Bronchodilators PDF

BRONCHODILATORS ADRENERGIC (SYMPATHOMIMETIC) BRONCHODILATORS  ADRENERGIC (SYMPATHOMIMETIC) BRONCHODILATORS GENERAL INDICATION FOR USE: Relaxation of airway smooth muscle in the presence of reversible airflow obstruction associated with acute and chronic asthma, bronchitis , emp...

BRONCHODILATORS ADRENERGIC (SYMPATHOMIMETIC) BRONCHODILATORS  ADRENERGIC (SYMPATHOMIMETIC) BRONCHODILATORS GENERAL INDICATION FOR USE: Relaxation of airway smooth muscle in the presence of reversible airflow obstruction associated with acute and chronic asthma, bronchitis , emphysema, bronchiectasis, and other obstructive airway diseases. No direct sympathomimetic innervation of airway smooth muscle. The sympathetic nervous system controls bronchial smooth muscle tone by circulating catecholamines (epinephrine and norepinephrine), which act on ᾳ and β adrenergic receptors on airway smooth muscle. β receptors are distributed from the trachea to the terminal bronchioles; the density of these receptors increases as the airway diameter becomes smaller. β agonists can cause relaxation of small airways.  ADRENERGIC (SYMPATHOMIMETIC) BRONCHODILATORS GENERAL INDICATION FOR USE: β2 receptors traditionally have been identified as the β receptor subtype on the airway smooth muscle responsive to circulating epinephrine (hormonal) In human lung, which has no direct sympathetic innervation of the airway smooth muscle, adrenergic receptors are all of the β2 type; and relaxation of human smooth muscle would be accomplished by stimulation of hormonal β receptors via circulating or exogenous catecholamines.  THREE SUBGROUPS OF ADRENERGIC BRONCHODILATORS: Ultra –short-acting (duration less than 3 hours): racemic epinephrine Short-acting (duration 4 to 6 hours): albuterol, levalbuterol, metaproterenol Long-acting (duration 12 to 24 hours): salmeterol, formoterol, arformoterol, indacaterol, and olodaterol, vilanterol  CATECHOLAMINES The sympathomimetic bronchodilators are all either catecholamines or derivatives of catecholamines. Dopamine, epinephrine, norepinephrine, and isoproterenol Sympathomimetic amines mimic the actions of epinephrine causing: -tachycardia -elevated blood pressure -smooth muscle relaxation of bronchioles and skeletal muscle blood vessels - glycogenesis -skeletal muscle tremors -CNS stimulation CATECHOLAMINES Adrenergic bronchodilators such as epinephrine, albuterol, and salmeterol have been produced synthetically as racemic mixtures, or 50:50 equivalent mixes of the (R)-isomers of the (S)-isomers. EPINEPHRINE stimulates ᾳ and β adrenergic receptors Occurs naturally in the adrenal medulla Side effects: tachycardia, blood pressure increase, tremor, headache and insomnia Onset and Duration: Rapid onset but short duration because of metabolism by cathecol O-methyltransferase (COMT) Route of administration: By inhalation and by subcutaneous injection-mngt of acute asthma attack Cardiac stimulant (β1 effects) The synthetic formulation is a racemic mixture giving ᾳ and β stimulation  CATECHOLAMINES KEY POINT: Modification of the catecholamine produces non-catecholamines which have a 4 to 6 hour duration when inhaled and are β2 preferential. METAPROTERENOL The hydroxyl group attachment at the carbon-4-site was shifted to the carbon-5 position duration of action:4-6H Can be taken orally ALBUTEROL (SALBUTAMOL) A modification of the catechol nucleus at the carbon - 3-site Oral extended release tablets, syrup, nebulizer solution and MDI β2–preferential effect Inhaled albuterol duration of action is 4 to 6 hours; peak effect in 30-60min Oral extended-release tablet – 12H duration Greater systemic side effects with oral form LEVALBUTEROL Pure (R)-isomer of racemic albuterol HFA-propelled MDI and nebulization solution and concentrate Higher peak effect in