Airway Therapeutics PDF

The coughing dog Sunday, 10 December 2023 1  Differential diagnoses for coughing dog Sunday, 10 December 2023 2  Differentials for coughing dog Foreign body Allergic/irritant...

The coughing dog Sunday, 10 December 2023 1  Differential diagnoses for coughing dog Sunday, 10 December 2023 2  Differentials for coughing dog Foreign body Allergic/irritant Tracheal/bronchial collapse Left atrial enlargement (compression of left main stem bronchus) Congestive heart failure Bronchitis Bronchopneumonia / fungal pneumonia Lungworm / Heartworm Neoplasia of lung or airway Sunday, 10 December 2023 3  Acute infectious tracheobronchitis (Kennel cough) Common URT disease – caused by multiple infectious agents (bacterial/viral) Presentation Acute onset hacking cough; may retch at end of cough Often history of recent exposure to other dog Usually clinically bright, active, eating Lung auscultation normal or slightly harsh upper airway sounds Cough may be induced on tracheal pinch Usually self resolves (signs may persist for up to 3 weeks) Young or geriatric dogs, immunocompromised dogs, or dogs with pre-existing URT issues may get more severe disease Sunday, 10 December 2023 4  Acute infectious tracheobronchitis (Kennel cough) Treatment Restrict exercise Minimizes cough triggered by increased tidal volume Avoid access to airborne pollutants or irritants Avoid attaching lead to collar - use harness or halter Give sloppy food; avoid dry biscuit Avoid moving from warm to cold air, e.g. last thing at night Class D - Doxycycline Antibiotics? Antitussives? Anti-inflammatories? Sunday, 10 December 2023 5  Acute infectious tracheobronchitis (Kennel cough) Vaccination Contain a live strain of canine parainfluenza and Bordetella. As such they can produce mild clinical signs in vaccinated dogs Vaccinated animals can spread B. bronchiseptica vaccine strain for six weeks and the canine parainfluenza vaccine strain for a few days after vaccination Administered intranasally – good luck! Sunday, 10 December 2023 6  My Surrey Attendance SA-RE-EF and KY-RX-FO Therapeutics of the Airway Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics Sunday, 10 December 2023 7  Learning Outcomes 1. To state the principle functional problems caused by diseases of the respiratory system 2. To identify drugs that can be used to maintain a clear airway and differentiate between commonly used agents 3. To identify peripherally active drugs that may be employed to improve treatment of respiratory disease 4. To give examples of possible uses of these agents to treat the most common diseases in dogs, cats and horses Sunday, 10 December 2023 8  Link to other modules VMS1005 VMS1006 VMS2004 Sunday, 10 December 2023 9  Functional problems caused by respiratory diseases Cough Mucus production Sneezing Ulceration Inflammation Tracheal/pharyngeal obstruction Bronchoconstriction Dyspnoea Trauma Sunday, 10 December 2023 10  Therapeutics Antitussive drugs Demulcents Centrally acting opiates Decongestants and mucolytics Bromhexine Bronchodilators Anticholinergics atropine, ipratropium β2-adrenoceptor agonists clenbuterol, salbutamol, terbutaline Methylxanthines theophylline Drugs to reduce airway inflammation Glucocorticoids prednisolone, dexamethasone, beclomethasone, fluticasone Mast cell stabilisers sodium cromoglycate Antimicrobials with good pulmonary penetration doxycycline, trimethoprim/sulphonamide, fluoroquinolones Sunday, 10 December 2023 11  Antitussives, decongestants and mucolytics Sunday, 10 December 2023 12  Antitussives Successful treatment of cough requires identification and management of underlying cause (e.g. CHF, lungworm, airway infection) Antitussives decrease frequency of coughing and are useful both to treat painful non-productive coughing or where coughing might result in additional injury e.g. emphysema or in conditions producing increased intracranial pressure Demulcents, such as honey and syrup, coat and soothe inflamed tissues and provide brief periods of relief from mild stimulus Low dose of