Respiratory Drugs Part 2
description
Transcript of Respiratory Drugs Part 2
![Page 1: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/1.jpg)
Respiratory Drugs Part 2
![Page 2: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/2.jpg)
V. Leukotriene inhibitorsA. Leukotrienes
• Leukotrienes (LT) are a family of eicosanoid, formed when arachidonic acid (released by phospholipids in cell membranes) is reacted upon by the lipooxygenase (LOX) enzymes.
![Page 3: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/3.jpg)
![Page 4: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/4.jpg)
• LT’s are synthesized by a number of different cells (i.e. mast cells, macrophages) in the airways.
![Page 5: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/5.jpg)
• Three LT’s in particular, LTC4, LTD4, and LTE4 are responsible for many of the effects which occur during an attack, especially bronchoconstriction.
![Page 6: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/6.jpg)
• There are 2 categories of LT inhibitors: receptor antagonists and LT synthesis inhibitors.
![Page 7: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/7.jpg)
• Both categories are effective in blocking antigen induced (grass, cat dander, ragweed, and mixed antigens),
![Page 8: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/8.jpg)
• as well as exercise-induced airway responses.
![Page 9: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/9.jpg)
• Neither category is as effective as inhaled corticosteroids in regard to alleviating symptoms, airway inflammation and bronchial reactivity.
![Page 10: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/10.jpg)
• However, they are equal to inhaled corticosteroids in reducing the frequency of asthma exacerbation.
![Page 11: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/11.jpg)
• An advantage the LT inhibitors have over the inhalation corticosteroids is that they are administered orally.
![Page 12: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/12.jpg)
• This is useful in patients who have poor compliance with the correct use of a MDI (children, the elderly).
![Page 13: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/13.jpg)
B. Receptor antagonists1. montelukast (Singulair)
• This works by blocking the binding of LT’s.
![Page 14: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/14.jpg)
• It’s safety and effectiveness has been demonstrated in children as young as 6 months of age. It is generally administered in the evening (PO 10 mg, children PO 4 mg).
![Page 15: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/15.jpg)
• Adverse effects in adults include headache, fatigue, cough and rash.
![Page 16: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/16.jpg)
• The same adverse effects, as well as otitis, sinusitis, nausea and diarrhea are seen in children.
![Page 17: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/17.jpg)
2. zafirlukast (Accolate)
• This is similar to Singulair in that it is a receptor antagonist of leukotriene.
![Page 18: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/18.jpg)
• Specifically, it is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphlaxis(SRSA).
![Page 19: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/19.jpg)
• It is administered either 1 hour before or 2 hours after meals (adults PO 20 mg, bid; children PO 10 mg bid).
![Page 20: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/20.jpg)
• Headache is the most frequently reported adverse effect.
![Page 21: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/21.jpg)
• Other adverse effects are similar to those reported for montelukast.
![Page 22: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/22.jpg)
C. Leukotriene synthesis inhibitor1. zileuton (Zyflo)
• This drug has a different mechanism of action, it inhibits formation of leukotrienes by inhibiting the enzyme 5-lipoxygenase (5-LO).
![Page 23: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/23.jpg)
• The dosage is 400-800 mg, 2-4 times a day. It is approved for the prevention and chronic treatment of asthma in patients aged 12 years and older.
![Page 24: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/24.jpg)
• In a clinical study, patients receiving Zyflo were able to reduce their use of inhaled beta-adrenergic drugs.
![Page 25: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/25.jpg)
• Headache is the most frequently reported adverse effect. There are also a few reports of liver toxicity (elevated liver enzymes) with this drug.
![Page 26: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/26.jpg)
VI. DecongestantsA. Decongestant actions
• Decongestants act as vasoconstrictors to reduce blood flow to mucous membranes in the nose, sinuses and pharynx.
![Page 27: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/27.jpg)
• They produce vasoconstriction by stimulating alpha receptors in the smooth muscle around blood vessels
![Page 28: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/28.jpg)
B. Oral decongestants
• The most common oral decongestants are:
![Page 29: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/29.jpg)
• 1. pseudoephedrine (Chlor-Trimeton, Dimetapp, Drixoral, Sudafed, Suphedrin, Triaminic, many generics).
