Tedral

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Tedral
Combination of
Theophylline phosphodiesterase inhibitor, adenosine receptor antagonist
Ephedrine stimulant, sympathomimetic
Phenobarbital barbiturate
Clinical data
Pregnancy
category
Identifiers
CAS Number
PubChem CID

Tedral, or theophylline/ephedrine/phenobarbital, is a medicine formerly used to treat respiratory diseases such as asthma, chronic obstructive lung disease (COPD), chronic bronchitis, and emphysema. [2] It is a combination drug containing three active ingredients - theophylline, ephedrine, phenobarbital. [2] This medication relaxes the smooth muscle of the airways, making breathing easier. [3] The common side effects of Tedral include gastrointestinal disturbances, dizziness, headache and lightheadedness. [3] [4] [5] However, at high dose, it may lead to cardiac arrhythmias, hypertension, seizures or other serious cardiovascular and/or central nervous system adverse effects. [6] [7] [8] Tedral is contraindicated in individuals with hypersensitivity to theophylline, ephedrine and/or phenobarbital. It should be also used in caution in patients with cardiovascular complications, such as ischemic heart disease and heart failure and/or other disease conditions. [3] [9] It can cause a lot of drug–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 Being used as a treatment option for respiratory diseases for decades, Tedral was withdrawn from the US market in 2006 due to safety concerns.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]

Contents

Medical uses

Asthma is a chronic condition that affects the airways in the lungs. The image shows the difference between a healthy bronchial airway (left) and a bronchial airway during an asthma attack (right). Exposure to asthma triggers can lead to inflammation and narrowing of airways in asthma patients, resulting in asthma attacks and breathing difficulties. And Tedral exerts its therapeutic effects by decreasing airway responsiveness to allergens and relaxing the smooth muscle of the airways, thereby, making breathing easier. Asthma attack-illustration NIH.jpg
Asthma is a chronic condition that affects the airways in the lungs. The image shows the difference between a healthy bronchial airway (left) and a bronchial airway during an asthma attack (right). Exposure to asthma triggers can lead to inflammation and narrowing of airways in asthma patients, resulting in asthma attacks and breathing difficulties. And Tedral exerts its therapeutic effects by decreasing airway responsiveness to allergens and relaxing the smooth muscle of the airways, thereby, making breathing easier.

Tedral is an oral bronchodilator, which contains three active ingredients, including (1) theophylline, (2) ephedrine, and (3) phenobarbital. [13] It was indicated for the symptomatic relief of asthmatic bronchitis, chronic bronchial asthma, COPD or other bronchospastic disorders. [14] It was usually used as an added-on therapy in asthmatic patients with inadequate symptomatic control even with inhaled bronchodilators or inhaled corticosteroids. [15] Besides, it could also be used as a prophylactic treatment for the prevention of asthmatic attacks. [16]

The image above shows the difference between a normal, healthy lung (left) and a COPD patient's lung (right). Chronic obstructive pulmonary disease (COPD), is a progressive lung disease. The term COPD includes two main conditions: (1) emphysema and (2) chronic bronchitis. Emphysema develops when the walls of alveoli are destroyed, forming fewer larger alveoli. Chronic bronchitis is triggered by repeated or constant irritation and inflammation in the lining of airways. Bronchioles thus, lose their shape and become clogged with mucus. These conditions result in difficulty in breathing. Symptoms can be improved by Tedral because of its bronchodilating property. Copd 2010Side.JPG
The image above shows the difference between a normal, healthy lung (left) and a COPD patient's lung (right). Chronic obstructive pulmonary disease (COPD), is a progressive lung disease. The term COPD includes two main conditions: (1) emphysema and (2) chronic bronchitis. Emphysema develops when the walls of alveoli are destroyed, forming fewer larger alveoli. Chronic bronchitis is triggered by repeated or constant irritation and inflammation in the lining of airways. Bronchioles thus, lose their shape and become clogged with mucus. These conditions result in difficulty in breathing. Symptoms can be improved by Tedral because of its bronchodilating property.

