Medical Pharmacology Chapter 5: Autonomic Pharmacology: Adrenergic Drugs
Between acute exacerbations there may be limited symptoms associated with asthma.
Even pulmonary function tests may be normal.
However, acute exacerbations results in many symptoms including wheezing, cough, and dyspnea.
In an acute asthma attack, wheezing will probably be most prominent, reflecting turbulent airflow through narrowed airways.
Although wheezing often becomes more prominent with progressive airway constriction, it is also possible that when obstruction becomes sufficient, wheezing declines as there is insufficient airflow to create sounds.
Cough associated with asthma can be nonproductive or associated with significant sputum.
Even in the absence of infection, sputum may be discolored, yellow, reflecting eosinophilic content and debris.
Obstructive severity, predicts the extent of dyspnea.
With significant airflow obstruction, dyspnea may be very prominent with patients sitting up to ease breathing.
Chest tightness may be associated with asthmatic patients with dyspnea, reflecting symptoms that otherwise would suggest angina.
Severity of expiratory airflow obstruction is reflected in FEV1 as well as in maximum mid-expiratory flow rate. Spirometric data, as discussed earlier, helps to quantify the extent of pulmonary impairment and provide a baseline against which therapeutic management may be compared.
Compare the two spirograms below:
In terms of pulmonary function test results for individuals experiencing acute asthma, FEV1 is often < 35% of normal with a maximum mid-expiratory flow rate of < 20% of normal. Also, flow-volume spirometric loops show what is referred to as an "downward scooping" seen in the expiratory part of the loop.
Severity of airway obstruction and pulmonary function test parameters60
Mild (no symptoms): FEV1 as % of predicted = 65%-80%; FEF25%-75% as % of predicted = 60%-75%; PaO2 (estimated, mmHg) = >60; PaCO2 (estimated, mmHg)= < 40
Moderate: FEV1 as % of predicted = 50%-64%; FEF25%-75% as % of predicted = 45%-59%; PaO2 (estimated, mmHg) = >60; PaCO2 (estimated, mmHg)= < 45
Marked: FEV1 as % of predicted = 35%-49%; FEF25%-75% as % of predicted = 30%-44%; PaO2 (estimated, mmHg) = <60; PaCO2 (estimated, mmHg)= > 50
Severe (e.g. status asthmaticus): FEV1 as % of predicted < 35%; FEF25%-75% as % of predicted < 30%; PaO2 (estimated, mmHg) = <60; PaCO2 (estimated, mmHg)= > 50
Asthma as a group of disorders60
Nocturnal asthma (sleep-induced airway smooth muscle tone changes; reduced circulating catecholamine levels; reduced cough reflex)
Aspirin along with many nonsteroidal anti-inflammatory drugs can induce bronchospasm in up to 20% of adult asthma patients.
Sensitive patients may exhibit airflow obstruction worsening and other symptoms within fifteen minutes to four hours following aspirin doses as little as 10 mg.
Aspirin-mediated inhibition of cyclooxygenase-promoted metabolism of arachidonic acid to prostaglandins which has the effect of increasing arachidonic acid conversion to leukotrienes, which are bronchoconstrictive, represents a possible mechanism of aspirin-induced bronchoconstriction.
About 5% of asthmatic patients are sensitive to certain food preservatives and antioxidants, some of which are present even in medications used to manage asthma.
Occupational asthma which affects about 5% to 10% of the world population is probably the most common occupational lung disease.
About 15% of newly identified asthma cases appear related to occupational exposure (USA).
Chlorine and ammonia are probably the most common causes of occupational asthma that do not exhibit significant latency between exposure and effect.
By contrast, other occupational agents may be IgE-dependent. Such immune system dependency requires a longer time period before symptoms manifest.
In terms of the operating room environment, latex sensitivity may cause an increase in expiratory obstruction in sensitive individuals.
This designation is for asthma (increased airway resistance) caused by acute inflammation due to pathogens, such as viruses, bacteria, or mycoplasma.
Bronchoconstriction due to this cause attenuates rapidly as the infection is treated
In recognition of the underlying inflammatory disease which characterizes asthma, administration of inhaled corticosteroids has become an important first-line of therapy in managing inflammatory component.
Acute increases in bronchomotor tone are managed often to the use of β2 adrenergic agonists. Anticholinergic agents, particularly ipratropium are effective in reducing parasympathetic tone which in turn reduces bronchomotor tone.
