Albuterol Side Effects and Mechanisms

• Bronchodilators are medications that help widen the airways, making it easier to breathe

Adrenergic (Sympathomimetic) Bronchodilators

• These bronchodilators are used in the presence of reversible airflow obstruction, which occurs in conditions like acute and chronic asthma, bronchitis, emphysema, bronchiectasis, and other obstructive airway diseases.
• Airway smooth muscle is controlled by the sympathetic nervous system, which releases catecholamines like epinephrine and norepinephrine.
• Circulating catecholamines act on ᾳ and ẞ adrenergic receptors on airway smooth muscle.
• Density of ẞ receptors increases as the airway diameter becomes smaller, predominately distributed from the trachea to the terminal bronchioles

Specific Beta Receptor Function

• ẞ2 receptors are traditionally seen as the ẞ receptor subtype on the airway smooth muscle that responds to epinephrine (hormonal).
• Human lungs lack direct sympathetic innervation, meaning adrenergic receptors are of the ẞ2 type.
• Relaxation of human smooth muscle is achieved through stimulation of hormonal ẞ receptors using catecholamines.

Subgroups

There are three subgroups based on the duration of action

• Ultra-short-acting: Duration less than 3 hours, includes racemic epinephrine.
• Short-acting: Duration 4 to 6 hours, includes albuterol, levalbuterol, metaproterenol.
• Long-acting: Duration 12 to 24 hours, includes salmeterol, formoterol, arformoterol, indacaterol, olodaterol, and vilanterol.

Catecholamines

• Sympathomimetic bronchodilators are either catecholamines or catecholamine derivatives.
• Dopamine, epinephrine, norepinephrine, and isoproterenol are examples of catecholamines.
• Sympathomimetic amines mimic epinephrine and cause tachycardia, elevated blood pressure, smooth muscle relaxation of bronchioles and skeletal muscle blood vessels, glycogenesis, skeletal muscle tremors, and CNS stimulation.
• Bronchodilators like epinephrine, albuterol, and salmeterol are synthetic racemic mixtures or 50:50 mixes of (R)- and (S)-isomers.
• Epinephrine stimulates both ᾳ and ẞ adrenergic receptors and occurs naturally in the adrenal medulla.
• Side effects of epinephrine include tachycardia, increased blood pressure, tremors, headache, and insomnia.
• Rapid onset and short duration of epinephrine is caused by metabolism by cathecol O-methyltransferase (COMT)
• Route of administration for epinephrine includes inhalation and subcutaneous injection for the management of acute asthma attacks.
• Synthetic epinephrine is a racemic mixture giving both ᾳ and ẞ stimulation
• A key structural modification that can result in non-catecholamines allows the bronchodilator to have a 4-6 hour duration when inhaled and has a preferential affinity for a ẞ2 preference.

Metaproterenol Specifics

• The hydroxyl group attachment was moved from the carbon-4 site of the catecholamine to the number 5 position.
• Duration of action is 4-6 hours; can be taken orally

Albuterol (Salbutamol) Specifics

• Albuterol is a modification of the catechol nucleus.
• Albuterol is offered via oral extended-release tablets, syrup, nebulizer solution, and MDI.
• Albuterol is preferential for acting on ẞ2 receptors.
• Inhaled albuterol has a duration of action of 4-6 hours and reaches peak effect in 30-60 minutes.
• Oral extended-release tablets have a 12-hour duration.
• Oral albuterol can cause greater systemic side effects.

Levalbuterol Specifics

• It is the pure (R)-isomer of racemic albuterol.
• HFA-propelled MDI and nebulization solution, higher peak effect in FEV1, duration of 8 hours, and equivalent side effects.

