Drugs causing respiratory depression
Barbiturates, benzodiazepines, and opioids are all known to cause respiratory depression. Barbiturates and benzodiazepines act by facilitating the effects of GABA (the main inhibitory neurotransmitter in the CNS) at the α-subunit of the GABAA receptor. Opioids act at μ receptors throughout the body, the effects of which can be both excitatory and inhibitory. These drugs depress the response of the respiratory center in the medulla to hypercapnia (↑ CO2) leading to respiratory depression.
26.1 Asthma and Chronic Obstructive Pulmonary Disease
Asthma is predominantly an inflammatory disease with associated bronchospasm, mucosal swelling, and increased mucus production. There is episodic bronchial obstruction causing wheezing, dyspnea, cough, and mucosal edema. In children, the only sign of asthma may be a persistent cough.
The etiology and immunopathogenesis of asthma are illustrated in Figs. 26.1 and 26.2. The role of inflammatory autocoids (e.g., histamine and leukotrienes) in relation to asthma is discussed in Chapter 32.
Atopy and asthma
Atopy describes a hereditary predisposition for type I hypersensitivity reactions, which are mediated by IgE. Atopic conditions include asthma, eczema, hay fever, and generalized allergies (e.g., to certain foods and dust). Gastroesophageal reflux disease (GERD) is also known to have a strong association with asthma, although the cause of this is unclear (see page 260).
Nonsteroidal Antiinflammatory Drug–induced bronchospasm
A significant proportion of adults with asthma experience bronchospasm after taking aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). This can be serious and sometimes fatal. Aspirin and other NSAIDs are therefore contraindicated in patients with asthma who have a history of hypersensitivity reactions and should be used with caution in all asthmatics. Acetaminophen can be used by asthmatics to treat mild to moderate pain (see Chapter 33).
Drug delivery via an endotracheal tube
In an emergency situation, drugs are sometimes given via an endotracheal tube (e.g., epinephrine, naloxone, atropine, and lidocaine). They can exert local or systemic effects.
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is the term used to describe chronic obstructive bronchitis and emphysema, which always coexist, to varying degrees. The characteristic symptoms of COPD are persistent cough, sputum, dyspnea (shortness of breath), and wheezing.
Chronic bronchitis is defined clinically as sputum production on most days for 3 months of 2 consecutive years. Inflammation (most commonly caused by cigarette smoke) causes the bronchial tubes to thicken and scar and produce excess mucus. This mucus cannot be expectorated given that cilia are destroyed as part of the disease process. These factors combine to cause narrowing of the airway lumen and obstruction.
Emphysema occurs when the walls of the alveoli are progressively destroyed. This decreases the surface area of the alveoli for oxygen exchange with the blood and caused the small airways to collapse during expiration, trapping air in the lungs. This may be caused by cigarette smoke or α1-antitrypsin deficiency.
Fig. 26.1 Asthma: genetic predisposition and trigger factors.
Bronchial hyperreactivity and the tendency to increased interleukin-4 (IL-4)–dependent immunoglobulin E (IgE) production may be inherited through genes on chromosome 5 in patients with allergic asthma. This type of asthma is commonly triggered by animal hair, dust mites, feathers, pollen, and mold. In nonallergic asthma, the bronchial hyperreactivity is caused by the inhalation of chemicals, cigarette smoke, viral infections, cold air, exercise, and stress. Drugs (e.g., aspirin) can also cause an attack.
Fig. 26.2 Asthma: immunopathogenesis.
Allergens attach to, and are taken up by, dendritic cells that lie in the ciliated respiratory epithelium. The interaction of the allergen (antigen), antigen presenting cells, and native T cells leads to the differentiation of the T cells to T-helper (TH2) cells, which release cytokines. IL-4 activates B cells, which differentiate into plasma cells and release IgE that attaches to the surface of mast cells. The mast cells then degranulate when the allergens bridge two IgE molecules on their surface, especially when they are activated by IL-3. This cascade of events releases inflammatory mediators that are responsible for the bronchoconstriction/bronchospasm, mucosal swelling, and increased mucus production in allergic asthma. (ECP, eosinophil cationic protein; MBP, major basic protein; PAF, platelet-activating factor.)
