RESPIRATORY PHARMACOLOGY (anaesthetic agents, bronchodilators, steroids, mucolytics)

1. RESPIRATORY PHARMACOLOGY (anaesthetic agents, bronchodilators, steroids, mucolytics) Presented by Dr. Amit Aggarwal Moderator - Dr. Jyoti Pathania

2. INHALATIONAL ANESTHETICS • all volatile anesthetics decrease tidal volume in a dose-dependent manner and an increase in respiratory rate.( Rapid shallow pattern of breathing) • As a result, decreased minute ventilation and an increase in resting arterial carbon dioxide tension takes place. • The alteration in ventilatory pattern caused by anesthetics has been attributed to relative sensitization of pulmonary stretch receptors that subsequently produce tachypnea and low tidal volumes • concentration-dependent inhibition of the ventilatory response to CO2 . mediated by depression of central medullary chemoceptor mechanisms. Also, selectively interference with intercostal muscle function contributing to loss of chest wall stabilization • Inhibition of peripheral chemoceptor responses to arterial hypoxemia.

3. INHALATIONAL ANESTHETICS • BRONCHODILATION Mechanisms of Action (depressing smooth muscle contractility ) decreases in Intracellular Ca2+ conc. inhibition of cell-membrane–associated Voltage dependent Ca Channels (VDCs), an action that reduces entry of Ca2+ into the cytosol. stimulating efflux of Ca2+ and increasing uptake of Ca2+ into the SR decrease in calcium sensitivity as a result of inhibition of protein kinase C activity volatile anesthetic–induced bronchodilation also occurs via modulation of airway cholinergic neural transmission

4. . • isoflurane and halothane dilate fourth-order bronchi at equivalent MAC values • The effects of volatile anesthetics on proximal versus distal airways may be related to differential effects on VDCs and the relative distribution of these channels • Volatile anaesthetic induced dilatation of distal bronchial segments partially depends on the presence of bronchial epithelium Focal epithelial damage or inflammation in the small airways of patients with asthma or after exposure to allergen,, the bronchodilatory response to volatile anesthetics may be reduced

5. Mucociliary Function and Surfactant Normal Mucociliary Function – • Ciliated respiratory epithelium extends throughout the respiratory tract as far as the terminal bronchioles Ciliary motion consists of a rapid stroke in a cephalad direction, followed by a slower recovery stroke in the opposite direction. Movements of cilia are closely coordinated to move matter toward the trachea efficiently(metachronism ). ATP-dependent • Mucus is a mixture of water, electrolytes, and macromolecules (e.g., lipids, mucins, enzymes) secreted by goblet cells and mucosal glands. Thicker layers of mucus slow the removal of surface particles from the airway, whereas low-viscosity mucus promotes more rapid ciliary transport • Volatile anesthetics and nitrous oxide diminish rates of mucus clearance by decreasing ciliary beat frequency, disrupting metachronism, or altering the physical characteristics or quantity of mucus. • smokers have significantly slower bronchial mucus transport velocity , volatile anesthetics may cause a further decrement in mucus transport

6. Effects of Inhaled Anesthetics on Surfactant • Pulmonary surfactant decreases the work of breathing by reducing surface tension at the fluid-gas interface. Surfactant is a mixture of proteins and phospholipids synthesized by alveolar type II cells. Both halothane and isoflurane transiently reduce phosphatidylcholine synthesis by alveolar cells in a dose-dependent manner. (By decreased Na+/K+ ATPase activity in alveolar type II cells ) • hydrophobic surfactant-associated protein C, which is synthesized exclusively by alveolar type II cells, confers the properties of rapid surface adsorption and reduction of surface tension to phospholipids . volatile anaesthetics decrease surfactant-associated protein C mRNA There is potentially additive and deleterious role of volatile anaesthetics and mechanical ventilation on surfactant production , particularly in the presence of acute lung injury

7. Hypoxic Pulmonary Vasoconstriction • hypoxic pulmonary vasoconstriction (HPV), is unique to the pulmonary circulation in that other vascular beds (e.g., coronary, cerebral) dilate in response to hypoxia • HPV is a locally mediated phenomenon that occurs when alveolar oxygen tension falls below 100 mm Hg and is maximal when oxygen tension is approximately 30 mm Hg. The specific mechanisms underlying HPV and the precise location of oxygen sensors remain unclear • HPV is an autoregulatory mechanism in the pulmonary vasculature that decreases blood flow to poorly ventilated areas of the lung, ensuring more blood flow is available for gas exchange in better ventilated areas of the lung • all known inhaled anesthetics attenuate HPV to some degree whereas most intravenous anesthetics do not.

