Pulmonary Pharmacology: Respiratory Medications Overview

• Respiratory medications target the lungs for pulmonary disease treatment.
• Asthma is a chronic inflammatory condition causing airway constriction, while COPD involves inflammation leading to trapped air.
• Asthma is treated with bronchodilators and anti-inflammatories, whereas bronchodilators serve as the primary treatment for COPD.

Pulmonary Pharmacology: Drug Delivery

• Inhalation is preferred for direct action and fewer systemic side effects.
• Oral medications are viable when inhalation is not possible, but need higher doses.
• Parenteral drugs, like intravenous biologics, are reserved for severely ill patients.

Pulmonary Pharmacology: Bronchodilators

• ẞ2 agonists and anticholinergic agents are bronchodilator classes.
• These drugs work by relaxing airway smooth muscle, which in turn prevents bronchoconstriction.
• Challenges include inflammation and structural changes in asthma, where corticosteroids are essential
• In COPD, challenges include progressive airflow obstruction and comorbidities complicating treatment.
• Inhalers and nebulizers are options for effective drug delivery
• Spacers are important for medication delivery to airways, not just mouth tissues.

Beta-2 Adrenergic Agonists: Action and Effects

• Inhaled ẞ2-selective agonists selectively bind to β receptors, causing smooth muscle relaxation.
• They stimulate bronchial smooth muscle relaxation through the Gs-adenylyl cyclase-cAMP pathway.
• These agonists inhibit bronchoconstrictor release, reduce mucosal edema, and decrease acetylcholine release.
• β2 agonists prevent microvascular leakage, preventing bronchial mucosal edema from mediators like histamine.
• They enhance mucociliary clearance, beneficial in asthma and COPD, by increasing mucus secretion.
• Short-acting beta-2 agonists provide rescue, while long-acting ones provide control for a longer period.

Short-Acting Beta-Agonists (SABAs)

• SABAs work by rapid-acting bronchodilation and are used when needed for symptom relief.
• They are a mainstay for rescue therapy for acute asthma symptoms
• SABAs should only be used on demand for symptom control and not frequently
• Albuterol and Levalbuterol are are examples of SABAs.
• Levalbuterol- has less cardiac activity.
• SABAs act rapidly within 1–5 minutes, with effects lasting 6 hours or less.

Long-Acting Beta-2 Agonists (LABAs)

• LABAs provide prolonged bronchodilation for long-term control, often with inhaled corticosteroids (ICSs).
• LABA and corticosteroid combination inhalers support adherence and synergistic effects.
• Action lasts 12 or more hours due to high lipid solubility, concentrating in smooth muscle cell membranes.
• These should always be used with a anti-inflammatory corticosteroid to reduce asthma attack risk.
• Black Box Warning: LABA monotherapy for asthma can raise mortality risk, only use as additional therapy with ICS.

Pulse Therapy with ICS

• A combination of Formoterol and ICS is recommended for rescuing asthma, more effective and avoids SABA overuse.
• LABAs, combined with glucocorticoids, manage moderate to severe symptoms, controlling rather than rescuing.
• Formoterol has a fast onset due to mid-level lipid solubility.
• They can suppress asthma symptoms for long time periods.
• LABAs improve symptoms and tolerance by reducing trapping and exacerbations
• Receptor desensitization can occur with long-term use.

Beta-2 Agonists: Side Effects

• Dose-related side effects of ẞ2 agonists include muscle tremor, tachycardia, hypokalemia, and ventilation-perfusion mismatch.
• Continuous use of corticosteroids prevents the development of tolerance in airway smooth muscle.

H1 Antihistamines

• H1 antihistamines are categorized into first-generation and second-generation drugs.
• These drugs used for preferred uses, side effect profiles, and their effects on histamine.
• Not going to study kallikreins and kinins as these have limited applications.