Alpha1-antitrypsin is a glycoprotein protease inhibitor produced in the liver that plays a role in controlling inflammation and repairing tissues, as well as in blood coagulation. Deficiency of α1-antitrypsin is a common inherited genetic disorder that causes uninhibited tissue breakdown by neutrophil elastase, mainly in the lungs (causing panacinar emphysema) and the liver.
Clinical signs of COPD
The clinical signs of COPD include observation that the patient is leaning forward with arms outstretched and palms on knees to assist breathing, pursed lips, use of accessory muscles of respiration (e.g., sternocleidomastoid, scalene, and intercostal muscles, which are not used during normal respiration), hyperinflation of the lungs, causing a barrel chest appearance, descended trachea, respiratory distress, crackles at the lung base, distant heart sounds, and wheezing. Cyanosis, hemoptysis (coughing up of blood) and finger clubbing (see below) are seen infrequently.
Finger clubbing is a clinical sign associated with numerous diseases and conditions, but it is most commonly associated with heart and lung diseases. It is characterized by softening of the nails and red, shiny skin next to the nail. This progresses to an increased convexity of the nail bed and a loss of the angle between the nail bed and the fold. The ends of the fingers also become larger. It has recently been found to be due to increased levels of prostaglandin E2 (PGE2) in the blood, which is a mediator of inflammation. The lung contains an enzyme that normally breaks this down, but in disease states where the lungs are compromised, it can build up, manifesting with finger clubbing.
Pink puffers and blue bloaters
Some patients with COPD increase their alveolar ventilation rate to try to cope with their shortness of breath. In this way, they manage to achieve a relatively normal 02 level in the blood, and their carbon dioxide (CO2) levels can be either normal or low. They are termed “pink puffers” because they are breathless and pink from the exertion. Other patients with COPD do not have the muscle or lung capacity to increase their ventilation rate. They have low blood 02 levels and high CO2 levels, and so appear blue. Right-sided heart failure may develop secondary to pulmonary hypertension (cor pulmonale), resulting in edema and “bloating.” Oxygen should be used with caution in “blue bloaters.” These patients rely on their hypoxic drive to breathe, as their respiratory centers have become used to the high level of CO2 in the body. Oxygen therapy may remove this stimulus to breathe in these patients, causing hypoventilation or apnea. This resolves when oxygen therapy is ceased.
26.2 Treatment of Asthma and Chronic Obstructive Pulmonary Disease
Budesonide, Ciclesonide, Flunisolide, Fluticasone, Mometasone, Beclomethasone, and Triamcinolone
Mechanism of action. These antiinflammatory agents decrease bronchial hyperreactivity and the formation of mucus. They are the most effective antiasthmatic drugs available.
– These agents are inhaled through metered dose inhalers or dry powder inhalers. In severe persistent asthma, they may be given orally. In asthma emergencies (status asthmaticus), they may be given intravenously (IV).
– They should be used at the lowest dose that provides adequate control of symptoms.
– Moderate to severe asthma
– Corticosteroids are generally not used in COPD patients unless bronchodilation cannot be achieved with β2-adrenergic receptor agonists and anticholinergic drugs.
– Throat irritation and dysphonia (speech impairment and hoarseness) may limit compliance.
– Oral candidiasis (thrush) is possible as a result of inhibition of normal host defenses. The chances of developing thrush may be reduced by using spacer devices with the inhaler, rinsing the mouth after use of the inhaler, and/or decreasing the steroid dosing frequency.
— Endocrine effects have rarely been reported, but the growth of children should be monitored to ensure there is no suppression of the hypothalamic-pituitary axis (see Chapter 16).
