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Salmeterol - Indications, Contraindications, Adverse Effects, Drug Interactions, and Overdosage

Published on Aug 04, 2022 and last reviewed on Nov 22, 2022   -  12 min read

Abstract

Salmeterol is a drug used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The below article gives a detailed insight into Salmeterol.

Contents

Introduction:

Salmeterol is a drug used to treat asthma and chronic obstructive pulmonary disease (COPD), a group of lung diseases including chronic bronchitis and emphysema. It belongs to the beta-2 adrenergic agonist class of medications or the long-acting beta-agonists (LABAs). The drug works by relaxing the air passages of the lungs and opening them, making it easier to breathe, thereby improving symptoms like wheezing, coughing, shortness of breath, and chest tightness in COPD patients.

Salmeterol xinafoate was approved for use on 4th February 1994. Following approval, the FDA (Food and Drugs Administration) approved a fixed-dose combination therapy that included Fluticasone propionate and Salmeterol (FP/SAL) for treating asthma and COPD. The combination therapy proved effective in providing sustained bronchodilation, improved lung function, prevention of exacerbation, and a reduced need for rescue medication.

Salmeterol was first manufactured and marketed by Glaxo (now called GlaxoSmithKline or GSK) in the 1980s and was released as Serevent in 1990. The medicine is available as a dry-powder inhaler (DPI), which releases a powdered form of the drug. Salmeterol was previously available as a metered-dose inhaler (MDI); however, its use was discontinued in the United States in 2002.

How Does Salmeterol Work?

Salmeterol belongs to a class of drugs called beta-2 agonists, which are G-protein linked second messengers. The Gs protein causes the stimulation of adenylyl cyclase, which converts ATP (adenosine triphosphate) to cAMP (cyclic adenosine monophosphate). cAMP then activates the protein kinase A that inhibits the myosin light chain kinase present in the smooth muscles of the respiratory system. This cascade of events causes bronchiolar smooth muscle relaxation, bronchodilation, and an increase in the bronchiolar airflow.

Salmeterol was also found to inhibit mast cell mediators like histamines, leukotrienes, and prostaglandins. This inhibition leads to a decrease in inflammation. However, studies have shown that bronchodilation is the primary function of Salmeterol, with anti-inflammatory effects being present to a much lesser extent.

The typical molecular structure of Salmeterol promotes its characteristic longer duration of action. The elongated lipophilic side-chain causes a repeated activation of the beta-2 receptors. This causes a single inhaled dose of Salmeterol to work 12 hours compared to Salbutamol, which works for only four to six hours. As a result, Salmeterol, administered twice daily to manage mild to moderate cases of asthma, responded better and was clinically superior compared to Salbutamol administered regularly or intermittently.

Indications and Uses:

Salmeterol and inhalational steroid medication are used to treat asthma in adults and children above four years of age. Salmeterol also helps prevent exercise-induced bronchospasm and is effective in adults and children older than four. Salmeterol is effective in both the maintenance and prevention of asthmatic attacks. It is usually recommended for cases of severe persistent asthma that short-acting beta-adrenergic agonists and corticosteroids do not control. Also, it is not indicated in patients with mild asthma who use short-acting beta-agonists well to manage the condition. Salmeterol, along with concomitant inhaled corticosteroids (ICS), is advised to reduce the risk of mortality, as Salmeterol monotherapy can cause mortality. However, Salmeterol monotherapy can be used for the maintenance of COPD cases.

Salmeterol was found to be ten times more effective when compared to its chemical analog, Salbutamol. Inhaled Salmeterol showed clinically superior results that included sustained bronchodilation and effective prevention of symptoms of asthma when compared to Salbutamol. The comparison results measured pulmonary function, peak expiratory flow, a need for supplemental bronchodilators, the severity of the daily asthma symptoms, and frequency of nocturnal awakening.

Contraindications:

However, not strictly contraindicated, Salmeterol must be used with caution in patients with existing convulsive disorders, cardiovascular disorders, diabetes mellitus, hyperthyroidism or thyrotoxicosis, hepatic dysfunction, or patients using other CYP3A inhibitors due to a risk of toxicity, thereby increasing the QT interval. Also, as there is a transient risk of hypokalemia, the drug must be used cautiously in hypokalemic patients.

