Download Cp min = 8mg /l

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1
Introduction:
______________________
Phenytoin is an anticonvulsant drug (of hydantoin type) ,that can be
useful in the treatment of different types of epilepsy like grand mal and
psychomotor epilipsy. It is also used in the treatment of certain types of
arythmias.
The primary site of action appears to be the motor cortex where spread of
seizure activity is inhibited , by inhibition of Na + channels recovery.
Also, phenytoin decreases activity of centres in the brain stem responsible
for the tonic phase of grand mal seizures. It has few sedative effects.
As an antiarrhythmic, phenytoin increases the electrical stimulation
threshold of heart muscle, although it is less effective than quinidine,
procainamide, or lidocaine.
Peak serum levels: oral, 4-8 hr. Since the rate and extent of absorption
depend on the particular preparation
Peak serum levels (following IM): 24 hr (wide variation). Therapeutic
serum levels: 5-20 mg/L. (IM = intra muscular)
Steady state: 7-10 days after initiation.
Biotransformed in the liver. Both inactive metabolites and unchanged
drug are excreted in the urine.
Onset: 30-60 min. Duration: 24 hr or more.
Uses:
____________
Chronic epilepsy, especially of the tonic-clonic, psychomotor type and
grand –mal type. Not effective against absence seizures and may even
increase the frequency of seizures in this disorder (which is petit –mal
epilipsy).
Parenteral phenytoin is sometimes used to treat status epilepticus and to
control seizures during neurosurgery.
It is Particularly useful for arrhythmias produced by digitalis toxicity
(ie. digitalis over dose induced ventricular fibrillation).
Contraindications:
____________________________________
Hypersensitivity to hydantoins, exfoliative dermatitis, sinus bradycardia,
second-and third-degree AV block, clients with Adams-Stokes syndrome,
SA block , Lactation.
How Supplied:
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___________________________
Phenytoin Chewable Tablet: 50 mg.
Suspension: 100 mg/4 mL, 125 mg/5 mL;
Phenytoin sodium, extended Capsule (Extended Release): 30 mg, 100 mg
Phenytoin sodium, parenteral Injection: 50 mg/mL.
Phenytoin sodium prompt Capsule: 100 mg .
Dosage:
_______________
•Oral Suspension, Chewable Tablets Seizures.
Adults, initial: 100 mg (125 mg of the suspension) ; adjust dosage at 7- to
10-day intervals until seizures are controlled; usual, maintenance: 300400 mg/day, although 600 mg/day (625 mg of the suspension) may be
required in some.
Pediatric, initial: 5 mg/kg/day in two to three divided doses; maintenance,
4-8 mg/kg (up to maximum of 300 mg/day).
Children over 6 years may require up to 300 mg/day.
Geriatric: 3 mg/kg initially in divided doses; then adjust dosage according
to serum levels and response. Once dosage level has been established, the
extended capsules may be used for once-a-day dosage.
•Capsules, Extended-Release Capsules Seizures.
Adults, initial: 100 mg ; adjust dose at 7- to 10-day intervals until control
is achieved. An initial loading dose of 12-15 mg/kg divided into two to
three doses over 6 hr followed by 100 mg t.i.d. on subsequent days may
be preferred if seizures are frequent. Pediatric: See dose for Oral
Suspension and Chewable Tablets.
Arrhythmias.
Adults: 200-400 mg/day.
•IV Status epilepticus.
Adults, loading dose: 10-15 mg/kg at a rate not to exceed 50 mg/min;
then, 100 mg PO or IV q 6-8 hr. Pediatric, loading dose: 15-20 mg/kg in
divided doses of 5-10 mg/kg given at a rate of 1-3 mg/kg/min.
Arrhythmias.
Adults: 100 mg q 5 min up to maximum of 1 g.
•IM Dose should be 50% greater than the oral dose.
Neurosurgery:
100-200 mg every 4 hr during and after surgery (during first 24 hr,
administer no more than 1,000 mg; after first day, give maintenance
dosage).
THERAREUTIC RANGE:
__________________________________________________
Normal therapeutic dose of phenytoin is 10-20 mg/L.
A plasma conc. Of 5-10 mg /L can be effective for some patients, but a
conc of 5mg/L will have no effect.
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Side effects:
____________________________
Phenytoin is associated with both dose-related side effects and
hypersensitivity reactions. Hypersensitivity reactions occur in up to 19%
of patients receiving this medication.
Dose related side effects include
 Blurred vision
 Ataxia
 G.I.T disturbances
 Mental confusion
-Gum hyper plasia , hirsutism and folate defficiency anaemia beside
hypersensitivity reactions are non dose related side effects.
-Gum hyper plasia can be can be minimized by maintaining good oral
hygiene with regular brushing, flossing and massaging of the gums.
-Ataxia and decreased mental capacity are C.N.S side effects(central
nervous system) that occur when conc. Of phenytoin exceeds 40 mg /L.
-Rapid parenteral administration may cause serious CV(cardio vascular)
effects, including hypotension, arrhythmias, CV collapse, and heart
block, as well as CNS depression.
Precautions:
___________________________
This drug should be used during pregnancy only if clearly needed. Small
amounts of phenytoin appear in breast milk.
Use of alcohol and other sedative type medications can lead to extreme
drowsiness. Try to limit their usage. This medication may decrease the
effectiveness of oral contraceptives(since oral contraceptives are enzyme
inducers). Your physician should have a whole idea about your clinical
history.
Drug interactions:
_______________________________________