– High doses inhaled or long-term systemic corticosteroid therapy for refractory asthma can lead to a Cushing-like response (see page 139).
Status asthmaticus is an acute, severe exacerbation of asthma characterized by a severe limitation of airflow and increased work of breathing, along with variable degrees of hypoxia (low tisssue O2). Treatment includes oxygen therapy, IV fluids for hydration and to thin mucus secretions, nebulized albuterol and ipratropium, and parenteral corticosteroids. Treatment may also include intramuscular or subcutaneous epinephrine (never IV) to induce rapid bronchodilation.
Beta2-Adrenergic Receptor Agonists
These agents are also discussed in Chapter 6.
Albuterol, Levalbuterol, Metaproterenol, Terbutaline, Salmeterol, and Formoterol
– Short-acting: Albuterol, Levalbuterol, Metaproterenol, Terbutaline
– Long-acting: Salmeterol, Formoterol
Mechanism of action. Beta2-adrenergic receptor agonists relax bronchial smooth muscle, thereby reversing bronchoconstriction. They do not significantly decrease the bronchial hyperresponsiveness or the primary inflammatory reactions responsible for the persistence of asthma.
– Short-acting agents act rapidly to provide symptomatic relief of acute asthma symptoms.
– Long-acting agents are used to treat asthma that is not well controlled by corticosteroids alone.
– These drugs form the cornerstone of bronchodilation therapy in COPD, often in combination with an anticholinergic drug.
– Tremor, anxiety, and restlessness
Ipratropium, Oxitropium, and Tiotropium
Mechanism of action. Anticholinergic drugs produce bronchodilation by blocking the bronchoconstrictive effects of acetylcholine acting on muscarinic receptors on bronchial smooth muscle. They have the further advantage of reducing mucus production by inhibiting vagal stimulation of goblet cells.
Uses. These drugs have limited efficacy in asthma but are useful add-ons to β2 agonists in moderate to severe COPD.
– Dry mouth, blurred vision, tachycardia, urinary retention, and constipation
Respiration and acid–base balance
The lungs, along with the kidneys, regulate acid–base balance. They do this by modulating the CO2 concentration in the blood. A respiratory alkalosis occurs as a result of hyperventilation: CO2 levels are reduced (as the patient is breathing out more CO2), and pH is increased. Causes of this include stroke, meningitis, COPD (“pink puffers”), anxiety, and hyperthyroidism. A respiratory acidosis (↑CO2; ↓ pH) is caused when CO2 becomes trapped in the body due to a failure of respiration, which can be neuromuscular, physical, or respiratory (e.g., emphysema) in origin.
Leukotrienes are potent bronchoconstrictors produced by cells involved in inflammatory responses, including mast cells and eosinophils (see Chapter 32).
Montelukast, Zafirlukast, and Zileuton
Mechanisms of action
– Montelukast and zafirlukast are leukotriene receptor antagonists (Fig. 26.3). They bind with high affinity to the cysteinyl leukotriene receptor 1 (cys-LT1) receptor, blocking the effects of the cysteinyl leukotrienes (LTC4, LTD4, and LTE4).
– Zileuton is a leukotriene synthesis inhibitor. It inhibits the enzyme lipoxygenase and thus inhibits the formation of all lipoxygenase products, including the cys-LTs and non-cys-LTs (Fig. 26.4).
Fig. 26.3 Atopy and antiallergy therapy.
Atopy is thought to be linked to the differentiation of T-helper lymphocytes toward the TH2 phenotype. Specific immunotherapy involves antigen injections that are intended to hyposensitize an individual by shifting T-helper cells toward TH1. Monoclonal antibodies (e.g., omalizumab) inactivate IgE and prevent it from binding to mast cells. Cromolyn prevents the release of inflammatory mediators from mast cells. H1 antihistamines and antileukotrienes block their respective inflammatory mediator at receptors. Glucocorticoids have significant antiallergic activity and act at various stages of the allergic response.