8. I.V inducing agents • Barbiturates- dose dependent depression of medullary and pontine ventillatory centres, and dec senstivity to co2. Induction doses of thiopentone decrease tidal volume with a smaller and inconsistent decrease in respiratory rate . Laryngeal reflexes not depressed until large doses, stimulation may cause laryngo or broncho spasm . At higher doses or in the presence of other respiratory depressants such as opioids, apnea can result. With the exception of uncommon anaphylactoid reactions, these drugs have little effect on bronchomotor tone • At equipotent doses, propofol produces a slightly greater degree of respiratory depression than thiopentone.. Propofol is less likely than barbiturates to provoke bronchospasm , Metabisulfite • The degree of respiratory depression due to etomidate is less than that due to thiopentone . Etomidate may induce hiccups • Induction doses of ketamine produce small and transient decreases in minute ventilation, but respiratory depression is less severe than with other general anesthetics . Laryngeal Reflexes maintained, Increased secretions, Ketamine is a potent bronchodilator due to its indirect sympathomimetic activity( increases catecholamines) and perhaps some direct bronchodilating activity( blocking of voltage dep ca channels)

9. opioids • Depression of ventillation- incidence of vent depression requiring intervention after convention dose of neuraxial/ IM /IV is about 1% • Agonist effect at mu2 receptors in brainstem ventillatory centres, decreased responsiveness to co2, • Also affect Pontine and medullary centres that regulate rhythm of breathing, leading to prolonged pauses b/w breathing • Neuraxial injection - depression of ventillation- Early(within 2 hrs of neuraxial inj)- systemic absorption of lipid soluble opioid like fentanyl Delayed (after 2 hrs)- cephalad migration in csf and interaction with receptors in ventral medulla, by reletively poor lipid soluble opioid like morphine. ( charactersticaly after 6-12 hrs) Hypoxia, hypercarbia, depressed conciousness, • Decreased ciliary ctivity, histamine release(morphine, codiene), depress cough(medullary cough centres) • Naloxone- 1-4 ug/kgIV (30-45 min duration) 5 ug/kg/hr

10. Benzodiazepines • Hypnotic doses of benzodiazepines are without effect on respiration in normal subjects • At higher doses, benzodiazepines slightly depress alveolar ventilation and cause respiratory acidosis • Midazolam 0.15mg/kg, diazepam 0.3mg/kg, midazolam 0.05+ fentanyl 2ug/kg IV

11. NITROUS OXIDE • very insoluble in blood and other tissues. • This results in rapid equilibration between delivered and alveolar anesthetic concentrations • Nitrous oxide causes modest increases in respiratory rate and decreases in tidal volume in spontaneously breathing patients. The net effect is that minute ventilation is not significantly changed and PaCO2 remains normal. • However, even modest concentrations of nitrous oxide markedly depress the ventilatory response to hypoxia

12. MDI/ DPI/ NEBULIZER The critical determinant of the delivery of any particulate matter to the lungs is the size of the particles. • Particles >10 um are deposited primarily in the mouth and oropharynx, whereas particles < 0.5 um are inhaled to the alveolae and subsequently exhaled without being deposited in the lungs. Particles with a diameter of 1 to 5 mm allow deposition of drugs in the small airways and therefore are the most effective. • rate of breathing and breath-holding after inhalation • MDI - It includes a pressurized metal canister that contains Pharmacological agent and Propellant (CFCs). oropharyngeal deposition,Only a minute fraction of the dose deposits in the lungs, starting a slow deep breath and then triggering the MDI, spacer can be used • nebulizers offer the advantage of not requiring hand-breathing coordination. In addition, nebulizer therapy can be delivered by facemask to young children or older patients who are confused or patients who have have poor inspiratory ability . pneumatic/ ultrasonic • dry-powder inhalers. These typically use lactose or glucose powders to carry the drugs. One disadvantage of these devices is that a relatively high airflow is needed to suspend the powder properly. Young children, the elderly, and those suffering from a significant asthma exacerbation may be unable to generate such airflow rates. The dry powder can be irritating when inhaled

