Phenytoin and carbamazepine are used to treat epilepsy. Both have concentration-dependent therapeutic effects and side effects. Phenytoin follows nonlinear, saturable kinetics, while carbamazepine induces its own metabolism through autoinduction. Therapeutic drug monitoring is important for both drugs to ensure concentrations remain in an optimal range for efficacy and safety.

3. Phenytoin
Phenytoin is used in the treatment of epilepsy.
• Use is associated with dose-independent side effects
which include hirsutism, acne, coarsening of facial
features, gingival hyperplasia, hypocalcaemia and folic
acid deficiency.
• However, phenytoin has a narrow therapeutic index
and has serious concentration - related side effects.

4. • Plasma concentration–response relationship
• <5 mg/L: generally no therapeutic effect
• 5–10 mg/L: some anticonvulsant action with
• approximately 50% of patients obtaining a therapeutic
• effect with concentrations of 8–10 mg/L
• 10–20 mg/L: optimum concentration for anticonvulsant effect
• 20–30 mg/L: nystagmus, blurred vision
• >30 mg/L: ataxia, dysarthria, drowsiness, coma.

5. • Distribution
• Phenytoin follows a two-compartment model
with a distribution time of 30–60 min.
• The apparent volume of distribution is 1 L/kg.

6. • Elimination
• The main route of elimination is via hepatic metabolism.
• However, this metabolic route can be saturated at normal therapeutic doses.
• This results in the characteristic non-linear dose/concentration curve.
• Therefore, instead of the usual first-order pharmacokinetic model, a
Michaelis– Menten model, used to describe enzyme activity, is more
appropriate.
• rate of metabolism = (Vmax ⋅ C) / (Km + C), where Vmax is the maximum
maximum rate of metabolism in mg/d, C is the phenytoin concentration in
in mg/L, Km is the substrate concentration in mg/L, and where the rate of
of metabolism = Vmax /2.
• Km is the plasma concentration at which metabolism proceeds at half the
maximal rate. The population average for this is 5.7 mg/L, although this
value varies greatly with age and race.

7. • Vmax is the maximum rate of metabolism of phenytoin and is
more predictable at approximately 7 mg/kg/day.
• Since clearance changes with blood concentration, the half-life
also changes.
• The usual reported value is 22 h, but this increases as
concentration increases. Therefore, it is difficult to predict when
the steady state will be reached.
• However, as a rule of thumb, 1–2 weeks should be allowed to
elapse before sampling after a dosage change

8. • 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:
• Cl = Vmax/(Km + C); Cl = (500 mg/d) / (4 mg/L +
10 mg/L) = 36 L/d
• Cl = (500 mg/d) / (4 mg/L + 20mg/L) = 21 L/d

9. • Practical implications
• Since the dose/concentration relationship is non-linear,
changes in dose does not result in proportional changes in
plasma concentration.
• Using the Michaelis–Menten model, if the plasma
concentration is known at one dosage, then Vmax may be
assumed to be the population average (7 mg/kg/day), since
this is the more predictable parameter to calculate Km.

10. • Care is needed when interpreting TDM data and making dosage
adjustments when phenytoin is given concurrently with other
anticonvulsants, since these affect distribution and metabolism of
phenytoin.
• Since phenytoin is approximately 90% protein bound, in patients
with a low plasma albumin and or uraemia, the free fraction
increases and therefore an adjusted total phenytoin should be
calculated or a free salivary level taken.
• To adjust the observed concentration in hypoalbuminaemia the
following equation can be applied:

11. • C adjusted = Cobserved / 0.9 x (Calbumin / 44) + 0.1
• Albumin conc is in g/L
• In ureamic patients with severe renal failure, the unbound
fraction is approximately doubled, so the target concentration
needs to be half the normal concentration or apply the adjusted
concentration equation if albumin level is known.
• The oral formulations of phenytoin show good bioavailability.
• However, tablets and capsules contain the sodium salt (S =
0.9), whereas the suspension and infatabs are phenytoin base
(S = 1).

