Respiratory Pharmacology for Asthma

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Bronchial Asthma
-Airway inflammation
-Bronchial Hyperreactivity
allergens, chemicals, Exercise, NSAIDS, infection

Symptoms
Chest tightness, bronchoconstriciton, secretions,
cought, wheeze, > decreased FEV1

Autopsy Histology
Epithelial Sloughing
Hypertrophy/hyperplasia airway SM
Airway thickness by inflammation, edema
mucous gland hypertrophy, hypersecretionmucous
plugginghyperinflation
Regulation of Bronchial Smooth Muscle
Resting tone sm. muscle affected by vagal (PNS)
innervation
* irritants cause vagal reflex-ACh
bronchoconstriction/increased mucous,
mast cell release

No sympathetic innervation, noninnervated beta2
receptors present
* activated by circulating catecholamines
bronchodilation mast cell release
increase ciliary activity (via cAMP)


Nonadrenergic/noncholinergic mediators from
sensory C fibers
* release substance P (increase mucous/permeability)
* release neurokinin A (spasmogen)
Asthma Attack

Early or immediate phase EAR
* bronchoconstriction due to preformed
mast cell mediator release
* Decreased FEV1


Late Phase LAR
* occurs in 50 % of adult asthmatic
* due to progressive inflammatory and allergic reaction
-Infiltration of Th2release cytokines
- Eosinophils-epithelial damage
*continued release of mediators and activation of C receptors
* Decreased FEV1
Reliever Drugs-Bronchodilator action plus effects on mucous production, cilia, mast cell mediator release
Drug Mechanism Pharm Use Adverse
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Theophylline
Inhibits Phosphodiesterase thus cAMP
by its degradation

Blocks adenosine receptor

Slower onset/less potency than drugs

es skeletal muscle contractility/
muscle fatigue
mucociliary clearance

GI
CNS stimulation (seizures)
Cardiac stimulation (arrhythmias)
Aminophylline
H2O soluble salt form (of theophylline)
for IV admin

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Epinephrine

Not selective for Beta2

OTC available but not recommended:
-short duration of axn
-B1 HR

Acute asthmatic emergency: admin SC
, -1 activity (tachycardia, arrhythmias)
Not used
Isproterenol

Not selective for beta2

Onset of action: 2 to 5 min

Dosing: up to 6 xs daily
OTC available but not recommended:
-short duration of axn
-B1 HR



-1 activity (arrhythmia)
Not used




Drug Mechanism Pharm Use Adverse
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Albuterol
(SABA)
Racemic mixture: S & R enantiomers

Bind beta2 receptors- rate of cAMP
synthesis by adenyl cyclase
relax airway smooth muscle
inhibit release of bronchoconstrictor
mediators from mast cells

Additional possible actions:
inhibit microvascular leakage
increase mucociliary transport by ing
ciliary activity
Onset of axn (via inhalation)
-initial = < 5 min
-max effect = 10-15 min

Duration of axn (via inhalation): 3 to 4 hr

Dosing: Q4-6h



Only agents immediately effective in
EAR/Acute Asthma attacks

Aerosol inhalation [preferred]
Selective -2 drugs [preferred]
S-albuterol may cause paradoxical
bronchospasm by Ca in smooth muscle

PO (same as terbutaline):
-skeletal muscle tremor
-nervousness
-weakness
-peripheral vasodilation dose related
Levalbuterol
(SABA)
R enantiomer (which binds -2 receptor
100xs > S)
Formulation:
-avail as inhalation soln via neb

Causes slightly less cardiac stimulation
(than albuterol)

Terbutaline
(SABA)

Acute asthmatic emergencies: admin SC
PO (same as albuterol):
-skeletal muscle tremor
-nervousness
-weakness
-peripheral vasodilation dose related
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Salmeterol
(LABA)
Formulations:
-salmeterol +/- fluticasone (Advair)

Onset of action: 10 to 20 min

Duration of axn: 12 hrs
-long duration blocks both early & late
asthmatic response when used
chronically

