Cardiac therapy: Bronchodilators- Ettinger Flashcards
(13 cards)
The classic indication for the use of bronchodilator therapy in humans is the treatment of reversible airway disease (i.e., asthma). Additionally, bronchodilators have also been used in the treatment of neonatal apnea, chronic respiratory failure and chronic pulmonary disease. The use of bronchodilators in veterinary medicine has been based on extrapolations from effective dose ranges and therapeutic actions in humans. Indications for bronchodilator usage in small animals include ……………, ……………., ……………., and ………………. In addition, bronchodilators are used as adjunct therapy in treating parenchymal lung disorders (inflammatory, infectious).
Clinical indicators include chronic coughing, evaluation of changes in the pattern of breathing (i.e., increased expiratory time), air trapping/hyperinflation on thoracic radiographs, forced expiratory effort, and tracheal collapse. There are no bronchodilators specifically approved for use in veterinary medicine.
The classic indication for the use of bronchodilator therapy in humans is the treatment of reversible airway disease (i.e., asthma). Additionally, bronchodilators have also been used in the treatment of neonatal apnea, chronic respiratory failure and chronic pulmonary disease. The use of bronchodilators in veterinary medicine has been based on extrapolations from effective dose ranges and therapeutic actions in humans. Indications for bronchodilator usage in small animals include asthma, chronic bronchitis, tracheal collapse, and tracheobronchitis. In addition, bronchodilators are used as adjunct therapy in treating parenchymal lung disorders (inflammatory, infectious).
Clinical indicators include chronic coughing, evaluation of changes in the pattern of breathing (i.e., increased expiratory time), air trapping/hyperinflation on thoracic radiographs, forced expiratory effort, and tracheal collapse. There are no bronchodilators specifically approved for use in veterinary medicine.
CONTROL OF BRONCHOMOTOR TONE
Bronchomotor tone is influenced by three systems: Which ones?
CONTROL OF BRONCHOMOTOR TONE
- The parasympathetic,
- The sympathetic
- The nonadrenergic, noncholinergic (NANC) system.
The parasympathetic system is thought to be the dominant airway constrictor in animals and is mediated by ……………..
…………….and…………… are the mediators of the sympathetic system. ………………….-receptors mediate the sympathetic …………. of airway smooth muscle. …………..-….. receptors are activated following sympathetic nerve stimulation and ……….-………. receptors respond to exogenously administered ……….-agonists.
The parasympathetic system is thought to be the dominant airway constrictor in animals and is mediated by acetylcholine.
Norepinephrine and epinephrine are the mediators of the sympathetic system. Beta-receptors mediate the sympathetic relaxation of airway smooth muscle. Beta-1 receptors are activated following sympathetic nerve stimulation and beta-2 receptors respond to exogenously administered beta-agonists.
It is generally believed that the neurotransmitters involved in the NANC system are neuropeptides such as ……………….. …………….. is a potent bronchodilator in human bronchial smooth muscle.
It is generally believed that the neurotransmitters involved in the NANC system are neuropeptides such as vasoactive intestinal peptide (VIP). VIP is a potent bronchodilator in human bronchial smooth muscle.
The three classes of bronchodilators are?
(1) the beta-2 adrenergic agonists (i.e., terbutaline),
(2) the methylxanthines (i.e., theophylline), and
(3) the anticholinergics (i.e., atropine).
METHYLXANTHINES
The N-methyl-substituted xanthines (i.e., theophylline, theobromine, and caffeine) are a family of closely related natural alkaloids found in various plants worldwide and in foods such as tea, coffee, and cocoa. Theophylline is the “parent” or active compound. Aminophylline (the ethylenediamine salt of theophylline) is a soluble complex for intravenous use. The amount of theophylline determines the activity of the formulation and recommendations for dosages must be based on theophylline content and not salt content. Theophylline is not water soluble and therefore can only be given orally. The salt preparations of theophylline are available for either oral or parenteral administration. Aminophylline is 80% theophylline, oxtriphylline is 65% theophylline, and glycinate and salicylate salts are 50% theophylline.
Methylxanthines are metabolized in the liver by the mitochondrial P-450 enzyme systems. Variable clearance rates and elimination half-lives among animals are a result of different rates of metabolism, and doses therefore vary. For example, the elimination rate constant of theophylline is less in cats, resulting in a longer half-life in the cat (7.8 hours) compared with the dog (5.7 hours). Therefore, the dose of theophylline in cats is lower.