Drugs which may increase phenytoin serum levels include:
chloramphenicol, tolbutamide, isoniazid, phenylbutazone, acute
alcohol intake, salicylates, chlordiazepoxide, phenothiazines,
diazepam,estrogens, ethosuximide, halothane, methylphenidate,
sulfonamides, cimetidine, trazodone.
These drugs either increase phenytoin level by inhibition of its
metabolism (eg.cimetidine , sulphonamides and metronidazole) , or by
displacing it in the protein binding sites(eg. Phenyl methazone).
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So these drugs will increase level in the plasma , t ½ (half life) will be
increased, and clearance will be reduced.
 Drugs which may decrease phenytoin levels include:
carbamazepine, chronic alcohol abuse, reserpine and phenobarbitone.
Key parameters:
__________________________________
Therapeutic plasma conc
F (bioavailability)
S
Vd(volume of distribution)
CL (clearance)
Vm( maximum rate)
Vm for children
Km
T 1/2 (half life)
α( free fraction)
10 to 20 mg/l
1.00
0.92
0.65mg/l
Conc dependant
7mg/kg/l
More than
7mg/kg/day
4mg/kg/l
Conc dependant
0.1
Protein binding:
_____________________________________
Phenytoin has a very high affinity to plasma albumin .90% of drug that
reaches circulation will bind to albumin, leaving a fraction of 0.1 in the
free state.
There are 3 main factors that are known to alter plasma protein binding of
phenytoin:
1. HYPO ALBUMINEMIA:
The following equation determines the plasma conc that would have
been observed with a normal albumin conc.
Cp\
Cp(normal binding)=____________________
(1- α)[p /pNL] + α
\
CP\= observed plasma concentration(conc) in the lab.
α =normal free fraction of phenytoin (= 0.1).
p\= patients serum albumin(in gm/dL).
pNL= normal serum albumin(= 4.4 gm /dL).
Cp = plasma conc of the drug.
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***********(1)
This equation is useful in patients with unusual serum albumin, but has
no diminished renal function.
2-RENAL FAILURE:
In patients suffering from end stage renal disease , the free fraction of
phenytoin in plasma will rise from 0.1 to 0.2 up to 0.35. This may happen
either due to decreased affinity to serum albumin or due to decreased
serum albumin conc in the plasma.
When the creatinine clearance is more than 25 ml/min, the binding
affinity changes will be minimum (can be ignored), and no need to adjust
the dose , however ,if it’s clearance is less than 10 ml, and the patient is
undergoing hemodialysis, binding changes are of significant values.
In this case (end stage renal disease) the factor that represents decreased
albumin affinity = 0.48.
So the previous equation can be altered to accommodate changes in both
serum albumin conc and phenytoin affinity , through multiplying patients
albumin by the factor 0.48.
Cp\
Cp (normal binding)= ________________________
(0.48)(1-α)[p\ /pNL] + 0.1
This equation can be only used for patients suffering from end – stage
renal disease and are receiving hemodialysis treatment. That is because
the factor 0.48 was derived for this type of patients.
3- DRUG DISPLACEMENT:
Many drugs can displace phenytoin from its binding sites on albumin .It
is very difficult to estimate extent of drug displacement, because we can
not know the concentration(conc) of displacing agentHowever valproic
acid is an exception. If its conc is less than 35mg/L, there will be no
problem and dispalcement will will be minimum , but if the conc rises to
more than 50mg/L displacement will be high, and adjustment of
phenytoin conc will be important.
Pharmacokinetics:
--------------------------------------------------------------
-Phenytoin is a weak acid and has erratic GI absorption(gastro intestinal).
Following ingestion, phenytoin precipitates in the stomach's acid
environment. This fact in particularly important in the setting of an
intentional overdose.
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-The parenteral form of phenytoin is dissolved in 40% propylene glycol
and 10% ethanol and adjusted to a pH of 12 with the addition of sodium
hydroxide to maintain solubility.
-Phenytoin administered intravenously at a rate greater than 50 mg/min
may cause hypotension and arrhythmias. These complications are
believed to be secondary to the diluent, propylene glycol(which is known
to have cardiac depressant properties).
- Extravasation of the solution may cause skin irritation or phlebitis.
Blood levels of phenytoin reflect only total serum concentration of the
drug. Only the free, unbound phenytoin has biological activity.
-Patients predisposed to elevated free phenytoin levels include neonates,
the elderly and patients with uremia, hypoalbuminemia or
hyperbilirubinemia. These patients may exhibit signs of toxicity when
drug levels are within the therapeutic range .
Bioavailability (f):
_______________________________________