Histamine Receptors

• Histamine receptors are GPCRs that produces effects.
• H1 receptor activation stimulates eNOS, producing nitric oxide which results smooth muscle relaxation.
• H1 mobilizes Ca2+ causing contraction, while H2 links through Gs to relaxation via PKA
• H1 and H2 receptors exist peripherally and in the CNS for both local and widespread effects.
• H3 receptors mainly in the CNS: basal ganglia, hippocampus, and cortex.
• H3 agonists promote sleep, H3 antagonists promote wakefulness.
• H4 receptors are found in eosinophils, dendritic cells, mast cells, monocytes, basophils, in the GI tract, dermal fibroblasts, CNS.

Histamine and Its Therapeutic Targeting

• Histamine plays a central role in immediate hypersensitivity and allergic responses.
• It also effects bronchial smooth muscle, blood vessels, leukocyte migration, and gastric acid secretion as it does this.
• Physiological Effects: influences diverse cardiovascular effects, such as vasodilation, and modulates leukocyte recruitment.
• Activation of H1 receptors on vascular endothelium enhances nitric oxide which causes relaxation in smooth muscle cells
• Note: H2’s will be discussed in GI.
• Histamine within the CNS: contains neurons which modulate sleep-wake cycles, circadian rhythms, learning, and memory.
• Histamine Receptors (H3 and H4): also implicated in wakefulness and neuronal modulation.
• Understanding the role of Histamine: understanding histamine's role is key for managing allergies, gastric issues, and acute instances of edema.

H1 Receptor Antagonists: Inhibition

• H1 antagonists inhibit histamine action on smooth muscle, capillary permeability, nerve endings, and are used to treat allergic reactions.
• First-generation H1 antagonists cause unwanted sedation and possess anticholinergic effects, whereas second-generation ones have fewer system effects.
• Preferred Second-generation antihistamines are preferered for geriatric patients for reduced sedative effects, and first-generation meds should not be given children often
• Examples: olopatadine, acrivastine, cetirizine, and loratadine.

Physiological Effects of these Antagonists

• Reduced pruritis, reduction of secretions; mast cell stabilizing effects with second generation H1 antagonists.
• The mechanism of Action will depending on CNS, by being suppressing or stimulating.
• There can be anticholinergic effects and the indications include: as allergic disease (rhinitis, urticaria, conjunctivitis

Smooth/Exocrine Muscle Interactions

• H1 antagonists inhibit most histamine effects on smooth muscle especially in respiratory tract
• For exocrine glands can be used for the respiratory tract

Feedback + Adverse Effects

• The Flare and Itch suppresses nerve interaction while immediate reactions effectively suppress allergic inflammation or itch.
• Immediate reactions of histamine can be reduced by H1 inhibitors such as edema formation but do not block asthma/hypotension
• Mast Cell stabilizing and H1-dependent in some reactions.
• Overall, some 2nd generation H1 antagonists may exhibit mast cell stabilizing.
• The central effect of histamines can be stimulating or depressing in CNS

Leukotriene Receptor Antagonists (LTRAs)

• LTRAs consist of inhibitors of 5-lipoxygenase and leukotriene receptor antagonists, for chronic asthma management.
• However, they are used mostly as control medications and not rescue medications.

Leukotrienes are Inflammatory Mediators

• Leukotrienes are mediators produced by activated leukocytes, which increases and causes lipoxygenase/cyclooxygenase formations
• Inhibitors of LTs may cause hepatic dysfunction and churg-strauss syndrome
• The Use of antileukotriene (anti-LT) Agents: like LTRA's reverse bronchoconstriction
• Zileuton inhibits 5-LOZ to mediate inflammtion and is given with steroids if it is already moderate asthma.

Antimuscarinic Respiratory Agents (SAMAs vs. LAMAs)

• These drugs involve the nicotinic/muscarinic receptors in the heart, exocrine glands, and function of brain.
• Key functions include bronchoconstriction.

Drug Actions

• Acetylcholine/Antimuscarinic action are by stimulating and influencing the type of hyperreactivity/muscorinic involvement

• Adminster through and SAMA or LAMA are best given at combination in pts.

• The degree of therapeutic outcome stems largely toward and with patients

• SAMAs have cautions for glaucoma or bladder conditions in elderly and can cause dry mouth