Mechanism of action

There are three active ingredients in Tedral and they have different mechanisms of action.

Theophylline

Theophylline Theophylline.svg
Theophylline

Theophylline relaxes the bronchial smooth muscle and pulmonary artery smooth muscle. In addition, it also reduces the airway responsiveness to allergens, adenosine, methacholine, and histamine by two distinct mechanisms: [3]

First, it acts as a competitive nonselective phosphodiesterase inhibitor to inhibit type III and type IV phosphodiesterase. The inhibition of type III and type IV phosphodiesterase leads to an increase in the concentration of intracellular cAMP, which then activates protein kinase A, and inhibits TNF-alpha, and leukotriene synthesis. Thereby, suppressing inflammation and innate immunity

Second, theophylline is also a nonselective adenosine 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 of nuclear factor-kappaB prevents the translocation of the pro-inflammatory transcription factor (NF-kappaB) to the nucleus, thereby reducing the expression of known inflammatory genes in conditions such as COPD and asthma. Additionally, it increases the secretion of interleukin-10, which has broad anti-inflammatory effects. This process also decreases poly (ADP-ribose) polymerase-1 (PARP-1), promotes apoptosis of inflammatory cells, including T cells and neutrophils, and increases levels of histone deacetylase 2 by inhibiting phosphoinositide 3-kinase-delta.

Ephedrine

Ephedrine Ephedrine.svg
Ephedrine

Ephedrine, a stereoisomer of pseudoephedrine, acts as a direct and indirect sympathomimetic amine. Its indirect mechanism makes it more unique than other sympathomimetic agents, for example, pseudoephedrine and phenylephrine. [9]

It directly binds to both alpha and beta receptors. However, its primary mechanism of action is indirectly achieved by the inhibition of neuronal norepinephrine reuptake and displacement of more norepinephrine from storage vesicles. These actions prolong the presence of norepinephrine in the synapse for binding to postsynaptic alpha and beta receptors. Thereby, leading to alpha- and beta-adrenergic stimulation. [9]

The stimulation of alpha-1-adrenergic receptors in vascular smooth muscle cells leads to an increase in systemic vascular resistance and, thus, systolic and diastolic blood pressure. Direct stimulation of beta-1 receptors by ephedrine and norepinephrine also increases cardiac chronotropy and inotropy. Lastly, stimulation of beta-2-adrenergic receptors in the lungs results in bronchodilation, however, the effect is less significant than those seen in the cardiovascular system. [9]

Phenobarbital

Phenobarbital Phenobarbital2DACS.svg
Phenobarbital

Phenobarbital prolongs the time that chloride channels are open. Thereby, depressing the central nervous system. This is accomplished by acting on GABA-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 to hyperpolarize, leading to a raise in the action potential threshold. [5]

Adverse effects

Theophylline

Due to the presence of theophylline in Tedral, the most common side effects of this drug include: [3] [6]

However, at high serum concentrations, some serious adverse effects may occur: [3] [6]

Other adverse side effects include: [6]

Ephedrine

Ephedrine has both alpha- and beta-agonist effects. Owing to its sympathomimetic effect, the common side effects of Tedral include: [18] [19]

Besides, ephedrine can cause cardiac arrhythmias. When ephedrine is used in long-term, the catecholamine excess can bring about contraction band necrosis of the myocardium, which predisposes the heart to ventricular arrhythmias. [9]

Phenobarbital

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 affect geriatric 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]

Contraindications

Theophylline

Because one of the active ingredients in Tedral is theophylline, Tedral is contraindicated if the patient has: [3] [6]

Ephedrine

Because Tedral also contains Ephedrine, Tedral is contraindicated for patients who have: [9]

Ephedrine raises both chronotropy and inotropy, increasing myocardial oxygen demand. Therefore, it has to be used in caution in patients with ischemic heart disease or heart failure. It should also be avoided in situations where tachycardia would be undesirable, for example aortic stenosis. [9]

