Theophylline Actions

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Actions of Theophylline in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Theophylline directly relaxes the smooth muscle of the bronchial airway and pulmonary blood vessels, thus acting mainly as a bronchodilator and smooth muscle relaxant. It has also been demonstrated that aminophylline has a potent effect on diaphragmatic contractility in normal persons and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airway disease. Theophylline is also a central respiratory stimulant.

For many years, the proposed main mechanism of action of the xanthines was inhibition of phosphodiesterase, which results in an increase in cyclic adenosine monophosphate (cAMP). However, this effect is negligible at therapeutic concentrations. Other effects that appear to occur at therapeutic concentrations and may collectively play a role in the mechanism of xanthines including inhibition of extracellular adenosine (which causes bronchoconstriction), stimulation of endogenous catecholamines, antagonism of prostaglandins, PGE2 and PGF2, direct effect on mobilization of intracellular calcium resulting in smooth muscle relaxation and β-adrenergic agonist activity on the airways.

Pharmacokinetics: Absorption: Theophylline is completely absorbed after oral administration. After administration of 400 mg Theophylline, mean peak plasma concentrations of about 4.65 mcg/mL were reached at a mean of 3.83 hrs. The area under the plasma curve (AUC) is 56.64 mcg·hr/mL.

Distribution: Average volume of distribution is 0.45 L/kg (range 0.3-0.7 L/kg). Theophylline does not distribute into fatty tissue, but readily crosses the placenta and is excreted into breast milk. Approximately 40% are bound to plasma proteins.

Metabolism and Excretion: Xanthines are biotransformed in the liver (85-90%) to 1,3-dimethyluric acid, 3 methylxanthine and 1-methyluric acid. Excretion is by the kidneys; <15% of the drug is excreted unchanged. The half-life of Theophylline is influenced by a number of known variables. It may be prolonged in chronic alcoholics, particularly those with liver disease (cirrhosis or alcoholic liver disease), in patients with congestive heart failure, and in patients taking certain other drugs. In cigarette smokers (1-2 packs/day), the mean half-life is much shorter than in non-smokers. The increase in clearance associated with smoking is presumably due to stimulation of the hepatic metabolic pathway by components of cigarette smoke.

How should I take Theophylline?

Follow the directions on your prescription label. Do not take Theophylline in larger or smaller amounts or for longer than recommended. Your doctor may occasionally change your dose to make sure you get the best results.

Do not use Theophylline to treat an asthma or bronchospasm attack. Use only a fast acting inhalation medication.

Your dose and the number of times you take Theophylline daily will depend on the reason you are taking this medication.

Your dosage needs may change if you are ill, or if your doctor changes your brand, strength, or type of Theophylline. You will need regular medical tests to be sure you are using the right dose. Do not change your medication dose or schedule without your doctor's advice.

Take this medicine with a full glass of water.

Follow your doctor's instructions about whether to take your medication with food or on an empty stomach. Take the medication the same way every time.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

This medication can affect the results of certain medical tests. Tell any doctor who treats you that you are using Theophylline.

Do not start or stop smoking without first talking to your doctor. Smoking changes the way your body uses Theophylline, and you may need to use a different dose.

Store at room temperature away from moisture, heat, and light.

Theophylline administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Follow the directions on your prescription label. Do not take Theophylline in larger or smaller amounts or for longer than recommended. Your doctor may occasionally change your dose to make sure you get the best results.

Do not use Theophylline to treat an asthma or bronchospasm attack. Use only a fast acting inhalation medication.

Your dose and the number of times you take Theophylline daily will depend on the reason you are taking this medication.

Your dosage needs may change if you are ill, or if your doctor changes your brand, strength, or type of Theophylline. You will need regular medical tests to be sure you are using the right dose. Do not change your medication dose or schedule without your doctor's advice.

Take this medicine with a full glass of water.

Follow your doctor's instructions about whether to take your medication with food or on an empty stomach. Take the medication the same way every time.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

This medication can affect the results of certain medical tests. Tell any doctor who treats you that you are using Theophylline.

Do not start or stop smoking without first talking to your doctor. Smoking changes the way your body uses Theophylline, and you may need to use a different dose.

Store at room temperature away from moisture, heat, and light.

Theophylline pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
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Mechanism of Action

Theophylline has two distinct actions in the airways of patients with reversible obstruction: smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Theophylline are not known with certainty, studies in animals suggest that bronchodilation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship

Bronchodilation occurs over the serum Theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Theophylline concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug's potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics

Overview

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology and co-administration of other drugs can significantly alter the pharmacokinetic characteristics of Theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Theophylline clearance.