centrally acting opiates (e.g. butorphanol, codeine) suppresses the medullary cough centre butorphanol Taken from Merck Veterinary Manual Sunday, 10 December 2023 13  Decongestants and mucolytics Cats with flu may be held in a basket and ‘steamed’. Little objective evidence that it helps but anecdotal benefit Mucolytics (e.g. bromhexine, dembrexine) stimulate an increase in secretion of fluid by the mucus glands of the respiratory tract and break down the network of acid glycoprotein fibres found in mucoid sputum (decrease sputum viscosity) By removing mucous plugs expectorants can prevent atelectasis in small airways that can progress to bronchiectasis if left unresolved bromhexine Sunday, 10 December 2023 14  Bronchodilators Sunday, 10 December 2023 15  The effect of constricted airways on respiration Resistance to airflow in and out of the lungs is strongly dependent upon the radius of the trachea Mucous and inflammation in smaller airways have a much larger effect on resistance in smaller airways. Taken from MSD Manual Poiseuille's Law Sunday, 10 December 2023 16  Sympathetic & parasympathetic inputs Adrenergic receptors Heart - mainly β1 Increase rate Airway - mainly β2 Bronchodilation Muscarinic receptors Heart – mainly M2 Slow rate Airway – mainly M3 Bronchoconstriction Sunday, 10 December 2023 17  Sympathetic & parasympathetic inputs Adrenergic receptors Heart - mainly β1 Increase rate Airway - mainly β2 Bronchodilation Muscarinic receptors Heart – mainly M2 Slow rate Airway – mainly M3 Bronchoconstriction Sunday, 10 December 2023 18  Bronchodilation Activation of muscarinic receptors causes contraction of airway smooth muscle -> bronchoconstriction So we want to block with a muscarininc receptor antagonist Activation of β2-adrenergic receptors causes relaxation of smooth muscle -> clenbuterol bronchodilation salbutamol atropine So we want to mimic with +ve a beta receptor agonist -ve ipratroipium Adapted from Cunningham’s Textbook of Veterinary Physiology Sunday, 10 December 2023 19  Bronchodilation Activation of muscarinic receptors causes contraction of airway smooth muscle -> bronchoconstriction So we want to block with a muscarininc receptor antagonist Activation of β2-adrenergic receptors causes relaxation of smooth muscle -> clenbuterol bronchodilation salbutamol atropine So we want to mimic with +ve a beta receptor agonist -ve ipratroipium Adapted from Cunningham’s Textbook of Veterinary Physiology Sunday, 10 December 2023 20  Bronchodilators – Muscarinic antagonists Blockade of muscarinic receptors prevents ACh stimulated airway smooth muscle contraction Also reduces respiratory tract secretions ipratropium bromide H is long-acting and given once a day via inhalation for the treatment of Reversible Airway Obstruction (RAO) in horses Systemic antimuscarinic actions (e.g. increased heart rate, decreased GI motility) may occur but unlikely with inhaled route of delivery atropine has bronchodilator effects but not routinely used for this purpose (Historically) part of anaesthesia pre-medication to diminish the risk of vagal inhibition and to reduce salivary and bronchial secretions Provides rapid improvement given iv in horses with acute RAO ipratropium Sunday, 10 December 2023 21  Bronchodilation Activation of muscarinic receptors causes contraction of airway smooth muscle -> bronchoconstriction So we want to block with a muscarininc receptor antagonist Activation of β2-adrenergic receptors causes relaxation of smooth muscle -> clenbuterol bronchodilation salbutamol atropine So we want to mimic with +ve a beta receptor agonist -ve ipratroipium Adapted from Cunningham’s Textbook of Veterinary Physiology Sunday, 10 December 2023 22  Bronchodilators – β2-adrenoceptor agonists salbutamol H (USA ‘albuterol’), terbutaline H predominantly stimulate β2- adrenoceptors causing an increase in cyclic AMP, resulting in relaxation of bronchial smooth muscle (bronchodilation) Treatment of bronchospasm in inflammatory airway disease and irritation in cats and dogs clenbuterol is highly selective