Download t.5

nortriptyline HCl
desipramine HCl
amitriptyline HCl
imipramine HCl
TRICYCLIC ANTIDEPRESSANT (TCA.)
Although they have been used clinically for about
40years, assay procedures for clinical monitoring have
only become available recently.
There are lots of antidepressant agents, but the focus
here will be on TCAs since there assay procedures are
widely available &therapeutic ranges are established.
Most clinicians adjust TCAs doses by monitoring the
drugs efficacy & side effects.
*Plasma levels are only monitored in specific situations.
 Dose adjustment of TCA when used for other cases ;
eg. (Enuresis, Attention Deficit Disorder ADD, other
mood disorder…)
based primarily on clinical observation & most clinicians
tend to use same therapeutic ranges established for
depression since only very little data available on target
plasma concentration for alternative use.
Plasma monitoring for TCA is difficult:
Inability to establish clear therapeutic defined end
point.
Complication or inability to relate measured plasma
concentration to therapeutic response due to :
· Active metabolite.
· Altered plasma protein binding.
High first fast hepatic clearance of TCA leads to :
· Variability in plasma concentration.
· Low, variable bioavailability.
*Parenteral dosage forms available but not commonly used
 Maximum therapeutic effect is usually not apparent
for several weeks following initiation of TCA.
Steady state plasma concentration is achieved within
one weak.
THERAPUTIC & TOXIC PLASMA CONENTRATION
Its difficult to interpret the plasma concentration of
these basic compounds (TCA) due to their plasma
protein binding to various blood elements:
They bind to plasma serum albumin.
Lipoproteins concentration may be important, since
degree of binding for Amitriptyline and Nortriptyline
has been associated with cholesterol & triglyceride
concentration.
 They bind to α1-acid lipoproteins (AAG) with
relatively high affinity but low capacity.
*AAG concentration are elevated in response to
certain inflammatory process and this will alter
plasma binding & potential therapeutic range for
TCAs.
 its difficult to determine the alternation of blood
protein binding for TCA . this is attributed to either :
·Patient variation.
·Collection techniques & the assay
methodologies used to determine the unbound drug
concentration.
 Plasma protein binding for TCA is not
identical.
 They all have the free fraction less than
10%
•
•
For most ;about 5% of the drug in plasma
is unbound or free. while higher free fractions
have been reported ,but it's unclear weather
these studies present:
-Actual variation in plasma protein
binding.
-Artifacts in the assay methodologies.
Therapeutic range:
· Imipramine ===metabolized=====>desipramine
(active
compund)
To date, no therapeutic difference between these 2 has
distinguished.
·Amirtiptiline
==metabolized====>noramitriptyline
(active compund)
For those drugs :
Their therapeutic range are distinguished as summation
of the 2 compounds
(Parent & metabolite).
Table. 1
Drug
Therapeutic range
Comments
Imipramine +
desipramine
150-240μg/L
But most clinicians
prefer wider range 180350 μg/L
Amirtiptiline +
noramitriptyline
Not clearly established:
120-250 μg/L
Conc. Range >450 μg/L
don't ↑response inpatients failed to
develop response at
lower conc. But may
develop anticholinergic
Side effects …
*One study said that:
Concentration >115 μg/L strongly correlated to positive therapeutic out come.
*Other study suggested that :
Plasma concentrations as low as 75 μg/L were potentially therapeutic.
BIOAVAILABILITY (F)
GIT absorption of orally administered TCA is almost
complete but since the drug passes through the liver &
suffers from first-pass metabolism (FPM); the (F) is
decreased to 50% in most patients.
For that (F) range is broad & difficult to estimate in any
individual patient.
Rate of absorption is variable with peak concentrations
occurring 2-8hr following a single dose.
In general different dosage forms of TCA are
bioequivalent.
There are some differences between oral & parenteral
dosage forms :
 For parentral administration less FPM affect or
non-, compared with oral administration.
This is important in case of compounds producing active
metabolites, which have different therapeutic effect because
ratio between parent drug & its metabolite product will
differ according to the rout of administration (orally or
parenteraly).
There is a little information suggesting that drug
interaction or food alters their absorption.
CLEARANCE (CL)
TCA are cleared exclusively by the liver
Less than 5% of them are eliminated by the kidney.
TCA's active metabolites should be considered while
plasma level monitoring.