Table I. Mean and range of total body clearance and half-life of Theophylline related to age and altered physiological states. NR =not reported or not reported in a comparable format.

** Median

Note: In addition to the factors listed above, Theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Theophylline.

Absorption

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single immediate-release dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/ mL) can be expected 1-2 hr after dose. Co-administration of Theophylline with food or antacids does not cause clinically significant changes in the absorption of Theophylline from immediate-release dosage forms.

Theophylline (Theophylline capsule) ® capsules contain hundreds of coated beads of Theophylline. Each bead is an individual extended-release delivery system. After dissolution of the capsules these beads are released and distributed in the gastrointestinal tract, thus minimizing the probability of high local concentrations of Theophylline at any particular site.

In a 6-day multiple-dose study involving 18 subjects (with Theophylline clearance rates between 0.57 and 1.02 mL/kg/min) who had fasted overnight and 2 hours after morning dosing, Theophylline (Theophylline capsule) ® given once daily in a dose of 1500 mg produced serum Theophylline levels that ranged between 5.7 mcg/mL and 22 mcg/mL. The mean minimum and maximum values were 11.6 mcg/mL and 18.1 mcg/mL, respectively, with an average peak-trough difference of 6.5 mcg/mL. The mean percent fluctuation [(Cmax–Cmin /Cmin) x 100] equals 80%. A 24-hour single-dose study demonstrated an approximately proportional increase in serum levels as the dose was increased from 600 to 1500 mg.

Taking Theophylline (Theophylline capsule) ® with a high-fat-content meal may result in a significant increase in the peak serum level and in the extent of absorption of Theophylline as compared to administration in the fasted state.

Following the single-dose administration (8 mg/kg) of Theophylline (Theophylline capsule) ® to 20 normal subjects who had fasted overnight and 2 hours after morning dosing, peak serum Theophylline concentrations of 4.8 ± 1.5 (SD) mcg/mL were obtained at 13.3 ± 4.7 (SD) hours. The amount of the dose absorbed was approximately 13% at 3 hours, 31% at 6 hours, 55% at 12 hours, 70% at 16 hours, and 88% at 24 hours. The extent of Theophylline bioavailability from Theophylline (Theophylline capsule) ® was comparable to the most widely used 12-hour extended-release product when both products were administered every 12 hours.

Distribution

Once Theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of Theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of Theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum Theophylline concentration. Generally, concentrations of unbound Theophylline should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theophylline and serum concentrations in adults with normal renal function are < 1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized Theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theophylline concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theophylline metabolism, non-linearity of elimination may begin in some patients at serum Theophylline concentrations < 10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum Theophylline concentrations. Accurate prediction of dose-dependency of Theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum Theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Theophylline concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the Theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Theophylline is excreted unchanged in the urine and since active metabolites of Theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children > 3 months of age. In contrast, the large fraction of the Theophylline dose excreted in the urine as unchanged Theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations in neonates with reduced renal function.

Serum Concentrations at Steady State

After multiple doses of Theophylline, steady state is reached in 30–65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean Theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Theophylline clearance. In patients with high Theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum Theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.

Special Populations

Geriatric

The clearance of Theophylline is decreased by an average of 30% in healthy elderly adults ( > 60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in elderly patients.

Pediatrics

The clearance of Theophylline is very low in neonates. Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Theophylline concentrations are required in pediatric patients.

Gender

Gender differences in Theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race

Pharmacokinetic differences in Theophylline clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Theophylline is excreted unchanged in the urine and since active metabolites of Theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children > 3 months of age. In contrast, approximately 50% of the administered Theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in neonates with decreased renal function.

Hepatic Insufficiency

Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with reduced hepatic function.

Congestive Heart Failure (CHF)

Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with CHF.

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on Theophylline clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum Theophylline concentrations. Children with rapid rates of Theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., > 22 mg/kg/day] to achieve a therapeutic peak serum Theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with sustained fever.

Miscellaneous

Other factors associated with decreased Theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Theophylline concentrations are required in patients with any of these conditions. Other factors associated with increased Theophylline clearance include hyperthyroidism and cystic fibrosis.

Clinical Studies

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled Beta agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that Theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.



References

  1. DailyMed. "THEOPHYLLINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. DailyMed. "GUAIFENESIN; HYDROCODONE BITARTRATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  3. NCIt. "Theophylline: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).

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