Pulmonary Pharmacology: Asthma & COPD

• Short-acting beta-agonists (SABAs) and long-acting beta-agonists (LABAs) are therapies for asthma and COPD

Pulmonary Pharmacology

• Pulmonary pharmacology is concerned with how drugs act on the lung, as well as treating pulmonary diseases
• It focuses on how affect airways, and therapies for airway obstruction
• Asthma includes chronic airway inflammation and smooth muscle contraction
• COPD involves respiratory tract inflammation, leading to air trapping, among other complications
• Asthma can be treated using bronchodilators and anti-inflammatory drugs
• COPD is mainly treated using bronchodilators

Routes of Drug Delivery

• Inhalation is preferred, because it allows direct action on airways and reduces side effects
• Oral routes are preferred for oral delivery, when inhalation is not an option, and dosages are typically higher than with inhalation
• Parenteral delivery is reserved for severely ill patients, and biologics

Bronchodilators

• Classes of bronchodilators include B2 adrenergic agonists, theophylline, and anticholinergic agents
• Bronchodilators operate by relaxing airway smooth muscle

Therapeutic challenges

• Asthma includes chronic inflammation and structural changes that cannot be cured using corticosteroids
• COPD presents progressive airflow obstruction and inflammation that are often complicated by comorbidities

Importance of Drug Delivery Device

• Various inhalers provide options for effective drug delivery
• Spacers help ensure the medication reaches the airways instead of the mouth tissues
• When choosing a device, consider the particle size and suitability for different age groups

Beta-2 Adrenergic Agonists

• These agonists have a modified catecholamine structure, conferring B receptor selectivity.

• Bronchial smooth muscle relaxation is achieved from the occupation of B2 receptors, through the Gs-adenylyl cyclase-cAMP-protein kinase A pathway

• The B2 agonists also provide added effects such as preventing mediator release, increasing mucus secretion, and reducing neurotransmission in airway cholinergic nerves

• Bronchial mucosal edema may be prevented by microvascular leakage

• Mucus secretion is enhanced, potentially reversing the defective clearance seen in asthma and COPD

• Short-acting beta-2 agonists are "rescue" medications, while long-acting beta-2 agonists are "control" medications

Short Acting Beta-2 Agonists

• Inhaled short-acting beta-2 agonists provide rapid bronchodilation for symptom relief

• SABAs are used for acute asthma therapy and act as rescue therapy

• SABAs should be used for symptom control on demand, and if they are used frequently, therapy should be stepped up

• Albuterol and levalbuterol are examples of commonly used SABAs

• Levalbuterol has less cardiac activity

• SABAs come in MDI and inhalable formulations

• They’re rapid acting in 1-5 minutes

Long-Acting Beta-2 Agonists

• LABAs are used for long-term control, often combined with inhaled corticosteroids

• Combination inhalers offer enhanced convenience, improved adherence, and synergistic actions

• Duration of action is 12 hours

• LABAs should always be combined with an anti-inflammatory corticosteroid to mitigate the risk of potentially fatal asthma attack

• Long-acting beta-2 agonists may elevate asthma-related death risks. The should only be used if medium dose, inhaled coriticosteroids do not provide adequate control

• For asthma, a combined ICS and Formoterol is recommended to avoid potential dangers of short acting B2 agonists overuse

• LABAs are used in combination with inhaled glucocorticoids for long-term control of moderate to severe symptoms

• Formoterol has "fast" onset of action compared to salmeterol, because of intermediate lipid solubility

• LABAs can suppress asthma symptoms for the long term.

• ICS/LABA inhalers are available

• LABAs improve symptoms and exercise tolerance in COPD by reducing air trapping and exacerbations

• Receptors can be desensitized after long-term use

• Muscle tremor, hypokalemia, and ventilation-perfusion mismatch are dose-related side effects

• Continuous use of corticosteroids prevents the development of tolerance in airway smooth muscle

H1 Antihistamines

• Important to consider sedation differences, preferred uses, and side effect profiles

• H1 antihistamines include histamine, bradykinin, and their antagonists

• H1 and H2 receptors are widespread through the periphery and the CNS

• H3 receptors reside mainly in the CNS, especially in the basal ganglia, hippocampus, and cortex

• H3 agonists stimulate sleep

• H4 receptors reside primarily on eosinophils, dendritic cells, mast cells

Histamine and its properties

• Histamine receptors are GPCRs, coupling to second-messenger systems and producing effects
• Vascular endothelium H1 receptor activation stimulate eNOS, increase nitric oxide (NO), and cause smooth muscle relaxation
• H1 receptor stimulate mobilization of mobilize Ca2 and cause contraction
• H2 receptor in same smooth muscle cell will link via Gs to enhanced cyclic AMP accumulation & activation of PKA
• All four receptors affect allergic reactions, urticaria, and gastric acid secretion management
• Histamine is synthesized from histidine, stored in mast cells and basophils, and released upon antigen stimulation
• Histamine plays roles in immediate hypersensitivity and allergic responses
• Histamine possesses diverse effects on the cardiovascular system
• Histamine-containing neuron receptors in CNS modulate various functions
• H1 antagonists block histamine effects on processes like smooth muscle contraction