Clearances estimated for TCA varies 3 to 5 times.
Average values are in the range 10ml/kg/min(0.6/kg/hr)
This wide range is due to:
·Intra- &inter-individual variation in hepatic metabolism
&drug reactions
·Many compounds & liver diseases appear to ↑Cp.
Levels of TCA. eg. of diseases: alcoholic liver or liver
diseases.
it's difficult to estimate the clinical significant of these
drug-drug inter action when these drugs are added or
deleted from the therapy regimen ,since in some patients
may they exhibit either:
· Substantial change in metabolism.
· Relatively little change in TCA Cp.
These are due to:
·Differences In intrinsic metabolism among
patients.
·Difficulties in prediction of the magnitude of
drug inter action.
Patients should be carefully monitored when
current drug therapy is changed.
Careful patient's clinical symptom observations are
warranted.
DRUG-DRUG INTERACTION FOR TCA
1.MAO. Inhibitors:
-MAO inhibitor + TCA contraindicated
-There should be 2 weeks elapse between discontinuation
of either one of them.
-Symptoms: hyperpraxia, confusion, diaphoresis,
myoclonus, rigidity, seizure, cardio vascular disturbance
& coma.
-Mechanism is unknown but attributed to excessive
serotonergic activity in CNS.
2.Hypotensive agents:
-Clonidine, reserpine, guanabenz +TCA↓hypotensive
action.
The ↓ed. effect may occur within 1 or 2 weeks of TCA
intake.
-Mechanism: TCA blocks intake of guanathidine into
adrenergic neurons.
Blood plasma levels should be monitored in 1st
several weeks of concurrent therapy.
3.CNS depressant:
-Sedatives, hypnotics, alchohols +TCApotentiation of
CNS depressant.
-Barbiturates + TCA
· Potentiate adverse reactions eg. Respiratory
depression.
· ↑Metabolism of TCA ↓therapeutic response & Cp.
-Ethchlorvynol + amitriptyline transient delirium should
be use with caution.
-Benzodiazepines +TCA CP not altered, possible
impaired motor function.
-Dizepam + amitriptylinemay ↑t.5 & ↑steady state
-Manufacturer of protriptyline states that TCA may ↑the
seizure risk in patients taking tramadol hydrochloride.
4.Antipsychotic Agents:
-Phenothiazines, haloperidol ↓ metabolizm of TCA↑Cp of
TCA.
Their concomitant administration should be combined with
careful dose adjustment.
5.Sympathomimetic and Anticholinergic Agents:
Isoproterenol,Phenylephrine,Noradrenaline,Adrenaline,Ampheta
mines+TCA
↑Sympathetic activity specially pressor & cardiac effect could
be Fatal
*Close drug monitoring in this case is must.
-Anticholinergic + TCAhyperthermia (particularly in hot
weather), paralytic ileus.
*Concomitant administration needs careful adjustment.
6.Drugs Affecting Hepatic Microsomal Enzymes:
TCA are metabolized by various microsomal isoenzymes of
Cytochrom-P450:
CYP1A2 CYP2D26 CYP3A4 CYP2C .
-Drugs ↓ activity of CYP2D26  may ↑ cp. of TCA.
Those drugs may be enzymes:
·nonsubstares eg.( quinidine, cimetidine)
·Substrates eg. (Flecainide, phenothiazines, propafenone,
selective serotonin-reuptake inhibitors [SSRIs], other antidepressants).
- constant stabilized dose of TCA + CYP2D26 inhibitor TCA
toxic blood level.
So in this case:
· Dose of either TCA or CYP2D26 inhibitor should be ↓.
· TCA dose should be ↑when  CYP2D26 inhibitors are
discontinued.
· Cp. monitoring of TCA is recommended.
U
7.Quinidine:
- Quinidine + (Imipramine or Desipramine) ↓clearance.
-Quinidine + Nortriptyline  substantial:
· ↑Plasma t.5 .
· ↑Area Under the plasma concentration-time curve.
· ↓ Clearance.
8.Cimetidine:
-It's CYP2D26 inhibitor.
-Cimetidine + (Imipramine, Desipramine, Amitriptyline) 
· ↑ Clearance.
· ↑Bioavailability .
· ↑Elimination t.5 or peak plasma and/or steady-state.
· ↑ Adverse reactions especially Anticholinergic side
effects.
So in this case:
· ↓ Dose of TCA.
