TEOPHYLLINE

Kelompok 7:
1. Nadya Zahra Henni (1511012009)
2. Vivi Dwi Maryeti (1511012010)
3. Syifa Mawaddah (1511012014)
4. Intan Fajrin (1511012015)
5. Melisa Oktavia (1511012021)
 INTRODUCTION
• Theophylline is a methylxanthine compound that is used
for the treatment of asthma, chronic obstructive
pulmonary disease (COPD; chronic bronchitis and
emphysema), and premature apnea.
• Theophylline is now considered to be adjunctive therapy,
and inhaled corticosteroids are considered the mainstay
of therapy
• Other drugs that are useful in patients with asthma are
cromolyn, nedocromil, oral corticosteroids, inhaled
anticholinergics, and leukotriene modifiers

Bauer, 2008: 745

The broncodilatory effect occur by two predominate
mechanisms of action are:
• inhibition of cyclic nucleotid phosphodiesterases which
increases intracellular cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP)
• antagonism of adenosine receptors

Other effects:
• increases diaphragmatic contractility
• increases mucociliary clearance
• exerts some
• antiinflammatory effects
Bauer, 2008: 745-746
THERAPEUTIC AND TOXIC CONCENTRATION
• Therapeutic range: 10-20 μg/mL for asthma or
COPD, 6-13 μg/mL for premature apnea
• Initial treatment of pulmonary disease: 5–15
μg/mL
• In the upper end of the therapeutic range (>15
μg/mL) adverse effects include nausea,
vomiting, dyspepsia, insomnia, nervousness, and
headache

Bauer, 2008: 746

• Concentrations exceeding 20–30 μg/mL 
cause various tachyarrhythmias including sinus
tachycardia.
• Concentrations >40 μg/mL  adverse effects
including ventricular arrhythmias (premature
ventricular contractions, ventricular tachycardia
or fibrillation) or seizures

Bauer, 2008: 746

CLINICAL MONITORIG PARAMETERS
• Pulmonary function tests  assesing response to
bronchodilator therapy
• FEV1 (forced expiratory volume over 1 s) 
monitor bronchodilator drug effect
• Spirometric tests for patients with COPD  vital
capacity (VC), total lung capacity (TLC), forced
vital capacity (FVC), and forced expiratory flow
over the middle 50% of the expiratory curve
(FEF25–75% or FEF50%)

Bauer, 2008: 746-747

• Clinical signs and symptoms  dyspnea,
coughing, wheezing, impairment of normal
activity
• Arterial blood gases  during acute
exacerbations or in severe cases of either
pulmonary disease state
• Frequency of apneic events  premature infants
with apnea
• Theophylline serum concentration

Bauer, 2008: 747

• The ideal situation is to administer an IV loading
dose that will achieve the desired concentration
immediately, then start an IV continuous
infusion that will maintain that concentration
LD = Css ⋅ VD
• Css = 3-5 t1/2, whereas t1/2 = 3-5 hours
(children), tobacco-smoking individuals to 50
hours or more in patients with severe heart or
liver failure.

Bauer, 2008: 747

Bauer, 2008: 747
Bauer, 2008: 748
BASIC CLINICAL PHARMACOKINETIC PARAMETERS
• Theophylline is primarily eliminated by hepatic metabolism
(>90%)
• Theophylline follows nonlinear pharmacokinetics
• Three different forms of theophylline are available:
1. anhydrous aminophylline contains  85% theophylline
2. aminophylline dihydrate contains  80% theophylline
3. Oxtriphylline contains  65% theophylline

Bauer, 2008: 748-749

• Aminophylline  ethylenediamine salt of theophylline
• Oxtriphylline  the choline salt of theophylline
• Theophylline and aminophylline  IV injection and oral.
Oxtriphylline  oral
• The oral bioavailability  generally equals 100%
• Theophylline plasma protein binding  40%
• The recommended dose of theophylline or one of its salt
forms is based on the concurrent disease states and
conditions present in the patient that can influence
theophylline pharmacokinetics.