Fig. 26.4 Leukotriene antagonists.
Cysteine leukotriene synthesis can be blocked by inhibiting lipoxygenase, the enzyme responsible for converting arachidonic acid to leukotrienes. This can be achieved by drugs such as zileuton. Montelukast, on the other hand, blocks leukotriene receptors on target tissues.
Pharmacokinetics. These drugs are administered orally and are well absorbed.
– Prophylaxis of asthma
– Allergic rhinitis (see page 254)
Side effects. Some patients experience headache with these drugs; otherwise, they are well tolerated.
Mast Cell Stabilizers
Mechanism of action. Cromolyn sodium inhibits mast cell degranulation and other allergy mediators by blocking Ca2+ channels in the cell membrane. This causes a reduction of bronchial hyperresponsiveness.
– Prophylaxis of asthma. It is not a bronchodilator and is of no use in acute asthma. It is not as effective as corticosteroids, but it has an excellent safety profile.
– Allergic rhinitis
Side effects. The side effects associated with cromolyn sodium are minimal.
Mechanism of action. Theophylline has several molecular actions, although which is responsible for the therapeutic effect in asthma is not clear. Classically, theophylline was categorized as a phosphodiesterase inhibitor. It has also been shown to have activity as a prostaglandin antagonist, an inhibitor of Ca2+ transport, a stimulator of endogenous catecholamine release, a β-agonist, and an adenosine antagonist. All of these could contribute to its ability to relax the bronchial smooth muscle.
– Prolonged-release oral formulations are most commonly used.
– Monitoring of serum levels is essential because of large interindividual variability.
Uses. Theophylline is used infrequently in the maintenance therapy of moderate to severe asthma.
– Life-threatening toxicity (seizures and cardiac arrhythmias) can occur at high doses without warning signs.
– Nausea, cramps, insomnia, and headache are common with loading doses.
Anti–immunoglobulin E Antibody
Mechanism of action. Omalizumab is a recombinant humanized monoclonal antibody directed against IgE that binds free IgE. This prevents IgE from binding to mast cells and basophils, thereby inhibiting IgE-dependent hypersensitivity reactions to allergens.
– Given by subcutaneous injection, every 2 to 4 weeks
Uses. Omalizumab is generally reserved for use in patients with severe, persistent, IgE-mediated allergic asthma who are inadequately controlled with the other medications discussed above. It has also been proposed for use in other type I allergic reactions.
Prolastin™, Zemaira™, and Aralast™
Note: There are no generic names for this type of drug.
Mechanism of action. These agents are α1-antitrypsin products that are derived from the plasma of blood donors.
– Given IV on a weekly basis
– Indicated for patients with panacinar emphysema who have α1-antitrypsin deficiency
26.3 Neonatal Respiratory Distress Syndrome
Neonatal respiratory distress syndrome (NRDS) is a hyaline membrane disease that is caused by a deficiency in surfactant.
Beractant and Colfosceril
Mechanism of action. Beractant is a modified bovine lung extract (a natural surfactant), and colfosceril is a synthetic surfactant.
– These agents are given by tracheal instillation.
– Used to modulate neonatal respiratory distress syndrome.
Pulmonary surfactants are lipoproteins produced by alveolar cells (type II pneumocytes), starting at around 24 to 28 weeks’ gestation. By week 35, most babies have developed an adequate amount. Surfactant acts to reduce the surface tension of the lung, thus increasing compliance (the ability of the lungs to stretch when pressure is applied) and preventing atelectasis (collapsing of the lung) at the end of expiration. Premature neonates born before lung maturation can be given steroids to promote type II pneumocyte differentiation and the production of surfactant.
Test for fetal lung maturity
Fetal lung maturity can be tested by extracting a sample of amniotic fluid and measuring the lecithin-sphingomyelin ratio (L/S ratio). A L/S ratio less than 2:1 indicates surfactant deficiency and therefore lung immaturity.