for the β2-adrenoceptor, providing intense bronchodilating properties with minimum effect on the cardiovascular system. Licenced in horses for treatment of respiratory disease where airway obstruction due to bronchospasm and/or accumulation of mucus is a contributing factor (stimulates mucociliary clearance in horses) salbutamol and terbutaline clenbuterol Sunday, 10 December 2023 23  Bronchodilators - Methylxanthines theophylline similar in structure to caffeine and theobromine. Relaxes smooth muscle, relieves bronchospasm, stimulant effect on respiration. Mechanisms of action are thought to include inhibition of phosphodiesterase enzyme, alteration of intra-cellular calcium, catecholamine release and adenosine and prostaglandin antagonism Also dilates coronary arteries and increases the strength of contraction of the myocardium. Acts on kidney to induce diuresis and is a potent stimulant of the CNS theophylline Sunday, 10 December 2023 24  Drugs to reduce airway inflammation Sunday, 10 December 2023 25  Immediate and late phases of inflammation in asthma Mast cell stabilisers Glucocorticoids Adapted from Rang & Dale (2016) Sunday, 10 December 2023 26  Mast cell stabilisers Whilst the precise mode of action is unclear, sodium cromoglycate H is thought to inhibit mast-cell degranulation of histamine on antigen challenge and may also have membrane-stabilizing properties It has no intrinsic activity of bronchial dilation – not for acute use Weak anti-inflammatory effects and short duration of action Reduces bronchial hyper-reactivity Prophylactic therapy for allergic respiratory diseases in horses, Sunday, 10 December 2023 27  Glucocorticoids Main drugs used for anti-inflammatory action Glucocorticoids have multiple affects. Of relevance to respiratory disease, exogenous glucocorticoids (e.g. prednisolone, dexamethasone, beclomethasone H, fluticasone H) inhibit the transcription of genes responsible for the production of mediators involved in airway inflammation (cytokines, chemokines, adhesion molecules) Manage exacerbations and establish control with prednisolone / dexamethasone Maintain patients on inhaled beclomethasone H / fluticasone H Prolonged release steroid, methylprednisolone, useful for cats with asthma fluticasone beclomethasone methylprednisolone Sunday, 10 December 2023 28  Homework Glucocorticoids have multiple affects. Of relevance to respiratory disease … We’ve already come across glucocorticoids in Therapeutics for Skin and Therapeutics for MSK, and we’ll see them again in Therapeutics for Haematopoietic and Endocrine Systems… Please read about them and we’ll have a quiz with prizes next Semester! Sunday, 10 December 2023 29 Sunday, 10 December 2023 30  β-lactam antibiotics β-lactam antibiotics (penicillins, cephalosporins) inhibit bacterial growth by interfering with the transpeptidation of bacterial wall synthesis - bactericidal amoxicillin is a broad spectrum penicillin effective against Gram +ve and Gram -ve bacteria. Clavulanate potassium is an irreversible inhibitor of bacterial β-lactamases and prevents hydrolysis of amoxicillin β-lactam antibiotics amoxicillin inhibit bacterial cell + wall synthesis clavulanate Taken from Katzung and Trevor’s Pharmacology Sunday, 10 December 2023 31  Tetracyclines Tetracyclines (e.g. oxytetracycline, doxycycline) inhibit protein synthesis in susceptible bacteria – bacteriostatic. Broad spectrum of activity, effective against Gram +ve and Gram -ve bacteria, including Pasteurella spp., Bordetella bronchiseptica, Staphylococcus aureus and other Staph. spp., and Streptococcus spp. Good lung penetration oxytetracycline Tetracyclines inhibit protein synthesis Taken from antibiotics-info.org Sunday, 10 December 2023 32  Trimethoprim trimethoprim is a folate antagonist – bacteriostatic Often combined with sulphonamides – ‘TMPS’ - bactericidal Combination has broad spectrum of activity, effective against Gram +ve and Gram -ve bacteria, including Streptococci, Staphylocci and Pneumococci spp) trimethoprim + Trimethoprim sulfadiazine is a folate