phenytoin.
• On average, the time to steady-state serum
concentrations is approximately 5 days at a dosage
rate of 300 mg/d and 15 days at a dosage rate of
‫ أيام‬5 ‫ يكون الوقت املستغرق لتركيزات املصل املستقرة حوالي‬، ‫في املتوسط‬
400 mg/d. .‫ يوم‬/ ‫ مجم‬400 ‫ يومًا بمعدل جرعة‬15 ‫ يوم و‬/ ‫ مجم‬300 ‫بمعدل جرعة‬

• Under steady-state conditions the rate of drug

administration equals the rate of drug removal.
.‫ فإن معدل إدارة الدواء يساوي معدل إزالة الدواء‬، ‫في ظل ظروف الحالة املستقرة‬

9
• Therefore, the Michaelis-Menten equation can be used to
compute the maintenance dose (MD in mg/d) required to
achieve a target steady-state phenytoin serum concentration
(Css in μg/mL or mg/L):
V max  Css
MD 
S ( Km  Css)

• when Km>>Css : phenytoin follows linear pharmacokinetics

• MD = (Vmax/Km)Css & since Vmax/Km is a constant = Cl &
MD = Cl ⋅ Css.
• when Css>>Km : the rate of metabolism becomes a constant
equal to Vmax.
• S is the fraction of the phenytoin salt form that is active
phenytoin (0.92 for phenytoin sodium injection and capsules)
& S =1.0 for phenytoin acid suspensions and tablets)
10
 ‫ يتم استقالب كمية ثابتة فقط من الفينيتوين يوميًا ألن نظام اإلنزيم مشبع‬، ‫في ظل هذه الظروف‬
.‫تمامًا وال يمكنه زيادة قدرته على التمثيل الغذائي‬

• Under these conditions only a fixed amount of

phenytoin is metabolized per day because the
enzyme system is completely saturated and cannot
increase its metabolic capacity.
• This situation is also known as zero-order
pharmacokinetics.
 Capacity-limited metabolism results in clearance
values ⇊with ⇈ plasma conc.
 Therefore, when the maintenance dose is increased,
the plasma Conc. Rises disproportionately
.‫ينتج عن األيض محدود السعة قيم تصفية ⇊ مع تركيبة البالزما‬

‫ يرتفع بشكل غير‬.‫ فإن تركيز البالزما‬، ‫ عندما يتم زيادة جرعة املداومة‬، ‫لذلك‬
‫متناسب‬
11
THERAPEUTIC DRUG CONCENTRATION
• Seizure disorder : 10 to 20 mcg/mL
• Neonate total concentrations: 6 to 14 mcg/mL.
• unbound concentrations: 1 to 2 mcg/mL
• Antiarrhythmic effects: 10 to 18 mcg/mL
• Trough levels are generally used to monitor therapy.
• Peak phenytoin levels may be helpful in a patient
who may be experiencing side effects.

12
 LOADING DOSE
Neonate and infants (<1 yr) 15-20 mg/kg

Children(1-<12 yr) 15-18 mg/kg

Adolescents (=>12 yr), adult and geriatrics 15-18 mg/kg

13
 MAINTENANCE DOSE
Neonate (<4 weeks) 3-5 mg/kg/day

Infants (4 week-<1 yr) 4-8 mg/kg/day

Children (1-<12 yr) 4-10 mg/kg/day

Adolescents (=>12 <18 yr), 4-8 mg/kg/day

Adult, and geriatrics 4-7 mg/kg/day

14
 SAMPLING TIME FOR LOADING DOSE
I.V > 2 hr after end of infusion

I.M > 4 hr

Oral About 24 hr after loading dose

15
 TIME TO PEAK CONCENTRATION
• Oral, extended PHENYTOIN SODIUM capsules: 4 to
12 hours
• Intravenous with loading dose: 20 to 25 minutes

16
 ONSET
• INITIAL RESPONSE:
• 1. Seizure disorder, oral without a loading dose: 7 to
10 days.
• 2. Seizure disorder, oral with a 1 gram loading dose: 8
to 12 hours.
• 3. Seizure disorder, intravenous with a 1 gram
loading dose: immediate onset.

