Tedral is a medicine formerly used to treat respiratory diseases such as asthma, chronic obstructive lung disease (COPD), chronic bronchitis, and emphysema. [1] It is a combination drug containing three active ingredients - theophylline, ephedrine, phenobarbital. [1] This medication relaxes the smooth muscle of the airways, making breathing easier. [2] The common side effects of Tedral include gastrointestinal disturbances, dizziness, headache and lightheadedness. [2] [3] [4] However, at high dose, it may lead to cardiac arrhythmias, hypertension, seizures or other serious cardiovascular and/or central nervous system adverse effects. [5] [6] [7] 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. [2] [8] 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 Being used as a treatment option for respiratory diseases for decades, Tedral was withdrawn from the US market in 2006 due to safety concerns. [9] [10]
Tedral is an oral bronchodilator, which contains three active ingredients, including (1) theophylline, (2) ephedrine, and (3) phenobarbital. [12] It was indicated for the symptomatic relief of asthmatic bronchitis, chronic bronchial asthma, COPD or other bronchospastic disorders. [13] It was usually used as an added-on therapy in asthmatic patients with inadequate symptomatic control even with inhaled bronchodilators or inhaled corticosteroids. [14] Besides, it could also be used as a prophylactic treatment for the prevention of asthmatic attacks. [15]
There are three active ingredients in Tedral and they have different mechanisms of action.
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: [17]
Other proposed mechanisms of action of theophylline include: [17]
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. [18]
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. [18]
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. [18]
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. [19]
Due to the presence of theophylline in Tedral, the most common side effects of this drug include: [20] [5]
However, at high serum concentrations, some serious adverse effects may occur: [20] [5]
Other adverse side effects include: [5]
Ephedrine has both alpha- and beta-agonist effects. Owing to its sympathomimetic effect, the common side effects of Tedral include: [21] [22]
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. [23]
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. [24]
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. [24]
Other reported adverse reactions include: [24]
Because one of the active ingredients in Tedral is theophylline, Tedral is contraindicated if the patient has: [25] [5]
Owing to the fact that Tedral also contains Ephrdrine, Tedral is contraindicated for patients who have: [8]
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. [8]
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. [8]
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. [23]
Tedral is also composed of phenobarbital, therefore, it is contraindicated for individuals with: [7] [4] [26]
Due to the presence of theophylline, Tedral interacts with: [27] [5]
Theophylline cause interactions of Tedral with the following diseases:
Because of the presence of ephedrine, Tedral interacts with: [28] [29]
Since ephedrine is one of the active ingredients in Tedral, Tedral interacts with the following disease:
Since Tedral contains phenobarbital, it interacts with: [7] [30]
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. [31] 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. [32]
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. [33]
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. [34] 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. [35]
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. [36] 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. [37]
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 xanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and cola.
A bronchodilator or broncholytic is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be originating naturally within the body, or they may be medications administered for the treatment of breathing difficulties, usually in the form of inhalers. They are most useful in obstructive lung diseases, of which asthma and chronic obstructive pulmonary disease are the most common conditions. Although this remains somewhat controversial, they might be useful in bronchiolitis and bronchiectasis. They are often prescribed but of unproven significance in restrictive lung diseases.
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.
Ephedrine is a central nervous system (CNS) stimulant 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.
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.
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.
Phenylephrine is a medication that is used as a nasal decongestant, used to dilate the pupil, used to increase blood pressure, used to relieve hemorrhoids and uncomplicated nasal congestion. It is a selective α1-adrenergic receptor agonist with minimal to no beta-adrenergic activity. It causes constriction of both arteries and veins. Phenylephrine can also be taken by mouth, given by injection into a vein or muscle, or applied to the skin.
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, such as Chronic obstructive pulmonary disease (COPD).
Isoprenaline, or isoproterenol, is a medication used for the treatment of bradycardia, heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropylamine analog of epinephrine (adrenaline).
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.
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.
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.
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.
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.
Olodaterol is an ultra-long-acting β adrenoreceptor agonist (ultra-LABA) used as an inhalation for treating people with chronic obstructive pulmonary disease (COPD). It is manufactured by Boehringer Ingelheim.
Autonomic drugs 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, such as glaucoma, asthma, urinary, gastrointestinal and cardiopulmonary disorders.
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.
Commonly prescribed drugs are drugs that are frequently provided by doctors in a prescription to treat a certain disease. These drugs are often first-line treatment for the target diseases and are effective in tackling the symptoms. An example of the target disease is ischemic heart disease. Some examples of commonly prescribed drugs for this disease are beta-blockers, calcium-channel blockers and nitrates.
Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.
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.