Long-Acting Beta-Adrenergic Agents

• Salmeterol, formoterol, aformoterol, indacaterol, olodaterol and vilanterol are administered via inhaled form.
• Extended-Release Tab Albuterol can be administered in a 4mg or 8mg tablet
• Can last from 8-12 hours

Long Acting Agent Chart

• Salmeterol xinafoate’s chemical form is a Racemic mixture of two enantiomers, and is delivered via DPI-Diskus; onset of action is slow around 10 min, peaks at 3-5 hr with duration over 12 hours.
• Formoterol's chemical form is a racemic mixture, delivered via DPI, faster onset within 2-3min, duration is 12 hours.
• Arformoterol's chemical form is a single isomer of formoterol that is delivered via nebule with a duration of 12 hours.
• Indacaterol’s delivery form is DPI with an onset of 5 minutes and duration of 24 hours
• Olodaterol is delivered via Respimat having a fast 5 min onset and duration of 24 hours
• Vilanterol is delivered via DPI-ellipta and duration is 24 hours

Common and Differentiating Features

• All adrenergic bronchodilators are ẞ2-selective agonists
• The efficacy of the drugs from highest to lowest include Formoterol, albuterol and than salmeterol
• Provide anti-inflammatory effects by both short-acting and long-acting ẞ-agonist
• Reduce inflammatory effects by inhibiting human mast cell activation and degranulation, preventing an increase in vascular permeability, decrease the attraction of airway inflammatory cells although its not visible in vivo
• Are not sufficient enough anti-inflammatory effects to replace corticosteroids

Clinical Applications

• Long-acting bronchodilators are useful in maintenance for asthma that's not controlled by regular low-dose inhaled corticosteroids.
• Useful for use in COPD, a chronic obstructive pulmonary disease, who need daily inhaled bronchodilator therapy.
• May prevent the need to increase inhaled doses of corticosteroids, and isn't recommended for rescue bronchodilation.
• Short-acting agonists are used to treat breakthrough attacks.
• Short and long-acting agonists are not substitutes for inhaled corticosteroids.
• Slow and long acting is salmeterol, fast and long acting is formoterol and finally ultra-long acting is olodaterol

FDA Requirements

• Long-acting agonists are not to be used without a controller medication or by patients who are controlled with low-dose inhaled corticosteroids.
• Long acting agonists can be only used if patients are not controlled with agents, used for short term use that should be discontinued once asthma is controlled, and used in children in conjunction with corticosteroid

Action Mechanism

• Beta 2 receptor stimulation causes relation of bronchial smooth muscles, some inhibition of inflammatory mediator release, and stimulation of mucociliary clearance.
• Some adrenergic bronchodilators produce additional effects mediated by ᾳ-receptor stimulation such as Vasocontriction and decongestion.
• Beta 1-receptor Stimulation which Causes Increased Myocardial conductivity.

Receptor Types

• Both ᾳ and ẞ receptors are G protein-linked receptors whose ᾳ Subunit differentiates the tissue.
• Alpha 1 Receptor, Gq Protein, Phospholipase C (PLC), Inositol Triphosphate which causes Vasoconstriction.
• Beta (Beta 1-3) Receptor, Gs Protein, Adenylyl Cyclase, CAMP (Increase), smooth muscle relaxation.

Clinical Significance

• Inhaled beta agonists stimulate the G protein, causing activation of stimulatory and increase synthesis of CAMP.
• Long-acting agonists contain a Nonpolar side attached attached to G protein in active “head” binding and helps to facilitate long duration of action.

Routes of Administration

• Routes of administration: inhalation, via MDI, nebulizer solution DPI and respimat.
• Oral administration is available
• Parenteral or injected route available.
• Not that not all agents are found in each form.
• Inhalation by aerosol is the preferred route especially during acute episodes where the duration dose starts as Intermittent doses and gradually increases.
• Inhalation comes with potential complications: cardiac arrhythmias, hypokalemia and hyperglycemia, and the patient must have constant monitoring with cardiac and electrolytes.
• Oral route is the easiest in terms of reproduction with the dosage. It however takes 1.5hour for Onset and the peak 1-2 hours and lasts betweeen 3-6. The cons are is loss of specificity.
• Parenteral method includes Subcutaneous epinephrine at .333mg every 15-20mins up to 1mg in 2 hours. And IV is last resort.

Adverse Side Effects

• Stimulation of ᾳ Adrenergic which are B 1 and B 2.
• Tremors are results from stimulation of Beta 2 adrenergic Receptors in skeletal Muscles.
• Cardiac effects cause Increase in Cardiac Output.
• Tachycardia monitoring.
• Electrolyte Imbalance mainly hypokalemia.

This lesson explores the side effects, appropriate responses, and mechanisms of action related to albuterol, a common bronchodilator. It emphasizes patient education and thorough physical examinations in managing albuterol therapy. It also covers the expected duration of bronchodilation after albuterol.