Bauer, 2008: 749

 Effects Of Disease States And Conditions On
Theophylline Pharmacokinetics And Dosing

• Normal Adult Patients

▫ T½ : 8 h (range: 6–12 h)
▫ Vd : 0.5 L/kg (range: 0.4–0.6 L/kg)
• Smoke patients (Tobacco and marijuana)
▫ T½ :5h
(smoke causes induction of hepatic CYP1A2 which
accelerates the clearance of theophylline.)

(Bauer,2008 : 749)
• Liver cirrhosis/acute hepatitis patients

▫ T½ : 24 h

• Liver cirrhosis/acute hepatitis & smoke patients

▫ T½ : 5 h (if some liver parenchyma is present and

tobacco-induced enzyme induction occurred)

▫ T½ : 50 h (if little or no liver tissue remains)

• An index of liver dysfunction can be gained by applying

the Child-Pugh clinical classification system to the
patient.
(Bauer,2008 : 749)
Disease States and Conditions That Alter
Theophylline Pharmacokinetics

(Bauer,2008 : 750)
(Bauer,2008 : 750)
(Bauer,2008 : 751)
 Child-Pugh Scores for Patients with Liver Disease

A Child-Pugh score greater than 8 is grounds for a decrease in the initial daily
drug dose for theophylline (t = 24 hours).

(Bauer,2008 : 751)
• Heart failure patients
▫ Mild : T½ = 12 h (range: 5–24 h)
▫ Moderate/severe : T½ = 24 h (range: 5–50 h)
• Obese patients (>30% above ideal body weight
or IBW) should have volume of distribution
estimates based on ideal body weight.

(Bauer,2008 : 752)
 DRUG INTERACTION
• Drug interactions with theophylline are common and
occur with a variety of medications.
• Serious inhibition drug interactions are those that
decrease theophylline clearance more than 30%.
• Clinicians should consider an arbitrary decrease in
theophylline dose of 30–50% for patients receiving these
agents until the actual degree of hepatic enzyme
inhibition can be assessed using theophylline serum
concentration monitoring.

(Bauer,2008 : 753)
Initial dosage determination method
1. Pharmacokinetic Dosing Method
HALF-LIFE AND ELIMINATION RATE CONSTANT
ESTIMATE
• Theophylline is predominately metabolized by liver
• Unfortunately, there is no good way to estimate the
elimination characteristics of liver metabolized
drugs using an endogenous marker of liver function
in the same manner that serum creatinine and
estimatedcreatinine clearance are used to estimate
the elimination of agents that are renally eliminated.
Ke = Cl/ VD
t ½ = 0.693/Ke
(Bauer, 2008: 755)
VOLUME OF DISTRIBUTION ESTIMATE
• Theophylline volume of distribution is relatively
stable in patients regardless of the disease states
and conditions that are present.
• Volume of distribution is assumed to equal 0.5
L/kg for non obese patients. For obese patients
(>30% above ideal body weight

(Bauer, 2008: 755)

SELECTION OF APPROPRIATE PHARMACOKINETIC
MODEL AND EQUATIONS
• When given by continuous intravenous infusion
or orally, theophylline follows a one
compartment pharmacokinetic model
• When oral therapy is required, most clinicians
utilize a sustained-release dosage form that has
good bioavailability (F = 1)
Css = [F(D/τ)] / Cl or D = (Css ⋅ Cl ⋅ τ) / F

(Bauer, 2008: 755)