Phenytoin has an f value =1, so it is completely absorbed.
It is found in different forms. Phenytoin injection and capsules are
in the form of Na+ salts(sodium) while chewable tablets and
suspensions are in the acid form.
 Peak level in plasma is reached in 3 to 12 hours, since it is of
limited solubility which makes absorption slow and thus the action
delayed.
 Bioavailability will not be 100% in patients with rapid
gastrointestinal transit times, and conc decreases in people receiving
nasogastric feeding.
 Phenytoin can be given I.V(intra venously), & orally. I.M route for
phenytoin should be avoided . The reason is that whenever phenytoin
is injected I.M , because of it’s low solubility , it will crystallize inside
the muscle. This will lead to a very slow absorption of the drug to the
circulation, and so , if it is used I.M after being used in the oral form, a
sudden and dramatic decrease in it’s conc in the blood occurs. This
decrease in the conc will be much more greater than the decrease in
absorption, that is because of capacity limited metabolism ( which
will be discussed later). One of the studies showed that , changing oral
doses into IM injection , has decreased the plasma level of phenytoin by
40 to 60 % , however the elimination rate was only reduced by 20%.
Volume of distribution:
_________________________________________________
 in a normal patient with a normal renal function and serum albumin
conc the vd will be = 0.65L/kg.
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 In patients with decreased binding affinity, the vd will increase , but
there is no nead to change the loading dose because the changes
occurred in vd will be accomodated by opposite changes in the drug
conc.
Metabolism:
__________________________
unlike most of the other drugs ,phenytoin has non linear kinetics.
 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
.
 At low conc (concentration) phenytoin will follow first order
metabolism (where increasing conc will increase rate of metabolism
i.e conc dependant rate). However in larger conc metabolism will
follow zero order kinetics(independent of conc) .This is due to
saturation of metabolic pathways. So high conc of the drug will be
toxic due to the complete saturation of enzymes responsible for
metabolising the drug.this is called (capacity limited metabolism).
This metabolic pattern of phenytoin is described by the following
equation: (michaelis and menten equation)
(Vm) * (Cp ssav.)
(s)(f)(dose/τ)=____________________________
( Km ) + ( Cpssav )
********************* (2)
Where: (s)(f)(dose/τ) = dc/dt =v
τ = time interval of drug doses.
Cpssav= plasma conc at steady state.
vm=max. metabolic capacity (or) max rate of metabolism
(unit=mg/day)
Km= substrate conc at which v (rate) will be half V max
= michaelis constant (unit=mg /L).
DC/DT= rate of metabolism.
By rearrangement of the previous equation (eq.no 2) , the following
one is obtained:
(Km) * (v)
Cpss =
_____________________ **********************(3)
(Vm) – (v)
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This equation shows the relation ship between Cp ss and rate of drug
administration.
 If v (rate of administration) was equal to max rate(Vm),then cp ss
will never be achieved since it’s value will = α (infinity).
 Also if v is more than Vm ,, the Cpss value will be negative (i.e Cpss
can’t be achieved also).