26.4 Treatment of Rhinitis
Rhinitis is inflammation of mucous membranes of the nasal cavity. Characteristic symptoms include sneezing, watery rhinorrhea, itching of the nose, eyes, ears, and throat, red and watering eyes, and nasal congestion. It can be caused by infection (usually viral) or allergy (Fig. 26.5).
Fig. 26.5 Allergic rhinitis.
Allergic rhinitis is triggered by the contact of an allergen with IgE-bearing mast cells in the nasal mucosa. The fact that mast cells have IgE attached suggests prior sensitization to the allergen. The mast cells release their mediators, causing sneezing, rhinorrhea, and contralateral hypersecretion in the unexposed nostril (due to a central reflex). The offending allergen can be identified by nasal allergen exposure or by a prick test.
Phenylephrine, Oxymetazoline, Naphazoline, Pseudoephedrine, and Phenylephrine
– Intranasal decongestants: Phenylephrine, oxymetazoline, naphazoline
– Oral decongestants: Pseudoephedrine, phenylephrine
Mechanism of action. Decongestants are sympathomimetics that decrease nasal blood flow by activating α1-adrenergic receptors (Fig. 26.6).
Pharmacokinetics. Intranasal agents have a more rapid onset of action and produce fewer systemic effects than oral agents, but oral agents have a longer duration of action.
Uses. Symptomatic treatment of rhinitis.
– Oral decongestants can cause systemic effects, such as central nervous system (CNS) stimulation, tachycardia, hypertension, and urinary retention.
– Rebound nasal congestion may occur upon withdrawal of the drug if used for more than 5 days. This is more common with intranasal agents.
Fig. 26.6 Medications used in rhinitis.
Cromolyn and nedocromil inhibit mast cell degranulation of histamine and other allergy mediators by blocking Ca2+ channels in the cell membrane. Nedocromil also has an antiinflammatory effect by inhibiting chemotaxis and migration of inflammatory cells. Alpha sympathomimetics are given by nasal spray or drops to reduce nasal swelling and congestion.
– Hypertension, coronary artery disease, or in patients on monoamine oxidase inhibitors (MAOIs) (see pages 87 and 88)
Note: Only H1 antihistamine agents that are used for allergic rhinitis are discussed here. See Chapter 32 for a full discussion of histamines and antihistamines.
Cetirizine, Loratadine, and Fexofenadine
– These are second-generation H1 antihistamines.
Mechanism of action. H1 antihistamines block H1 receptors and prevent histamine-induced reactions (e.g., increased vascular permeability, smooth muscle contraction, mucus production, and pruritus [itching]). They also inhibit the “wheal and flare” response of the skin (Fig. 26.7).
– Usually given orally but may be given intranasally.
– These agents do not enter the brain as readily as first-generation H1 antihistamines and so produce little, if any, sedation.
– First-line treatment for mild to moderate allergic rhinitis. In moderate to severe cases, intranasal corticosteroids are more effective than H1 antihistamines.
– Also used for other allergy conditions
– Mild sedation can occur with cetirizine at recommended doses and with loratadine in higher-than-recommended doses.
– Gastric effects: loss of appetite, constipation or diarrhea, nausea, and vomiting
Fig. 26.7 Antihistamines for rhinitis.
Antihistamines competitively inhibit histamine at its receptors. The newer second- and third-generation H1 antihistamines (shown) are more effective and less sedative than older agents. They reduce hypersecretion, pruritis, and sneezing in patients with allergic rhinitis, allergic conjunctivitis, and urticaria (hives), but they do not have any effect on mucosal swelling.
Mast Cell Stabilizers
Cromolyn Sodium and Nedocromil
Uses. These agents are administered intranasally several times a day for the symptomatic treatment of allergic rhinitis (Fig. 26.6).
