Veterinary Pharmacology of the Respiratory Tract PDF

PHARMACOLOGY AND THERAPEUTICS II PHARMACOLOGY OF THE RESPIRATORY TRACT Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected] BIBLIOGRAPHY Principal...

PHARMACOLOGY AND THERAPEUTICS II PHARMACOLOGY OF THE RESPIRATORY TRACT Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected] BIBLIOGRAPHY Principal Secundary TABLE OF CONTENTS Quick revision: anatomy of and physiology of the respiratory system Control of respiratory secretions Antibiotics and Anti-inflammatory drugs Cough and cough suppressants Broncodilators Sildenafil Doxapram Inhalation therapy ANATOMY AND PHYSIOLOGY ANATOMY AND PHYSIOLOGY CONTROL OF RESPIRATORY SECRETIONS Mucolytic drugs Expectorants Decongestants MUCOLYTICS They make the secretion more fluid and easier to eliminate naturally through the mucociliary apparatus, coughing and sneezing. Limited effectiveness. Sterile saline solution - applied intranasally or via nebulizer. Acetylcysteine - breaks the disulfide bonds in mucus molecules and decreases viscosity. It is usually aerosolized and inhaled, but a powder form is available that can be formulated for oral use. Bromhexine - hydrolyzes the mucopolysaccharides that contribute significantly to mucus viscosity. Does not alter mucus proteins. May increase the concentration of certain antibiotics in the alveoli, altering the permeability of the alveolar/capillary membranes. EXPECTORANTS They make bronchial secretions less viscous, but their effectiveness is questionable. Potassium iodide - an oral saline expectorant that irritates the gastric mucosa. Through vagal stimulation, gastric irritation can lead to increased secretion from the bronchioles, hence the controversial use. Guaifenesin - used in human medicine, has little efficacy and use in veterinary medicine. Same problem as vagal stimulation: used in horses to induce muscle relaxation and immobilization, as an adjunct to balanced anesthesia. DECONGESTANTS They work by reducing inflammation and decreasing irrigation of the nasal mucosa, allowing air to pass through more freely. Antihistamines (diphenhydramine, dimenhydrinate, chlorpheniramine, hydroxyzine) - efficacy in animals is highly questionable. Sympathomimetics (α receptor agonists) - can be administered orally or as nasal sprays to avoid their systemic effects. However, nasal sprays are not well tolerated in animals. Their primary effect is the constriction of the precapillary arterioles, the reduction of blood flow and the reduction of extracellular fluid in the nasal mucosa. Ephedrine Pseudoephedrine Phenylephrine - has been used to relieve anaesthesia-induced nasal congestion and edema in horses. ANTIBIOTICS Antibiotics effective in the respiratory tract Cephalosporins Trimethoprim + Sulfadiazine Amoxicillin Amoxicillin + clavulamic acid Doxycycline Fluoroquinolones ANTI-INFLAMMATORY Glucocorticoids Very important in the treatment of antigen-induced bronchial inflammatory disease, such as chronic obstructive pulmonary disease (ORVA) in horses and feline chronic bronchitis (asthma), as well as chronic bronchitis in dogs. They reduce mucus hypersecretion, thickening of the bronchial mucosa and constriction of airway smooth muscle. Intermediate-acting oral glucocorticoids (Prednisolone and Prednisone) are widely used. Fluticasone - an inhaled glucocorticoid that is being used more frequently in animals. Available in a multi-dose inhaler for humans. For administration, a mask and spacer are required for animals or pediatric ones can be used. Only 30% of the administered dose reaches the airways of the lung. ANTI-INFLAMMATORY NSAIDs Flunixin meglumine to treat inflammatory respiratory problems in cattle and as an adjunct treatment of bovine respiratory disease (BRD), and is included in one of the antibiotic combinations used to treat BRD. Diseases in which NSAIDs may have a benefit include pulmonary thromboembolism (for which antiplatelet doses of Aspirin® are used), pulmonary effects from endotoxin in horses and dogs (for which flunixin meglumine has been used). ANTI-INFLAMMATORY Leukotriene receptor antagonists are another new option. Leukotrienes are potent bronchoconstrictors and trigger inflammatory responses such as edema formation. Drugs that antagonize leukotriene receptors are zafirlukast, zileuton, and montelukast. Zafirlukast has been tested in cats with experimental asthma and found not to be beneficial. Serotonin receptor inhibition may be beneficial for feline asthma Cyproheptadine is the only drug in this category currently thought to be beneficial. Cromolyn (Intal®) – stabilizer of mast cells in animals with asthma and hypersensitive airways. Used in nebulizers