Theophylline, is a methylxanthine drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
As a member of the xanthine family,.
It is structurally and pharmacologically similarity to theobromine and caffeine, and is readily found in nature, and is present in tea (Camellia sinensis) and cocoa.
US: C-Risk not ruled out.
Routes of administration by mouth, IV, rectal.
100% Protein binding, with 40%, primarily to albumin
Metabolism hepatic.
Elimination half-life 5–8 hours.
A bronchodilator response occurs above plasma concentrations of 10 mg/L.
Higher concentrations are associated with increased toxicity.
Has a narrow therapeutic window restricts its current use as a fourth line agents in patients who are refractory to more potent and better tolerated inhaled bronchodilators.
The main actions involve:
relaxing bronchial smooth muscle
increasing heart muscle contractility and efficiency; as a positive inotrope
increasing heart rate: (positive chronotropic)
increasing blood pressure
increasing renal blood flow
anti-inflammatory effects
central nervous system stimulatory effect mainly on the medullary respiratory center.
The main therapeutic uses of theophylline are aimed at:
chronic obstructive pulmonary disease
asthma
infant apnea
It blocks the action of adenosine.
Adenosine is an inhibitory neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle.
It must be monitored by direct measurement of serum theophylline levels to avoid toxicity.
Use can cause nausea, diarrhea, increase in heart rate, abnormal heart rhythms, CNS excitation, and seizures.
Toxicity is increased by erythromycin, cimetidine, and fluoroquinolones.
Toxic levels can be reached when taken with fatty meals, ref2242ed to as dose dumping.
Its toxicity can be treated with beta blockers.
Should not be used in combination with SSRI Fluvoxamine.
Mechanisms of action: It is both a competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha, and inhibits leukotriene, synthesis, and reduces inflammation and innate immunity, nonselective adenosine receptor antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects.
Inhibits TGF-beta-mediated conversion of pulmonary fibroblasts into myofibroblasts in COPD and asthma via cAMP-PKA pathway.
Suppresses COL1 mRNA, which codes for collagen.
It may reverse steroid insensitivity in patients with COPD and asthmatics who are active smokers.
Theophylline is naturally found in cocoa beans.
Trace amounts of theophylline are also found in brewed tea.
The drug is distributed in the extracellular fluid
Theophylline is distributed in the extracellular fluid, and in the central nervous system.
In pregnancy it is distributed in the placenta, and in the mother’s milk.
The protein binding is 40%.
The volume of distribution may increased in neonates, cirrhotics or those with malnutrition, and decreased in obesity.
Up to 70% is metabolized in the liver, undergoing N-demethylation via cytochrome P450.
Metabolism may become non-linear, so that small dose increases may result in disproportionately large increases in serum concentration.
Both THC and nicotine have been shown to increase the rate of theophylline metabolism.
It is excreted unchanged in the urine in up to 10%.
Its clearance is increased in children, teenagers, adult smokers, elderly smokers, as well as in cystic fibrosis, and hyperthyroidism.
Its clearance is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illness.
Elimination half-life varies: 30 hours for premature neonates, 24 hours for neonates, 3.5 hours for children ages 1 to 9, 8 hours for adult non-smokers, 5 hours for adult smokers, 24 hours for those with hepatic impairment, 12 hours for those with congestive heart failure NYHA class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly.