| Combination of | |
|---|---|
| Theophylline | phosphodiesterase inhibitor,adenosine receptor antagonist |
| Ephedrine | stimulant,sympathomimetic |
| Phenobarbital | barbiturate |
| Clinical data | |
| Pregnancy category |
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| Identifiers | |
| CAS Number | |
| PubChemCID | |
Tedral, ortheophylline/ephedrine/phenobarbital, is a medicine formerly used to treat respiratory diseases such asasthma,chronic obstructive lung disease (COPD),chronic bronchitis, andemphysema.[2] It is a combination drug containing threeactive ingredients -theophylline,ephedrine,phenobarbital.[2] This medication relaxes thesmooth muscle of the airways, making breathing easier.[3] The common side effects of Tedral includegastrointestinal disturbances,dizziness,headache andlightheadedness.[3][4][5] However, at high dose, it may lead tocardiac arrhythmias,hypertension,seizures or other serious cardiovascular and/or central nervous system adverse effects.[6][7][8] Tedral is contraindicated in individuals withhypersensitivity to theophylline, ephedrine and/or phenobarbital. It should be also used in caution in patients with cardiovascular complications, such asischemic heart disease andheart failure and/or other disease conditions.[3][9] It can cause a lot ofdrug–drug interactions. Therefore, before prescribing patient with Tedral, drug interactions profile should be carefully checked if the patient had other concurrent medication(s). Being used as a treatment option for respiratory diseases for decades, Tedral was withdrawn from the US market in 2006 due to safety concerns.[10][11]
Tedral is an oralbronchodilator, which contains threeactive ingredients, including (1)theophylline, (2)ephedrine, and (3)phenobarbital.[13] It was indicated for the symptomatic relief of asthmatic bronchitis, chronic bronchialasthma,COPD or otherbronchospastic disorders.[14] It was usually used as an added-on therapy in asthmatic patients with inadequate symptomatic control even withinhaled bronchodilators orinhaled corticosteroids.[15] Besides, it could also be used as aprophylactic treatment for the prevention ofasthmatic attacks.[16]
There are three active ingredients in Tedral and they have differentmechanisms of action.
Theophylline relaxes thebronchialsmooth muscle andpulmonary artery smooth muscle. In addition, it also reduces the airway responsiveness toallergens,adenosine,methacholine, andhistamine by two distinct mechanisms:[3]
First, it acts as acompetitivenonselectivephosphodiesterase inhibitor to inhibit type III and type IVphosphodiesterase. The inhibition of type III and type IV phosphodiesterase leads to an increase in the concentration of intracellular cAMP, which then activatesprotein kinase A, and inhibitsTNF-alpha, andleukotriene synthesis. Thereby, suppressing inflammation andinnate immunity
Second, theophylline is also a nonselectiveadenosine receptor antagonist, which acts on A1, A2, and A3 receptors with almost the same affinity. This possibly explains theophylline's cardiac effects. Adenosine-mediated channels also enhance diaphragmatic muscle contractility by promoting calcium uptake.
Other mechanisms of action of theophylline have also been proposed.[3] These include the inhibition ofnuclear factor-kappaB prevents the translocation of the pro-inflammatorytranscription factor (NF-kappaB) to the nucleus, thereby reducing the expression of known inflammatorygenes in conditions such asCOPD and asthma. Additionally, it increases the secretion ofinterleukin-10, which has broadanti-inflammatory effects. This process also decreases poly (ADP-ribose) polymerase-1 (PARP-1), promotesapoptosis of inflammatory cells, includingT cells andneutrophils, and increases levels ofhistone deacetylase 2 by inhibitingphosphoinositide 3-kinase-delta.