to treat RAO in horses. It inhibits mast cell release of histamine and leukotrienes with no intrinsic bronchodilator action. COUGH SHOULD WE SUPPRESS COUGH EVERYTIME? COUGH SUPRESSANTS Peripherally acting antitussives include anti-inflammatory drugs, mucolytics and bronchodilators. By reducing the stimulus that triggers the cough, we reduce it. COUGH SUPRESSANTS Central-acting antitussives - reduce the sensitivity of the cough center to afferent stimuli. The antitussive drugs directly depress the cough center in the medulla. The site of action may be either μ- or κ-opiate receptors. Opiate drugs that act on these receptors are effective. The neurokinin receptor (NK) may also play a role in antitussive activity of such non-opiates. COUGH SUPRESSANTS Morphine – used in low doses to avoid other effects Codeine - dogs and cats. One of the most effective, with an antitussive effect that is far superior to its analgesic effect. Hydrocodone - only used in dogs. Similar mechanism of action than codeine but more potent. Hydrocodone + homatropine (anti-cholinergic added to discourage the abuse). Hydrocodone + paracetamol (anti-inflammatory added to control respiratory inflammation) Butorphanol - 100 × more effective as a cough suppressant than codeine. Can be administered orally or parenterally to dogs and cats. It has short-lasting analgesia, but a longer-lasting sedative effect and minimal respiratory depression. Poorly bioavailable because of oral first-pass metabolism – best to use injectable forms. High doses lead to sedation Tramadol – some antitussive properties and well tolerated by dogs. COUGH SUPRESSANTS Dextromethorphan - a semi-synthetic opioid found in many cough preparations, but its mechanism has not been fully proven. It does not bind with opioid receptors (κ- or μ-). Produces mild analgesia, acting as an NMDA antagonist. PO: Not effective and leads to vomiting. IV: CNS reactions. BRONCHODILATORS BRONCHODILATORS Parasympatholytics/Anticholinergics Sympathomimetics/ß-adrenergic agonists (selective and non-selective) Methylxanthines derivatives PARASYMPATHOLYTICS/ANTICHOLINERGICS The parasympathetic cholinergic nerves arise in the brain stem and course through the vagus nerve to synapse in local ganglia within the walls of the alveoli. Ganglionic transmission is mediated by acetylcholine via neuronal nicotinic receptors, whereas smooth muscle contraction is mediated by acetylcholine via muscarinic receptors. M3 muscarinic receptor subtypes mediate airway smooth muscle constriction, plus vasodilation and mucus secretion. Anticholinergic drugs will inhibit vagal stimulus, causing bronchodilation. PARASYMPATHOLYTICS/ANTICHOLINERGICS Atropine – injectable Glycopyrrolate – injectable (Robinul – V) Ipratropium - aerosol by inhaler. Anticholinergic drugs administered parenterally have significant side effects, including decreased gastrointestinal peristalsis, dryness of the mucous membranes, tachycardia and urinary bladder relaxation. These side effects limit the chronic use of parenteral anticholinergic drugs. SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS Bronchodilation response to the adrenergic nervous system primarily involves the activation of β2-adrenoreceptors that are distributed throughout the lung in all species. Relaxation is mediated by the intracellular accumulation of cAMP, which inactivates myosin light chain kinase. SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS There are α1- and α2-adrenergic receptors in the lung of several species. The α1-receptors also mediate airway muscle contraction in the guinea pig, rabbit, and dog. SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS Selective β2-agonists are used clinically as bronchodilators but they are not 100% selective for β2-receptors and concurrently stimulate some β1-receptors. Since β1- and β2-receptors are distributed throughout the body, including the heart, overdosing these drugs may cause tachycardia, excitement, and sweating (horses). These drugs may also transiently decrease systemic arterial blood pressure, which increases heart rate via the baroreceptor reflex. The β2-receptor stimulation in the respiratory tract also increases the ciliary beat frequency and mucociliary clearance rate. They have some anti-inflammatory activity and can decrease the release of mediators from mast cells. SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS They have some anti-inflammatory activity because they interact and stabilise mast cells. They decrease the release of mediators from mast cells. If the inflammation is mediated by eosinophils and neutrophils this property is less important. It is important to do a cytology