13. b2 Adrenergic Receptor Agonists • b2 adrenergic receptors. Stimulation activates the Gs adenylyl cyclase-cyclic AMP pathway with a consequent reduction of in smooth muscle tone • also increase the conductance of large Ca2+-sensitive K+ channels in airway smooth muscle, leading to membrane hyperpolarization and relaxation. • b2 adrenergic receptors on cell types in the airways other than bronchial smooth muscle- stimulation of b2 adrenergic receptors inhibits the function of numerous inflammatory cells, including mast cells, basophils, eosinophils, neutrophils, and lymphocytes. • ROUTES- iv, inhalation, sc, oral • Isoproterenol - potent, nonselective b receptor agonist with very low affinity for a receptorsit lowers peripheral vascular resistance, positive inotropic and chronotropic relaxes bronchial smooth muscle when the tone is highparenterally /aerosol. It is metabolized primarily in the liver and other tissues by COMT. • Terbutaline b2-selective bronchodilator. orally, subcutaneously, or by inhalation. s,/c 0.25 mg s/c , 0.01mg/kg in children • Albuterol- selective b2 receptor agonist - inhalation or oral . When administered by inhalation, it produces significant bronchodilation within 15 minutes, and effects persist for 3 to 4 hours. 2.5-5mg (0.5 to 1 ml of 0.5 % solution in 5 ml NS), every 15 min upto 4 doses , duration 4 hrs

14. Glucocorticoids • Glucocorticoids do not directly relax airway smooth muscle and thus have little effect on acute bronchoconstriction. • these agents are effective in inhibiting airway inflammation , by modulation of cytokine and chemokine production; inhibition of eicosanoid synthesis; marked inhibition of accumulation of basophils, eosinophils, and other leukocytes in lung tissue • beclomethasone , budesonide ,fluticasone (MDI/ NEBULIZED / DPI • Oral prednisolone 1-2 mg/kg/day to a maximum of 60 mg/day..

15. Theophylline • inhibits cyclic nucleotide PDEs, thereby preventing breakdown of cyclic AMP and cyclic GMP to 5c-AMP and 5c-GMP, accumulation of cyclic AMP and cyclic GMP, thereby increasing signal transduction through these pathways. Leading to bronchodilationTheophylline is a competitive antagonist at adenosine receptors. Adenosine can act as an autacoid and can cause bronchoconstriction in asthmatics antiinflammatory action -activates histone deacetylases in the nucleus -could decrease the transcription of several proinflammatory genes In premature infants, episodes of prolonged apnea lasting more than 15 seconds can be eliminated by methylxanthines • When theophylline is used alone, serum concentrations between 8-12 mcg/mL provide a modest improvement is FEV1. Serum levels of 15-20 mcg/mL are only minimally more effective and are associated with a higher incidence of cardiovascular adverse events.

16. Leukotriene-Receptor Antagonists and Leukotriene-Synthesis Inhibitors • cys-LTs are potent constrictors of bronchial smooth muscle. On a molar basis, LTD4 is approximately 1000 times more potent than is histamine as a bronchoconstrictor • Cys-LTs can increase microvascular leakage, increase mucous production, and enhance eosinophil and basophil influx into the airways • Zafirlukast and montelukast are selective high-affinity competitive antagonists for the cys-LT1 receptor • The formation of leukotrienes depends on lipoxygenation of arachidonic acid by 5-lipoxygenase. Zileuton is a potent and selective inhibitor of 5-lipoxygenase activity and thus inhibits the formation of all 5-lipoxygenase products