Adverse Effects:

The commonly noted adverse effects in asthmatic patients who use Salmeterol include the following:

The commonly noted adverse effects noted in COPD patients include:

In some patients, immediate hypersensitivity reactions can be triggered by the use of Salmeterol, which includes:

Salmeterol is a beta-2 agonist, but it still causes some beta-1 effects that lead to cardiac effects. Severe side effects due to excess beta-adrenergic stimulation of the heart occur due to an overdose of Salmeterol. Symptoms like tachycardia, angina, hypertension, arrhythmia, palpitation, hypotension, and fatigue can occur. These symptoms occur due to reflex activation caused due to the direct stimulation of beta-adrenoreceptors of the heart. Bronchospasm, laryngospasm, or throat swelling are the other adverse effects. In COPD patients, the use of long-acting beta-agonists increases the risk of heart failure.

For the Patients:

What Is Asthma?

Asthma is an inflammatory disease in the airways, making breathing difficult. As a result, there is a swelling of the lining of the airways, accumulation of mucus, and tightening of the surrounding muscles. During an asthmatic attack, coughing and chest tightness are the characteristic features of asthma.

What Are the Causes of Asthma?

Asthma is more common in children; however, it may even occur in adults. They are a variety of causes of asthma like genetics, a history of severe viral infections in childhood like respiratory syncytial virus infection (RSV), and hygiene hypothesis, according to which the weak immune system of babies makes them more susceptible to allergic conditions like asthma.

The common triggering factors for asthma include:

  1. Environmental irritants.

  2. Allergens.

  3. Pests.

  4. Exercise.

  5. Respiratory infections.

  6. Extreme weather conditions.

  7. Intense emotions.

  8. Medications like Aspirin or NSAIDs (non-steroidal anti-inflammatory drugs).

What Are the Symptoms of Asthma?

The symptoms of asthma include:

How Is Asthma Diagnosed and Managed?

Doctors diagnose asthma based on medical history, family history, physical examination, and breathing tests like pulmonary function tests (PFT) and spirometry. Pulmonary function tests are non-invasive tests that help know about the functioning of the lungs.

Asthma can be of different types like allergic, non-allergic, occupational, exercise-induced, nocturnal, Aspirin-induced, and cough-variant asthma. Treatment depends on various factors like the patient's age, triggering factors, and the type of asthma.

Treatment is categorized into four main types that include:

  1. Quick relief medications.

  2. Long-term medications.

  3. A combination of quick relief and long-term medications.

  4. Biologics, injections, or infusions are recommended only in cases of severe asthma.

For the Doctors:

Description: Salmeterol is a long-acting beta-2 adrenergic receptor agonist drug. Its structure consists of aralkyloxy-alkyl substitution on the amine. It functions by acting as a bronchodilator when administered through an inhalational route.

Chemical Name: Salmeterol is a 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol. It is a phenol containing a hydroxymethyl group at C-2 and a 1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl group at C-4; and a derivative of phenylethanolamine.

Molecular Formula: C25H37NO4.

Molecular Weight: 415.6 g/mol.

Physical Description: Solid.

Boiling Point: 603.

Melting Point: 75.5 to 76.5 degrees Celsius.

Solubility: Sparingly soluble.

Clinical Pharmacokinetics:

There is limited data available on pharmacokinetics. Also, there is no sufficient data on the extent to which Salmeterol undergoes first-pass metabolism. The low plasma concentrations observed after inhalation of therapeutic doses of the drug account for the lack of sufficient information. It acts on the lung locally through its action on the lung receptors.

When Salmeterol is inhaled, the plasma concentrations of the drug could not be detected even after 30 minutes of administration. Larger doses had proportionally larger blood concentrations.

Healthy volunteers who inhaled single doses of 50 and 400 micrograms of Salmeterol were observed to have plasma concentrations of 0.1 to 0.2 and 1 to 2 micrograms per liter, respectively, after 5 minutes to 15 minutes. Patients who inhaled 50 micrograms of Salmeterol twice daily for a period of ten months had a second peak concentration of 0.07 to 1 micrograms per liter, 45 minutes to 90 minutes after inhalation, probably due to the GI (gastrointestinal) absorption of the swallowed drug. Salmeterol Xinafoate dissociates to form Salmeterol and 1-hydroxy-2-naphthoic acid in a solution. The absorption, distribution, metabolism, and excretion of the two compounds were done independently. The Xinafoate component did not have significant pharmacological activity. It was found to be predominantly protein bound, with 99 % of it bound to albumin, and had a half-life of 12 days to 15 days. Due to this reason, the drug accumulated in the plasma in considerable amounts.

The cytochrome P450 enzyme system is responsible for the metabolism of Salmeterol by hydroxylation. Alpha hydroxy salmeterol is the major metabolite formed that was found to be eliminated predominantly through feces. About 57.4 % was eliminated through feces and 23 % in the urine. Most of the drug was recovered within 24 hours to 72 hours of administration.