17
 BIOAVAILABILITY (F)
• Oral, PHENYTOIN SODIUM capsules: 70% to 100%
• The bioavailability of PHENYTOIN varies from the
different manufacturers from 20% to 90%.
• In neonates, oral and intravenous phenytoin doses
resulted in similar serum concentrations.

٪100 ‫ إلى‬٪70 :‫ كبسوالت الفينيتوين الصوديوم‬، ‫عن طريق الفم‬

.٪90 ‫ إلى‬٪20 ‫ من الشركات املصنعة املختلفة من‬PHENYTOIN ‫• يختلف التوافر البيولوجي لـ‬

.‫ أدت جرعات الفينيتوين الفموية أو الوريدية إلى تركيزات مماثلة في املصل‬، ‫• في حديثي الوالدة‬

18
 EFFECTS OF FOOD
• increases the absorption of phenytoin especially in
infants, and in less extant in older children and adults

‫آثار الغذاء‬

‫ ويقل انتشاره عند األطفال‬، ‫• يزيد من امتصاص الفينيتوين خاصة عند الرضع‬
‫األكبر سنًا والبالغني‬

19
 DISTRIBUTION SITES cont’d
• Brain, high: 89% to 128% of the plasma conc.
• Placenta, high
• Saliva, unquantified

‫مواقع التوزيع تابع‬

.‫ من تركيز البالزما‬٪128 ‫ إلى‬٪89 :‫• ارتفاع املخ‬

‫ عالية‬، ‫• املشيمة‬

‫• لعاب غير محدد الكمية‬

20
 DISTRIBUTION KINETICS
• Volume of Distribution (Vd): 0.7 L/kg

21
 METABOLISM
• Liver, extent unknown (98%).
• PHENYTOIN is hydroxylated in the liver by a saturable
enzyme system.
• There is some evidence that phenytoin enhances its
own elimination through enzyme induction.

.‫الفينيتوين هيدروكسيل في الكبد عن طريق نظام إنزيم قابل للتشبع‬

‫• هناك بعض األدلة على أن الفينيتوين يعزز التخلص منه من خالل تحريض‬
.‫اإلنزيم‬

22
 EXCRETION
• BREAST MILK: Controversial

• RENAL EXCRETION: 2%

• Bile, most of the dose ‫ مثير للجدل‬:‫حليب الثدي‬

٪2 :‫• اإلبادة الكالمية‬

‫ معظم الجرعة‬، ‫• الصفراء‬

23
 HALF-LIFE
• HALF-LIFE: 22 hours
• ranges from 7 to 42 hours; value is variable due to
the saturation kinetics
• During the first 7 days of life, the half-life ranged
from 6 to 140 hours in predominantly full-term
newborns
• After intravenous administration, half-life ranges
from 10 to 15 hours
‫ ساعة ؛ القيمة متغيرة بسبب حركية التشبع‬42 ‫ إلى‬7 ‫تتراوح من‬

‫ إلى‬6 ‫ تراوحت فترة نصف العمر من‬، ‫• خالل األيام السبعة األولى من العمر‬
‫ ساعة عند حديثي الوالدة في الغالب‬140

‫ ساعة‬15 ‫ إلى‬10 ‫ يتراوح عمر النصف من‬، ‫• بعد اإلعطاء في الوريد‬

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 EXTRACORPOREAL ELIMINATION

• HEMODIALYSIS: Dialyzable No

• PERITONEAL DIALYSIS: Dialyzable: No.

• PLASMAPHERESIS: Dialyzable: Yes

25
 Side Effects:
• Normal Phenytoin therapeutic plasma conc.=10-20 mg/L ,In some people 5-10 mg/L
• Not effective if < 5 mg/L
• Side effects >20 mg/L , sometimes > 30, 40mg/L

“P.H.E.N.Y.T.O.I.N.”