FEV1 8H duration Equivalent side effects with albuterol LONG-ACTING Β-ADRENERGIC AGENTS Salmeterol Formoterol Aformoterol Inhaled form Indacaterol Olodaterol Vilanterol Extended-Release Albuterol – 4mg or 8 mg tablet with 8 to 12 H duration of effect  LONG-ACTING β-ADRENERGIC AGENTS Generic Name Chemical Form Delivery Form Onset of Action Peak Effect Duration Special Feature Salmeterol Racemic mixture DPI-Diskus Slow 3-5 hours >12 hours lipophillic Xinafoate of two At least 10 (Seretide) enantiomers min Formoterol Racemic mixture DPI Faster 12 hours lipophillic (Foradil) (2-3 minutes) Arformoterol Single isomer of nebule 12 hours formoterol ULTRA-LONG ACTING Indacaterol DPI 5 min 24 hours Olodaterol Respimat Fast (5min) 24 hours lipophillic Vilanterol DPI-Ellipta 24 hours (Relvar, Anoro) COMMON AND DIFFERENTIATING FEATURES All are β2-selective agonists Efficacy: formoterol >albuterol>salmeterol ANTIINFLAMMATORY EFFECTS: Both short and long acting β-agonist In vitro: Inhibit human mast cell activation and degranulation Prevent an increase in vascular permeability with inflammatory mediators Diminish the attraction and accumulation of airway inflammatory cells –not shown in vivo No sufficient effect to replace anti-inflammatory drugs such as corticosteroids CLINICAL USE LONG-ACTING BRONCHODILATORS Maintenance of asthma that is not controlled by regular low-dose inhaled corticosteroids COPD needing daily inhaled bronchodilator therapy May prevent the need to increase the inhaled dose of corticosteroid Not recommended for rescue bronchodilation ---toxicity SHORT-ACTING β AGONISTS Treatment of breakthrough attacks Short and long acting β agonists are not substitute for inhaled corticosteroids in asthma maintenance or for other anti-inflammatory medications if such are required. Slow and long acting – salmeterol Fast and long acting – formoterol Ultra-long acting - olodaterol CLINICAL USE OF Β-AGONISTS FDA Requirements on the Use of Long-acting β2 agonists in the treatment of Asthma Long-acting β2 agonists are not to be used: 1. without a controller-medication 2. by patients who are controlled on low-dose inhaled corticosteroids Long-acting β2 agonists should be used only 1. If patients are not controlled with agents such as inhaled corticosteroids 2. For short term use ( should be discontinued once asthma is controlled) 3. In conjunction with corticosteroid in children  MECHANISM OF ACTION β2 receptors stimulation: 1. relaxation of bronchial smooth muscle 2. some inhibition of inflammatory mediator release and 3. stimulation of muco-ciliary clearance. Additional effects of some adrenergic bronchodilators: ᾳ- receptor stimulation: vasoconstriction (vasopressor effect); in the upper airway(nasal passages, this can provide decongestion) Β1-receptor stimulation: increased myocardial conductivity, heart rate, and contractile force  ADRENERGIC RECEPTOR TYPES: G PROTEINS, EFFECTOR SYSTEMS, SECOND MESSENGERS, AND CELL RESPONSES Both ᾳ and β receptors are G protein-linked receptors whose ᾳ subunit differentiates the type of G protein. The G protein couples the adrenergic receptor to the effector enzyme, which initiates the cell response by a particular intracellular second messenger. Receptor G Effector Second Messenger Response Protein ᾳ1 Gq Phospholipase Inositol Vasoconstriction C(PLC) triphosphate(IP3), -release of calcium diacylglycerol(DAG) -activates protein kinase C ᾳ2 Gi Adenylyl cAMP (inhibits) Inhibition of cyclase(inhibits) neurotransmitter release Β (β1-3) Gs Adenylyl cyclase cAMP (increases) Smooth muscle (stimulates) relaxation  MECHANISM OF ACTION OF BETA AGONISTS (ADRENERGIC DRUGS) MECHANISM OF ACTION OF LONG-ACTING Β AGONISTS The lipophilic nonpolar side-chain (“tail”) attaches to an EXOSITE in the β receptor with the active “head” binding and activating the β-receptor at the same location as albuterol. This provides ongoing stimulation of the β-receptor and is the basis for the persistent duration of action of long-acting agents.  