Drug Interactions:

The systemic concentrations of the drug were found to be negligible. As the therapeutic doses of the drug are significantly less, there is less chance of clinically significant drug interactions on co-administration of Salmeterol with other medications like Fluticasone Propionate that CYP3A is also metabolized. The systemic effects were noted only when higher doses of inhaled medicine led to proportionally high blood concentrations of the drug.

Monitoring:

The parameters that need to be monitored during Salmeterol use include blood pressure, heart rate, pulmonary function, forced expiratory volume, peak expiratory flow, central nervous system stimulation, nocturnal awakening frequency, and the frequency and occurrence of asthma symptoms.

It is also recommended to monitor the blood glucose, thyroid function, hepatic function, potassium, and QT interval in cases where the patient is simultaneously on other CYP3A4 inhibitors.

Patients with hepatic impairment also need close monitoring as compromised liver function can accumulate Salmeterol in the plasma.

Toxicity:

Reports have suggested that sympathomimetic syndrome with hyperlactatemia and metabolic acidosis was observed in patients who inhaled Salmeterol for suicidal attempts. The symptoms of overdose include chest pain, heart palpitations, hypokalemia, hypophosphatemia, lactic acidosis, sinus tachycardia, and ST-segment depression. The other symptoms of toxicity include angina, hypotension, hypertension, nausea, dizziness, fatigue, insomnia, and muscle cramps. An overdose of Salmeterol can also lead to prolongation of QT interval, causing ventricular arrhythmias.

The standard therapy for a symptomatic overdose of Salmeterol must include intravenous fluid administration, potassium supplementation, cardiac monitoring, and administration of a cardioselective beta-blocker.

General Instructions on the Usage of the Drug:

How Should Salmeterol Be Used?

Salmeterol is supplied as a dry powder to be inhaled by mouth using a specially designed inhaler. It is recommended to use the medicine twice daily, with a gap of 12 hours, at around the same time every day, probably in the morning and at night. In cases where Salmeterol is used to prevent breathing difficulties during exercise, it has to be used at least 30 minutes before exercise. Also, if a patient uses Salmeterol regularly twice daily, an additional dose before exercise should not be used.

The medicine has to be taken as directed by the physician and exactly the recommended dosage, not more or less. Salmeterol should not be used to treat sudden attacks of asthma or COPD. The medicines must not be changed or used without a doctor's recommendation.

What Are the Steps to Be Followed When Using an Inhaler?

The following steps are to be followed when using an inhaler:

  1. An inhaler being used for the first time must be removed from the box, and the foil must be unwrapped.

  2. The inhaler label must be filled with the details about when it was first opened and the date of six weeks from it that it must be disposed of.

  3. The inhaler has to be held in one hand, and the thumb of the other hand must be placed on the thumb grip.

  4. The thumb must be pushed away as far as it can go until the mouthpiece appears and snaps into position.

  5. The inhaler must be held in a horizontal position with the mouthpiece facing the patient. The lever must then be slid until it clicks.

  6. A dose is ready to be inhaled whenever the lever is pushed back. The number on the dose counter goes down with every inhalation.

  7. The inhaler has to be held in a flat position, with the mouthpiece near the lips. Then, the patient must breathe in quickly and deeply through the inhaler, not through the nose.

  8. The inhaler must then be removed from the mouth, and the breath must be held for at least ten seconds before breathing out.

  9. The thumb must then be placed on the thumb grip that must be slid backward. The device will click shut.

What Are the Special Precautions to Be Followed Before Using Salmeterol?

The doctor must be informed about the following things before starting the medicine, that includes:

What Are the Dietary Instructions That Have to Be Followed While Using Salmeterol?

The patient can continue with the regular diet unless the doctor instructs them to change.

What Should Be Done in Case of a Skipped Dose?

A skipped dose can be ignored and continued with a regular dosing schedule. However, an extra dose must not be inhaled to compensate for the missed dose.

What Are the Side Effects of Salmeterol Use?

The following side effects may be noted with Salmeterol use:

Serious side effects include:

What Are the Symptoms of Salmeterol Overdosage?

The following symptoms can occur with the drug overdosage:

How Should Salmeterol Be Stored and Disposed Of?

  1. The medicine must be kept in the container in which it came in with the lid tightly closed when not in use.

  2. It must be kept out of reach of children.

  3. It must be kept away from direct sunlight, heat, and moisture.

  4. The inhaler must be disposed of after six weeks of unwrapping the foil or when the dose indicator reads zero, whichever comes first.

  5. If the medicine is no longer needed, it must be disposed of in a safe way to ensure that children, pets, or anyone do not use it.

  6. The medicine must not be flushed down a toilet. Instead, it must be disposed of through a medicine take-back program. A local pharmacist or a recycling department would provide more information on the program in the community.

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Frequently Asked Questions


1.

Are Salmeterol and Fluticasone Propionate Steroids?

Salmeterol is not a steroid, while Fluticasone is a steroid used along with Salmeterol (long-acting bronchodilator) to prevent asthmatic attacks. They are effective in relieving symptoms such as wheezing and shortness of breath. These drugs are not used in treating mild cases of asthma and are only used in cases of severe and persistent asthma cases.

2.

How Does Salmeterol Work?

Salmeterol is a bronchodilator, and the administered route is through inhalation. They work by relaxing and dilating the lungs’ airways; therefore, it eases breathing in patients affected by asthma, COPD (chronic obstructive pulmonary disease), exercise-induced bronchospasm, etc. They are effective in stimulating the beta-2 receptors of the lungs’ airways which helps in relieving the symptoms. 

3.

How Does Salmeterol Work?

Salmeterol is a bronchodilator, and the administered route is through inhalation. They work by relaxing and dilating the lungs’ airways; therefore, it eases breathing in patients affected by asthma, COPD (chronic obstructive pulmonary disease), exercise-induced bronchospasm, etc. They are effective in stimulating the beta-2 receptors of the lungs’ airways which helps in relieving the symptoms. 

4.

Can I Take Salmeterol Along With Fluticasone?

Yes, Salmeterol is a long-acting beta-agonist, and Fluticasone is a steroid, and they are used to treat the symptoms of asthmatic attacks and chronic obstructive pulmonary disorder (COPD). They are available in an inhalational form and are recommended to prevent frequent asthmatic attacks in adults and children (above four years). However, taking more than the recommended dose may lead to adverse effects.

5.

What Is Salmeterol Xinafoate?

Salmeterol is commercially available as Salmeterol Xinafoate, and it contains both Fluticasone (steroid) and Salmeterol (long-acting beta-agonist). It is very effective in preventing symptoms such as wheezing or shortness of breath. Therefore, it is suggested that lung disorders such as bronchitis, emphysema, asthma, etc.

6.

When Is Salmeterol Not Indicated?

Salmeterol is contraindicated in the following cases:
- History of adverse reactions to the drug.
- Status epilepticus.
- Hypersensitivity.
- Salmeterol is indicated with a long-acting beta-agonist due to severe complications.

7.

When Is Salmeterol Indicated?

The indications of Salmeterol include:
- To treat asthma.
- Prevents asthmatic attacks.
- Chronic obstructive pulmonary disease (COPD).

8.

What Kind of Drug Is Salmeterol?

Salmeterol is a long-acting beta-agonist, and it is used in the treatment and prevention of asthmatic attacks in both children (above four years of age) and adults. It helps in treating breathing difficulties and chronic obstructive pulmonary disease (COPD). It works by dilating and relaxing the air passages present in the lungs. Thus, it helps in reducing breathing difficulties.

9.

Is Salbutamol and Salmeterol the Same?

Salmeterol and Salbutamol are both beta-agonists, and they work by activating the beta -2 receptors in the airway of the lungs. Thus, the airways relax, and breathing becomes easy. However, Salmeterol is considered superior to Salbutamol as it is:
- Effective in preventing asthmatic attacks.
- Longer-acting (action lasts for 12 hours).

10.

Does Taking Salmeterol Lead To Hypertension?

Salmeterol should be used with precaution in individuals with systemic disorders such as diabetes, cardiovascular disease, etc. Salmeterol may lead to elevation of blood pressure and heart rate and cause nervousness, cough, headache, rapid heartbeat, and other adverse effects. In addition, it is essential to avoid taking more than the prescribed dose to avoid such adverse effects. Therefore, discuss with the doctor the existing health condition before taking Salmeterol.

11.

Can Salmeterol Be Taken for a Long?

The doctor usually suggests Salmeterol for persistent and severe asthmatic attacks. This drug is effective, long-acting, and treats breathing difficulties in adults and children. However, this drug is suggested by the specialist to control the symptoms of asthma, and taking more than the prescribed dose may lead to adverse effects.

12.

Does Salmeterol Relieve or Prevent Disease?

More commonly, Salmeterol is considered a drug to relieve and prevent the symptoms of the following lung disorders:
- Severe asthmatic attacks.
- Exercise-induced bronchospasm.
- Chronic bronchitis.
- Emphysema.

Last reviewed at:
22 Nov 2022  -  12 min read

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