P = P-450 interactions “enzyme inducer”

H = Hirsutism (due to androgen)

E = Enlarged gums

N = Nystagmus (Far-lateral Nystagmus ,conc >20 mg/L)

*involuntary eye movement

Y = Yellow-browning of the skin “jaundice as hepato toxic”

T = Teratogenic “this woman is pregnant”

O = Osteomalacia “bone for legs”

I = Interferes with Folate metabolism leads to

anemia. “plant and RBC go hand in hand”

N = Neuropathies: vertigo, ataxia, headaches, confusion

26
 Adverse Reactions
• I.V. effects: Hypotension, bradycardia, cardiac
arrhythmias, cardiovascular collapse (especially
with rapid I.V. use), venous irritation and pain,
thrombophlebitis.
• Effects not related to plasma phenytoin
concentrations: Hypertrichosis, gingival
hypertrophy, thickening of facial features,
carbohydrate intolerance, folic acid deficiency,
peripheral neuropathy, vitamin D deficiency,
osteomalacia, systemic lupus erythematosus

27
 Adverse Reactions cont’d
• Dose-related effects: Nystagmus, blurred vision,
diplopia, ataxia, slurred speech, dizziness,
drowsiness, lethargy, coma, rash, fever, nausea,
vomiting, gum tenderness, confusion, mood
changes, folic acid depletion, osteomalacia,
hyperglycemia.

28
 Adverse Reactions cont’d
• Related to elevated concentrations:
• >20 mcg/mL: Far lateral nystagmus
• >30 mcg/mL: 45° lateral gaze nystagmus and
ataxia
• >40 mcg/mL: Decreased mentation
• >100 mcg/mL: Death

29
 Adverse Reactions cont’d
• >10%:
• Central nervous system: Psychiatric changes, slurred
speech, dizziness, drowsiness
• Gastrointestinal: Constipation, nausea, vomiting,
gingival hyperplasia
• Neuromuscular & skeletal: Trembling

30
 Example 1
• TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial
seizures who requires therapy with oral phenytoin. He has
normal liver and renal function.
• Suggest an initial phenytoin dosage regimen designed to
achieve a steady-state phenytoin concentration equal to 12
μg/mL.
Solution
1. Estimate Michaelis-Menten constants according to disease states and
conditions present in the patient.
• The Vmax for a non obese adult patient with normal liver and renal
function is 7 mg/kg/d.
• For a 75-kg patient, Vmax = (7x75 = 525 mg/d)
• For this individual, Km = 4 mg/L.

31
2. Compute dosage regimen.
• Oral extended phenytoin sodium capsules will be prescribed to this patient
(F = 1, S = 0.92).The initial dosage interval (τ) will be set to 24 hours.
(Note: μg/mL = mg/L and this concentration unit was substituted for Css in the
calculations so that unnecessary unit conversion was not required.)
• The dosage equation for phenytoin is:

V max  Css (525mg / d ).(12mg / l )

MD  
S ( Km  Css) 0.92(4mg / l  12mg / l )

• MD = 428 mg/d, rounded to 400 mg/d

• A steady-state trough total phenytoin serum concentration should be
measured after steady state is attained in 7–14 days.
• Phenytoin serum concentrations should also be measured if the patient
experiences an exacerbation of their epilepsy, or if the patient develops
potential signs or symptoms of phenytoin toxicity.
‫يجب أيضًا قياس تركيزات مصل الفينيتوين إذا كان املريض يعاني من تفاقم‬
.‫ أو إذا ظهر على املريض عالمات أو أعراض محتملة لسمية الفينيتوين‬، ‫صرعه‬
32
 Example 2
• MN is a 24-year-old, 55-kg (5 ft 5 in) female with complex partial seizures
who requires therapy with intravenous phenytoin sodium. She has normal
liver and renal function (bilirubin = 0.8 mg/dL, albumin = 3.6 g/dL, serum
creatinine = 1.2 mg/dL).
• Suggest an initial intravenous phenytoin sodium dosage regimen designed
to achieve a steady-state phenytoin concentration equal

Solution
1. Estimate Michaelis-Menten constants and volume of distribution
according to disease states and conditions present in the patient.
• The Vmax for a non obese adult patient with normal liver and renal
function is 7 mg/kg/d.
• For a 55-kg patient, Vmax = (7x55 = 385 mg/d)
• For this individual, Km= 4 mg/L.
• The volume of distribution for this patient : V = 0.7 L/kg X 55 kg = 39 L.

