Pharmacology: Lung

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

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

β2-agonists
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.

Selective Toxicity: Selective for beta-2 over beta-1

Indications: Quick-acting symptom relief for asthma
albuterol
Administration: MDI or neb
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

Long-acting
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

Administration:
salmeterol
 Salmeterol: Does not fully occupy beta-2 receptors so can use short-acting drugs as needed as rescue
formoterol
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)

 Inhaled Administration: Nebulizers vs Metered-dose inhalers (MDIs)
MDI Nebulizer
 Enhances drug delivery to site of action
 Doesn’t require coordination like MDI
Advantages (droplet size optimized to hit deep airways)
 Delivers more medication
 ↓ systemic absorption, toxicity
 Coordination & understanding required  More expensive than MDI
Disadvantages
 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:
ipratropium  block muscarinic receptors in airway smooth muscle
o (inhibit resting cholinergic bronchoconstror tone by reducing cGMP levels).
bromide
 Also block vagus reflex bronchoconstriction (block sensory afferent input)
o augments parasympathetics so more bronchodilation.
tiotropium
Indications: short-acting asthma rescue
Administration: more robust response when combined with albuterol
Other: tiotropium's use in asthma is off-label

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.
 Glucocorticosteroids
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.

inhaled Administration: 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).
neocromil
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 Arachidonate presented to 5-lipoxygenase by FLAP (5-lipoxygenase

activating protein)  LTA4 (unstable intermediate).
o LTA4 can be converted to LTB4 (via LTA4 hydroxylase) or LTC4 (via
LTC4 synthase) depending on cell type
o 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
Metabolism: montelukast:
 Rapid GI absorption; plasma [] peak in 3-4 hrs; half-life 2.75-5.5 hrs. Metabolized by CYP3A4 and 2C9.
montelukast
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.
Zileuton 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 Indications: > 12 years old with

(Xolair)  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.