Since v = (s)(f) (dose)/ τ ,then there is a direct relation ship
between steady state and maintenance dose , so adjusting the dose will
be very important in order to maintain steady state.
 V max value lies usually between 5 to 15 mg/kg/day.
 The plasma conc corresponding to the metabolic rate (v) when it is
equal to ½ V max , ranges from 1 to 20 mg /l.
Conc. Dependant clearance:
______________________________________________________________

It is clear from equation (2) the direct relation ship between
clearance and Cpss in blood.
Where :
CL= Vm / (Km + Cpss) ****************(4)

at low conc of the drug, Cpss will be very small compared
to Km , so CL = Vm/ Km( both of Vm and Km are constants
, so CL will be constant ( ie: follows 1st order kinetics).
 As Cpss increases untill it approaches km or exceeds it, the
CL will be no more constant. (ie CL will decrease as
phenytoin conc increases in body).
Conc. Dependant t ½:
________________________________________________

normal t1/2 of phenytoin = about 22 hrs .
as clearance t1/2 is also not costant at high conc., since t ½

is dependant on clearance.
CL = Vm
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/ (Km + CpSS ).
T½
So
= (0.693 )/ kd
t ½ = (0.693 * vd) / CL ***********(5)
= {(0.693) * (vd) * ( km + Cpss) } / Vm
__________________________________________________________________

The following relation ship between rate of drug administration and
drug elimination for a 1 st order drug, can explain the problems
associated with (capacity limited metabolism) :
Ra - Re = Δ amount / t
******************(6)
Where:
-Ra = rate of drug administration.
-Re = rate of drug elimination.
 as Ra exceeds Re , accumulation takes place in the body, which on
prolonged period causes toxicity.
 while, if Re is more than Ra the amount in the body per unit time
will decrease , and drug will be lost from the body.
- Re = CL * Cp
(w/hr v/hr w/v)
so the following equation is obtained
R a - (CL *Cp) = Δ amount / t
*****************(7)
- when ( CL* Cp) approaches Ra , change in the amount of drug
in plasma will be minimum , so steady state will be obtained.


This was In case of 1 st order kinetics .
however in case of capacity limited matabolism , at higher conc of
drug
by substituting eq. 4 in eq. 7 :
Ra - [(Vm* Cp) / (Km +Cp)] = Δ amount / t ************(8)
-as Cp increases and become near in value to Km , Re value will
become as much as possible near to Ra , so change in the amount of the
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drug in the plasma will be minimum , which is required to achieve steady
state.
Time to reach steady state:
____________________________________________________________
the following equation represents the time required for phenytoin to
achieve (90%) s.s (ie. Steady satate)
(Km) * (vd)
t (90%) =
__________________________________
[(2.3 vm) – (0.9)(s)(f)(dose/day)]
[(vm – (s)(f)(dose/day)]2
****************(9)


this equation Used when initial conc =0
if initial plasma conc lies between 0 and Cp ss the time to
reach S.S will be decreased (ie S.S is achieved sooner).
 The dose is in mg/day normalized for a 70 kg patient
When can we consider the conc of phenytoin in plasma at
steady state?
The following equation explains:
[(115) + (35) (cp)] *Cp
90% t = ____________________________________
(S) (f) (dose)
***************(10)