Anti-inflammatory agents (corticosteroids & cromolyn):
Corticosteroids which reduce inflammation are used in a prophylactic context in asthma, given that their effects are not immediate. Corticosteroids which appear effective in controlling chronic asthma, reducing the likelihood of an acute attack, is preferably given by inhalation.
Oral administration would presumably increased the likelihood of systemic side effects.
The inhaled drug directly promotes an anti-inflammatory effect at the bronchial smooth musclel. Reduction in airway inflammation has the effect of reducing airway hyperreactivity although the period maximum benefit may be obtained only after the treatment has been in place for several months. Agents which are available for administration by inhalation include beclomethasone, triamcinolone, flunisolide, fluticasone, and budesonide
Pharmacokinetics: Most of an inhaled corticosteroids dose is swallowed (80%-90%). This drug and will be available systemically eventually passing to the liver. This leaves about 10% to 20% of the drug available for action at the bronchial level. This drug still has access to the systemic circulation, but drug's lipophilic character favors entry into the airway cells, their principal site of action, where the steroids can inhibit gene transcription for cytokines that promote airway inflammation.
Local and systemic side effects occur following corticosteroids inhalation.
Local effects include: hoarseness (dysphonia), pharyngitis, glossitis, oropharyngeal candidiasis.
Laryngeal muscle myopathy may cause dysphonia, which will be reversed following cessation of treatment.
Infection incidence is not increased by inhaled corticosteroids.
Systemic side effects are determined by the amount of systemic absorption.
Although corticosteroids may suppress the hypothalamic-pituitary- adrenal axis, inhaled corticosteroids amounts used in asthma management are not likely to have significant effect on pituitary-adrenal function. The inhaled corticosteroids do not appear to exert metabolic effects, alter bone metabolism, or interfere with growth.
Furthermore, parturients may be safely administered inhaled corticosteroids.
The classification of cromolyn as an anti-inflammatory agent is based on its apparent ability to inhibit chemical mediator release from mast cells, thus inhibiting inflammation. This agent is inhaled and is effective prophylaxsis, when used, for example, prior to expected exposure to a provocative activity or substance. For example, it should be used prior to exercise in patients known to have exercise-induced bronchospasm.
Leukotriene Inhibors: These agents are discussed in another section.
As discussed earlier these agents bind to β2 adrenergic receptors and activate them.
Activation of the second messenger system results in an increase in cAMP production and ultimately in relaxation of smooth muscle.
These agents are helpful in management of acute bronchospasm with albuterol perhaps being the most commonly used agent.
Albuterol is administered by metered-dose inhaler, using 2-3 deep inhalations, separated by 1-5 minutes.
This dosage may be repeated every 4-6 hours. Side effects are minimized by this route of administration; however, some systemic effects occur and are understood in terms of β adrenergic receptor stimulation. Side effects include cardiac arrhythmias, including tachycardia, as well as potassium intracellular shifting.
Individuals exhibit varying degrees of parasympathetic bronchiolar tone, which is bronchoconstrictive in effect.
Accordingly, the effects of antimuscarinic agents will be proportional to the degree of underlying parasympathetic tone.
Metered-dose inhalation of ipratropium is effective in reducing parasympathetic-mediated bronchiolar smooth muscle tone.
Ipratropium is effective in management of bronchoconstriction in COPD patients; moreover it is helpful in management of asthma although the magnitude of the effect would be typically less than that observed with beta 2 adrenergic agonists.
Significant bronchodilator effect caused by ipratropium would usually be observed within 15-30 minutes of administration and the effect may persist at some level for 4-6 hours.
Ipratropium possesses a quaternary nitrogen and is therefore permanently positively charged.
This condition of permanent positive charge explains the relatively limited systemic effects as a result of poor adsorption
Ipratropium Bromide (Atrovent)
Management of status asthmaticus60
Definition: Status asthmaticus is a bronchospastic state that does not resolve during the initial, standard treatment, and bronchospasm is sufficiently severe such that a condition could be life-threatening.
In the emergence setting, effective treatment typically involves administration of β2 receptor agonist by inhaler. For patients under 45 years of age, β2 agonist dosage may be repeated every 15-20 minutes up to 3-4 repetitions prior to significant systemic effects (hemodynamic). Concurrently, corticosteroids would be administered by IV.
Regimens for corticosteroid administration include either:
(a) cortisol 2mg/kg IV to be followed by 0.5 mg/kg/hour or
(b) methylprednisolone at 60-125 mg IV every 6 hours.
Administration of supplemental oxygen may be required to ensure arterial oxygen saturation > 95%.
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