12. • Because phenytoin follows nonlinear pharmacokinetics, an 8% difference
in dose can result in major changes in phenytoin serum concentrations.
• For example, if a patient is stabilized on a dose of intravenous phenytoin
sodium 300 mg/d (300 mg/d phenytoin sodium × 0.92 = 276 mg phenytoin)
with a steady-state concentration of 17 μg/mL, switching the patient to
phenytoin suspension 300 mg/d could result in steadystate phenytoin
concentrations exceeding 20 μg/mL (15–30% increase or more) and result
in toxicity
• MD = Vmax . Css / Km +Css
• Css = Km . MD / Vmax - MD

13. • Intramuscular phenytoin is slowly and unpredictably
absorbed, due to crystallisation in the muscle tissue,
and is therefore not recommended.
• Fosphenytoin, a prodrug of phenytoin, is better
absorbed from the intramuscular site.
• Doses should be expressed as phenytoin equivalent.
• Fosphenytoin sodium 1.5 mg is equivalent to phenytoin
sodium 1 mg.

14. • Phenytoin can be given intravenously or orally.
• The loading dose is generally 10–20 mg/kg.
• If given orally, this dose should be divided into three doses (e.g. 1000
mg given as 400 mg initially, 300 mg two hours later and 300 mg two
hours after that) to ensure optimal oral absorption.
• If given intravenously, the full dose can be given at a maximum rate of
50 mg/min (higher rates can lead to hypotension and cardiac
compromise).
• Subsequent maintenance doses are usually in the range of 5–7
mg/kg/day (300–400 mg/day)

15. • Corrected Phenytoin levels with normal renal
function
• Corrected phenytoin (mg/L)= Observed
phenytoin (mg/L) (O.2 x albumin [g/dL]) + 0.1
• Impaired renal function
• Corrected phenytoin (mg/L)= Observed
phenytoin (mg/L) (O.1 x albumin [g/dL]) + 0.1

16. Monitoring
• One hour after IV – 24 hours after oral loading
dose
• Within 3 – 4 days after maintenance dose
• Within in 6 – 7 days after dose adjustment

17. • plasma phenytoin concentrations < 7 μg/ml, a
dosage increase of 100 mg/day is recommended;
• for plasma concentrations between 7 and 12 μg/
ml, the dose may be increased by 50 mg/day;
• if the plasma concentration is greater than 12 μg/
ml, the dose may increase by 30 mg/day.
• Dose increases when the plasma level is above 16
μg/ml should only be done with caution as even a
small increase may result in toxicity

18. Carbamazepine
• Carbamazepine is indicated for the treatment of partial and
• secondary generalised tonic-clonic seizures, primary generalised
tonic-clonic seizures, trigeminal neuralgia, and prophylaxis of
bipolar disorder unresponsive to lithium.
• There are a number of dose-independent side effects, including
various dermatological reactions and, more rarely, aplastic
anaemia

19. Mechanism of action
• Carbamazepine inhibits sustained repetitive firing by blocking
use-dependent sodium channels.
• Pain relief is believed to be associated with blockade of synaptic
transmission in the trigeminal nucleus and seizure control with
reduction of post-tetanic potentiation (synaptic plasticity) of
synaptic transmission in the spinal cord.
• Carbamazepine also possesses anticholinergic, central
antidiuretic, antiarrhythmic, muscle relaxant, antidepressant
(possibly through blockade of norepinephrine release), sedative,
and neuromuscular-blocking properties.