33
2. Compute dosage regimen.
• Phenytoin sodium injection will be given to this patient (F = 1, S = 0.92).
• The initial dosage interval (τ) will be set to 12 hours.
• (Note: μg/mL = mg/L and this concentration unit was substituted for Css in
the calculations so that unnecessary unit conversion was not required.)
• The dosage equation for phenytoin is:

V max  Css (385mg / d ).(12mg / l )

MD  
S ( Km  Css) 0.92(4mg / l  12mg / l )
• MD = 314 mg/d rounded to 300 mg/d

Vd  Css (39 L).(12mg / l )

LD  
S 0.92

LD = 509 mg rounded to 500 mg

34
• The maintenance dose would be given as 150 mg every 12
hours.
• Maintenance and loading dose infusion rates should not
exceed 50 mg/min.
• A steady-state trough total phenytoin serum concentration
should be measured after steady state is attained in 7–14 days.
• Phenytoin serum concentrations should also be measured if
the patient experiences an exacerbation of their epilepsy, or if
the patient develops potential signs or symptoms of phenytoin
toxicity.

35
 Example 3
• Calculate the phenytoin loading dose required to achieve a
plasma concentration of 20 mg/L in B.F., a 70-kg male.
• Describe how this loading dose should be administered by the
oral and IV routes.
The answer
• The volume of distribution for phenytoin is assumed to be 0.65
L/kg, the volume of distribution for B.F. would be 45.5 L (70 kg ×
0.65 L/kg).
• In this case, we are assuming that B.F. has not been receiving
phenytoin and therefore the C observed or the phenytoin
concentration that is present is zero.
• The salt factor (S) is 0.92 for the oral capsules and injectable
phenytoin dosage forms (phenytoin for inject ion and
fosphenytoin) and the bioavailability is 100% (F = 1.0).
36
• This loading dose of 989 mg = 1.000 mg or 15 mg/kg.
• If this loading dose is administered intravenously as phenytoin
for inject ion, it should be administered slowly to avoid the
cardiovascular toxicities associated with the propylene glycol
diluent.
• A maximum rate of 50 mg/min (administered over 20 minutes)
should be used until the entire loading dose is administered or
toxicities are encountered

37
• If the 1,000-mg loading dose is to be given orally, a 400-mg
dose followed by two 300-mg doses (≈ 5 mg/kg) at 2-hour
intervals is recommended so that the entire loading dose is
administered over 4 hours.
• The oral loading dose is divided into three separate doses to
decrease the possibility of nausea and vomiting, which may be
associated with a single large dose, and to decrease the time to
peak concentration.
• When the loading dose is administered orally, slow absorption
causes the peak concentration to be delayed and lower than
the expected 20 mg/L even if a prompt absorption product is
used.
‫تنقسم جرعة التحميل عن طريق الفم إلى ثالث جرعات منفصلة لتقليل احتمالية الغثيان‬
.‫ ولتقليل وقت ذروة التركيز‬، ‫ والتي قد تترافق مع جرعة واحدة كبيرة‬، ‫والقيء‬

‫ يؤدي االمتصاص البطيء إلى تأخير ذروة‬، ‫عندما يتم تناول جرعة التحميل عن طريق الفم‬
.‫ لتر املتوقعة حتى لو تم استخدام منتج سريع االمتصاص‬/ ‫ مجم‬20 ‫التركيز وأقل من‬
38
 ‫ يكون تركيز الذروة عادةً حوالي نصف القيمة‬، ‫بعد تناول كبسوالت االمتصاص املمتدة عن طريق الفم‬
:‫املحسوبة بواسطة نموذج جرعة البلعة الوريدية كما هو متوقع بواسطة املعادلة التالية‬
Following oral administration of the extended absorption capsules, the peak
concentration is usually about one-half of the value calculated by the IV bolus
dose model as predicted by the following equation:

• The above equation is based on the slow absorption associated with the
phenytoin extended oral products, and the fluctuation in plasma concentration
will probably be more than predicted by Equation 10.29 with the prompt
absorption products.
• The peak concentration is very likely to be less than 20 mg/L following oral
administration, it is uncommon to give larger oral doses to compensate for the
delay in absorption.
• Oral absorption is relatively unpredictable, and increasing the oral dose is not
likely to reliably correct the problem.
• If it were imperative, from a clinical standpoint, to achieve a phenytoin level of
20 mg/L, it would be best to give the phenytoin by the IV route.

39