Beclomethasone and Flunisolide
Uses. These agents are administered intranasally to provide a topical reduction of inflammation in allergic rhinitis. The reduction in systemic effects that is achieved by this method of delivery reduces the adverse effects associated with corticosteroid use (see page 154).
26.5 Treatment of Cough
Antitussive medication, such as opiates, the opiate analogue dextromethorphan, antihistamines, and decongestants may have beneficial effects in patients with an acute cough, depending on the cause. Persistent or chronic cough lasting more than 1 week may indicate an underlying infection (pertussis [whooping cough] or tuberculosis), a drug reaction (angiotensin-converting enzyme [ACE] inhibitors), another disorder (chronic bronchitis), or an environmental cause (smoke or occupational exposure).
The use and effectiveness of cough suppressants and over-the-counter cold medicines are controversial, especially in patients younger than 15 years. The risks of drug overdose, morbidity, and mortality may outweigh the benefits.
Codeine and Dextromethorphan
Codeine is available in some over-the-counter cold remedies.
Dextromethorphan is an opiate analogue that is not analgesic or addictive; however, it is an antitussive (see Chapter 13).
Mechanism of action. All opiates have central antitussive activity by acting on the cough center in the medulla to elevate the cough threshold.
Antihistamines and Decongestants
Diphenhydramine, Chlorpheniramine, Pseudoephedrine, and Phenylephrine
– First-generation antihistamines: Diphenhydramine and chlorpheniramine
– Decongestants: Pseudoephedrine and phenylephrine
Mechanism of action. First-generation antihistamines possess anticholinergic drying activity and are used in combination with decongestants to decrease cough by decreasing postnasal drip, which stimulates the cough reflex.
26.6 Treatment of Excess Mucus Production
Expectorants facilitate the removal of fluids from the lungs.
Mechanism of action. Guaifenesin increases the volume and reduces the viscosity of bronchial secretions. This may make it easier for coughing to remove the secretions, but the effectiveness to reduce cough is questionable.
– Given orally
Uses. Although guaifenesin is found in over-the-counter medicines, its effectiveness in cough and colds is controversial. Its only approved use is to loosen phlegm in patients forming an abnormal amount of sputum (chronic bronchitis), but this usage is also of questionable efficacy.
Mucolytic drugs decrease the viscosity of mucus.
Mechanism of action. Acetylcysteine has a free sulfhydryl group that opens the disulfide bonds in mucoproteins and lowers mucus viscosity.
– Given by inhalation or taken orally
– Acetylcysteine is used to decrease mucus viscosity in acute and chronic bronchopulmonary diseases, during surgery, in cystic fibrosis, and in diagnostic bronchial procedures.
– Acetylcysteine is also given orally to treat acetaminophen overdose (see page 356).
Cystic fibrosis is an autosomal recessive disease in which there is a defect in the epithelial transport protein CFTR (cystic fibrosis transmembrane conduction regulator) found in the lungs, pancreas, liver, genital tract, intestines, nasal mucosa, and sweat glands. This alters Cl– transport in and out of cells and inhibits some Na+ channels. In the lungs, Na+and water are absorbed from secretions that then become thick and sticky. In the pancreas, secretions are thick and sticky because duct cells cannot secrete Cl–via the CFTR and water normally follows this ion movement. Sweat is salty because Cl–is not being absorbed via the CFTR and so Na+ also remains in the duct lumen. Symptoms include cough, wheezing, repeated lung and sinus infections, salty taste to the skin, steatorrhea (foul-smelling, greasy stools), poor weight gain and growth, meconium ileus (in newborns), and infertility in men. Complications of this disease include bronchiectasis (abnormal dilation of the large airways), deficiency of fat-soluble vitamins (A, D, E, K), diabetes, cirrhosis, gallstones, rectal prolapse, pancreatitis, osteoporosis, pneumothorax, cor pulmonale, and respiratory failure. Treatment involves daily physical therapy to help expectorate secretions from the lungs, antibiotics to treat lung infections, mucolytics, and bronchodilators.