Ephedrine's alpha-adrenergic stimulation causes contraction of the smooth muscle at the base of the bladder, resulting in resistance to urine output. It is, therefore, the use of Tedral in patients with urinary retention and prostatic hyperplasia has to be cautious. [9]

In addition, due to excessive norepinephrine availability at the synapse, which could induce a hypertensive crisis via the indirect sympathomimetic effect of ephedrine, Tedral should be avoided or used with caution within 14 days of monoamine oxidase inhibitor (MAOI) therapy. [9]

Phenobarbital

Tedral is also composed of phenobarbital, therefore, it is contraindicated for individuals with: [8] [5] [20]

Drug interactions

Theophylline

Due to the presence of theophylline, Tedral interacts with: [21] [6]

Theophylline cause interactions of Tedral with the following diseases:

Ephedrine

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:

Phenobarbital

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:

History

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 a barbiturate such as pentobarbital or phenobarbital was later added to enhance the sedative effects of the medication and improve patient compliance. [27]

Tedral was first marketed by the pharmaceutical company Eli Lilly and Company in the 1950s as a treatment for asthma and other respiratory conditions, and later sold to Novartis 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 and COPD, such as inhaled corticosteroids, long-acting beta-agonists, leukotriene modifiers and immunomodulators. [29]

Tedral was withdrawn from the US market in 2006 due to safety concerns related to the use of ephedrine. The US Food and Drug Administration (FDA) had previously issued warnings about the use of ephedrine-containing products due to their potential for serious side effects, including heart 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]

See also

Related Research Articles

<span class="mw-page-title-main">Theophylline</span> Drug used to treat respiratory diseases

Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other methylxanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.

<span class="mw-page-title-main">Beta blocker</span> Medications for abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

<span class="mw-page-title-main">Ephedrine</span> Medication and stimulant

Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in nasal congestion. It can be taken by mouth or by injection into a muscle, vein, or just under the skin. Onset with intravenous use is fast, while injection into a muscle can take 20 minutes, and by mouth can take an hour for effect. When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours.

<span class="mw-page-title-main">Bronchospasm</span> Lower respiratory tract disease that affects the airways leading into the lungs

Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylatoxins. It causes difficulty in breathing which ranges from mild to severe.

<span class="mw-page-title-main">Sympathomimetic drug</span> Substance that mimics effects of catecholamines

Sympathomimetic drugs are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart rate, force of cardiac contraction, and blood pressure. The primary endogenous agonists of the sympathetic nervous system are the catecholamines, which function as both neurotransmitters and hormones. Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.

<span class="mw-page-title-main">Phenylephrine</span> Decongestant medication

Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among numerous others, is a medication used as a decongestant for uncomplicated nasal congestion, used to dilate the pupil, used to increase blood pressure, and used to relieve hemorrhoids. It can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, applied to the skin, or as a rectal suppository.

The ECA stack is a drug combination used in weight loss and as a stimulant. ECA is an initialism for ephedrine, caffeine, and aspirin, with variants of it including the EC stack, which removes the aspirin for those who can not tolerate it. Dietary supplements based on or including elements of ECA were popular through the 1990s and early 2000s, but the marketing of ephedra- or ephedrine-containing stimulant combinations for weight loss and bodybuilding is now restricted or illegal in the United States and the Netherlands due to reports of heart attack, stroke, and death associated with these supplements.

Beta<sub>2</sub>-adrenergic agonist Compounds that bind to and activate adrenergic beta-2 receptors

Beta2-adrenergic agonists, also known as adrenergic β2 receptor agonists, are a class of drugs that act on the β2 adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation. β2 adrenergic agonists' effects on smooth muscle cause dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin. They are primarily used to treat asthma and other pulmonary disorders. Bronchodilators are considered an important treatment regime for chronic obstructive pulmonary disease (COPD) and are usually used in combination with short acting medications and long acting medications in a combined inhaler.