Cp in mg /l , is also normalized for 70 kg patient.
90% represent the minimum time through which the
patient should take the drug before Cp in blood is considered
a steady state.
 This equation when was derived , it was assumed that Km
= 2 mg/L( so in patients with Km more than 2mg/l, the time
will be shorter to achieve S.S)
Rate of phenytoin decline:
________________________________________________________
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The following equation describes the decline of phenytoin in blood, after
stopping drug intake.
[ (Km) * ln (cp0/ cp1) ) ] + (cp0 – cp1)
t=
______________________________________________________ ********************(11)
( Vm / Vd )
where :
cpo = initial palsma conc.
Cp1= plasma conc. At t=1.
From the equation it is clear that the time required for phenytoin to
decline from blood is controlled by Vm and Vd, whenever cp o and cp1 are
more than Km .
This equation is used whenever the patient has received an over dose of
phenytoin.
Drug monitoring and Time to sample :
__________________________________________________________________________________
 since phenytoin does not follow first order kinetics in it’s all
pharmacokinetical parameters in high doses, it is very important to
monitor blood level of phenytoin periodically, to ensure that patient’s
plasma conc of phenytoin is within the therapeutic range , to prevent
any undesirable side effects associated with increased level of
phenytoin in plasma).
 The time to sample phenytoin varies from patient to patient ,
depending mainly on the disease state the patient is treated from and
his clinical condition.
 at first, drug conc is monitored every 2 to 3 days, to make sure that
it’s metabolism is not remarkably different from values estimated
theoretically,(in acute cases).
 within a period of 5 to 7 days , and it was found that phenytoin conc
didn’t change , drug monitoring can be done every week or more.
 the previous information are for patients suffering from acute cases
,and needing rapid achievement and maintenance of drug conc ,
however in chronic patient who have been recieving the drug for a
long period of time, drug level in plasma is monitored within 3 to 12
months.
 in patients taking the drug orally , in the form of divided doses, the
time of sampling is not of that importance , since orally absorption
takes place very slowly and so fluctuations between max and
minimum levels will be reduced.
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 Cpssmin can be adjusted to calculate the average plasma conc of
phenytoin received intravenously and orally.
Cp ssav = Cp ssmin + [ (0.5) (s) (f) (dose)/ vd]
******(12)
Cp ssav = Cp ssmin + [(0.25) (s) (f) (dose) / vd]
******(13)
Cpssmin = minimum plasma conc at steady state
Cpssav= average plasma conc
 equation 12 is for I.V route .
it says that cpssav lies in the middle between min and max cp values.
 equation 13 is for oral route
the factor 0.25 illustrates that fluctuations between min and max Cp
values in the oral route is half that in the I.V route.
 due to slow absorption of the drug when administered orally
compared to I.V route the peak conc in the plasma will be delayed and
will be lower than the expected value 20mg/, actually it will be half
the value estimated in the I.V route.
ΔCp = 0.5 ( (s) (f) (dose) / (vd) )
********(14)
Missed Dose:
-----------------------------------------------
If you miss a dose and take 1 dose daily: take as soon as remembered
unless you do not remember until the next day. In that case , skip the
missed dose and resume your usual dosing schedule the following day. If
you take several doses daily and should miss a dose: take as soon as
remembered unless it is within 4 hours of the next dose. In that case, skip
the missed dose and resume your usual schedule. Check with your doctor
if you miss doses for more than 2 days in a row.
Do not double the dose to catch up
Storage:
____________________
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.
Store at room temperature away from moisture and sunlight. Do not
store in the bathroom.
Clinical cases on phenytoin:
_____________________________________________________________
1) a 70 kg male , needed a phenytoin loading dose to achieve therapeutic
plasma conc of 20mg/l.
what is this loading dose?
DL = (Vd Cp)/ (s)(f)
Normal vd of phenytoin = 0.65l/kg
So vd in this case = 0.65 * 70 = 45.5 L
So DL= (45.5*20)/ (0.92*1)
= 989 mg ~ 1000mg
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
as said before rapid administration of the loading dose I.V will
cause toxicity specially cardiovascular toxicity caused by the diluent
propylene glycol.
So the dose is injected gradually , by a max rate injection of 50mg / min.
 Also when administered orally , the loading dose of phenytoin
should not be given as a whole but should be devided to prevent
nausea and vomiting associated with a single large dose
 The oral 1000 mg dose is divided into one 400 mg dose followed by
two 300 mg doses over 4 hrs.
-----------------------------------2) a 70 kg male , was given 300mg / day phenytoin . on drug monitoring
, it was found that plasma conc of the drug was = 8 mg /l.
what is the dose required for this patient to achieve Cpss =15mg /L.?
*dose = 300mg/l
* Cp at ss = 15mg/l
*Cp ssav =8 mg/l
*s=0.92
*f=1
* Km = 4mg/l
by rearrangement of equation 2 , we can calculate Vm
Vm = [(s*f*dose/τ) (Km+Cpssav)]/ Cpssav
= (0.92*1.0*300mg/day)(4+8)/ 8
= 414 mg/day.
Now by using the original equation (no 2) , we can find the dose
required to reach 15 mg / l ss
S*f*dose/τ = (vm * Cpssav)/ (Km +Cpssav)
0.92*1*dose/1day= (414 *15) / (4 + 15)
so dose = 355 mg.
It is difficult to give a daily dose of 355mg, so the patient is given at
first a dose rounded to 350mg, then 300 mg and 400 mg doses are given
to the patient in an alternative manner .
--------------------------------------------------
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3)
for the same patient find the loading dose that will rise plasma conc of
phenytoin from 5 to 15 mg/l.
Cp min = 8mg /l
Cp max = 15 mg /l
DL= Vd * Cpssav / (s) (f)
Since Cp ssav= Cp max – Cp min
So
DL= 45.5*(15-8)/ (0.92*1)
= 346 mg.
This dose must be associated with a maintenance dose of 350mg/day.
-----------------------------------------------
4)
an 80 kg patient was recieving a 300mg/day phenytoin dose for 21
days. The plasma level was monitored ,and it was found to be 14mg/l
however this conc can not be considered a steady state conc. WHY?
Since phenytoin suffers from capacity limited metabolism,(ie it is not
eliminated by first order kinetics), so it will need a long time to reach
steady state.
This can be explained by using the following equation :(equation no
11)
(which is used to calculate the time needed for phenytoin to reach a
steady state):
t 90% = [115 + (35)(cp)] cp/ (s) (f) (dose)
*cp = 14mg /l ( given)
*dose = 300mg /day( given)
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the dose should be normalized to 70 kg:
dose = 300*70/80= 262.5 mg.
So t 90% = [115+35(14)]*14/ 0.92*1*262.5
= 35 days.
 This calculated period is longer than the time of treatment (21 days)
which gives an indication that the period of 21 days is not enough
to reach steady state , so the plasma conc achieved does not represent a
steady state value.
 If an additional dose was given within that period or if the value of
Km was more than 2 mg /l , a steady state may have been achieved
within the 21 days.
--------------------------------------------------
5)
a 60 kg female , was given a DL= 1000mg and a DM= 300mg.
Monitored cp was found to be = 11mg/l after 8 days of taking the DL.
Should the dose be adjusted to achieve conc of 10 to 20 mg /l??
From the eq of DL = vd*cp/ s*f
Cp0 = 0.92 * 1 * 1000/ (0.65*60)
= 23.5mg/l