STEADY-STATE CONCENTRATION SELECTION
• The generally accepted therapeutic ranges for
theophylline are 10–20 μg/mL for the treatment of
asthma or chronic obstructive pulmonary disease
• 6–13 μg/mL for the treatment of premature apnea.
Recent guidelines suggest that for initial treatment
of pulmonary disease,
• Many patients requiring chronic theophylline
therapy will derive sufficient bronchodilatory
response with a low likelihood of adverse effects at
concentrations of 8–12 μg/mL.
• Theophylline therapy must be individualized for
each patient in order to achieve optimal responses
and minimal side effects.
(Bauer, 2008: 757)
Literature-Based Recommended Dosing
• In general, the expected theophylline Css used to
compute these doses was 10 μg/mL
• Tabel of Theophylline Dosage Rates for Patients
with Various Disease States and conditions
• Because the doses are given in terms of theophylline, doses for other
theophylline salt forms need to be adjusted accordingly (S = 0.85 for
anhydrous aminophylline, S = 0.8 for aminophylline dihydrate, S =
0.65 for oxtriphylline).
• If theophylline is to be given orally, the dose given in Table 18-4 (in
mg/kg/h) must be multiplied by the appropriate dosage interval for
the dosage form being used: D = (theophylline dose ⋅ Wt ⋅ τ)/S,
where Wt is patient weight, τ is the dosage interval, and S is the
appropriate salt form correction factor for aminophylline or
oxtriphylline.
• If theophylline is tobe given as a continuous intravenous infusion
the following equation is used to compute the infusion rate: k
0 = (theophylline dose ⋅ Wt)/S, where Wt is patient weight and S is
the appropriate salt form correction factor for aminophylline.
Use Of Theophylline Serum Concentrations
To Alter Doses
• Because of the large amount of pharmacokinetic variability among
patients, it is likely that doses computed using patient population
characteristics will not always produce theophylline serum
concentrations that are expected or desirable.
• Because of pharmacokinetic variability, the narrow therapeutic
index of theophylline, and the severity of theophylline adverse side
effects, measurement of theophylline serum concentrations is
mandatory for patients to ensure that therapeutic, nontoxic levels
are present.
• In addition to theophylline serum concentrations, important patient
parameters (pulmonary function tests, clinical signs and symptoms
of the pulmonary disease state, potential theophylline side effects,
etc.) should be followed to confirm that the patient is responding to
treatment and not developing adverse drug reactions.
 Linear Pharmacokinetics Method
• Because theophylline follows linear, dose-
proportional pharmacokinetics in most
patients with concentrations within and below
the therapeutic range, CSS change in proportion
to dose according to the following equation:
Dnew/Cssnew = Dold/Cssold or
Dnew = (Cssnew/Cssold)Dold
 Pharmacokinetic Parameter Method
• The pharmacokinetic parameter method of
adjusting drug doses was among the first
techniques available to change doses using
serum concentrations.
• It allows the computation of an individual’s own,
unique pharmacokinetic constants and uses
those to calculate a dose that achieves desired
theophylline concentrations.
• The pharmacokinetic parameter method
requires that steady state has been achieved and
uses only CSS
• During a continuous intravenous infusion, the following equation is
used to compute theophylline clearance (Cl): Cl = (S ⋅ k0)/Css,
where S is the
fraction of the theophylline salt form that is active theophylline (S =
1 for theophylline, S = 0.85 for anhydrous aminophylline, S = 0.80
for aminophylline dihydrate) and k0 is the dose of theophylline salt
in milligrams per hour.
• If the patient is receiving oral theophylline therapy, theophylline
clearance (Cl) can be calculated using the following formula: Cl = [F
⋅ S (D/τ)] / Css, where F is the bioavailability fraction for the oral
dosage form (F = 1 for most oral theophylline sustained-release
products), S is the fraction of the
theophylline salt form that is active theophylline (S = 0.85 for
anhydrous aminophylline, S = 1 for theophylline, S = 0.80 for
aminophylline dihydrate, S = 0.65 for oxtriphylline)
• Occasionally, theophylline serum concentrations are
obtained before and after an intravenous loading dose.
Assuming a one-compartment model, the volume of
distribution (V) is calculated using the following
equation:
• V = (S ⋅ D)/(Cpostdose - Cpredose)
• D is the dose of theophylline salt in milligrams,
Cpostdose is the postloading dose concentration in
milligrams per liter and Cpredose is the concentration
before the loading dose was administered in milligrams
per liter (both concentrations should be obtained within
30–60 minutes of dosage administration)
• Occasionally, theophylline serum concentrations are
obtained before and after an intravenous loading dose.
Assuming a one-compartment model, the volume of
distribution (V) is calculated using the following
equation:
• V = (S ⋅ D)/(Cpostdose - Cpredose)
• D is the dose of theophylline salt in milligrams,
Cpostdose is the postloading dose concentration in
milligrams per liter and Cpredose is the concentration
before the loading dose was administered in milligrams
per liter (both concentrations should be obtained within
30–60 minutes
of dosage administration)
 CHIOU Method
For some patients, it is desirable to individualize
theophylline infusion rates as rapidly as possible before
steady state is achieved. Examples of these cases include
patients with heart failure or hepatic cirrhosis who have
variable theophylline pharmacokinetic parameters and long
theophylline half-lives. In this situation, two theophylline
serum concentrations obtained at least 4–6 hours apart
during a continuous infusion can be used to compute
theophylline clearance and dosing rates.
Where S is the fraction of the theophylline salt form that is
active theophylline (S = 1 for theophylline, S = 0.85 for
anhydrous aminophylline, S = 0.80 for aminophylline
dihydrate), k0 is the infusion rate of the theophylline salt, V
is theophylline volume of distribution, C1 and C2 are the
first and second theophylline serum concentrations, and t1
and t2 are the times that C1 and C2 were obtained .
Bayesian Pharmacokinetic Computer Program
Computer programs are available that can assist in
the computation of pharmacokinetic parameters for
patients. The most reliable computer programs use a
nonlinear regression algorithm that incorporates
components of Bayes’ theorem. Nonlinear regression is a
statistical technique that uses an iterative process to
compute the best pharmacokinetic parameters for a
concentration/time data set. Briefly, the patient’s drug
dosage schedule and serum concentrations are input into
the computer. The computer program has a
pharmacokinetic equation preprogrammed for the drug
and administration method (oral, intravenous bolus,
intravenous infusion, etc.).
 Dosing Strategies
Initial dose and dosage adjustment techniques using serum
concentrations can be used in any combination as long as
the limitations of each method are observed. Some dosing
schemes link together logically when considered according
to their basic approaches or philosophies .
 USE OF THEOPHYLLINE BOOSTER DOSES TO
IMMEDIATELY INCREASE SERUM CONCENTRATIONS