Dosing: Q12h

Due to its slow onset:
-prophylactic control (esp. nocturnal
attacks)

DO NOT USE for acute attacks
FDA Warning (2003): small, but
significant asthma-related deaths
Formoterol
(LABA)
Faster onset of axn

Duration of axn: 12 hrs
-long duration blocks both early and late
asthmatic response when used
chronically

*NOTE: B-Agonist Chronic Tx Concerns
-tolerance: tachyphylaxis, receptor
down-regulation, peak effect,
duration of axn
-rebound bronchoconstriction
-worsening asthma symptoms
- bronchial hyperreactivity
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Ipratropium
Block ACh receptors in airway

NOTE: ACh is released form Vagus nerve
endings and results in contraction of
smooth muscle and ed secretion of
mucus
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Blocks muscarinic receptor
sputum volume w/o viscosity
Claimed not to inhibit mucociliary
clearance

Onset (slow): 1-2 hrs
-NOT for emergencies

Duration (modest bronchodilator): 4-6 h


Asthma
-usually combined with beta-2 drug in
asthma (ipratropium + albuterol)
Respiratory dryness
Irritation
Cough
Tiotropium (Spiriva)
Onset (slow)

Duration of axn: 24 hrs
Formulation: PO inhalation (dry powder)
COPD
-LA anticholinergic bronchodilator

Controller Drugs: Anti-inflammatory
Drug Mechanism Pharm Use Adverse
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Specific:
Beclomethasone
Budesonide
Ciclesonide
Flunisolide
Fluticasone
Mometasone
Triamcinolone
Inhibit expression of genes for many
inflammatory proteins via intracellular
receptor activation

Stabilize mast cells
synthesis of PGs/leukotrienes
Immunosuppressive ( WBCs/
eosinophils/IgE Ab production)

PO/IV for acute conditions
Aerosol (inhalation):
-dysphonia
-oropharyngeal candidiasis
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Cromolyn/
Nedocromil
Inhibit antigen-induced release of
mediators from sensitized mast cells
Inhibits sensory nerve reflexes
Inhibits activation of membrane Cl
channels to dec Ca activation
Long term use lessens EAR and LAR
Lessens response to EIA/cold air/
allergens



Formulation:
-nebulizer/aerosol spray


Asthma (prophylactic use) NOT a
bronchodilator

Allergic rhinitis (nasal spray)

Food allergy in GI tract (PO soln)


Local irritation (eyes, nose)
Bronchospasm/cough/wheezing
Bad taste
HA/dizziness
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Zafirlukast
Antagonism of the LTD4 receptor binding

Leukotriene receptor (cysLT1)
antagonists; NOTE: cysLT1 is the receptor
1 for LTD4

NOTE:
-LTC4, LTD4 are potent inflammatory
mediators synthesized by mast cells
-LTB4 is a potent neutrophil
chemoattractant
Activity begins w/1
st
dose
-requires days weeks for full effect

Drug Ix:
-inhibits P450 enzymes (2C9- phenytoin,
warfarin) and (3A4)


Prophylactic/chronic control asthma

Used to reduce/control chronic
inflammation of asthma AND-
Allow reduction of reliever/steroid drug
dosages

Aspirin-induced asthma
GI (n/v)
HA/dizziness
LFTs
Myalgia/back pain
Infection

Note: Rare eosinophilic vasculitis/
granuloma formation, Churg-Strauss
syndrome, observed w/this drug class
Montelukast (Singulair)

**STAR DRUG***
More specific cys-LT1 blocker (esp. LTD4)

Drug Ix: none significant to date
HA/dizziness
Rash
GI
Nasal/ear/throat/resp congestion/infxns

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Omalizumab
Humanized MoAb binds circulating IgE
Prevents IgE binding on mast cells
Admin: SC Q3-4 weeks based on body wt
and serum IgE level

Peak serum conc.: 7-8 days

t : 26 days
Moderate-severe persistent asthma
uncontrolled by inhaled steroids

Annual cost: $10-12,000
Injection-site rxns
Risk anaphylaxis/anaphylactoid rxn