<span class="mw-page-title-main">Aminophylline</span> Chemical compound

Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate.

<span class="mw-page-title-main">Levosalbutamol</span> Chemical compound

Levosalbutamol, also known as levalbuterol, is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Evidence is inconclusive regarding the efficacy of levosalbutamol versus salbutamol or salbutamol-levosalbutamol combinations, though levosalbutamol is believed to have a better safety profile due to its more selective binding to β2 receptors versus β1.

<span class="mw-page-title-main">Levobunolol</span> Chemical compound

Levobunolol is a non-selective beta blocker. It is used topically in the form of eye drops to manage ocular hypertension and open-angle glaucoma.

A cardiac stimulant is a drug which acts as a stimulant of the heart – e.g., via positive chronotropic action and/or inotropic action. They increase cardiac output.

<span class="mw-page-title-main">Cilomilast</span> Chemical compound

Cilomilast is a drug which was developed for the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). It is orally active and acts as a selective phosphodiesterase-4 inhibitor.

<span class="mw-page-title-main">Beta-adrenergic agonist</span> Medications that relax muscles of the airways

Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.

<span class="mw-page-title-main">Doxofylline</span> Chemical compound

Doxofylline is a phosphodiesterase inhibiting bronchodilator used in the treatment of chronic respiratory diseases such as asthma and COPD. Like theophylline, it is a xanthine derivative.

β2-adrenoceptor agonists are a group of drugs that act selectively on β2-receptors in the lungs causing bronchodilation. β2-agonists are used to treat asthma and COPD, diseases that cause obstruction in the airways. Prior to their discovery, the non-selective beta-agonist isoprenaline was used. The aim of the drug development through the years has been to minimise side effects, achieve selectivity and longer duration of action. The mechanism of action is well understood and has facilitated the development. The structure of the binding site and the nature of the binding is also well known, as is the structure activity relationship.

Autonomic drugs are substances that can either inhibit or enhance the functions of the parasympathetic and sympathetic nervous systems. This type of drug can be used to treat a wide range of diseases an disorders, including glaucoma, asthma, and disorders of the urinary, gastrointestinal and circulatory systems.

Adrenergic blocking agents are a class of drugs that exhibit its pharmacological action through inhibiting the action of the sympathetic nervous system in the body. The sympathetic nervous system(SNS) is an autonomic nervous system that we cannot control by will. It triggers a series of responses after the body releases chemicals named noradrenaline and epinephrine. These chemicals will act on adrenergic receptors, with subtypes Alpha-1, Alpha-2, Beta-1, Beta-2, Beta-3, which ultimately allow the body to trigger a "fight-or-flight" response to handle external stress. These responses include vessel constriction in general vessels whereas there is vasodilation in vessels that supply skeletal muscles or in coronary vessels. Additionally, the heart rate and contractile force increase when SNS is activated, which may be harmful to cardiac function as it increases metabolic demand.

Adrenergic neurone blockers, commonly known as adrenergic antagonists, are a group of drugs that inhibit the sympathetic nervous system by blocking the activity of adrenergic neurones. They prevent the action or release of catecholamines such as norepinephrine and epinephrine. They are located throughout the body, causing various physiological reactions including bronchodilation, accelerated heartbeat, and vasoconstriction. They work by inhibiting the synthesis, release, or reuptake of the neurotransmitters or by antagonising the receptors on postsynaptic neurones. Their medical uses, mechanisms of action, adverse effects, and contraindications depend on the specific types of adrenergic blockers used, including alpha 1, alpha 2, beta 1, and beta 2.

Theophylline ephedrine, or theophylline/ephedrine, sold under the brand name Franol among others, is a fixed-dose combination formulation of theophylline, an adenosine receptor antagonist, and ephedrine, a norepinephrine releasing agent and indirectly acting sympathomimetic agent, which has been used as a bronchodilator in the treatment of asthma and as a nasal decongestant. It was first studied and used to treat asthma in the 1930s or 1940s and combinations of the two drugs subsequently became widely used. A ratio of 5:1 theophylline to ephedrine is usually used in combinations of the drugs. Later research found that the combination was no more effective for asthma than theophylline alone but produced more side effects however.

