Pharmacology: Lung

Drugs for Asthma .................................................................................................................................................................... 2

Drugs for Asthma
Anti-inflammatory Acute therapy (quick relief meds: rescue!)  Systemic steroids      Inhaled steroids Systemic steroids Montelukast / Zafirlukast Zileuton Neocromil / Cromolyn Bronchodilators  Short-acting β2 agonists  Ipratropium bromide  Theophylline  Long-acting β2 agonists

Prophylaxis / Maintenance (long-term meds: prevent Sx!)

Structurally related to isoproterenol (pure nonselective β-agonist) Short-acting: for quick relief
Mechanism of Action: Short-acting beta-2 agonists (anti-asthma) Effects: Relaxes smooth muscle (bronchodilation) by stimulating adenyl cyclase, increasing cAMP.
Other distant effects too (importance less than bronchodilation in asthma): suppresses histamine / leukotrine release from pulmonary inflammatory cells, enhances mucociliary clearance, decreases microvascular permeability.

albuterol metaproterenol terbutaline Toxicity: due to excessive stimulation of beta receptors. levalbuterol  CVS (tachycardia, palpitations, exacerbastes CAD, arrhythmias). isoetharine  CNS (anxiety, apprehension, tremor, anxiety).
 Metabolic (hypoK, hyperglycemia). Resistance: Tolerance has been documented at high doses with chronic treatment. Special Members of Class: Levalbuterol: R-isomer of albuterol; 100x more affinity than S-isomer, more expensive but probably equally effective; occasionally use in kids

Selective Toxicity: Selective for beta-2 over beta-1 Indications: Quick-acting symptom relief for asthma Administration: MDI or neb

Mechanism of Action: Long-acting beta-2 agonists (anti-asthma) Effects: Like short-acting (see above), but longer duration.  Also inhibits inflammatory mediator release from lung Indications: Long-acting maintenance / prevention for asthma.  12h protection against bronchoconstricting stimuli; esp. nocturnal / exercise-induced asthma

salmeterol formoterol

Administration:  Salmeterol: Does not fully occupy beta-2 receptors so can use short-acting drugs as needed as rescue meds (can still use albuterol).  Formoterol: Dry powder aerolizer. q12h (10h plasma halflife). o Faster onset than salmeterol (1-3 min vs 10-20 min) Metabolism: Formoterol metabolized by multiple CYP enzymes Toxicity: Black box warning: make sure to counsel on how to use (not for rescue!); o/w like short-acting Resistance: Tolerance (like short-acting)

Advantages Disadvantages

Inhaled Administration: Nebulizers vs Metered-dose inhalers (MDIs) MDI Nebulizer  Enhances drug delivery to site of action  Doesn’t require coordination like MDI (droplet size optimized to hit deep airways)  Delivers more medication  ↓ systemic absorption, toxicity  Coordination & understanding required  More expensive than MDI  Compliance can be an issue (use too much)  Delivers more medication

Tolerance:  If you give methecholine challenge & measure FEV1 < 20%, β-2 agonists can raise the level.  Less effect after time for asthmatic patient: tolerance develops (feedback regulation)  Take-home: lowest dose for least amount of time to be effective.

Anticholinergic agents
Structural analogs of atropine
Mechanism of Action: anticholinergic agent (for asthma) Effects:  block muscarinic receptors in airway smooth muscle o (inhibit resting cholinergic bronchoconstror tone by reducing cGMP levels).  Also block vagus reflex bronchoconstriction (block sensory afferent input) o augments parasympathetics so more bronchodilation. Indications: short-acting asthma rescue Administration: more robust response when combined with albuterol Other: tiotropium's use in asthma is off-label

ipratropium bromide tiotropium

Methylxanthines (theophylline)
Mechanism of Action: methylxanthine anti-asthma agent. Tons of possible mechanisms of action:  Inhibit PDE so more cAMP and cGMP, more smooth muscle relaxation.  Adenosine antagonists so bind to A2 receptors (stimulate membrane bound adenyl cyclase).  Short-term: may increase catecholamine levels & enhance effect on adrenergic receptors) Effects: relaxes smooth muscle. Positive effects & negative effects related; + can be – in some pts! Good (can be bad too) Bad ↓ drowsiness, clearer flow of thought, less nausea, anxiety, tremor, CNS fatigue. Stimulates medullary respiratory center. insomnia, seizures. ↑ cardiac contractility, may ↑ catecholamine ↑ ventricular instability theophylline CVS sensitivity. ↓ PVR & venodilates in patients with CHF Skeletal mm ↓ fatigue. Renal diuretic effects GI ↑ secretion of gastric acid & pepsin Metabolic ↑ BMR and free plasma fatty acids. Administration: with basic compound to enhance solubility.  aminophylline = 80% theophylline, 20% ethylene diamine Toxicity: See above; related to dose (more toxic episodes with increased [serum]) Other: methylxanthine potency: theophylline > caffeine > theobromine.