17. Cholinergic receptor agonists • Methacholine - differs from ACh chiefly in its greater duration and selectivity of action. • Its action is more prolonged because the added methyl group increases its resistance to hydrolysis by cholinesterases • Increases tracheobronchial secretions, bronchial smooth muscle contraction • (also pilocarpine, bethnechol). • Asthmatic patients respond with intense bronchoconstriction, secretions, These actions form the basis of the methacholine challenge test used to diagnose airway hyperreactivity

18. Muscarinic receptor antagonists • Muscarinic receptor antagonists prevent the effects of ACh by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells; in peripheral ganglia; and in the CNS. In general, muscarinic receptor antagonists cause little blockade at nicotinic receptor sites • The parasympathetic nervous system plays a major role in regulating bronchomotor tone. A diverse set of stimuli cause a reflex increase in parasympathetic activity that contributes to bronchoconstriction.

19. Muscarinic receptor antagonists • M1 muscarinic receptors in parasympathetic ganglia located in the airway wall • M3 muscarinic receptors in airway smooth muscle, submucosal glands • naturally occurring alkaloids- atropine and scopolamine • synthetic congeners- selective for particular subtypes of muscarinic receptors. homatropine and tropicamide( shorter duration of action ) • ipratropium, and tiotropium, quaternized ,do not cross the blood-brain barrier • Glycopyrrolate- quarternery ammonium, poorly lipid soluble • Effects- Inhibition of bronchoconstriction( In large and medium airways) , decreased tracheo bronchial secretions • Inspissation of secretion leading to airway obstruction can occur(not single dose)

20. Muscarinic receptor antagonists • The cholinergic receptor subtype responsible for bronchial smooth muscle contraction is the muscarinic M3 receptor. Although iprotropium and related compounds block all five muscarinic receptor subtypes with similar affinity, it is likely that M3-receptor antagonism alone accounts for the bronchodilating effect. • Ipratropium is more effective than beta agonists in producing bronchdilation in patients with chronic brochitis or emphysema, emphasizing the role of cholinergic tone in these patients • Bronchoconstriction in response to tracheal intubation is thought to be irritant reflex mediated by parasymp nerves, thus inhaled ipratropium may releave spasm. • tiotropium has high affinity for all muscarinic receptor subtypes, but it dissociates from the receptors much more slowly that ipratropium

21. adrenaline • Adrenergic b2 receptors - on tracheal and bronchial smooth muscle – relaxation • Bronchial glands - Decreased secretion by a1, increased secretion by b2 receptors. • inhibition of antigen-induced release of inflammatory mediators from mast cells, mediated by b2 receptors

22. HISTAMINE • Almost all mammalian tissues contain histamine in low amounts .The mast cell is the predominant storage site for histamine in most tissues ,the concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial tree mucosa , in the blood, it is the basophil • Metabolism- by monoamine oxidase (MAO), and this reaction can be blocked by monoamine oxidase (MAO) inhibitors

23. mucolytics • The respiratory secretions create inner hydrophilic (water soluble) layer, and a outer hydrophobic (water insoluble) layer.. • This outer layer is composed of a meshwork of mucoprotein strands held together by disulfide bridges • This meshwork traps particles and debris in the airways, and the combination of the mucoprotein meshwork and the trapped debris determines the viscoelastic behavior of the respiratory secretions. • Saline Instillation saline cannot liquify or reduce the viscosity of respiratory secretions saline injection provides a vehicle for transporting bacteria into the lower airways. Oral expectorants bromhexine, guaphenesine – act by vagally mediated increase in airway secretions decreasing mucus viscosity, have not been shown to be effective

24. mucolytics • Mucolytic Therapy N-acetylcysteine (Mucomyst) sulfhydryl-containing tripeptide acts by disrupting the disulfide bridges between mucoprotein strands in sputum aerosol spray( irritating to the airway), or injected directly through tracheal tube bronchoscopy (the NAC is then applied directly to the mucous plug). • Daily use of NAC is not advised because the drug solution is hypertonic (even with the saline additive) and can provoke bronchorrhea., bronchospasm • Free DNA significantly increase the viscosity of mucus, Recombinant DNAase (dornase alfa) improves pulmonary function in chronic management of cystic fibrosis

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