![Page 30: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/30.jpg)
• Also found in many combination products (Actifed Cold and Sinus) which contain antihistamine/pain reliever (aspirin, acetaminophen, or ibuprofen).
![Page 31: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/31.jpg)
• The dosage is 60 mg every 4-6 hours, or 120 mg extended release every 12 hours, or 240 mg extended release, once a day.
![Page 32: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/32.jpg)
• As pseudoephedrine has been used in the illicit manufacture of methamphetamine, Federal regulations require that all OTC medications that contain pseudoephedrine be kept behind the counter in the pharmacy.
![Page 33: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/33.jpg)
• In addition, people buying these products must provide a photo ID and sign a logbook.
![Page 34: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/34.jpg)
2. phenylephrine
• Some drug companies are concerned that the Federal regulations regarding pseudoephedrine may keep people from buying their products, so they have reformulated their products by removing the pseudoephedrine and substituting phenylephrine for it.
![Page 35: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/35.jpg)
• Pseudoephedrine and phenylephrine
![Page 36: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/36.jpg)
• Note the long list of medications that contain phenylephrine:
• Sudafed PE, PediaCare Children’s decongestant, Actifed Cold and Allergy, Benadryl Allergy & Cold, Benadryl Allergy & Sinus, Children’s Sudafed Cough & Cold, Children’s Tylenol Plus Cold, Children’s Tylenol Plus Cold & Allergy, Excedrin Sinus Headache, Sudafed PE Nightime Nasal decongestant, Sudafed PE Sinus & Allergy, Sudafed PE Cold & Cough, Sudafed PE Multisymptom, Theraflu Cold & Cough, Theraflu Cold & Sore Throat, Theraflu Daytime Severe Cold,
![Page 37: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/37.jpg)
• Theraflu Daytime Flu & Sore Throat, Theraflu Nighttime Severe Cold, Triaminic Cold & Allergy, Triaminic Daytime Cold & Cough, Triaminic Nighttime Cold & Cough, Tylenol Allergy MultiSymptom, Tylenol Cold Head Congestion, Tylenol Cold MultiSymptom, Tylenol Cold MultiSymptom Daytime, Tylenol Cold MultiSymptom Nighttime, Tylenol Sinus Congestion & Pain Daytime, Tylenol Sinus Congestion & Pain Nighttime, Tylenol Sinus Congestion Severe, Vicks Day Quil Sinus, Vicks Day Quil Cold/Flu, Vicks Formula 44D Cough & Head Congestion Relief.
![Page 38: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/38.jpg)
• Congressman Henry Waxman, among others, have expressed concerns that these newly formulated drugs are not working well enough for their intended purpose.
![Page 39: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/39.jpg)
• In a peer-reviewed letter to the editor published in late 2006 in the Journal of Allergy and Clinical Immunology, two University of Florida researchers concluded that there is "virtually no evidence to show that phenylephrine oral nasal decongestants at the FDA-sanctioned dose of 10mg are effective”.
![Page 40: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/40.jpg)
• To address the issue, Waxman has twice called upon the US Food and Drug Administration (FDA) to launch an investigation into the use of phenylephrine in these drugs, based on a study by Schering-Plough.
![Page 41: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/41.jpg)
• According to Schering-Plough, phenylephrine was "not significantly different from placebo in decreasing nasal congestion" while pseudoephedrine was "significantly more effective," in a clinical trial involving 38 people.
![Page 42: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/42.jpg)
• Both phenylephrine and pseudoephedrine oral have a prolonged duration of action compared to topical decongestants, but they also have more adverse effects.
![Page 43: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/43.jpg)
• These include excitability, nervousness, and insomnia.
![Page 44: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/44.jpg)
C. Topical decongestants
• 1. Oxymetazoline (Afrin, Dristan 12 hours nasal, NeoSynephrine 12 hour, various generics). The recommended dosage for this 0.05% solution is 2-3 sprays per nostril, two times a day.
![Page 45: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/45.jpg)
• 2. Phenylephrine containing nasal sprays (Neo Synephrine)
![Page 46: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/46.jpg)
• This is available in 0.25, 0.5 and 1.0% solutions. The recommended dosage is 2-3 sprays per nostril, two times a day. This nasal spray form of phenylephrine is more effective than the pill form
![Page 47: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/47.jpg)
• 3. xylometazoline (Otrivin)
• This is available in 0.05 and 0.1% solutions. The recommended dosage is 2-3 sprays per nostril, every 8-10 hours.
