Lecture 25: Respiratory

Question 1

Endogenous products that play important role in pathophysiology of lung:

Answer 1

• Prostaglandins, Acetylcholine, β2–adrenergics , Histamine and Adenosine
• ACE –angiotensin converting enzyme –Converts AT1 (Angiotensin I) to ATII
• ACE inactivates bradykinin, which is enhanced by ACEI (e.g. captopril) that cause cough and angioedema.
• Macrophages clears waste products
• Ciliated columnar cell brush away mucus secretions

Question 2

Asthma: clinical manifestations

Answer 2

• Shortness of breath (SOB), Cough, Wheezing, Prolonged expiratory duration (↓I/E ratio), Use of accessory muscles of respiration & Chest tightness.
• ↓O2 ,–late sign, ↑RR, ↑HR, ↑Resonance
• Dx: Spirometry: ↓FEV1 / FVC; ↑RV & TLC (total lung capacity)

Question 3

Asthma Rx

Answer 3

• Antigen & IgE on mast cells: Omalizumab
  
  • Patients who remain symptomatic in spite of compliance with inhaled corticosteroid treatment addition of long acting β2 agonists are recommended; and for uncontrolled allergic asthma, Omalizumab is added.
• Early response: Beta agonists, theophylline, muscarinic antagonists
• Late inflammation: steroids, anti-leukotriene, cromolyn

Contra-indications

• Beta blockers
• chol drugs (carbechol)
• adenosine
• Prostaglandin-derivates
• Aspirin

Question 4

β2-adrenergic agonists that are commonly used for asthma:

Answer 4

• Albuterol, Pirbuterol and Terbutaline are called SABAs (Short Acting β2 Agonists) – they are used for acute symptoms.
  
  • also used for premature labour (uterine contractions)
• Salmeterol & Formoterol – they are called LABAs (Long Acting β2 Agonists) –not used for acute symptoms
• Epinephrine, Isoproterenol are Nonspecific β –agonists:

Question 5

Clinically important actions of isoproterenol

Answer 5

• non-selective Beta-agonists
• Beta2: bronchodilation
• Beta2: peripheral vasodilation
• Beta1: incr CO

Question 6

Drugs acting on arachidonic acid products in asthma

Answer 6

• corticosteroids
• Zileuton
• NSAIDS
• Zafirlukast, Montelukast

Question 7

Inhaled steroids used in the management of chronic asthma:

Answer 7

• Beclomethasone
• Flunisolide
• Triamcinolone
• Fluticasone
• Budesonide

PK

• only 10% deposited in lung
• systemic doses at higher does; prevent by using a spacer

Question 8

Safety to use anti-asthma drugs in pregnant women:

Answer 8

• Pregnantwomenwithasthmacanbetreatedas aggressively as non pregnant asthmatic patients.
• Risks of poorly controlled asthma include: pre- eclampsia, perinatal mortality, preterm labor and low birth weight.
• Use of ICS during the 1st trimester: Congenital malformation may occur with ICS >1000 mcg/day
• AnotherstudywithICSuseduringpregnancy: Risks of endocrine and metabolic abnormalities

Question 9

Anticholinergics as bronchodilators:

Answer 9

• Ipratropium (Atrovent): A short acting inhaled anticholinergic can be used in asthma, QID.
  
  • Prevent vagal-mediated bronchoconstriction and drug induced bronchospasm such as β blockers.
  • Adverse: dry mouth
• Tiotropium is a long-acting anticholinergic, used once daily dosing, in COPD.

Question 10

Zileuton (Zyflo)

Answer 10

• inhibits 5-lipoxygenase, which catalyzes the formation of leukotrienes from arachidonic acid.
• used for prophylaxis (does not bronchodilate)

Question 11

Zafirlukast (Accolate)

Answer 11

LTD 4 receptor antagonist

Question 12

Montelukast (Singulair)

Answer 12

• LTD4 receptor antagonist
• used for prophylaxis (does not bronchodilate)

Question 13

Leukotriene uses

Answer 13

• Route of administration leukotriene inhibitors: PO
• Clinical role of Leukotriene inhibitors in asthma:
• Useful in prevention of exercise, antigen, and aspirin induced asthma.
• They prevent bronchoconstriction and airway inflammation. Leukotriene inhibitors are used for chronic maintenance therapy of mild asthma; they are not beneficial in acute bronchospasm

Question 14

Zafirlukast & Montelukast

Answer 14

• Rarely patients develop as vasculitis and systemic eosinophilia resembling Churg-Strauss syndrome.

Question 15

Anti-IgE antibody –Omalizumab:

Answer 15

• It is administered parenterally and an expensive drug.
• MOA: It binds to the IgE on sensitized mast cells and prevents activation by triggers – prevents release of LTs and other mediators.
• Used for prophylactic management in asthmatic patients and in cases of inadequate control with inhaled ICS in patients aged above 12 years.
• Like other protein and antibody drugs, omalizumab causes anaphylaxis (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.

Question 16

Theophylline MOA

Answer 16

• Methylxanthine derivative that inhibits phosphodiesterase, the enzyme responsible for the metabolism of cAMP to AMP. Increased levels of cAMP result in bronchodilation. Theophylline has no significant anti-inflammatory effects.
• Blocks adenosine receptors.
• Theophylline role in asthma:
• Limited, because it has a very small therapeutic window

Drug interactions with theophylline:

• Cimetidine, erythromycin and quinolones(cipro) increase theophylline plasma levels.
• Drugs that decrease plasma levels of theophylline:
• Phenytoin, phenobarbitone and carbamazepine

Complications with theophylline overdose:

• The most common are tremor, insomnia, GI distress, and nausea. Hypokalemia and hyperglycemia may occur.
• most dangerous are seizures and arrhythmias.

Question 17

CROMOLYN SODIUM AND NEDOCROMIL

Answer 17

• Mechanism of action of cromolyn sodium (Intal) and nedocromil (Tilade):
• They are effective prophylactic agents that stabilize the membranes of mast cells and prevent the release of inflammatory mediators.
• They are not used for treating acute attacks of asthma:
• They are used as prophylactic agents. Pretreatment with cromolyn or nedocromil blocks allergen- and exercise-induced bronchoconstriction.
• Other uses: for preventing food allergy and hay fever
• Available as oral, aerosol and drops
• Potential toxicities o fcromolyn and nedocromil:
• Cromolyn–infrequent laryngeal edema, cough, and wheezing
• Nedocromil–unpleasant taste

Question 18

Treatment of all types of asthmatic patients

Answer 18

Mild:

• > 80% FEV1
• SABA when needed

Moderate

• 50 to 79% FEV1
• one or more bronchodilators + Inhaled GC (IGC)

Severe

• 30 to 49%
• one or more bronchodilators + Inhaled GC (IGC) + antibiotic

Very severe

• <30 or chronic respiratory failure symptoms
• one or more bronchodilators + Inhaled GC (IGC) + antibiotic + assisted vent

Question 19

MNEMONIC FOR ASTHMA MEDICATION FOR EXACERBATIONS

Answer 19

• Albuterol / Pirbuterol / Terbutaline Steroids
• Theophylline
• Humidifier O2
• Magnesium (severe exacerbations) –when Beta2- agonist and anti-cholinergics are unsuccessful; or Heliox (mixture of 79% helium and O2 21%) inhalation…
• Anticholinergics

Question 20

Determine the severity of COPD with FEV1 and treatment choices

Answer 20

Question 21

MNEMONIC FOR COPD Treatment:

Answer 21

• Corticosteroids
• Oxygen
• Prevention (cigarette smoking cessation, infection control; pneumococcal and influenza vaccine)
• Dilators (anticholinergics and β2–agonists)

Question 22

N-acetylcysteine (abbreviated NAC) –cough:

Answer 22

• It is a used primarily as a mucolytic agent and in the management of acetaminophen overdose.
• Useful in cystic fibrosis (CF). Breaks disulfide bonds in mucus and liquefies it making it easier to cough out.

Question 23

RHINITIS AGENTS:

Answer 23

• Cromolyn sodium
• Antihistamines
• α- Adrenergic agonists
• Corticosteroids commonly used to treat chronic rhinitis:
• Beclomethasone and flunisolide.
• Chronic rhinitis does not show improvement until 2 weeks after the start of therapy.

Question 24

Commonly used antihistamines in the treatment of rhinitis are:

Answer 24

• Diphenhydramine, Chlorpheniramine, Cyproheptadine –they cross BBB and produce drowsiness.
• Loratadine (Claritin); Fexofenadine (Allegra); Cetirizine (Zyrtec) are non-drowsy antihistamines

Question 25

Mechanism of action of α-adrenergic agonists:

Answer 25

• Phenylephrine and pseudoephedrine
• Phenyephrine is also used to dilate pupil and to ↑BP
• Effects of prolonged use of nasal decongestants:
• Rebound nasal congestion often occurs after discontinuation from prolonged use.

Question 26

Dextromethrophan

Answer 26

• Mechanism of action of dextromethorphan :
• It suppresses the response of the cough center, but it does not have any analgesic or addictive potential and is less constipating than codeine.

Question 27

Adverse effects of systemic corticosteroids such as prednisone:

Answer 27

abnormalities in glucose metabolism, increased appetite, weight gain, hypertension, and adrenal suppression, PUD

• These symptoms can be minimized by limiting systemic therapy to few days.