The monitored cp was = 11mg /l, while the initial conc of drug in
the plasma =23.5mg/l , which means that the drug in plasma when it
was monitored was in the state of decline , and so a the DM of
300mg/l will cause continues decline of its level in plasma.
 by calculating the amount eliminated/time in the body , we can
estimate the value of DM that will keep the drug’s plasma conc
constant .
Re = Ra – ( Δamount /t)
( this equation is a rearrangement of equation no. 6)
17
-where Re = elimination rate = amount eliminated per time
-Ra = rate of administration =(s)(f)(dose)
vd = 60*0.65=39 L
Δ amount = cp2 – cp1
In this case, cp1 is considered to be initial plasma conc(cp0 )and cp2 is the
monitored one.
Re = (s)(f)(dose/τ) - [(cp2-cp1)(vd)] / t
Re = (0.92*1*300) - [(11-23.5) (39)]/ 8
Re = 337 mg /day ( for acid phenytoin )
=366 mg/ day (for Na+ phenytoin)
so the amount eliminated of phenytoin per day = 366mg
in this case a DM of 360 mg will give an average phenytoin conc
between 11 and 23 mg /l.
So
-------------------------------------------
6) a 60 kg female ,treated with phenytoin . she has a chronic renal
failure . she under goes hemodialysis treatment 3 times a weak.
Her serum albumin is 3.3 gm/dl, and her phenytoin dose is 300mg /day
Cp ss was found to be 5mg/l
Should her dose be inceased?
What is her phenytoin conc if she had a normal serum albumin?