Mechanism of Action: anti-inflammatory agents.  Suppress release of leukotrine & prostaglandin mediators from inflammatory cells  (inhibit phospholipase A2, ? phospholipase C). Indications: in asthma, prophylaxis only (NOT rescue). MAINSTAY of controller treatment. Administration: inhaled inhaled glucocorticosteroids Toxicity:  Candida infections (mouth/throat).  Dysphonia (laryngeal myopathy) - less with slow inhalation, using a spacer, gargling.  systemic side effects possible with large doses (inhibit hypothal-pituitary-adrenal axis).  bruising & purpura at high doses.  May inhibit growth in children (but outweighed by benefits)

Mast cell stabilizers
Mechanism of Action: "Mast cell stabilizers" - antiasthma agents Effects: NOT bronchodilators.  Inhibit mediator release (histamine, leukotrine, platelet activating factor) from pulm inflammatory cells; prevent degranulation. chromoglycate  Low concentration: suppresses chemotactic factors' effects (on PMNs, eos, monos). (Cromolyn)  May prevent bronchoconstriction neurally o (bradykinin / SO2-mediated bronchoconstriction; maybe C-fiber sensory nerve involved).


Indications: prevention of cold- and exercise-induced asthma.  chromoglycate especially effective against cough.  can work against both acute & delayed effects (single dose).

Leukotriene antagonists
 Leukotrienes: arachidonate metabolites
o o o Arachidonate presented to 5-lipoxygenase by FLAP (5-lipoxygenase activating protein)  LTA4 (unstable intermediate). LTA4 can be converted to LTB4 (via LTA4 hydroxylase) or LTC4 (via LTC4 synthase) depending on cell type LTC4LTD4LTE4 via enzymes in tissues / circulation

Mechanism of Action: leukotriene antagonist anti-asthma agents. Effects: Inhibits cysteinyl-LT (enzyme involved in downstream conversion of leukotrines to effectors). Indications: Prophy/maintenance of asthma sx. Increases FEV1% and reduces asthma symptoms  Montelukast at least as effective as zafirlukast

zafirlukast montelukast

Metabolism: montelukast:  Rapid GI absorption; plasma [] peak in 3-4 hrs; half-life 2.75-5.5 hrs. Metabolized by CYP3A4 and 2C9. Toxicity:  zafirlukast: inhibits CYP450 enzymes (drug interactions with theophylline, warfarin, prednisone o Churg-Strauss vasculitis & hepatic toxicity too.  montelukast: doesn’t inhibit CYP450s; less of other side effects too


Mechanism of Action: leukotrine antagonist antiasthma agent. Inhibits 5-lipoxygenase Effects: 5-lipoxygenase mediates conversion of arachidonate to LTA4 in the leukotrine metabolite pathway. Indications: Not first line; may use as alternative to corticosteroids if contraindicated. Administration: 600 mg QID Metabolism: rapidly absorbed, Tmax = 2hrs, T1/2 = 2.5 hrs. Hepatic glucuronidation.

Anti-IgE mAb
Mechanism of Action: anti-IgE mAB(anti-asthma) Effects:  binds free IgE (released from mast cells & basophils in pts with allergic component to asthma);  down-regulation of IgE receptors results (long-lasting effect: 100-fold reduction in IgE)

omalizumab (Xolair)

Indications: > 12 years old with  moderate/severe persistent asthma &  reactivity to allergen with symptoms inadequtely controlled by inhaled corticosteroid  (e.g. tons of hosp visits or severe symptoms) Administration: IV or SQ q 4 wks Other: EXPENSIVE (annual cost $6-12k) - cost-effective if preventing many hospital visits in allergic patients.

Summary (from slides)
 The fastest bronchodilator response is provided by inhaled beta-2 agonists.  More prolonged bronchodilator response may be achieved with salmeterol, formoterol or theophylline. Reducing or preventing inflammation is an important aspect of asthma treatment.  Inhaled corticosteroids are the drugs of choice for preventing or blunting the inflammatory response. Zafirlukast or montelukast may offer a convenient, oral alternative to or adjunct with inhaled corticosteroids.  Bronchodilator treatment may augment or, in selected patients, replace anti-inflammatory agents.  Systemic (oral or intravenous) corticosteroids should be reserved for severe cases in which less hazardous treatments have failed.  Omalizumab is a novel treatment for asthma, but its cost and the uncertainty of long-term safety suggest that it should be reserved for patients with severe asthma who are frequently admitted to the hospital.

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