antagonist Taken from Katzung and Trevor’s Pharmacology Sunday, 10 December 2023 33  Antifungals Henrietta Kodilinye-Sims itraconazole, voriconazole, fluconazole - belong to azole class of antifungals Mechanism of action - highly selective binding for fungal cytochrome P-450 isoenzymes. Inhibit the synthesis of ergosterol, which is essential component of cell membranes for fungi. Also affect membrane-bound enzyme function and membrane permeability, resulting in structural degeneration of the fungus itraconazole Sunday, 10 December 2023 34  Key Points LO – To state the principle functional problems caused by diseases of the respiratory system Respiratory disease is common. Functional problems include cough, excessive mucus production, sneezing, ulceration, inflammation, obstruction, bronchoconstriction, dyspnoea Sunday, 10 December 2023 35  Key Points LO – To identify local and peripherally acting drugs that can be used to maintain a clear airway and treat respiratory disease Antitussives (e.g. demulcents such as honey / syrup, or centrally acting opiates, including butorphanol) decrease the frequency of coughing Mucolytics (e.g. bromhexine) stimulate an increase in secretion of fluid by respiratory mucus glands and decrease sputum viscosity Sunday, 10 December 2023 36  Key Points LO – To identify local and peripherally acting drugs that can be used to maintain a clear airway and treat respiratory disease Bronchodilators reverse bronchoconstriction through antagonism of airway muscarinic receptors (e.g. ipratropium, atropine), β2-adrenoceptor agonism (e.g. salbutamol, terbutaline, clenbuterol) or PDE inhibition (e.g. theophylline) Mast cell stabilizers (e.g. cromoglycate) decrease airway inflammation through inhibition of histamine degranulation Glucocorticosteroids (such as prednisolone, dexamethasone) are potent and the main drugs used for anti-inflammatory action. Inhaled glucocorticoids (e.g. beclomethasone, fluticasone) are used to reduce unwanted systemic effects Sunday, 10 December 2023 37  Key Points LO – To identify local and peripherally acting drugs that can be used to maintain a clear airway and treat respiratory disease A number of antibiotics with broad spectrum activity against Gram +ve and Gram -ve bacteria are used to treat respiratory infections β-lactam antibiotics (penicillins, cephalosporins) are bactericidal. They inhibit bacterial growth by interfering with the transpeptidation of bacterial wall synthesis. Amoxicillin-clavulanate is protected against bacterial β-lactamase and has broad spectrum activity Tetracyclines (e.g. oxytetracycline, doxycycline) are bacteriostatic. They inhibit protein synthesis in susceptible bacteria Trimethoprim is a folate antagonist and is also bacteriostatic. It is often combined with sulphonamides (TMPS) to enhance activity (bactericidal). Sunday, 10 December 2023 38  Further Reading Rang & Dale’s Pharmacology, 8th Edition, Rang HP et al (2016) – Chapter 28 – Section on Pulmonary disease and its treatment pp 345- 354 – Chapter 33 – Section on Glucocorticoids pp 409-413 – Chapter 52 – Antibacterial drugs pp 626-640 Luis Fuentes, V., Johnson, L., & Dennis, S. (2016). BSAVA manual of canine and feline cardiorespiratory medicine (Second ed.). – Chapter 19 – Management of chronic respiratory disease pp 160-165 Sunday, 10 December 2023 39  It’s time for the Are you fit enough to give CPR to a Great Dane? challenge !!! Sunday, 10 December 2023 40  https://todaysveterinarypractice.com/cardiopulmonary- resuscitation-the-recover-guidelines/ Sunday, 10 December 2023 41  Advanced Life Support Vasopressor therapy – increasing systemic vascular resistance will increase coronary and cerebral blood flow Epinephrine is a non-selective adrenergic agonist α1-adrenergic stimulation causes peripheral vasoconstriction β1-adrenergic stimulation has positive inotropic and chronotropic effects Low-dose epinephrine (0.01 mg/kg) recommended for routine use every other BLS cycle (every 3 to 5 minutes). Epinephrine 1:1000 = 1 mg in 1 ml Sunday, 10 December 2023 42