Respiratory Lecture 2 PDF

AW Decongestants, Antitussives, Lecture Objectives...

AW Decongestants, Antitussives, Lecture Objectives Describe common indications for use, activity, and pharmacological mechanisms, and advantages and disadvantages associated with specific decongestants Expectorants Understand and recognize common indications for use, activity, pharmacological mechanisms, and advantages and disadvantages associated with specific antitussives Describe and recognize common indications for use, RESPIRA TORY M ODULE activity, pharmacological mechanisms, and advantages JASON ERIKSEN, PHD and disadvantages associated with different types expectorants OCTOBER 28, 2024 Goodman and Gilman. The Pharmacological Basis of Therapeutics. Oct 28 1 2 The Human Nasal Cycle Allergic Rhinitis Physiological Rhythm: Alternating Inflammatory Cascade: Cellular Response: congestion/decongestion cycle occurs I'm IgE-mediated mast cell Eosinophil infiltration every 4-8 hours activation T-helper cell activation Release of inflammatory Neural Control: Regulated by mediators Cytokine release patterns sympathetic and parasympathetic inputs Mucosal edema and hyperemia Neurogenic Vascular Mechanisms: Involves response Amplification: Immediate delayed alternating vasoconstriction and Vascular Changes: Sensory nerve stimulation vasodilation Increased capillary Neuropeptide release hint permeability Functional Significance: Optimizes Local axon reflexes Enhanced glandular airflow dynamics and respiratory defense secretion Pathophysiological Impact: Cycle Vasodilation of submucosal vessels amplification during inflammatory states mmmm moat Measuring and Characterizing the Human Nasal Cycle Roni Kahana-Zweig,1,* Maya Geva-Sagiv,1 Aharon Weissbrod,1 Lavi Secundo,1 Nachum Soroker,2,3 and Noam Sobel1,* 3 4 Thisprocess iswhat our pharmacology interacts with Muscle highsidffconst jogging w iggffigntmdications The Pharmacology of Alpha- An Introduction to Decongestants Adrenoceptor Agonists Molecular Mechanism: Pharmacological Receptor Distribution: Contractile Mechanism: α-adrenergic receptor Selectivity: α1 predominance in Myosin light chain activation Predominant α1 effects arterioles phosphorylation Vascular smooth muscle Variable α2 activity α2 presence in venous Actin-myosin cross-bridge circulation formation contraction exvisaged Reduced capillary Tissue-specific responses Differential tissue expression Sustained contractile response perfusion Physiological Impact: Signal Transduction: Feedback Regulation: Tissue Effects: Reversible Gq coupling to Receptor desensitization vasoconstriction phospholipase C G Decreased mucosal patterns blood volume Maintained tissue IP3/DAG second oxygenation Cellular adaptation Reduced tissue edema messenger cascade mechanisms Enhanced nasal patency Modified secretory function G Ca2+ mobilization pathways Tachyphylaxis development pcartintracell determinescontractileresponse 5 6 distinctdist btwn 21 t a 2  topian First-Generation Topical Decongestants Pharmacological Adverse Effects iii IIi Receptor-Mediated Vascular Adaptations: Iiii.fi Molecular Pharmacodynamic II Characteristics: Properties: Effects: Endothelial cell α1/α2 activation responses Direct α-adrenergic Rapid onset of action patterns agonism Duration-dependent Tissue-specific responses Smooth muscle plasticity Variable receptor subtype classification Temporal response Compensatory selectivity Receptor occupancy profiles vasodilation Limited systemic patterns yes Tachyphylaxis Systemic absorption Local Tissue Effects: Mechanism: Consequences: Duration Determinants: binding receptor Receptor internalization Cardiovascular reflexes Mucosal blanching Receptor binding kinetics Second messenger Central sympathetic Reduced tissue volume adaptation effects Local drug concentration Modified secretory activity Cellular compensatory changes Baroreceptor t.TLahE Vascular retention time modulation 7 lossofsignalingefficacy Rhinitis medicomentosa fff iorinE ag 8 Dangerous forchildren Ialsofound in CirculatorySystem ifacid injest targetPNS get vasodilation Bp tackycardia Miettinen death etc Second-Generation Topical ariskofmedicamentos LyftDecongestants Lumafy Oral Decongestants Absorption Kinetics: Pharmacological Brimonidine is a medication Adaptation Mechanisms: used to treat open-angle Modified receptor First-pass metabolism Differences: glaucoma, ocular trafficking Direct vs. indirect Live hypertension, and rosacea. Altered desensitization Bioavailability patterns sympathomimetics ontargets Receptor as Selectivity: patterns Improved tolerance Distribution volumes rateof Gradual drug Receptor Interactions Duration of receptor occupation Enhanced α2 specificity profile concepin Metabolic transformation Reduced α1 activation Systemic α-adrenergic patterns activation Emilia Optimal binding kinetics Pharmacological Cellular Response Patterns: Advantages: Tissue-specific responses Gradual receptor activation Vascular Response Pattern: Difference in mechanism of Concentration-effect Reduced rebound Reduced local Preferential venous effects phenomena action of α-adrenergic receptor relationships concentration effects Maintained arterial flow agonists for relief of ocular Decreased tachyphylaxis redness. Modified adaptation Reduced tissue ischemia Improved safety margin responses 9 10 Cough Common Causes of Cough in Systemic Decongestants Adults coughsuppChromic okforacute butnot becanmask Temporal Patterns: Pharmacokinetic Systemic Integration: Neural Pathways: Parameters: Cardiovascular responses Vagal afferent Acute phase Distribution patterns mechanisms iii