Aminophylline is well absorbed after oral administration in dogs and cats (with a bioavailability of at least 90%). In dogs, the peak plasma drug concentration of base theophylline occurs 1.5 hours after oral administration. Peak concentrations of IV or oral (sustained release) products are higher in cats when dosed in the evening compared with the morning. It is well documented in human medicine that theophylline metabolism can be affected by certain drugs (i.e., various antibiotics, anticonvulsants, antiarrhythmics) and some disease states (i.e., liver disease, cor pulmonale). The plasma therapeutic range of theophylline in humans is 5 to 20 mcg/mL. Immediate release theophylline dose requirements vary from bid for the cat to qid for the dog. Recognizing that owner compliance with these recommendations might be poor, slow-release preparations have been studied in dogs and cats. The extent of absorption varies with the preparation. The dose of sustained-release formulations may be higher than that recommended for aminophylline because of the decreased drug absorption that allows for once-daily dosing. Selected sustained release theophylline products (Theo-dur and Slo-bid Gyrocaps) have been shown to be safe and effective in dogs and cats. Unfortunately, these products have been taken off the market. The extended release theophylline product specifically produced by Inwood Labs has shown good pharmacokinetics in dogs (10 mg/kg PO bid) and cats (sid). Generic substitutions are not recommended.
METHYLXANTHINES
The N-methyl-substituted xanthines (i.e., theophylline, theobromine, and caffeine) are a family of closely related natural alkaloids found in various plants worldwide and in foods such as tea, coffee, and cocoa. Theophylline is the “parent” or active compound. Aminophylline (the ethylenediamine salt of theophylline) is a soluble complex for intravenous use. The amount of theophylline determines the activity of the formulation and recommendations for dosages must be based on theophylline content and not salt content. Theophylline is not water soluble and therefore can only be given orally. The salt preparations of theophylline are available for either oral or parenteral administration. Aminophylline is 80% theophylline, oxtriphylline is 65% theophylline, and glycinate and salicylate salts are 50% theophylline.
Methylxanthines are metabolized in the liver by the mitochondrial P-450 enzyme systems. Variable clearance rates and elimination half-lives among animals are a result of different rates of metabolism, and doses therefore vary. For example, the elimination rate constant of theophylline is less in cats, resulting in a longer half-life in the cat (7.8 hours) compared with the dog (5.7 hours). Therefore, the dose of theophylline in cats is lower.
Aminophylline is well absorbed after oral administration in dogs and cats (with a bioavailability of at least 90%). In dogs, the peak plasma drug concentration of base theophylline occurs 1.5 hours after oral administration. Peak concentrations of IV or oral (sustained release) products are higher in cats when dosed in the evening compared with the morning. It is well documented in human medicine that theophylline metabolism can be affected by certain drugs (i.e., various antibiotics, anticonvulsants, antiarrhythmics) and some disease states (i.e., liver disease, cor pulmonale). The plasma therapeutic range of theophylline in humans is 5 to 20 mcg/mL. Immediate release theophylline dose requirements vary from bid for the cat to qid for the dog. Recognizing that owner compliance with these recommendations might be poor, slow-release preparations have been studied in dogs and cats. The extent of absorption varies with the preparation. The dose of sustained-release formulations may be higher than that recommended for aminophylline because of the decreased drug absorption that allows for once-daily dosing. Selected sustained release theophylline products (Theo-dur and Slo-bid Gyrocaps) have been shown to be safe and effective in dogs and cats. Unfortunately, these products have been taken off the market. The extended release theophylline product specifically produced by Inwood Labs has shown good pharmacokinetics in dogs (10 mg/kg PO bid) and cats (sid). Generic substitutions are not recommended.
Several mechanisms have been proposed to explain the actions of theophylline on the respiratory system. Theophylline’s mode of action was originally attributed to phosphodiesterase (PDE) inhibition, resulting in increased cAMP. This mechanism is controversial, however, because theophylline does not inhibit PDE at therapeutic concentrations. Although theophylline does not affect total PDE, it may inhibit a specific isoenzyme leading to bronchodilation. Other possible mechanisms are adenosine antagonism, catecholamine release, prostaglandin antagonism, and alteration of intracellular calcium. The beneficial effects of theophylline on the respiratory system include smooth muscle relaxation (bronchodilation), antiinflammatory effects (including inhibition of mast cell degranulation and inflammatory mediator release), enhanced mucociliary clearance, stimulation of the respiratory center, increased sensitivity to Paco2, and increased strength of respiratory muscles.
Several mechanisms have been proposed to explain the actions of theophylline on the respiratory system. Theophylline’s mode of action was originally attributed to phosphodiesterase (PDE) inhibition, resulting in increased cAMP. This mechanism is controversial, however, because theophylline does not inhibit PDE at therapeutic concentrations. Although theophylline does not affect total PDE, it may inhibit a specific isoenzyme leading to bronchodilation. Other possible mechanisms are adenosine antagonism, catecholamine release, prostaglandin antagonism, and alteration of intracellular calcium. The beneficial effects of theophylline on the respiratory system include smooth muscle relaxation (bronchodilation), antiinflammatory effects (including inhibition of mast cell degranulation and inflammatory mediator release), enhanced mucociliary clearance, stimulation of the respiratory center, increased sensitivity to Paco2, and increased strength of respiratory muscles.