This patient is suffering from both renal failure and reduced
normal albumin.
 As said before , renal failure will decrease binding affinity to
albumin and decreased albumin level in body. This will cause an
increase in the free fraction of phenytoin (which s normally 0.1), so
lower plasma conc of phenytoin will give the same therapeutic action
as that produced by higher conc in non uremic paytients.
 So the dose given for this patient should not be increased .
by using equation no 1 we can calculate conc in blood if she had a normal
albumin level.
Where cp\ = 5mg /l
P\ =patients albumin = 3.3mg /dl
18
α = normal free fraction
p NL= normal albumin level =4.4mg /dl
Cp NB = 5/[(1-0.1)(0.48)(3.3/4.4)] +1
= 11.9 mg /l
so a conc of 5 mg/l in uremic patient is comparable to a conc of
12 mg /l, in a normal non uremic patient.
In this case we see , if the seizure is controled, no adjustment of the
maintenance dose is required.
However if the seizure is not well controlled, we have to adjust the dose.
The comparable plasma conc calculated for a normal patient , (12mg/l)
Should be used in calculations
Dialysis have no effect on phenytoin, (i.e phenytoin is not dialysed), also
it has no effect on protein binding. So on the basis of dialysis there is no
need to adjust the dose.
----------------------------------------------7)
60kg male , having glomerular nephritis .serum albumin= 2 gm /dl
phenytoin dose = 300mg/day , cpss= 6 mg/l
what would be his phenytoin conc if he had a normal serum albumin?
We use the same equation used in the previous example
So Cp NB = 11.8 mg/ l
8)
a 60 kg male, has been taking a phenytoin dose(In the acid form) of
350mg/day , and his plasma level was measured and it was =3mg/l.this
patient came to the hospital suffering from poor control of seizure . He
then was given a 350mg/day Na+ phenytoin, and his plasma level was
then reported after 5 days as 18 mg /day. The question is , has this patient
reached the steady state??
By using this equation
90% t =[(115)+(35) (cp)][cp] / (s)(f)(dose)
as this conc is used for 70 kg patients, the dose should be
adjusted for 70 kg.
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350mg/l ------------ for 60 kg
x
------------for 70 kg
x = dose = 408.333 mg/l
so 90% t = [(115) +(35)(18)][18] /(0.92)(1)(408.33)
= 35.7 days.
As the patient has only been receiving the drug for 5 days, 18mg/l
does not represent a steady state.
Amount eliminated /t=(0.92*1*350mg/day)-[(18-3).65*60]/5
=205mg/day.
-----------------------------------------9)
an 80 kg male , had been given 300mg/day phenytoin dose, but his
seizure was poorly controlled, and his plasma conc was only 8mg/l, so the
dose was increased to 350mg/l,and the plasma level was reported to be
20mg/l , now he complains from minor CNS side effects.
Renal and hepatic functions are normal.
If both plasma values in the 2 cases were assumed to be steady state
values,
find 1- Vm
2- Km
3- dose that will give a 15mg/l SS level?
This problem can be solved graphically and theoretically .
Graphically: by plotting rate of drug administration ( dose/τ) VS
clearance ( D/(τ* Css) , the following graph is obtained:
1) where the intercept represents Vm.
so from the graph Vm = 400mg /day.
2)also from the graph slope = -Km
slope = (R1 – R2 )/[(R1/Cpss1)-(R2/Cpss2)]
= (350 – 300)/[(350/20)-(300/8)]
=-2.5mg/l
so Km = - slope = -(-2.5) = 2.5 mg /l
now if you calculated the value of Vm theoretically a close answer
would be obtained
Vm = (s)(f)(dose/τ)(Km+Cpssav)/ (Cpssav)
= (0.92*1*300)(2.5+8 )
20
/8
=393.75 mg /day.
3)dose = (Vm)(Cpssav)(τ) /(s)(f)(Km +Cpssav)
= 400*15*1
= 372 mg
/ 0.92*1*(2.5+15)
500
RATE
400
300
200
100
0
0
10
20
30
40
CL
--------------------------------------------------
10)
for the same patient , if the drug was stopped, what is the suugested
time needed for the drug to decline in plasma from 20mg/l to 15 mg/l?
t = [(Km)(ln cp0/cp1) + (cp0 – cp1)] /(Vm /Vd)
= [0.25 * ln (20/15) + (20 –15 ) ] /(400/(80*0.65)
= 0.74 days.
----------------------------------------11)
what is the effect of phenobarbital on the steady state of phenytoin
conc?
Clinically , phenobarbital does not alter steady state conc of
phenytoin.
That is because , phenobarbital is an enzyme inducer , so it will
increase metabolism of phenytoin, so it increases it’s metabolic capacity,
(i.e Vm is increased).also competition between the 2 drugs on the
enzymes will lead to increasing Km.
Vm increase will lead to increase CL and decreasing the conc in plasma.
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On the opposite side, increasing Km will decrease Cl and increase conc.
The net result will be no effect on SS conc.This equation explains what
has been said
[Cpss = [(Km) (s) (f) (dose/τ)] / [Vm – (s) (f) (dose/τ)]
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