· ↑ Dose of TCA when Cimetidine is discontinued.
Ranitidine appears to be less likely to interact with TCA than
9.Selective Serotonin-Reuptake Inhibitors (SSRI):
-They are Cytochrom-P450 isoenzymes inhibitor but in variable
extent.
e.g.(citalopram, fluoxetine, paroxetine, sertraline)
-The clinical importance depends on:
· extent of inhibition of the cytochrome isoenzymes
· pharmacokinetics of the concomitantly administered SSRI
- Fluoxetine potent CYP1A2 inhibitor +TCA
·↑Cp. of TCA about(1-8fold)
·↑Clinical toxic signs: (sedation, decreased energy,
lightheadedness,
and
psychomotor retardation, dry mouth, constipation, memory impairment).
So in this case; when TCA are used with SSRI:

·↓ Dose of TCA.
· At least 5 weeks should elapse before initiating TAC therapy
in a
patient being withdrawn from fluoxetine, given the
long t.5 of fluoxetine and its active metabolite.
OTHER DRUG-DRUG INTERACTIONS…
Table.2
Drugs
Event
Comments
Levodopa &
phenylbutazone
May be inactivated since
they are absorbed from the
intestine
Because TCA ↓ gastric
emptying.
Careful dosage monitoring
is needed.
Dicumarol
+(Nortriptyline
,amitriptyline)
↑ Dicumarol Cp.
Warfarin (patients
stabilized on it.)
↑the prothrombin time
due to↑ the time available
for absorption of the
anticoagulant.
This is due to either:
↓Of anticoagulant
metabolism.
↓Intestinal motility.
Levothyroxine &
liothyronine
Accelerate the onset of
therapeutic effects of TCA.
May produce to cardiac
arrhythmia.
TCA should be given
cautiously to
(Hyperthyroid or receiving
thyroid agents) patients.
Methylphenidate
↓metabolism of TCA 
↑TCA effectivness
They may also ↑their
toxicity
Chlorpropamide 250 mg
daily
+
Initiation of nortriptyline
125 mg daily
Substantial hypoglycemia
in one patient with type 2
diabetes mellitus
Table. 3
Drug
Bioavailabilty
Imipramine
20-70 %
Desipramine
30-50 %
Amitriptyline
30-60 %
Nortriptyline
45-70%
VOLUME DISTRIBUTION (Vd)
TCAs are widely distributed through the body,
considering their extensive binding to plasma protein;
their tissue binding is impressive.
 Estimation for Vd of TCA varies ,but values mostly
used ranges between 15-20L\kg.
It's a phrmacokinetic parameter, which is not used
clinically since loading doses of TCA are not
administered.
Due to the large Vd & high protein binding it appears
that hemodialysis is not likely to remove significant
amounts of drug from the body.
HALF-LIFE (t.5)
 Because of ↑Vd & ↑Cl  result average t.5 ≈ 20 hrs.
 But it also varies to wide range 9-50hrs as Vd & Cl.
 The wide range is attributed to either :
· True alternation in pharmacokinetc parameters.
· Limitation that exist when attempting to estimate a drug t.5 within the
dosing interval that’s ≈ the drug's t.5 .
But it's difficult to know which one of these 2 is exactly responsible for the
wide range.
Its unclear weather t.5 of the drug would be used clinically to establish
dose interval for TCAs.
Lag between onset of clinical response relative to Cp. Palateau suggested
that therapeutic response is associated with either:
· More slow equilibrating deep tissue compartment.
· Some other biochemical change.
Both associated with TCA therapy.
So daily changes in blood level may not be important to therapeutic
control of depression but could be an issue with regard to side effects of
TCAs.
TIME TO SAMPLE
Most clinicians waits at least 2 weeks before obtaining Cp., unless
there are overt signs of toxicity .
Any samples obtained before achieving steady-state are not
recommended since they are miss leading.
Using steady-state conc. Adjustment in the dosing regimens can be
made in proportional to the change in Cp.
Appropriate time to obtain plasma sample with the dosing interval
is a bit difficult.
Since the rate of absorption is variable ; trough conc. are often
inconvenient , that’s why peak conc. obtained a few hours after the
dose is administered can be miss leading.
