Topic 3

Group 1 Class A :
1. Asha Nayshalya Jafri (1511011004)
2. Winny Rhamadani (1511011005)
3. Nadya Prafita (1511011007)
4. Indriyani (1511011008)
5. Hurul Aini (1511011011)
 Theophylline  methylxanthine compound that is used for the
treatment of asthma, chronic obstructive pulmonary disease (COPD;
chronic bronchitis and emphysema), and premature apnea.
 In the chronic management of asthma or chronic obstructive pulmonary
disease patients, theophylline is now considered to be adjunctive
therapy.
 Asthma is now recognized as an inflammatory disease, and inhaled
corticosteroids are considered the mainstay of therapy.
 Inhaled selective β2-agonists are used as bronchodilators in asthmatic
patients.
 Other drugs that are useful in patients with asthma are cromolyn,
nedocromil, oral corticosteroids, inhaled anticholinergics, and
leukotriene modifiers.
(Bauer,2008: 745)
 Theophylline is also useful in these patients when they are unable or
unwilling to use multiple metered dose inhaler (MDI) devices or if an
intravenous drug is needed.
 For the treatment of premature apnea, most clinicians prefer to use
caffeine, a related methylxanthine agent, instead of theophylline
because of smoother apnea control and reduced adverse effects.
 In addition to bronchodilation, theophylline increases diaphragmatic
contractility, increases mucociliary clearance, and exerts some
antiinflammatory effects.
 Theophylline is a general central nervous system stimulant and
specifically stimulates the medullary respiratory center. These are the
reasons why it is a useful agent in the treatment of premature apnea.

(Bauer,2008: 746)
 The generally accepted therapeutic ranges = 10–20 μg/mL for the
treatment of asthma or COPD, or 6–13 μg/mL for the treatment
of premature apnea.
 Clinical guidelines suggest that for initial treatment of pulmonary
disease, clinical response to theophylline concentrations between
5–15 μg/mL should be assessed before higher concentrations are
used.
 However, theophylline therapy must be individualized for each
patient in order to achieve optimal responses and minimal side
effects

(Bauer,2008: 746)
 In the upper end of the therapeutic range (>15 μg/mL) some
patients will experience minor caffeine-like side effects owing to
theophylline treatment.
 adverse effects  nausea, vomiting, dyspepsia, insomnia,
nervousness, and headache.
 Theophylline concentrations exceeding 20–30 μg/mL can cause
various tachyarrhythmias including sinus tachycardia.
 At theophylline concentrations above 40 μg/mL, serious life-
threatening adverse effects including ventricular arrhythmias
(premature ventricular contractions, ventricular tachycardia or
fibrillation) or seizures can occur.

(Bauer,2008: 746)
 Measurement of pulmonary function tests are an important
component of assessing response to bronchodilator therapy in
patients with asthma or chronic obstructive pulmonary disease.
 Forced expiratory volume over 1 second (FEV1) should be
measured on a regular basis for asthmatic patients, and peak-flow
meter monitoring can be routinely performed by these
individuals at home

(Bauer,2008: 746)
 For dose adjustment purposes, theophylline Scr should be
measured at steady state after the patient has received a
consistent dosage regimen for 3–5 t ½ .
 T ½ (children and tobacco-smoking individual)s = 3 to 5 hours
 T ½ (in patients with severe heart or liver failure) = 50 hours or
more.

(Bauer,2008: 747)
(Bauer,2008: 747)
 Theophylline is primarily eliminated by hepatic metabolism
(>90%).
 Hepatic metabolism is mainly via the CYP1A2 enzyme system
with a smaller amount metabolized by CYP3Aand CYP2E1.
 About 10% of a theophylline dose is recovered in the urine as
unchanged drug.
 Theophylline follows nonlinear pharmacokinetics

(Bauer,2008: 748)
 Three different forms of theophylline are available.
 Aminophylline is the ethylenediamine salt of theophylline,
 Anhydrous aminophylline contains about 85% theophylline
while aminophylline dihydrate contains about 80% theophylline.
 Oxtriphylline is the choline salt of theophylline and contains
about 65% theophylline.
 Theophylline and aminophylline are available for intravenous
injection and oral use.
 Oxtriphylline is available only for oral use.

(Bauer,2008: 748)
 The oral bioavailability of all three theophylline-based drugs is
very good and generally equals 100%.
 Theophylline plasma protein binding is only 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: 748)
 T ½ (Normal adluts) = 8 hours (range: 6–12 hours)
 Vd for Normal adults = 0.5 L/kg (range: 0.4–0.6 L/kg)
 Tobacco and marijuana smoke causes induction of hepatic
CYP1A2 which accelerates the clearance of theophylline.
 T ½ ( who smoke tobacco and marijuana) = 5 hours
 T ½ ( patients with liver cirrhosis or acute hepatitis) = 24 hours

(Bauer,2008: 749)
(Bauer,2008: 750)
(Bauer,2008: 750)
(Bauer,2008: 751)
 The Child-Pugh score for a patient with normal liver function is
5
 A Child-Pugh score greater than 8 is grounds for a decrease in
the initial daily drug dose for theophylline (t1/2 = 24 hours).

(Bauer,2008: 751)
(Bauer,2008: 752)
 Patient age has an effect on theophylline Cl and t ½ .
 Newborns have decreased theophylline Cl because hepatic
drug–metabolizing enzymes are not yet fully developed at birth.
 T ½ (Premature neonates 3–15 days after birth )= 30 hours
 T ½ (Premature neonates 25–57 days after birth )= 20 hours
 T ½ (Full term infants 1–2 days after birth )= 25 hours
 T ½ (Full term infants 3–30 weeks after birth) = 11 hours
 T ½ (Children between the ages of 1–9 years) = 3.5 hours
(range: 1.5–5 hours)
 For elderly patients over the age of 65theophylline CL is slower
and t ½ is longer (average half-life = 12 hours, range: 8–16
hours)
(Bauer,2008: 752-753)
 Serious inhibition drug interactions are those that decrease
theophylline CL more than 30%.
 Cimetidine given at higher doses (≥1000 mg/d) on a multiple daily
dosage schedule decreases theophylline CL by 30–50%.
 Other cimetidine doses (≤800 mg/d) given once or twice daily decrease
theophylline CL by 20% or less.
 Ciprofloxacin and enoxacin, both quinolone antibiotics, and
troleandomycin, a macrolide antibiotic, also decrease theophylline CL
by 30–50%.
 Estrogen and estrogen-containing oral contraceptives, propranolol,
metoprolol, mexiletine, propafenone, pentoxifylline, ticlopidine,
tacrine, thiabendazole, disulfiram, nefazodone, interferon, zileuton, and
fluvoxamine can also decrease theophylline clearance by this extent

(Bauer,2008: 753-754)
 The calcium channel blockers, verapamil, and diltiazem, have
been reported to cause decreases in theophylline CL by 15–25%.
 Clarithromycin and erythromycin, both macrolide antibiotics,
and norfloxacin, a quinolone antibiotic, can also decrease
theophylline CL by this magnitude.
 At doses of 600 mg/d or above, allopurinol has been reported to
decrease theophylline CL by 25%.

(Bauer,2008: 754)
A. Pharmacokinetic Dosing Method
◦ T ½ and Ke Estimate
k = 0.693/t ½
◦ Vd estimate
Vd (nonobese patients) = 0.5 L/kg
◦ Selection of appropriate pharmacokinetic model and equation
Css = [F ⋅ S (D/τ)]/Cl
D = (Css ⋅ Cl ⋅ τ)/(F ⋅ S)
Cl = kV

(Bauer,2008: 755)
- S = 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, S = 0.65 for oxtriphylline),
- D = the dose of theophylline salt in milligrams
- τ = the dosage interval in hours.
- Cl = theophylline clearance in liters per hour

(Bauer,2008: 755)
◦ Css Selection
The generally accepted therapeutic ranges for theophylline
are 10–20 μg/mL for the treatmentof asthma or chronic
obstructive pulmonary disease,
The generally accepted therapeutic ranges for
theophylline(for the treatment of premature apnea.) = 6–13
μg/mL

(Bauer,2008: 755)
B. Literature Based Recommended Dosing
 In general, the expected theophylline Scr used to compute these
doses was 10 μg/mL

(Bauer,2008: 760)
 For obese individuals (>30% over ideal body weight), ideal body weight
should be used
 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 to be given as a continuous intravenous infusion the
following equation is used to compute the infusion rate:
k0 = (theophylline dose ⋅ Wt)/S

(Bauer,2008: 761)
A. Linear Pharmacokinetic Method
Dnew/Css,new = Dold/Css,old
Dnew = (Css,new/Css,old)Dold

B. Pharmacokinetic Parameter Method

◦ During a continuous intravenous infusion, the following equation is used to
compute theophylline Cl:
Cl = (S ⋅ k0)/Css,
◦ If the patient is receiving oral theophylline therapy, theophylline Cl can be
calculated using the following formula:
Cl = [F ⋅ S (D/τ)] / Css,

(Bauer,2008: 764,766)
 Occasionally, theophylline serum concentrations are obtained
before and after an IV LD . Assuming a one-compartment model,
the Vd is calculated using the following equation:
V = (S ⋅ D)/(Cpostdose − Cpredose)

(Bauer,2008: 767)
 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 t ½ .
 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.
 In addition to this requirement, the only way theophylline
can be entering the patient’s body must be via iv infusion.