20. • However, the more common side effects are concentration related.
• Plasma concentration–response relationship when used in the treatment of
epilepsy
• • <4 mg/L: little therapeutic benefit
• • 4–12 mg/L: optimum therapeutic range for monotherapy
• • >9 mg/L: possible side effects of nystagmus, diplopia,
• drowsiness and ataxia, particularly if patients are on other
• anticonvulsant therapy
• • >12 mg/L: side effects common, even on monotherapy

21. • Distribution
• Carbamazepine is distributed widely in various organs, with the
highest concentration found in liver and kidneys.
• Carbamazepine is 70–80% protein bound and shows a wide
variation in the population average apparent volume of distribution
(0.8–1.9 L/kg).
• This wide variation is thought to be due to variations in absorption
(since there is no parenteral form) and protein binding.

22. • Elimination
• Carbamazepine is eliminated almost exclusively by
metabolism, with less than 2% being excreted
unchanged in the urine.
• Elimination is a first-order process, but
carbamazepine induces its own metabolism (auto-
induction).

23. • Therefore, at the beginning of therapy, clearance is
0.01–0.03 L/h/kg, rising to 0.05–0.1 L/h/kg on chronic
therapy.
• Auto-induction begins in the first few days of
commencing therapy and is maximal at 2–4 weeks.
• Since clearance changes with time, so does half-life,
with reported values as long as 35 h after a single
dose, decreasing to 5–7 h on regular dosing.

24. • Absorption
• Absorption after oral administration is slow, with peak
concentrations being reached 2–24 h post-dose (average 6 h).
• Absorption is incomplete, with bioavailability estimated at
approximately 80% (F = 0.8).
• Practical implications
• Use of pharmacokinetic equations is limited, due to the
autoinduction effect.
• However, there are a number of important practical points:

25. • Blood samples should not be drawn before the
steady state, which will not be achieved until 2–4
weeks after starting therapy to allow for auto-
induction, or 3–4 days after subsequent dose
adjustments.
• • When sampling, the trough level should be
measured because of the variable absorption
pattern.

26. • Complex calculations are not helpful, but as a rule
of thumb each 100 mg dose will increase the
plasma concentration at the steady state by
approximately 1 mg/L in adults.
• A number of other drugs (including phenytoin)
when given concurrently will affect carbamazepine
metabolism and subsequent blood levels

27. • Usual Adult Carbamazepine Dose for Epilepsy:
• Loading: 20 – 30 mg/Kg
• Initial dose: 200 mg orally twice a day (immediate and
extended release) or 100 mg orally 4 times a day
(suspension).
• Increase dose at weekly intervals in 200 mg/day increments
using a twice daily regimen of extended release or a three
times a day or four times a day regimen of the other
formulations.
• Maintenance dose: 800 to 1200 mg/day.
• Dosage generally should not exceed 1200 mg/day.
• However, doses up to 1600 mg/day have been used in rare
instances.
•

28. • Usual Adult Carbamazepine Dose for Trigeminal Neuralgia:
• Initial dose: 100 mg orally twice a day (immediate or extended
release) or 50 mg orally 4 times a day (suspension).
• May increase by up to 200 mg/day using increments of 100 mg
every 12 hours (immediate or extended release), or 50 mg four
times a day. (suspension), only as needed to achieve freedom
from pain. Do not exceed 1200 mg/ day.
• Maintenance dose: 400 to 800 mg/day.
• Some patients may be maintained on as little as 200 mg/day
while others may require as much as 1200 mg/day. At least
once every 3 months throughout the treatment period, attempts
should be made to reduce the dose to the minimum effective
level or to discontinue the drug.

29. • Usual Adult Carbamazepine Dose for Bipolar Disorder:
•
• Initial dose: 200 mg orally in tablet or capsule form every 12
hours or 100 mg of oral solution 4 times a day.
•
• Tablets and solution:
• Following autoinduction, higher doses will be necessary to
maintain drug levels within the therapeutic range of 6 to 12
mcg/mL. The daily dose should be increased in 100 to 200 mg
increments at 1 to 2 week intervals.
• Maintenance dose: up to 1200 mg daily in 3 or 4 divided doses
may be necessary to maintain plasma levels in the therapeutic
range.
•