If a patient has a subtherapeutic theophylline serum

concentration in an acute situation, it may be desirable to increase the
theophylline concentration as quickly as possible. A modified loading
dose equation is used to accomplish computation of the booster dose
(BD) which takes into account the current theophylline concentration
present in the patient:
BD = [(Cdesired - Cactual)V]/S
where Cdesired is the desired theophylline concentration, Cactual is the
actual current theophylline concentration for the patient, S is the
fraction of the theophylline salt form that is active theophylline (S = 1
for theophylline, S = 0.85 for anhydrous aminophylline, S = 0.80 for
aminophylline dihydrate), and V is the volume of distribution for
theophylline
 CONVERSION OF THEOPHYLLINE DOSES FROM
INTRAVENOUS TO ORAL ROUTE OF ADMINISTRATION
• In general, oral theophylline dosage forms, including most
sustained-release tablets and capsules, have a bioavailability equal
to one. Assuming that equal theophylline serum concentrations are
desired, this makes conversion between the intravenous [k0 = (Css ⋅
Cl)/S] and oral [D = (Css ⋅ Cl ⋅ τ)/(F ⋅ S)] routes of administration
simple since equivalent doses of drug (corrected for theophylline
salt form) are prescribed: k0 = Dpo/(24 h/d ⋅ Siv) or Dpo =Siv ⋅ k0 ⋅
24 h/d, where k0 is the equivalent intravenous infusion rate for the
theophylline salt in milligrams per hour, Dpo is equivalent dose of
oral theophylline in milligrams per day, and Siv is the fraction of the
intravenously administered theophylline salt form that is
active theophylline
 REMOVAL OF THEOPHYLLINE BODY STORES IN
MANAGEMENT OF THEOPHYLLINE OVERDOSE

In addition to supportive care, treatment of seizures

with anticonvulsant agents, and treatment of cardiac
arrhythmias with antiarrhythmic agents, removal of
theophylline from the body should be considered in
cases of acute and chronic overdoses. Extracorporeal
methods to remove theophylline in emergency situations
include hemodialysis and charcoal hemoperfusion.
Theophylline can also be removed from the body using
oral doses of activated charcoal.
 REFERENCE
Bauer, Larry A. 2008.Applied Clinical
Pharmacokinetics 2nd ed.New York: Mc Graw
Hill
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