TCA.s are dosed at bed time so clinicians attempt to standardize the
sampling in the morning ≈ after about 12hrs. after oral dose.
mid-interval plasma conc.s should approximate steady-state conc ;
thus any revision of pharmacokinetc parameter will focus on estimate
of Cl & F.
by utalizing the principle of mean residence time ;which
recommnends measuring a Cp. Conc at specified point in a
time (usually24-36hrs after an initial oral dose) ≈ 1.5 halflives.
Clinicians usually limit TCA level monitoring to specific
circumstances & rely on clinical observasion.
Many clinicians believe that Cp. Should be measured only to
support clinicaly abserved SE …………..
Drg conc. may also used for diffrentiation between
noncompliant patients from who are unresponsive .
TCA.s levels are used to documentsuspected drug toxicity:
 · Conc.>500µg/L  asociated with SE.
· · Conc.>1000µg/L inappropriate & warrant withholding
*Table .3
DOSAGE FORMS AVAILABLE
Drug
Tablet
Capsul
Injectable
Imiprami
ne
(10,25,50)mg
(75,100,125,150)
mg Tofranil-PM
(12.5mg\ml2
ml)
ampules
Desiprami
ne
(10,25,50,75,100,150)
mg
(25,50)mg
Amitripty
line
(10,25,50,75,100,150)
mg
Nortriptyl
ine
(10,25,75)mg
10mg/ml,10
ml
(multidose
vial)
Oral
solutio
n
10mg/2
ml
*The usual maximum recommended adult daily dose is ≈ 300mg
Table .4
s
KEY PARAMETER
Parameter
Imipramine
Desipramine
Amitriptyine
Nortriptyline
Therapeut
ic range
180-350µg/L
100250µg/L
120250µg/L
50-150µg/L
Free
fraction
< 0.1
< 0.1
< 0.1
< 0.1
F
0.4
0.4
0.4
0.5
Vd
20L/kg
20L/kg
15L/kg
20L/kg
Cl
0.9 L/kg/hr
0.6 L/kg/hr
0.7L/kg/hr
0.4 L/kg/hr
t.5
20hrs
20hrs
20hrs
30hrs
Case #1:
A.R., a 39years-old, 65Kg female, is to be given
desipramine for depression. She has no other
significant medical history & takes acetaminophen or
ibuprofen rarely for headaches. Describe a reasonable
starting dose & schedule for increasing her
maintenance regimen.
Answer:
Because the bioavailability & intrinsic hepatic Cl of TCAs varies over a wide
range, most clinicians start therapy with conservative doses in a divided daily
schedule. Doses are increased only after the initial dose has achieved steadystate & SE. can be evaluated.
since A.R. has no other concurrent illnesses or medication that would be
expected alter her TCA metabolism ; a starting Desipramine dose of 25mg
twice daily is reasonable. Given the expected t.5 ≈ 20 hrs. , Steady state should
be achieved probably in ≈4 days, although most clinicians will prefer to wait 57 days before considering an ↑ in the her maintenance schedule. Although Cp.
of desipramine can be expected to plateau relatively rapidly but full response
will not be evident for several weeks. If at the end of the 1st week of therapy
A.R. is having no SE, the dose may be ↑ed. 75-100mg, even though the full
therapeutic benefit is from the initial dose is unlikely to be evident.
Maintenance doses are ↑ed. before the full therapeutic effect is achieved
because an excessively long titration period would accrue if the interval
between dose escalation were a month or more. If A.R had significant SE. from
the drug. eg. (CNS depression or anticholinergic SE), any dose ↑ would be
withheld. With time if ES.s diminish …↑ing daily dose may be permitted
Case#2:
After 3 weeks of titration, A.R. has been stabilized on
150mg/day of desipramine for 1 week. She has relatively
few SE. but her depression has improved minimally
would plasma levels of desipramine be useful? What
would one expect the average steady-state disipramine
concentration to be?
Answer:
One wouldn't expect to see full therapeutic effects of the TCA
within 3 weeks of initiating therapy. Some clinicians believe that
early Cp monitoring may help identify those patients with low Cp.
& therefore at higher risk for therapeutic failure.
Depending upon therapy the severity of A.R.'s depression, one
approach would be to continue her current regimen for another few
weeks. If a satisfactory response is not obtained; the dose could be
↑ed. to ≈200mg/day in an attempt to achieve adequate control of
her depression. It wouldn't be irrational, however, to obtain a Cp.