Adverse effects seen with the methylxanthines include gastrointestinal upset (nausea and vomiting), diuresis, cardiac stimulation (i.e., tachycardia, arrhythmias) and central nervous system effects (i.e., restlessness, tremors and seizures). Central nervous system toxicity is likely mediated through adenosine antagonism. The side effects of theophylline are dose dependent. There are species differences in susceptibility to theophylline toxicity (i.e., dogs are apparently more tolerant than humans) as well as differences due to the route of administration (i.e., intravenous vs. oral) and duration of therapy (i.e., acute vs. chronic). Adverse effects are more common with the combined use of bronchodilators and this is rarely warranted.
Adverse effects seen with the methylxanthines include gastrointestinal upset (nausea and vomiting), diuresis, cardiac stimulation (i.e., tachycardia, arrhythmias) and central nervous system effects (i.e., restlessness, tremors and seizures). Central nervous system toxicity is likely mediated through adenosine antagonism. The side effects of theophylline are dose dependent. There are species differences in susceptibility to theophylline toxicity (i.e., dogs are apparently more tolerant than humans) as well as differences due to the route of administration (i.e., intravenous vs. oral) and duration of therapy (i.e., acute vs. chronic). Adverse effects are more common with the combined use of bronchodilators and this is rarely warranted.
BETA-ADRENERGIC AGONISTS
Beta-agonists are the most effective bronchodilators because they act to reverse …………….. regardless of the source of the stimulus. Beta-2 receptors are located on several lung cell types, including …………… and………….. cells. Beta-agonists bind to cell receptors and stimulate the enzyme ………………. to increase production of …………
Increased levels of intracellular ……… result in bronchial smooth muscle ………….. In addition, beta-agonists decrease mediator release from …………………., increase ………… beat frequency, modify ……………… tone, and play a role in the modulation of ……………..edema by decreasing microvascular leakage.
BETA-ADRENERGIC AGONISTS
Beta-agonists are the most effective bronchodilators because they act to reverse bronchoconstriction regardless of the source of the stimulus. Beta-2 receptors are located on several lung cell types, including smooth muscle and inflammatory cells. Beta-agonists bind to cell receptors and stimulate the enzyme adenylate cyclase to increase production of cAMP.
Increased levels of intracellular cAMP result in bronchial smooth muscle relaxation. In addition, beta-agonists decrease mediator release from mast cells, increase ciliary beat frequency, modify parasympathetic tone, and play a role in the modulation of mucosal edema by decreasing microvascular leakage.
Use of nonselective beta-agonists (i.e., both beta-1 and beta-2 stimulation) such as …………….., ……………., and ……………….may cause adverse cardiac effects (i.e., ……………, ……………..) because of beta-…….-receptor stimulation.
Use of nonselective beta-agonists (i.e., both beta-1 and beta-2 stimulation) such as epinephrine, ephedrine, and isoproterenol may cause adverse cardiac effects (i.e., tachycardia, hypotension) because of beta-1-receptor stimulation.
Beta-2 selective agonists can cause beta-…… side effects at high doses. Both epinephrine and ephedrine have ………….-adrenergic activity which may contribute to …………….. as well as ……………….. and systemic…………………
It is preferable to utilize beta-2–specific agonists (i.e., albuterol, terbutaline) in the treatment of bronchoconstriction. In asthmatic cats, injectable …………………. (0.01 mg/kg SQ) provides relief from bronchoconstriction in 10 to 15 minutes. Some beta-agonists may also be administered by aerosol.
Beta-2 selective agonists can cause beta-1 side effects at high doses. Both epinephrine and ephedrine have alpha-adrenergic activity which may contribute to bronchoconstriction as well as vasoconstriction and systemic hypertension.
It is preferable to utilize beta-2–specific agonists (i.e., albuterol, terbutaline) in the treatment of bronchoconstriction. In asthmatic cats, injectable terbutaline (0.01 mg/kg SQ) provides relief from bronchoconstriction in 10 to 15 minutes. Some beta-agonists may also be administered by aerosol.
ANTICHOLINERGICs
Anticholinergic drugs compete with ……………… at ……………..receptor sites. In the respiratory tract, anticholinergic drugs antagonize vagally mediated ………………… by competing against ……………….. for receptor sites on the bronchial ………………cells.
Compared with beta-2 adrenergic bronchodilators, the anticholinergic bronchodilators are less effective and have a slower onset of action. Atropine’s lack of specificity result in adverse side effects that limit its use as a chronic treatment.
ANTICHOLINERGICs
Anticholinergic drugs compete with acetylcholine at muscarinic receptor sites. In the respiratory tract, anticholinergic drugs antagonize vagally mediated bronchoconstriction by competing against acetylcholine for receptor sites on the bronchial smooth muscle cells. Compared with beta-2 adrenergic bronchodilators, the anticholinergic bronchodilators are less effective and have a slower onset of action.
Atropine’s lack of specificity result in adverse side effects that limit its use as a chronic treatment. Undesirable side effects of atropine include?
Drying of respiratory tract secretions, interference of normal mucociliary clearance mechanisms, tachycardia, meiosis and possible alterations in urinary and gastrointestinal function. Atropine is the treatment of choice for bronchoconstriction induced by anticholinesterases (organophosphate toxicity).