(Bauer,2008: 770)
 Thus, the last dose of sustained-release theophylline must have
been administered no less than 12–16 hours before this technique
is used, or some residual oral theophylline will still be absorbed
from the gastrointestinal tract and cause computation errors.
 The following equation is used to compute theophylline Cl using
the theophylline concentrations:
k0 = (Css ⋅ Cl)/S

(Bauer,2008: 771)
 S = 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 = the infusion rate of the theophylline salt
 V = Vd theophylline (assumed to equal 0.5 L/kg; use ideal body
weight for obese patients >30% overweight),
 C1 and C2 = the first and second theophylline serum concentrations
 t1 and t2 = the times that C1 and C2 were obtained. Once
theophylline CL is determined, it

(Bauer,2008: 771)
1. Enter patient’s demographic, drug dosing, and serum
concentration/time data into the computer program.
2. Compute pharmacokinetic parameters for the patient using
Bayesian pharmacokinetic computer program
3. Compute dose required to achieve desired theophylline serum
concentrations.

(Bauer,2008: 773)
 Initial dose and dosage adjustment techniques using serum
concentrations can be used inany combination as long as the
limitations of each method are observed.

(Bauer,2008: 774)
 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.
 In this setting, it would not be acceptable to simply increase the
maintenance dose and wait 3–5 t ½ for therapeutic serum
concentrations to be established in the patient.
 A rational way to increase the serum concentrations rapidly is to
administer a booster dose of theophylline, a process also known
as “reloading” the patient with theophylline, computed using
pharmacokinetic techniques.

(Bauer,2008: 774)
 A modified LD 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
 Cdesired = the desired theophylline concentration,
 Cactual = the actual current theophylline concentration for the
patient
 S = 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),
 Concurrent with the administration of the booster dose, the
maintenance dose of theophylline is usually increased

(Bauer,2008: 775)
 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
 k0 = the equivalent iv infusion rate for the theophylline salt ( mg /h)
 Dpo = equivalent dose of oral theophylline (mg/day_
 Siv = the fraction of the iv administered theophylline salt form that is
active theophylline.

(Bauer,2008: 776)
 Extracorporeal methods to remove theophylline in emergency
situations include hemodialysis and charcoal hemoperfusion.
 Hemoperfusion is a technique similar to hemodialysis except the
blood is passed through a column of activated charcoal instead of
through an artificial kidney.
 Charcoal hemoperfusion is very effective in removing
theophylline from the blood with an extraction ratio across the
column in excess of 90%

(Bauer,2008: 776)
 Theophylline serum concentrations can rebound 5–10 μg/mL
upon discontinuation of the procedure as theophylline in the
tissues come into equilibrium with the blood.
 Theophylline serum concentrations should be closely monitored
when charcoal hemoperfusion is instituted.
 Other complications of charcoal hemoperfusion include
hypotension, hypocalcemia, platelet consumption, and bleeding.

(Bauer,2008: 776)
 Theophylline can also be removed from the body using oral
doses of activated charcoal.
 This method to reduce theophylline body stores is about as
effective as hemodialysis removal.
 Activated charcoal physically adsorbss theophylline rendering it
nonabsorbable from the gastrointestinal tract.
 If the patient is vomiting, appropriate antiemetic therapy must be
instituted so that the charcoal is retained in the stomach

(Bauer,2008: 777)
 After acute and chronic theophylline overdoses, a single dose of
oral activated charcoal is recommended if the theophylline Scr is
20–30 μg/mL.
 For theophylline Scr >30 μg/mL, multiple doses of oral activated
charcoal should be used.
 Patients should be monitored for signs and symptoms of
theophylline toxicity and treated appropriately. Theophylline
serum concentrations should be measured every 2–4 hours in
order to guide further therapy.
Bauer, L. A. (2008). Applied Clinical
Pharmacokinetic (Second Edition).
Washington: Mc Graw Hill