From A.R. now to determine if it's anywhere near the therapeutic
range (100-250 μg/L) if her Cp. is low & compliance could be
assured it would be logical to escalate her dose at this time. This
saves waiting the additional 3weeks to evaluate the full therapeutic
response & diminishes the total time required to achieve the
optimal dose titration.
S=1.o
,  Dose = 150,000µg
F=0.4
,   = 24 hr
Cl = (0.6L/Kg * 65Kg)=39 L/hr
Cpss ave= (S)(F)(dose)
Cl*
= 1*0.4*150,000 = 64.1 µg/L
39 * 24
Case#3:
S.U., a 68 years-old, 68 Kg. Male, is in good
health following a mild myocardial infraction
(MI) two years ago. He has been treated
intermittently for the past twenty years for
endogenous depression and is now to be started
on nortriptyline. His most frequent complaints
have been a general lack of interest in usual
activities. What would be a reasonable starting
dose? Would Cp. Monitoring be useful?
Answer:
S.U.'s age and history of cardiac disease place him at higher risk for TCA toxicity
than other patient. Therefore, he should started on the lowest available dose (10-25
mg/day). Even though these low doses are unlikely to result in a therapeutic
response, concern for both the cardiovascular and other SE effect in the elderly is
sufficient to warrant caution. Most clinicians would carefully evaluate S.U. weekly
and if no SE are observed eg. (changes in visual acuity, dry mouth, orthostatic
hyptension, cardiac arrhythmias), ↑ the dose by approximately 10 to 25 mg until he
is stabilized on a dose of a 50 to 75 mg/day has not responded adequately after a
sufficient time interval and there are no obvious SE, it will be necessary to decide
whether or not a further increase in dose is appropriate. Many clinicians feel that
the elderly and patients with pre-existing cardiac disease are candidates for
therapeutic dry level monitoring. Thus, it might be appropriate to obtain a plasma
nortriptyline level at this point. If the plasma conc. are low and an adequate
therapeutic response has been attained, the dose should not be increased. If,
however, low conc. are associated with a poor therapeutic response, a further
escalation of the dose is probably warranted. If nortriptyline conc. are within the
usual therapeutic range (50-150µg/L) and there is an inadequate therapeutic
response, a decision to increase the dose would be difficult. As an alternative drug
with a lower toxicity profile could be considered.
Case#4:
N.H., a 27 year-old male, has been stabilized on
imipramine 100mg/day (500mg BID) with good response
to his depression. 2 week ago his physician prescribed
100mg capsules (tofranil PM) at bed time to simplify the
regimen, unfortunately, N.H continued to take 2 doses a
day (200mg) at bed time & now presents with confusion,
dry mouth, blurred vision. Would a drug plasma level be
useful to establish a course of action for N.H & apparent
imipramine toxicity? s
Answer:
Many clinicians believe that cases of suspected TCA. toxicity are
indications for obtaining Cp.. plasma levels help the clinicians
distinguish tricyclic- induced dementia from the potential causes.
However, relationship between TCA conc. and SE. is variable and
cannot be relied upon absolute indicator. Many clinicians believe
that any Cp. > 500 µg/L is reason to withhold or reduce Dm. and
that conc. >1000µg/L warrant withhold the drug and monitoring
the patient for Cardiovascular SE. In N.H.'s case, the diagnoses is
not in question; therefore, the use of Cp for this purpose is not
warranted. If an imipramine Cp could be rapidly obtained, it might
provide the clinician with enough information to determine if an
N.H's side effect could be treated an outpatient setting. This would
also depend upon the severity of the SE. Some clinicians obtain Cp
for medical legal reason, even if it will not alter the immediate care
of patient.
Case#5:
O.N., a 38-year old, 60Kg. Female, is being titrated on
increasing doses of desipramine and., for the past month,
has been receiving 150 mg. HS. In the past she has
complained of dry mouth; lately she doesn't feel this is a
problem and has no other symptoms which might be
considered SE. of desipramine. She takes no other
concurrent medication except for Acetaminophen
occasionally and smokes one pack of cigarettes a day.
Estimate her desipramine concentration.