ROUTES OF ADMINISTRATION INHALATION: MDI, nebulizer solution, DPI, Respimat ORAL: tablets and syrup PARENTERAL: Injection Not all agents are found in each form  ROUTES OF ADMINISTRATION INHALATION (AEROSOL) is the preferred route especially during acute episodes Intermittent doses: 2.5mg-5mg nebulization x 3 doses every 20 min Continuous nebulization: 10-15 mg/hr nebulization Not a standard therapy POTENTIAL COMPLICATIONS: cardiac arrhythmias, hypokalemia, hyperglycemia Regular monitoring with cardiac and electrolyte monitoring ASSIGNMENT: READ p271-275 in BASIC LAB …BY WHITE  ROUTES OF ADMINISTRATION ORAL Ease, simplicity, short time required for administration and exact reproducibility snd control of dosage Onset of action: 1.5 hours Peak effect: 1-2 hours Duration: 3-6 hours Loss of β2 specificity with oral route— Extended tablet(ER) forms offer 12 hours effect PARENTERAL Subcutaneous epinephrine 0.3mg(0.3ml of 1:1000 strength) every 15- 20 mins up to 1 mg in 2 hours IV: last resort  ADVERSE SIDE EFFECTS Stimulation of ᾳ adrenergic, β1 adrenergic and β2 adrenergic receptors Tremor is due to stimulation of β2 adrenergic receptors in skeletal muscles Cardiac Effects: ᾳ adrenergic and β1 adrenergic and possible β2 receptors Increase cardiac output Albuterol and terbutaline – peripheral vasodilation and increase in myocardial contractility without increasing oxygen demand—reducing the afterload to the heart (useful in CHF) Tachycardia monitoring: not more than 20% increase in heart rate from the baseline pretreatment heart rate CNS: headache, nervousness, irritability, anxiety and insomnia Electrolyte imbalance: hypokalemia CLINICAL CASE PROBLEM: The respiratory therapist (RT) has administered an aerosol treatment of albuterol using an MDI with a holding chamber to a 67-year-old patient with newly diagnosed COPD who was admitted for an acute exacerbation and shortness of breath. When the RT returns for the second treatment that day, the patient informs the RT that he began to feel very shaky and nervous, beginning about 30 minutes after the previous treatment. He also noticed a tremor when he held his water cup and took a drink. His pulse during the earlier treatment was 84 beats/min. Clinical assessment shows that he is coherent, has good color, is not diaphoretic, and is in no respiratory distress. His respiratory rate is 16 breaths/min and regular, and his pulse is 82 beats/min and regular. Auscultation reveals mild wheezing and scattered rhonchi, with little change from earlier breath sounds. A mild tremor is apparent when he holds his hand out. On questioning, he states that he is now feeling better, and the “shakiness” has subsided a bit. DISCUSSION: This patient’s situation exemplifies a common reaction to inhaled adrenergic bronchodilators. Although albuterol is beta-2 preferential, it is still an epinephrine-like drug and can produce side effects secondary to sympathetic stimulation. The description of the symptoms is suggestive of common adrenergic side effects (tremor, shakiness). The timing of the symptoms coincides with the pharmacokinetics of albuterol (peak effect in 30 to 60 minutes). As presented in the case description, it is important to rule out other complications. The physical examination shows no changes from the earlier treatment in his vital signs. It is important to caution patients about “normal” expected side effects and to reassure them that the side effects decrease with tolerance to the medication. In addition, the RT needs to be alert to the possibility that patients may have deteriorated or changed their respiratory status.