Theophylline by Dp 307 936,933,946,956

8/6/2019 Theophylline by Dp 307 936,933,946,956

1/10

CLINICAL PHARMACY

1CLINICAL PHARMACY

SYED MUHAMMAD SHOUZEB ALI (DP-307-933)

MUHAMMAD ABDULLAH (DP-307-936)

MUHAMMAD JAWAD AKBAR (DP-307-946)

MUHAMMAD SHAKEEL SHAFIQUE (DP-307-956)


2/10

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4/10

CLINICAL PHARMACY

4

ABSORPTION:

90-100% Bioavailability

After a fatty meal absorption slows down, without affecting the bioavailability

DISTRIBUTION:

Theophylline Distributed in

Extracellular fluid

Placenta

Mother's milk Central nervous system

Volume of distribution may increase in neonates and those suffering from cirrhosis

Volume of distribution may decrease in those who are obese

METABOLISM:

Metabolized extensively in the liver (up to 70%)

Undergoes N-demethylation via cytochrome P450 1A2

Smokers and people with hepatic impairment metabolize it differently

ELIMINATION:

Excreted unchanged in the urine (up to 10%)

Clearance of the drug is increased in these conditions

1. Adult smokers

2. Elderly smokers

3. Cystic fibrosis

4. Hyperthyroidism

Clearance of the drug is decreased in these conditions:

1. Elderly patient2. Acute congestive heart failure

3. Cirrhosis

4. Hypothyroidism

5. Febrile viral illnes

PHARMACOKINETICS


5/10

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6/10

CLINICAL PHARMACY

6

Hypotension

Cardiac arrhythmias Metabolic acidosis

Seizures

Cardiac arrhythmias

Neurotoxicity

THEOPHYLLINEDrugInteractions

CIMITIDINE

ALLOPURINOL

CIPROFLOXACIN

InhibitionofthehepaticmetabolismoftheophyllineTHEOPHYLLINEclearancemaybedecreasedwithlargedosesofALLOPURINOL(600mg/day),leadingtoincreasedplasmaTHEOPHYLLINElevelsandpossibletoxicity.InhibitionofthehepaticmetabolismofTHEOPHYLLINE.

Moderate

Moderate

Moderate

OTHERS DRUGS TO BE INTERACTING:

ALCOHOL

CLARITHROMYCINE

DEMECLOCYCLINE

EPHEDRINE

FLUCONAZOLE

INFLUENZA VACCINE

KETOCONAZOLE

METHOTREXATE

NICOTINE

VERAPAMIL (HCL)

SIDEEFFECTSOFTHEOPHYLLINE


7/10

CLINICAL PHARMACY

7PRACTICAL IMPLEMENTATION OF PHARMACOKINETIC STUDIES OF

THEOPHYLLINE

EFFECTS OF DISEASE STATES AND CONDITIONS ON THEOPHYLLINE

PHARMACOKINETICS AND DOSING

IN NORMAL: Normal adults without the disease states and conditions given later in this section

with normal liver function have an average theophylline half-life of 8 hours(range: 612 hours) and volume of distribution of 0.5 L/kg

IN SMOKERS:

Tobacco and marijuana smoke causes induction of hepatic CYP1A2 whichaccelerates the clearance of theophylline

In patients who smoke these substances the average theophylline half-life is 5hours

When patients stop smoking these compounds, theophylline clearance slowlyapproaches its baseline level for the patient over a 6- to 12-month period if thepatient does not encounter second-hand smoke produced by other users

If the patient inhales a sufficient amount of second-hand smoke,theophyllineclearance for the ex-smoker may remain in the fully induced state or at someintermediate induced state

IN PATIENTS WITH LIVER CIRRHOSIS & ACUTE HEPATITIS:

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

Effect that liver disease has on theophylline pharmacokinetics is highly variable anddifficult to accurately predict

i. In patient with liver dysfunction, initial doses are meant as starting points fordosage titration based on patient response and avoidance of adverse effects

ii. Theophylline serum concentrations and the presence of adverse drug effectsshould be monitored frequently in patients with liver cirrhosis

IN PATIENTS WITH HEART FAILURE:

Heart failure causes reduced theophylline clearance because of decreasedhepatic blood flow secondary to compromised cardiac output

Venous stasis of blood within the liver may also contribute to the decrease intheophylline clearance found in heart failure patients

Patients with mild heart failure have an average theophylline half-life equal to 12hours (range: 524hours) while those with moderate to severe heart failure havean average theophylline half-life of 24 hours (550 hours)


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CLINICAL PHARMACY

8

Effect that heart failure has on theophylline pharmacokinetics is highly variableand difficult to accurately predict

For heart failure patients,initial doses are meant as starting points for dosagetitration based on patient response and avoidance of adverse effects

Theophylline serum concentrations and the presence of adverse drug effects

should be monitored frequently in patients with heart failure

IN OBESE PATIENTS(>30% ABOVE IDEAL BODY WEIGHT OR IBW):

If weight-based dosage recommendations (mg/kg/d or mg/kg/h) are to be used,ideal body weight should be used to compute doses for obese individuals

IN PATIENT WITHFEBRILE ILLNESSES:

There is an temporarily decrease the clearance of theophylline and require animmediate dosage decrease to avoid toxicity

The mechanism of this acute change in theophylline disposition is unclear, butprobably involves decreased clearance as a result of the production ofinterleukins

Children seem to be at an especially high risk of theophylline adverse reactionssince febrile illnesses are prevalent in this population and high theophyllinedoses (on a mg/kg/d basis) are prescribed

IN RENAL COMPROMISED PATIENTS:

Because only a small amount of theophylline is eliminated unchanged in theurine(22 mg/kg/day] to achieve a


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CLINICAL PHARMACY

9

therapeutic peak serum theophylline concentration when afebrile) may be atgreater risk of toxic effects from decreased clearance during sustained fever

Careful attention to dose reduction and frequent monitoring of serum theophyllineconcentrations are required in patients with sustained fever

IN GERIATRIC:

The clearance of theophylline is decreased by an average of 30% in healthyelderly adults (> 60 yrs) compared to healthy young adults

Careful attention to dose reduction and frequent monitoring of serum theophyllineconcentrations are required in elderly patient

IN PEDIATRICS:

The clearance of theophylline is very low in neonates

Theophylline clearance reaches maximal values by one year of age, remainsrelatively constant until about 9 years of age and then slowly decreases byapproximately 50% to adult values at about age 16.

Renal excretion of unchanged theophylline in neonates amounts to about 50% ofthe dose, compared to about 10% in children older than three months and inadults. Careful attention to dosage selection and monitoring of serumtheophylline concentrations are required in pediatric patients

IN DIFFERENT GENDER:

Gender differences in theophylline clearance are relatively small and unlikely tobe of clinical significance.

Significant reduction in theophylline clearance, however, has been reported inwomen on the 20th day of the menstrual cycle and during the third trimester ofpregnancy.

RACE:

Pharmacokinetic differences in theophylline clearance due to race have not beenstudied

Only a small fraction, e.g., about 10%, of the administered theophylline dose isexcreted unchanged in the urine of children greater than three months of age andadults

Since little theophylline is excreted unchanged in the urine and since activemetabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate toclinically significant levels even in the face of end-stage renal disease, no dosageadjustment for renal insufficiency is necessary in adults and children >3 months


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CLINICAL PHARMACY

10

of age. In contrast, approximately 50% of the administered theophylline dose isexcreted unchanged in the urine in neonates

REFERENCES:

REMINGTON THE SCIENCE & PRACTICE OF PHARMACY

APLLIED BIOPHARMACEUTICS & PHARMACOKINETICS BY

SHARGEL

APPLIED CLINICAL PHARMACOKINETICS BY LARRY A BAUER

CLINICAL PHARMACY & THERAPEUTICS BY ROGER WALKER

STOKLEY DRUG INTERACTION

FACTS ABOUT DRUG INTERTACTIONS 2009

THE WASHINGTON MANUAL OF MEDICAL THERAPEUTICS

BRITISH NATIONAL FORMULARY

A-Z DRUG FACTS

www.drugs.com

www.druginfosys.com

Documents

Theophylline by Dp 307 936,933,946,956