Metabolic effects activation Metabolic pathways Autonomic modulation Brainstem integration Subacute progression Elimination kinetics Chronic pathway Molecular Interactions: Efferent motor adaptation Cellular Mechanisms: Enzyme system effects responses Neurotransmitter Transporter protein Pathophysiological modulation involvement Inflammatory Basis: Receptor population Receptor cross-talk Mediators: Airway inflammation effects mechanisms Cytokine cascades Neurogenic Signal amplification Neuropeptide release mechanisms cascades Receptor sensitization Mechanical stimulation avoidusew MAOinhibitors 11 12 Pops HkgE women egnant be flow Blood tofetus Ifit41 iitiitsmcoughmcn  2 Medication Antitussive Pharmacology DextromethorphanEEEknas.iq Central Mechanisms: Neural Integration: Molecular Targets: Cellular Effects: μ-opioid receptor Afferent signal processing NMDA receptor Neurotransmitter activation NMDA receptor signal Reflex arc modification Motor output regulation antagonism futhmodulation targeted Sigma-1 receptor binding Calcium flux alterations modulation Voltage-gated channel Signal transduction Brainstem center inhibition Receptor Populations: effects changes Distribution patterns Peripheral Actions: Metabolic Processing: Therapeutic Impact: Subtype specificity Sensory nerve CYP2D6 metabolism Cough center modulation desensitization Cellular response characteristics Active metabolite Receptor desensitization Mechanoreceptor formationDextrophan Neuroplasticity effects modulation Pharmacokinetic variation Local irritant suppression 13 14 morphism 3 prodrug 4h 4 Codeine Mechanisms Benzonatate Pharmacology Receptor Metabolic Molecular Mechanisms Safety-Critical Kinetics Pharmacology Considerations Voltage-gated Na+ channel blockade Rapid absorption through oral mucosa μ-opioid receptor CYP2D6 polymorphisms Rapid onset of membrane stabilization Immediate cardiac/CNS toxicity risk activation Morphine formation Concentration-dependent neural block Fatal effects possible with single capsule Pro-drug conversion kinetics Bioavailability factors Local Anesthetic Properties Therapeutic Requirements Receptor subtype Physiological Complete neural blockade if released Intact capsule maintenance essential selectivity rapidly Effects Controlled release necessary for safety Neural Integration Respiratory center Potentially lethal oral/pharyngeal Age restrictions for administration Medullary center effects depression anesthesia Peripheral nerve Vagal nerve modulation Rapid systemic absorption if crushed modulation Neurotransmitter fifth Sensory processing alterations alteration TargetsCentral Periph ns 15 16 Eritrea.mn Pairftiiiii 9ampa Mucoactive Agents: The Nature of Factors Affecting Mucus Mucus Properties Mucins are complex Physical Factors: glycoproteins that form Water content, pH, and protective barriers ionic strength Different mucin subtypes Molecular Components: serve specific functions in Mucin subtypes, various tissues glycosylation patterns Mucin production and Structural Elements: Human Mucin Subtypes secretion are tightly Cross-linking, polymer regulated processes networks Alterations in mucin Environmental Influences: composition affect Temperature, shear forces respiratory health 17 18  Mucoactive Agents Affect Mucus Layer Organization Clearance of Mucus Structural Organization: - Outer loose layer: Mobile, ACTIONS USES readily cleared Mucus Adhesion: Acute Respiratory Conditions - Inner adherent layer: Forms Increased epithelial adhesion reduces protective barrier clearance Chronic Airway Diseases ❖ Functional Differences: Physical properties affect cough Post-surgical Pulmonary Care effectiveness - Outer layer traps particles Mucus Clearance Disorders and pathogens Environmental Factors: - Inner layer maintains sterility Dehydration increases mucus viscosity Lung Cilia at epithelial surface Ionic composition affects mucus rheology ❖ Layer-specific Properties: Therapeutic Effects: - Different mucin Enhanced secretion volume improves concentrations and hydration compositions Direct effects on mucus viscoelasticity 19 20 WIN Mucoactive Agents Affect Clearance of Mucus Guaifenesin Expectorants: Mechanism of Action: Clinical Considerations: pitsiosity FUI Enhance airway hydration and secretion volume Common combination Increases respiratory tract Modify mucus surface tension and adhesion hydration ingredient Mucolytics: Reduces mucus viscosity Generally well-tolerated Break disulfide bonds between mucin molecules Enhances ciliary transport GI effects relate to Reduce mucus viscosity through direct chemical mechanism action Pharmacological Mucokinetics: Effects: Improve ciliary beat frequencyClear Enhance mucus transport mechanisms faster longs Modifies mucus rheology Improves mucociliary clearance Mucoregulators: Facilitates productive Modulate inflammatory response cough Control mucin gene expression Source 21 22 fibrosis app Mucolytics Cystic N-Acetylcysteine DNAse I DnaLviscosity Cuts Molecular Mechanism: Mechanism of Action Cleaves disulfide bonds in Hydrolyzes extracellular DNA mucin proteins Reduces mucus viscosity Reduces mucus cross-linking Improves mucus clearance Alters mucus viscoelasticity Therapeutic Clinical Applications: Considerations: Cystic fibrosis mucus Specific for CF-related modification DNA accumulation Acetaminophen overdose Requires direct pulmonary Confocal micrograph showing mucin polymers (Texas red-UEA) and DNA antidote delivery polymers (Green - YoYo1) in bronchitis Limited oral bioavailability Enhanced efficacy in (left) and cystic fibrosis (right) sputum. DNA-rich secretions Source 23