Answer:
In order to calculate O.N.'s steady-state desipramine conc. , it will 1st be
necessary to select a pharmacokinetic modle. Its calculated as follow:
Cpss ave= (S)(F)(dose)
Cl*
S=1.o
,  Dose = 150,000µg
F=0.4
,   = 24 hr
Cl = (0.6L/Kg/hr * 60Kg)=36 L/hr
=1*0.4*150,000 = 69.44 ≈ 70 µg/L
36 * 24
since expected desipramine t.5≈20 &  =24 , the continuous infusion
model is not appropriate .
the intermittent steady-state bolus dose model is appropriate
when non-sustained release product is used & absorption occurs
over a short time period relative to the drug t.5 .
Cpssmin = (S)(F)(dose)(℮-kd)
Vd (1-℮-kd)
= 1* 0.4 * 150,000 * ℮ - (0.0347 * 24)
1200 * (1-℮ - (0.0347 * 24)
S=1.o
F=0.4
,  Dose = 150,000µg
,   = 24 hr
Vd= (20L/kg * 60kg ) = 1200 L
Cl = (0.6L/Kg/hr * 60Kg) =36 L/hr
 kd=(0.693/20hr) =0.0347hr –1
= 38.4 ≈ 40 µg/L
Note that while there is a differences in the calculate (Cpss
ave) & trough conc. (Cpssmin), they are somewhat similar, if
the measured conc. differs from the predicted levels, it
would be difficult to explain. For example, if a measured
(Cpssmin) reported to be 60µg/L , one could revise the
(F),(Cl) or (Vd) ,since all these parameter can vary
significantly. However, while Vd is a variable, it would
require an exceedingly large Vd to ↑ the (Cpssmin ) to
60µg/L when the (Cpss ave) is expected to be 69.4µg/L .
therefore the most common approach would be to adjust the
Cl value since this parameter is thought to be removed to be
more variable than either F or Vd for most of TCA.s .
however, hepatic Cl & (FPM) effect are predominant
reasons for the low F ;thus is a patient has a lower-thanaverage Cl ,one would should anticipate an ↑in her F.
Case#6:
O.N. didn't respond well to her therapy and trough
desipramine level was obtained, the laboratory reported a
value of 68 ng/ml (μg/L) . Because she is not responding,
the physician plans to increase O.N.'s desipramine
concentration to 100 to 150 ng/ml (μg/L). What dose
adjustment is likely to achieve this goal?
Answer:
One approach is to calculated a new pharmacokinetic parameter ,it's by interpretation
of plasma drug conc. : the peak conc. 1st estimated by adding the observed trogh conc.
(Cpssmin) to the expected change associated with the dose
DM(S)(F) = (Cpssmax*Vd )- (Cpssmin *Vd ) =rearrangement=>
=>Cpssmax =[ Cpssmin] + [(S)(F)(dose)/Vd]
= [68] + [(1)(0.4)(150,000)/ 1200]
F=0.4 ,  Cpssmin = 68µg/L
=118µg/L
Vd= (20L/kg*60kg )=1200L
S=1.0 ,  DM= 150,000µg
the revised elimination constant (Kd) can be calculated & also the t.5 :
Kd = In (Cpmax / Cpmin ) = In (118/68)  Kd = 0.023 hr -1
∆
24
t.5 = 0.693 =
Kd
0.693
 t.5=30 hrs
0.023 hr
This data can be used to calculate the dose needed to achieve the target plasma conc.
assuming (Cpssmin) is the trough value…
Cpssmin = 150µg/L
Cpssmin = (S)(F)(dose) (℮-kd)
Vd (1-℮-kd )
=↕rearrangement↕=
) (Vd) (1-℮-kd )
(S)(F) (℮-kd)
=150 *1200 *(1-℮ - (0.023 * 24) ) = 331,25 ≈ 300 g
dose= (Cpssmin
1 * 0.4 *℮ - (0.023* 24)
S=1.o
, ?? Dose ??
F=0.4
,   = 24 hr
Vd= (20L/kg * 60kg ) = 1200 L
 kd=0.023 hr -1
it's unlikley that the maintenance dose (DM) would be
↑ed. by this amount because it's a large % ↑ in the dose
(thogh it will give us the desired ↑ in Cp.) & the new dose
is exceeding the max. therapeutic recommended dose
.while it may be necessary to ↑O.N.'s dose to the range of
300mg/day to achieve the Cp=150µg/L, most clinicians
would↑ O.N.'s dose by ≈(25-50 mg/day) & observe her for
clinical immprovment & SE.
this step wise approach is more rational since some
patients response at lower Cp.s & the chances of SE. are
subsatntial with larger doses.