ASTHMA ASTHMA BRONCHIALBRONCHIAL

Kelompok VIKelompok VI

Tri prasetya Har adiTri prasetya Har adi

Resa ambun suriResa ambun suri

Chintya FresticaChintya Frestica

Jerry FebrialdinoJerry Febrialdino

Febri LusianaFebri Lusiana

Theophyllin is a methylxanthine compound that is used for the treatment of asthma, chronic obstructive pulmonary disease (COPD; chronic bronchitis and emphysema), and premature apnea.

The bronchodilatory effects of theophylline are useful primarily for patients with asthma because bronchospasm is a key component of that disease state.

Theophylline is also a central nervous system stimulant which explains its usefulness in the treatment of premature apnea.

THEOPHYLLINTHEOPHYLLIN

THERAPEUTIC AND TOXIC CONCENTRATIONS

The generally accepted therapeutic ranges for theophylline 10–20 μg/mL for the treatment of asthma or COPD 6–13 μg/mL for the treatment of premature apnea.

theophylline therapy must be individualized for each patient in order to achieve optimal responses and minimal side effects.

In the upper end of the therapeutic range (>15 μg/mL) some patients will experience minor caffeine-like side effects owing to theophylline treatment.

These adverse effects include 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.

Theophylline-induced seizures are an ominous sign as they respond poorly to antiepileptic therapy and can result in postseizure neurologic sequelae or death.

seizures caused by theophylline therapy have been reported to occur in patients at theophylline concentrations as low as 25 μg/mL.

CLINICAL MONITORING PARAMETERSMeasurement 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.

In addition to the use of FEV1 to monitor bronchodilator drug effect, other spirometric tests useful for patients with COPD include vital capacity (VC) total lung capacity (TLC) forced vital capacity (FVC) forced expiratory flow over the middle 50% of the expiratory

curve (FEF25–75% or FEF50%).

For dose adjustment purposes, theophylline serum concentrations should be measured at steady state after the patient has received a consistent dosage regimen for 3–5 drug half-lives.

Theophylline half-life varies from 3 to 5 hours in children tobacco-smoking individuals to 50 hours more in patients with severe heart or liver failure.

The theophylline volume of distribution (V in liters) would have to be known to compute the loading dose (mg)

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Theophylline is primarily eliminated by hepatic metabolism (>90%).

Hepatic metabolism is mainly via the CYP1A2 enzyme system with a smaller amount metabolized by CYP3A and CYP2E1.

About 10% of a theophylline dose is recovered in the urine as unchanged drug.

theophylline follows nonlinear pharmacokinetics.Occasionally, theophylline serum concentrations

increase in a patient more than expected after a dosage increase for an unidentifiable reason, and nonlinear pharmacokinetics may explain the observation.

Three different forms of theophylline are available. Aminophylline is the ethylenediamine salt of theophylline, and

anhydrous aminophylline contains about 85% theophylline. 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.The oral bioavailability of all three theophylline-based

drugs is very good and generally equals 100%.

EFFECTS OF DISEASE STATES AND CONDITIONS ON

THEOPHYLLINE PHARMACOKINETICS AND DOSINGNormal adults without the disease states and

conditions given later in this section with normal liver function have average theophylline half-life of 8 hours (range: 6–12

hours) volume of distribution of 0.5 L/kg (range: 0.4–0.6 L/kg;

Table 18-1).

Disease States and Conditions That Alter Theophylline Pharmacokinetics

Tobacco and marijuana smoke causes induction of hepatic CYP1A2 which accelerates the clearance of theophylline.

SmokingSmoking

• Patients with liver cirrhosis or acute hepatitis have reduced theophylline clearance which results in a prolonged average theophylline half-life of 24 hours

Liver DysfunctionLiver Dysfunction

Child-Pugh Scores for Patients with Liver Disease

The Child-Pugh score for a patient with normal liver function is 5 while the score for a patient with grossly abnormal serum albumin, total bilirubin, and prothrombin time values in addition to severe ascites and hepatic encephalopathy is 15.

A Child-Pugh score greater than 8 is grounds for a decrease in the initial daily drug dose for theophylline (t1/2 = 24 hours).

Obese patients (>30% above ideal body weight or IBW) should have volume of distribution estimates based on ideal body weight.

ideal body weight should be used to compute doses for obese individuals.

• Heart failure causes reduced theophylline clearance because of decreased hepatic blood flow secondary to compromised cardiac output.

• Theophylline serum concentrations and the presence of adverse drug effects should be monitored frequently in patients with heart failure.

Heart FailureHeart Failure

ObesityObesity

Patient age has an effect on theophylline clearance and half-life. Newborns have decreased theophylline clearance because

hepatic drug–metabolizing enzymes are not yet fully developed at birth.

Children between the ages of 1–9 years have accelerated theophylline clearance rates resulting in an average half-life of 3.5 hours.

For elderly patients over the age of 65, theophylline clearance and half-life are the same as in younger adults while other investigations have found that theophylline clearance is slower and half-life is longer (average half-life = 12 hours, range: 8–16 hours)

AgeAge

Febrile illnesses can temporarily decrease the clearance of theophylline and require an immediate dosage decrease to avoid toxicity.

Hypothyroid patients have decreased basal metabolic rates, and require smaller theophylline doses until a euthyroid condition is established.

FeverFever

HypothyroidismHypothyroidism

Theophylline is removed by hemodialysis, and, if possible, doses should be held until after the dialysis procedure is complete.

Dialysis and HemoperfusionDialysis and Hemoperfusion

Renal DysfunctionRenal Dysfunction

Because only a small amount of theophylline is eliminated unchanged in the urine (<10% of a dose), dosage adjustments are not necessary in patients with renal impairment.

DRUG INTERACTIONSCimetidine given at higher doses (≥1000 mg/d) on a

multiple daily dosage schedule decreases theophylline clearance by 30–50%.

Other cimetidine doses (≤800 mg/d) given once or twice daily decrease theophylline clearance by 20% or less.

Ciprofloxacin and enoxacin, both quinolone antibiotics, and troleandomycin, a macrolide antibiotic, also decrease theophylline clearance 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.

The calcium channel blockers, verapamil, and diltiazem, have been reported to cause decreases in theophylline clearance by 15–25%.

Clarithromycin and erythromycin, both macrolide antibiotics, and norfloxacin, a quinolone antibiotic, can also decrease theophylline clearance by this magnitude.

At doses of 600 mg/d or above, allopurinol has been reported to decrease theophylline clearance by 25%.

Phenytoin, carbamazepine, phenobarbital, rifampin, and moricizine all increase theophylline clearance.

INITIAL DOSAGE DETERMINATION METHODS

Pharmacokinetic Dosing Method HALF-LIFE AND ELIMINATION RATE CONSTANT

ESTIMATE VOLUME OF DISTRIBUTION ESTIMATE SELECTION OF APPROPRIATE

PHARMACOKINETIC MODEL AND EQUATIONS STEADY-STATE CONCENTRATION SELECTION

Literature-Based Recommended DosingUSE OF THEOPHYLLINE SERUM

CONCENTRATIONS TO ALTER DOSES Linear Pharmacokinetics Method Pharmacokinetic Parameter Method

CHIOU METHODBAYESIAN PHARMACOKINETIC

COMPUTER PROGRAMS

Theophylline Dosage Rates for Patients with Various Disease States and Conditions

DOSING STRATEGIES

ReferencesBaure, Larry A.2008. Applied Clinical Pharmacokinetics Second Edition. Washington : MacGrawHill Medical

Baure, Larry A. 2006. Clinical Pharmacokinetics Handbook. Washington : MacGrawHill Medical

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