![Page 48: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/48.jpg)
• These topical decongestants are recommended for the acute treatment of congestion related to the common cold.
![Page 49: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/49.jpg)
• They should not be used for longer than 3 days, as they tend to cause rebound congestion.
![Page 50: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/50.jpg)
VII. ExpectorantsA. Expectorant actions
• Expectorants reduce the viscosity or thickness of sputum so that patients can more easily cough it up
![Page 51: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/51.jpg)
• The use of expectorants, especially in the treatment of a common cold, is controversial.
![Page 52: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/52.jpg)
• Traditional colds involve the upper respiratory tract, whereas expectorants are designed to facilitate mucus removal from the lower respiratory tract.
![Page 53: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/53.jpg)
![Page 54: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/54.jpg)
• In addition, many clinicians have questioned their effectiveness in actually facilitating the clearance of mucous.
![Page 55: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/55.jpg)
B. Expectorant agents
• 1. Guaifenesin (Mucinex, Robitussin, numerous generics)
![Page 56: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/56.jpg)
• Guaifenesin is the only FDA approved OTC expectorant, 100 – 400 mg every 4 hours.
![Page 57: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/57.jpg)
• It is an ingredient also in many combination products which come in several forms, including capsules, tablets, and liquids.
![Page 58: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/58.jpg)
• It may be combined with antihistamines, antitussives, or decongestants.
![Page 59: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/59.jpg)
VIII. Antitussives
• Antitussives are agents which suppress a cough. Their main purpose is to control nonproductive dry coughs.
![Page 60: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/60.jpg)
• They are not indicated in the treatment of productive cough as they may allow accumulation of secretions which lead to airway obstruction.
![Page 61: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/61.jpg)
A. nonopioid
• 1. dextromethorphan (Benylin, Delsym, Robitussin, Vicks, various generics)
![Page 62: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/62.jpg)
• Dextromethorphan is a non-opioid antitussive without analgesic or addictive properties.
![Page 63: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/63.jpg)
• This is often found in combination products along with antihistamine/decongestant/expectorant. The recommended dosage is 10-20 mg every 4 hours or 30 mg every 6-8 hours.
![Page 64: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/64.jpg)
B. opioid
• Opioids are the most effective drugs available for cough suppression. This is achieved at doses below those used to produce an analgesic effect.
![Page 65: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/65.jpg)
• The specific mechanism of antitussive action of opioids is not known, however, it appears that the receptors involved in their antitussive effects are different from those associated with their analgesic effects.
![Page 66: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/66.jpg)
• 1. codeine
• 10-20 mg every 4-6 hours as needed, but not to exceed 120 mg in 24 hours
![Page 67: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/67.jpg)
2. hydrocodone
• There are a number of FDA approved hydrocodone-containing antitussives marketed in the U.S.
![Page 68: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/68.jpg)
• In terms of cough suppression, hydrocodone is about 3 times more potent than codeine. It can lead to both physical and psychological dependence.
![Page 69: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/69.jpg)
• hydrocodone and chlorpheniramine (Tussionex suspension):
• This formulation contains an antihistamine (chlorpheniramine) along with the antitussive hydrocodone.
![Page 70: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/70.jpg)
• The dosage is 5 mL of the suspension every 8-12 hours. Side effects include dry mouth, dizziness, drowsiness, euphoria, nausea, vomiting and constipation.
![Page 71: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/71.jpg)
• hydrocodone and homatropine (Hycodan, Tussigon): This formulation contains an anticholinergic, homatropine, which is effective in drying up secretions.
![Page 72: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/72.jpg)
• It is available both in a suspension and tablet form: 1 tablet/tsp every 4-6 hours. Side effects include dizziness, nausea, vomiting and constipation
![Page 73: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/73.jpg)
IX. Mucolytic agents
• These agents interfere with the chemical structure of mucous making it less viscous
![Page 74: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/74.jpg)
• 1. acetylcysteine or N-acetylcysteine (Mucomyst)
![Page 75: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/75.jpg)
• Acetylcysteine is used to help break up the thick, viscous, mucous that is often present in people suffering from respiratory ailments.
![Page 76: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/76.jpg)
• It accomplishes this by breaking the disulfide bonds in mucoproteins thereby lowering their viscosity.
![Page 77: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/77.jpg)
• It is indicated as an adjuvant treatment for the following:
![Page 78: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/78.jpg)
• amyloidosis,
• bronchiectasis,
• bronchitis,
• cystic fibrosis,
• emphysema,
• pneumonia
• tuberculosis
![Page 79: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/79.jpg)
• The usual dosage is 2-20 ml of a 10% solution via a nebulizer, but high dose oral N-acetylcysteine has recently been used to treat inflammation in cystic fibrosis patients
![Page 80: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/80.jpg)
• 2. dornase alpha (Pulmozyme)
• Dornase alfa is a solution of recombinant human deoxyribonuclease (rhDNase).
![Page 81: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/81.jpg)
• This is a treatment used by cystic fibrosis patients to clear the mucus that accumulates in the airways and leads to infection (Pseudomonas aeruginosa).
![Page 82: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/82.jpg)
• Their sputum contains a higher concentration of DNA.
![Page 83: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/83.jpg)
• This is believed to be derived from the nuclei of degenerating WBC’s, and results in an increase in viscosity of their sputum.
![Page 84: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/84.jpg)
• It was approved by the FDA in 1993.
• It is administered as a 2.5 mg single ampule inhaled once a day via a nebulizer.
• It must be kept refrigerated.
![Page 85: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/85.jpg)
• Side effects of its use include cough, laryngitis and hoarseness.
![Page 86: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/86.jpg)
X. SurfactantsA. Lung surfactant
• In premature infants, a deficiency of lung surfactant often leads to respiratory distress syndrome (RDS) of the newborn, believed to account for approximately 15-20% of all neonatal deaths in Western countries.
![Page 87: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/87.jpg)
• This syndrome is characterized by a 2 to 15 times greater surface tension than normal, due to a deficiency of lung surfactant.
![Page 88: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/88.jpg)
• Lung cells which produce surfactant (arrows)
![Page 89: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/89.jpg)
![Page 90: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/90.jpg)
• Lung surfactant is found in the liquid layer that lines the alveoli of the lungs.
![Page 91: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/91.jpg)
• The primary role of lung surfactant is to decrease the surface tension of the liquids lining the alveoli.
![Page 92: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/92.jpg)
• There are several important physiological effects of a decrease in surface tension brought about by the presence of a surfactant in the alveoli:
![Page 93: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/93.jpg)
• prevention of alveolar collapse;
![Page 94: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/94.jpg)
• a decrease in surface tension increases compliance (stretching), which means that less work is needed to expand the alveoli;
![Page 95: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/95.jpg)
• and a decrease in surface tension prevents water from leaking into the alveoli from the lung capillaries.
![Page 96: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/96.jpg)
• RDS of the newborn is most common in infants whose gestational age is less than 34 weeks.
![Page 97: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/97.jpg)
• There is a test which can be performed before birth, which helps predict the maturity of the fetal lung.
![Page 98: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/98.jpg)
• In this test, a sample of amniotic fluid is tested to determine its L/S (Lecithin/Sphingomyelin) ratio
![Page 99: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/99.jpg)
• (Surfactant is composed of about 85-90% lipid, and most of this is dipalmitoylphosphatidylcholine, or lecithin).
![Page 100: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/100.jpg)
• sphingomyelin
![Page 101: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/101.jpg)
• A ratio of 2 or greater is desired, and is normally found at the gestational age of about 4 weeks up to term.
• If the ratio is between 1.5 and 1.9, there is slightly less than a 50% chance of developing RDS.
• The risk increases greatly to about 75% when the L/S ration is less than 1.5
![Page 102: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/102.jpg)
B. Treatments1. Antenatal treatment
• Antenatal treatment with corticosteroids for women in preterm labor.
![Page 103: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/103.jpg)
• These corticosteroids induce a significant and rapid acceleration of lung maturation.
![Page 104: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/104.jpg)
• They are currently recommended in a setting of preterm labor at 24-34 weeks gestation unless delivery is imminent.
![Page 105: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/105.jpg)
• The treatment with corticosteroids continues for 48 hours while attempting to halt labor.
![Page 106: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/106.jpg)
• Generally, either two 12 mg doses of betamethasone IM, 24 hours apart
• or
• four 6mg doses of dexamethasone IM, 12 hours apart
![Page 107: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/107.jpg)
2. Exogenous surfactant a. beractant (Survanta, derived from bovine
lung extract)
• 4 ml/Kg of birth weight in four divided doses through a catheter placed into the endotracheal tube, with the infant manually ventilated for a minimum of 30 seconds, or until stable between each dose.
![Page 108: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/108.jpg)
• Repeated after 6 hours if there is continuing respiratory distress
![Page 109: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/109.jpg)
• This is specifically recommended by the manufacturer for prophylactic therapy in infants weighing less than 1,250 g, within 15 minutes of birth.
![Page 110: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/110.jpg)
• In addition, it is indicated within 8 hours of birth for infants with evidence of RDS.
![Page 111: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/111.jpg)
b. poractant alfa (Curosurf, derived from porcine lung extract),
• 2.5 ml/Kg of birth weight in two divided doses through a catheter placed into the endotracheal tube, with the infant manually ventilated with 100% oxygen for 1 minute.
![Page 112: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/112.jpg)
• A 1.25 ml/Kg of birth weight subsequent dose, is repeated twice at 12 hour intervals if needed. Maximum dose of 5 ml/Kg of birth weight.
![Page 113: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/113.jpg)
c. calfactant (Infasurf, derived from bovine lung extract)
• 3 ml/Kg of birth weight to an intubated infant in two divided doses if administered by side-port delivery or 4 doses if by catheter delivery, with the infant mechanically ventilated for up to 2 minutes between doses
![Page 114: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/114.jpg)
d. recombinant human surfactant protein D (rhSP-D)
• In a study published in February 2010 in the American Journal of Respiratory and Critical Care Medicine, premature lambs were treated with either Survanta or Survanta containing rhSP-D.
![Page 115: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/115.jpg)
• In lambs given Survanta alone, manual ventilation resulted in pulmonary inflammation.
• In the group given Survanta with rhSP-D, there was an inhibition of lung inflammation. This agent has potential for use in premature human infants.
![Page 116: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/116.jpg)
C. Adverse effects of surfactant therapy
• Adverse effects of surfactant therapy include: acute obstruction of the airway resulting in hypoxemia and bradycardia with a large volume in a single dose, rather than small repetitive additions;
![Page 117: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/117.jpg)
• apnea;
• and pulmonary hemorrhage (generally in infants weighing less than 700 g at birth)
![Page 118: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/118.jpg)
XI. Phosphodiesterase inhibitorsA. Phosphodiesterase
• There are 11 families of phosphodiesterase, numbered PDE1-PDE11. Of particular interest are phosphodiesterase-3 (PDE3), and phosphodiesterase-4 (PDE4) found in airway smooth muscle and epithelial cells.
![Page 119: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/119.jpg)
• PDE4 hydrolyzes cAMP, and there is compelling scientific rationale (i.e they are anti-inflammatory in animal models as well as in in vitro studies) for developing PDE3 and 4 inhibitors for use in the treatment of COPD.
![Page 120: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/120.jpg)
B. Clinical trials
• A 6 month Phase II trial tested the efficacy of one of these PDE4 inhibitors, cilomilast (Ariflo).
![Page 122: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/122.jpg)
• It was administered orally, and reached the most distal portions of the lungs via the systemic circulation.
![Page 123: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/123.jpg)
• Not all inhaled bronchodilators are capable of penetrating this deeply, which is significant in that inflammation is often continually present in these small airways.
![Page 124: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/124.jpg)
• There was a significant improvement in airflow, compared to placebo (40 ml difference in FEV1), as well as a (more subjective) quality of life improvement, as measured by a questionnaire.
![Page 125: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/125.jpg)
• Currently, a Phase III clinical trial has been completed (May 2009) but the results have not yet been published.
![Page 126: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/126.jpg)
• Similar findings occurred with a different PDE4 inhibitor.
![Page 127: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/127.jpg)
• In July 2009, an application was filed with the FDA for approval of once daily oral roflumilast (Daxas).
![Page 128: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/128.jpg)
• A study from 4 clinical trials with roflumilast was expected to be published sometime in 2009 or 2010.
![Page 129: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/129.jpg)
• Patients involved in studies conducted with both cilomilast and roflumilast experienced a time delay between exacerbations of their COPD when receiving a PDE4 inhibitor.
![Page 130: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/130.jpg)
• The scientists conducting the studies believe that the systemic distribution of the PDE4 inhibitors to the distal airways may be the key to the effectiveness of these drugs.
![Page 131: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/131.jpg)
• Although resting lung volumes were not tested in their trials, they believe that improvement in this parameter would be seen if measured in future trials.
![Page 132: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/132.jpg)
• Ibudilast (development codes AV-411, MN-166) does not have FDA approval in the U.S., but is available in Japan, where it is used as an anti-inflammatory agent in the treatment of asthma.
![Page 133: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/133.jpg)
• Studies indicate that it has a better safety profile and is more potent than theophylline.
![Page 134: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/134.jpg)
• Some of the adverse effects associated with PDE inhibitors are GI related (i.e. dyspepsia, nausea).
![Page 135: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/135.jpg)
• This has limited their development as potential candidates in the treatment of COPD.
• Ibudilast has acceptable GI tolerability.
![Page 136: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/136.jpg)
XII. Protease inhibitorsA. Alpha-1 antitrypsin
• Neutrophil elastase is a protease enzyme which degrades elastic fibers in connective tissue.
![Page 137: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/137.jpg)
• Alpha-1 antitrypsin (AAT), also known as Alpha-1-Proteinase is a protein made by the liver and released into the circulation.
![Page 138: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/138.jpg)
• Alpha-1 antitrypsin is a protease inhibitor which degrades neutrophil elastase and therefore plays a protective role in the places where unchecked neutrophil elastase activity can have serious consequences, particularly the lungs and liver.
![Page 139: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/139.jpg)
• If the breakdown of tissue occurs in the alveolar wall, it can lead to emphysema.
![Page 140: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/140.jpg)
• Alpha-1 antitrypsin deficiency (AATD) is an inherited condition that causes low alpha-1 antitrypsin (AAT) levels in the blood.
![Page 141: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/141.jpg)
• This predisposes those with the most severely deficient phenotype (PI*ZZ), to emphysema and liver disease (neonatal jaundice, cirrhosis, hepatoma).
![Page 142: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/142.jpg)
• people with normal alleles for AAT are designated PI*MM
• heterozygotes are designated PI*MZ
![Page 143: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/143.jpg)
• Of the approximately 300 million Americans, about 100,000 have the severe AATD (PI*ZZ), and approximately 8 million are heterozygotes.
![Page 144: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/144.jpg)
![Page 145: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/145.jpg)
• This condition is found most often in Caucasians of European ancestry, the Z allele is not common in Americans of Asian and African descent.
![Page 146: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/146.jpg)
• Symptoms of AATD include jaundice in a newborn or infant that lasts for an extended period of time (more than a week or two);
![Page 147: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/147.jpg)
• and wheezing, a chronic cough or bronchitis, and shortness of breath after exertion in a person under 40 years of age (especially when the patient is not a smoker, and has not been exposed to known lung irritants).
![Page 148: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/148.jpg)
B. AATD drug therapy
• There are, currently, 4 agents approved by the FDA for the treatment of AATD.
![Page 149: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/149.jpg)
• These products are derived from human plasma and are extremely expensive (up to $100,000 per year, per patient).
![Page 150: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/150.jpg)
• These agents are indicated only for patients with the PI*ZZ phenotype, and not for individuals with cigarette-smoking related emphysema with PI*MM or PI*MZ phenotypes, or those with liver disease due to AATD, unless they also have lung disease.
![Page 151: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/151.jpg)
• The 4 agents are Prolastin, Zemaira, Aralast and Glassia.
![Page 152: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/152.jpg)
• Glassia is the newest alpha-1 antitrypsin inhibitor, receiving FDA approval in July 2010. Baxter International in October 2010 received the exclusive distribution rights for Glassia in the U.S., Canada, Australia, and New Zealand from Kamada Ltd. (Israel) for $20 million.
![Page 153: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/153.jpg)
• All 4 of these agents are administered IV, once a week (recommended dosage of 60 mg/Kg of body weight).
![Page 154: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/154.jpg)
![Page 155: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/155.jpg)
• Clinical trials are currently underway in Europe for an inhaled version of an alpha-1 antitrypsin inhibitor. Approval for this is expected in 2012 in Europe, with the U.S. to follow shortly after.
![Page 156: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/156.jpg)
• There is a randomized, placebo-controlled, double-blind, study conducted by CLS Bering to assess whether the progression of emphysema can be halted by continuous, long term therapy with Zemaira.
![Page 157: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/157.jpg)
• The study began in January of 2006 and is expected to end in March 2011. The effect of Zemaira on the progression of emphysema will be assessed by the decline of lung density, measured by computerized tomography (CT).
![Page 158: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/158.jpg)
XIII. Tumor necrosis factor inhibitorsA. Tumor necrosis factor
• During the inflammatory response triggered normally by infection, but also by cigarette smoking, macrophages are activated, and release cytokines.
![Page 159: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/159.jpg)
![Page 160: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/160.jpg)
• Cytokines are proteins which mediate communication among the cells of the immune system, as well as between the cells of the immune system and other body systems.
![Page 161: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/161.jpg)
• There are 3 major categories of cytokines: interleukins, tumor necrosis factor (TNF) and interferons.
![Page 162: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/162.jpg)
• The cytokine of interest here is TNF which induces programmed cell death, primarily in tumor cells, but also in any cell with a receptor.
![Page 163: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/163.jpg)
![Page 164: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/164.jpg)
• The sputum of COPD patients has increased levels of TNF-α.
![Page 165: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/165.jpg)
• It is believed that an increase in circulating TNF-α leads to the skeletal muscle apoptosis that is associated with the severe wasting in some advanced COPD patients.
![Page 166: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/166.jpg)
B. TNF blockers
• TNF blockers such as infliximab (Remicade) have been effective in other chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) and, therefore, may be effective in COPD patients.
![Page 167: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/167.jpg)
• However, in a 6 month study of 234 smokers, 40 years or older, it was shown that infliximab was not beneficial in patients with moderate to severe COPD (based on the Chronic Respiratory Questionnaire, prebronchodilator forced expiratory volume in 1 second [FEV1], and 6 minute walk distance.
![Page 168: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/168.jpg)
• This study was published in the May 2007 issue of The American Journal of Respiratory and Critical Care Medicine.
![Page 169: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/169.jpg)
• It should be noted that infliximab is a chimeric (mouse/human) recombinant antibody construct which results in a large antigenic trigger.
![Page 170: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/170.jpg)
• Newer TNF binding proteins have been engineered, and trials of anti-TNF therapies specifically for patients with COPD are currently underway.
![Page 171: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/171.jpg)
• The anti-TNF-α agents currently available, include infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira).
![Page 172: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/172.jpg)
• Remicade was first approved in the United States for the treatment of Crohn’s disease in 1998 and later approved for the treatment of Ulcerative colitis in September 2005.
![Page 173: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/173.jpg)
• Enbrel was approved for the treatment of rheumatoid arthritis in 1998.
![Page 174: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/174.jpg)
• So far, Humira has been approved by the FDA for the treatment of moderate to severe rheumatoid arthritis in 2002, moderate to severe Crohn's disease in 2007 and moderate to severe psoriasis in 2008.
![Page 175: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/175.jpg)
• Before any of these drugs can be approved for the treatment of COPD, clinical trials must be completed and the results, published.
![Page 176: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/176.jpg)
• Another approach may be to target the enzyme which is responsible for releasing TNF, TNF-α-converting enzyme (TACE).
![Page 177: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/177.jpg)
C. Other potential therapeutic targets for drug development in COPD
• A recent study has assessed the ability of 36 different biomarkers to confirm the presence of COPD exacerbation and predict its severity.
![Page 178: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/178.jpg)
• This study found that • C-reactive protein (CRP), • IL-6, • myeloid progenitor inhibitory factor (MPIF)-1, • pulmonary and activation–regulated chemokine
(PARC), • adiponectin (ACRP-30), and • soluble intercellular adhesion molecule (sICAM)-
1
![Page 179: Respiratory Drugs Part 2](https://reader038.fdocuments.us/reader038/viewer/2022102819/568143f4550346895db07f93/html5/thumbnails/179.jpg)
• significantly vary between baseline and exacerbation of COPD.
• These biomarkers are potential therapeutic targets