References

  1. ↑ "Tedral". drugs.com.
  2. 1 2 "Tedral (Oral)". Drugs.com. Retrieved 2023-04-09.
  3. 1 2 3 4 5 6 7 8 Jilani TN, Preuss CV, Sharma S (2023). "Theophylline". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   30085566 . Retrieved 2023-04-09.
  4. ↑ "Ephedrine". Martindale: The Complete Drug Reference. Retrieved 2023-04-09.
  5. 1 2 3 4 5 6 Lewis CB, Adams N (2023). "Phenobarbital". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   30335310 . Retrieved 2023-04-09.
  6. 1 2 3 4 5 6 "Theophylline: Drug information". UpToDate. Retrieved 2023-04-09.
  7. ↑ "Ephedrine (systemic): Drug information". UpToDate. Retrieved 2023-04-09.
  8. 1 2 3 "Phenobarbital: Drug information". UpToDate. Retrieved 2023-04-09.
  9. 1 2 3 4 5 6 7 8 9 Statler AK, Maani CV, Kohli A (2023). "Ephedrine". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   31613441 . Retrieved 2023-04-09.
  10. ↑ "FDA Announces Final Rule on Ephedrine Alkaloids". U.S. Food and Drug Administration. 2004.
  11. ↑ "Novartis Voluntarily Withdraws Tredral from the Market". U.S. Food and Drug Administration. 2006.
  12. ↑ "Asthma - Symptoms | NHLBI, NIH". www.nhlbi.nih.gov. 24 March 2022. Retrieved 2023-04-09.
  13. ↑ "Tedral Advanced Patient Information". Drugs.com. Retrieved 2023-03-27.
  14. ↑ "Ephedrine and theophylline: International drug information (concise)". UpToDate. Retrieved 2023-03-27.
  15. ↑ Barnes PJ (October 2013). "Theophylline". American Journal of Respiratory and Critical Care Medicine. 188 (8): 901–906. doi:10.1164/rccm.201302-0388PP. PMID   23672674.
  16. ↑ "Ephedrine and theophylline: International drug information (concise)". UpToDate. Retrieved 2023-03-27.
  17. ↑ "COPD - What Is COPD? | NHLBI, NIH". www.nhlbi.nih.gov. 24 March 2022. Retrieved 2023-04-09.
  18. ↑ "Ephedrine (systemic): Drug information". UpToDate. Retrieved 2023-03-31.
  19. ↑ "Ephedrine". Martindale: The Complete Drug Reference. Retrieved 2023-03-31.
  20. ↑ "Phenobarbital: Drug information". UpToDate. Retrieved 2023-04-09.
  21. ↑ "Theophylline Drug Interactions". Drugs.com. Retrieved 2023-04-09.
  22. ↑ "Ephedrine Drug Interactions". Drugs.com. Retrieved 2023-04-09.
  23. ↑ "UpToDate". www.uptodate.com.
  24. ↑ "Phenobarbital Drug Interactions". Drugs.com. Retrieved 2023-04-09.
  25. ↑ "Theophylline" (PDF). American Thoracic Society.
  26. ↑ "Ephedrine". MedlinePlus. 2022.
  27. ↑ "Pentobarbital". MedlinePlus. 2022.
  28. ↑ "Tedral product information" (PDF). Eli Lilly and Company. 2008.
  29. ↑ "Global Strategy for Asthma Management and Prevention". Global Initiative for Asthma.
  30. ↑ "FDA Announces Final Rule on Ephedrine Alkaloids". U.S. Food and Drug Administration. 2004. Retrieved 2023-04-09.
  31. ↑ "Novartis Voluntarily Withdraws Tredral from the Market". U.S. Food and Drug Administration. 2006. Retrieved 2023-04-09.
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