of the respiratory fluid It is also reported that they increase mucociliary clearance in the respiratory tract SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS Clinical use In general, they are useful for short-term relief of bronchospasm The ß receptors change during a chronic administration due to downregulation and desensitization For long-term maintenance, use corticosteroids NON-SELECTIVE SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS Agonists of the receptors (α+β1+β2). For the acute and emergency treatment of bronchoconstriction. Epinephrine Ephedrine Isoproterenol SELECTIVE SYMPATHOMIMETICS/ß-ADRENERGIC AGONISTS Selective agonists of the receptors β2.Less adverse effects. Preferred for repeated use. Terbutaline - orally or parenterally for severe bronchoconstriction in cats. Used in horses with RAO Isoetarin - has been aerosolized and used in small animals. Albuterol - has been aerosolized and used in horses and small animals. It has good β2/β1 selectivity and is considered beneficial for treating hypoxemia in anaesthetized horses. Regular use is not recommended for asthma in cats because it can increase airway inflammation Clembuterol - administered orally. Partial agonist of the β2 receptors, considered less effective. It also inhibits the release of pro- inflammatory cytokines. Adverse effects include muscle tremors, sweating, restlessness, urticaria and tachycardia. Not permitted in food animals. Prolonged administration is not recommended. Caution in animals with concomitant diabetes, hyperthyroidism, hypertension, seizure disorders or heart disease with arrhythmias METHYLXANTINES DERIVATIVES They are phosphodiesterase inhibitors, which induce bronchodilation by blocking the degradation of cyclic AMP by phosphodiesterase in airway smooth muscle cells and by inhibiting myosin light chain kinase. They also antagonists of adenosine receptors, and adenosine may cause bronchoconstriction in asthmatic patients. They are CNS stimulants. They have an anti-inflammatory effect at lower concentrations: Decreased response to histamine and other mediators Diminished activity of inflammatory and immune cells, especially eosinophils. METHYLXANTINES DERIVATIVES Theophylline Good absorption and availability via the oral route. It is mainly used to induce bronchodilation in RAO in horses. They have an indepent It is often used in patients with heart failure and/or pulmonary edema, where sympathomimetics are not recommended. Side effects include nausea and vomiting, restlessness, increased gastric acid secretion, diarrhea, polyphagia, polydipsia and polyuria. In horses, they include nervousness, excitability, tremors, tachycardia and ataxia and it is banned in horse races. In severe cases, convulsions or cardiac arrhythmias may occur. Beware of other drugs that can inhibit CYP450 (e.g. cimetidine and fluoroquinolones) because they compete for the same enzyme. Not effective in cattle. SILDENAFIL Sildenafil decreases pulmonary hypertension. Pulmonary artery blood pressure may elevate due to an increase in vascular resistance. Pulmonary hypertension has been reported in dogs with many respiratory diseases with Dirofilaria immitis infestation being most common. Sildenafil is a phosphodiesterase type V inhibitor, and it has been administered orally to induce vasodilation and reduce pulmonary hypertension in dogs and humans. Sildenafil decreases pulmonary arterial pressure by inducing potent relaxation of arterial smooth muscle. Cyclic GMP is a potent vascular smooth muscle relaxant; sildenafil increases cyclic GMP levels in vascular smooth muscle cells, which is due to its inhibition of degradation of cyclic GMP by phosphodiesterase V. DOXAPRAM Doxapram hydrochloride is an analeptic and a centrally acting respiratory stimulant When injected IV to dogs, the respiratory rate and tidal volume (minute ventilation) increase. Used to aid in the visual evaluation of laryngeal paralysis in the lightly anesthetized dog. Evaluation of laryngeal motion requires deep sedation, which unfortunately also reduces laryngeal movement making visual evaluation difficult and frequently incorrect. Injecting doxapram IV while observing the larynx of a deeply sedated dog significantly enhances laryngeal movement but has no effect on the paralyzed larynx making evaluation more reliable. May stimulate respiratory effort in newborn animals but is not a substitute for endotracheal intubation and mechanical ventilation for resuscitation. INHALATION THERAPY Applied Pharmacology for Veterinary Technicians INHALATION THERAPY Handbook of Veterinary Pharmacology THANK YOU VERY MUCH! Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected]