Treatment of Asthma and COPD Flashcards
Describe MOA of Sympathomimetics (B2-adrenergic receptor agonists)
Increase levels of cAMP, which promotes bronchodilation
- Intracellular levels of cAMP can be increased by B-agonists (increase rate of its synthesis by adenylyl cyclase) or by PDE-inhibitors such as theophylline, which slos the rate of degradation.
- Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists
Some inhibitory effect on the release of mediators from mast cells and on **microvascular permeability **
Promote to a small degree **mucociliary transport **
Name the sympathomimetic bronchodilators
Non-specific: Epinephrine, Ephedrine, Isoproterenol
B2-specific (quick onset-short duration): Albuterol, Terbutaline
B2-specific (slow onset-long acting i.e. LABA): Salmeterol, Formoterol (used only in combination with steroids as they donot prevent inflammation)
What are the adverse reactions of sympathomimetics?
- N/V, headache
- Fall in BP and increased HR (because heart has B2AR) and cardiac arrythmias (hypokalemia leading to QT prolongation)
- Arterial oxygen tension (PaO2) may decrease
- CNS toxic effects which include agitation, convulsions, coma and respiratory vasomotor collapse
Name the Cholinergic Antagonists (Bronchodilators)
Atropine: competitive Ach-muscarinic blockade
- reduces airway smooth muscle constriction
- decrease in mucus secretion
- enhane B2-mediated bronchodilation
- adverse reactions: pupillary dilation and cycloplegia, on contact
Ipratropium: quaternary compound, is poorly absorbed with no significant systemic effects
What is the drug that is a combined anti-cholinergic and B2 agonist?
Combivent
Combined therapy produces a greater improvement in lung fucntion than either ipratropium or albuterol alone
Indicated for COPD
What are the methylxanthines?
Aminophylline (theophylline + diethylamine)
Theophylline
They are combined bronchodilators and anti-inflammatory agents!
What are the actions of methylxanthines?
Inhibits PDE, which results in accumulation of cAMP that produces bronchodilation. Anti-inflammatory by blocking the effect of adenosine on mast cells and also causes the deacetylation of histones.
- Increased levels of cAMP
- Inhibits muscle adenosine receptors
- Decreased release of mediators
- Bronchodilation
- Anti-inflammatry effects
- Positive inotropic and chronotropic effects
- Increased CNS activity
- Increased gastric acid secretion
- Weak diuretic
- Increased skeletal muscle strength (diaphgram)
What are the adverse reactions to Methylxanthines?
- 5-10ug/mL serum levels may cause n/v, nervousness, headache and insomnia
- Serum levels >20ug/mL cause vomitting, hypokalemia, hyperglycemia, tachycardia, cardiac arrythmias, tremor, neuromuscular irritability and seizures
Cromolyn Sodium (Anti-inflammatory) MOA
MOA:
- May alter the activity of Cl- channels
- Inhibit degranulation of mast cells in the lung
- Inhibit inflamatory response by acting on eosinophils
- Inhibit cough by thier action on airway nerves
- Reduce bronchial hyperactivity associated with excercise- and antigen-inhaled asthma
Cromolyn Sodium (Anti-inflammatory) Adverse Effects
No systemic toxicity
Unpleasant taste
Irritation of trachea: cough, and bronchospasm can occur after inhalation
Rare adverse effects: chest pain, restlessness, hypotension, arrhythmias, n/v, CNS depression, seizures and anorexia
Name the Glucocorticoids/Corticosteroids (Anti-inflammatory)
All end in “sone” or “sonide”
Which of the corticosteroids has the best pharmacokinetics?
Ciclesonide has the best PK
- very rapidly cleared from the mouth so will not cuase the oropharyngeal candidiasis
- high lipophilicity
- high binding to the glucocoriticoid receptors
- high protein binding which reduces systemic absorption
What are the pharmacological actions of corticosteroids?
- Decrease production of inflammatory cytokines
- Reduce mucus secretion
- Reduce bronchial hyperactivity
- Enhance the effect of B-2 adrenergic agonists
What are the adverse consequences of corticosteroids?
Inhaled
- oropharyngeal candidiasis, hoarseness and dry mouth
- decreased bone mineral density in premenopausal women
- decreased rate of growth in children
Oral (prolonged use)
- glucose intolerance
- increase BP and weight
- bone mineralization
- cataracts
- immunosuppresion
- retarded growth in children
Explain Cushingoid Syndrome
Related to the excessive use of glucocoritcoids
- Weight gain, especially abdomen, face (moon face), neck and buffalo hump
- Thinning and leg/arm muscle weakness
- Thin skin, with easy bruising and stretch marks
- Increased acne, facial hair growth, and scalp hair loss in women
- A ruddy complexion on the face and neck
- Often a neck skin darkening (acanthosis)
- Child obestiy and poor growth in height
- High BP (usually)
Name the two LT receptor blockers and describe their MOA (Anti-inflammatory)
LTB4 is a neutrophil chemoattractant
LTC4 and LTD4 mimic many Sx of asthma including bronchial hyper-reactivity, bronchoconstriction, mucosal edema, and increased mucus secretion
Monteleukast and Zafirlukast block LTD4 receptors
- decrease bronchial reactivity and bronchoconstriction
- decrease mucosal hypersecretion and mucosal edema
- decrease airway inflammation
- especially good for asprin-induced asthma
What are the adverse effects of the LT antagonists?
Zafirlukast: GI disturbances, mild headache and elevation of liver enzymes in some patients. High doses in rodents have caused hepatic and bladder cancer and histocytic carcinoma
Monteleukast: GI disorders, layrngitis, pharyngitis, nausea, otitis, sinusitis and viral infections (more frequent in peds population). Possible association with suicidal ideation.
Name the only LT synthesis inhibitor (Anti-inflammatory) and describe MOA
Zileuton
- inhibits LTB4, C4, D4, E4 formation
- decreases smooth muscle contraction and blood vessel permeability and reduces leukocytes migration to teh damaged area
- causes hepatic enzyme elevation - LFTs required
- CYP1A2 substrate and inhibitor - interaction with theophylline
- most other effects mild and self-limiting
- under evaluation for other inflammation-related diseases like RA, ulcerative colitis and acne
Name the only anti-IgE antibody and describe the MOA
Omalizumab
- binds to IgE and prevents IgE-instigated release of inflammatory mediators, which decreases allergic response
- reduces severity and frequency of asthma attacks
- reduces requirement of inhaled corticosteroids, improves long term asthma control
What are the adverse effects of Omalizumab?
- serious allergic rxns: difficulty breathing, closing of throat, swelling of face, lips or tongue, and hives
- less erious effects: redness, bruising, warmth, burning, stinging, itching, pain or inflammation at injection site or sore throat or cold Sx
- initial concenrs for tumors
- increase in CV complications: MI, CAD, arrhythmias
- contraindications: no known drug interactions
What is COPD?
Progressive loss of airflow in lungs resulting in broncho-constriction that is not fully reversible. Primarily caused by chronic inflammation. The two common forms are bronchitis and emphysema.
- Elastic parenchymal tissue is replaced by inelastic fibrotic tissue such that elastic recoil of lung is lost. Collapse of airways mid-exhalation leads to air trapping, loss of capacity and, in some cases, impaired gas exchange.
Asthma vs. COPD
- Age
- Sx
- Allergic Etiology
- Treatment response to: bronchodilators, corticosteroids, smoking status, airflow limitation
Asthma
- young (child)
- variable dyspnea
- allergic etiology in >50%
- Treatment response to bronchodilators (reversible), corticosteroids (good), smoking status (nonsmokers affected), airflow limitation (can normalize after resolution of episode)
COPD
- older (>40 y/o)
- progressive dyspnea
- no allergic etiology association
- Treatment response to bronchodilators (partially reversible), corticosteroids (poor), smoking status (usually long smoking hx), airflow limitation (cannot normalize; progressive deterioration wtih advancing age)
COPD Treatment Options
Smoking cessation (welbutrin)
Bronchodilators (B2 adrenergic receptor agonists)
- Short acting to releive Sx: albuterol or terbutaline
- Long acting: salmeterol/fluticasone, formoterol/budesonide, indacaterol, vilanterol/fluticasone
Antimuscarinic Agents: Ipratopium, Umeclidinium bromide/Vilanterol
Theophylline and derivatives
Contraindicated Drugs in Airway Disease
- Sedatives
- Beta Blockers (if you need to use, then use selective B1 blockers such as atenolol)
- Aspirin adn other COX inhibitors
- ACE-I (increased levels of bradykinin and PGE2)
- Local anesthetics containing epinephrine
What is one respiratory stimulant?
Doxapram
- post-anesthesia respiratory depression
- drug-induced respiratory depression
- acute hypercapnia in COPD
- activates peripheral carotid receptors
- narrow margin of safety
- short acting (given IV)