Ephedrine, astereoisomer ofpseudoephedrine, acts as a direct and indirectsympathomimetic amine. Its indirect mechanism makes it more unique than other sympathomimetic agents, for example, pseudoephedrine andphenylephrine.[9]
It directly binds to bothalpha andbeta receptors. However, its primary mechanism of action is indirectly achieved by the inhibition of neuronalnorepinephrine reuptake and displacement of more norepinephrine from storage vesicles. These actions prolong the presence of norepinephrine in thesynapse for binding to postsynaptic alpha and beta receptors. Thereby, leading to alpha- and beta-adrenergic stimulation.[9]
The stimulation ofalpha-1-adrenergic receptors invascular smooth muscle cells leads to an increase insystemic vascular resistance and, thus,systolic anddiastolic blood pressure. Direct stimulation ofbeta-1 receptors by ephedrine and norepinephrine also increases cardiacchronotropy andinotropy. Lastly, stimulation ofbeta-2-adrenergic receptors in the lungs results in bronchodilation, however, the effect is less significant than those seen in thecardiovascular system.[9]
Phenobarbital prolongs the time thatchloride channels are open. Thereby, depressing thecentral nervous system. This is accomplished by acting onGABA-A receptor subunits. When phenobarbital binds to these receptors, the chloride ion gates open and remain open, allowing these ions to enter neuronal cells steadily. This action causes the cell membrane tohyperpolarize, leading to a raise in theaction potential threshold.[5]
Due to the presence of theophylline in Tedral, the most common side effects of this drug include:[3][6]
However, at highserum concentrations, some seriousadverse effects may occur:[3][6]
Other adverse side effects include:[6]
Ephedrine has both alpha- and beta-agonist effects. Owing to itssympathomimetic effect, the common side effects of Tedral include:[18][19]
Besides, ephedrine can cause cardiac arrhythmias. When ephedrine is used in long-term, thecatecholamine excess can bring aboutcontraction band necrosis of themyocardium, which predisposes the heart toventricular arrhythmias.[9]
Phenobarbital also results in the adverse effects of Tedral. The most common side effects caused by phenobarbital are dizziness,sedation, incoordination, and impaired balance. However, these adverse effects affectgeriatric patients to a greater extent.[5]
Concerning the adverse effects of phenobarbital after long-term usage, loss of appetite, depression,irritability, achiness in the bones, joints, or muscles, and liver damage may occur.[5]
Other reported adverse reactions include:[5]
Because one of the active ingredients in Tedral is theophylline, Tedral is contraindicated if the patient has:[3][6]
Because Tedral also contains Ephedrine, Tedral is contraindicated for patients who have:[9]
Ephedrine raises bothchronotropy andinotropy, increasing myocardial oxygen demand. Therefore, it has to be used in caution in patients withischemic heart disease orheart failure. It should also be avoided in situations where tachycardia would be undesirable, for exampleaortic stenosis.[9]
Ephedrine's alpha-adrenergic stimulation causes contraction of thesmooth muscle at the base of thebladder, resulting in resistance to urine output. It is, therefore, the use of Tedral in patients withurinary retention andprostatic hyperplasia has to be cautious.[9]
In addition, due to excessivenorepinephrine availability at thesynapse, which could induce ahypertensive crisis via the indirectsympathomimetic effect of ephedrine, Tedral should be avoided or used with caution within 14 days ofmonoamine oxidase inhibitor (MAOI) therapy.[9]
Tedral is also composed of phenobarbital, therefore, it is contraindicated for individuals with:[8][5][20]
Due to the presence of theophylline, Tedral interacts with:[21][6]
Theophylline cause interactions of Tedral with the following diseases:
Because of the presence of ephedrine, Tedral interacts with:[22][23]
Since ephedrine is one of the active ingredients in Tedral, Tedral interacts with the following disease:
Since Tedral contains phenobarbital, it interacts with:[8][24]
With phenobarbital being one of the active ingredients in Tedral, Tedral interacts with the following disease:
The history of Tedral can be traced back to the early 20th century when theophylline was first isolated from tea leaves and later found to have bronchodilator properties.[25] In the 1920s and 1930s, ephedrine was introduced as a treatment for asthma and other respiratory conditions due to its bronchodilating effect and ability to increase blood flow to the lungs.[26]
The combination of theophylline and ephedrine was first used in the 1940s as a treatment for asthma, and the addition of abarbiturate such aspentobarbital or phenobarbital was later added to enhance the sedative effects of the medication and improvepatient compliance.[27]
Tedral was first marketed by the pharmaceutical companyEli Lilly and Company in the 1950s as a treatment for asthma and other respiratory conditions, and later sold toNovartis Pharmaceuticals Corporation.[28] It was widely used throughout the 1960s and 1970s, but its popularity declined in the 1980s due to the development of newer, more effective medications for asthma andCOPD, such asinhaled corticosteroids,long-acting beta-agonists,leukotriene modifiers andimmunomodulators.[29]
Tedral was withdrawn from the US market in 2006 due to safety concerns related to the use of ephedrine. TheUS Food and Drug Administration (FDA) had previously issued warnings about the use of ephedrine-containing products due to their potential for serious side effects, includingheart attack,stroke, and death.[30] In response, many pharmaceutical companies voluntarily removed their ephedrine-containing products from the market. In the case of Tedral, its manufacturer, Novartis Pharmaceuticals Corporation, voluntarily withdrew the medication from the market in 2006 after the FDA issued a warning letter to the company citing safety concerns related to the use of ephedrine.[31]