Respiratory System-

Drugs for Asthma

Classification of drugs

Drugs used to treat asthma

Drugs used to treat allergic rhinitis
Drugs used to threat chronic
obstruction pulmonary diseases (COPD)
Drugs used to treat cough
Definitions of Asthma
Clinical - Asthma a disease that makes airways
prone to narrowing in response to a variety of
stimuli leading to wheezing, coughing and
shortness of breath with reduced airflow in the
lungs
Pathological- Asthma is a disease of the airways
characterized by chronic inflammation with
infiltration of lymphocytes, eosinophils and mast
cells together with epithelial desquamation, smooth
muscle thickening and disorganization of the tissues
of the airway
From Lippincotts 4th edition
Characteristics of airways
in asthma
inflammation of the mucosa
increased sensitivity of airway smooth
muscle to stimuli
Airway remodeling
increased thickness of mucosa and muscle
increased number of mucus gland cells
mucus gland cells found in smaller branches of
bronchioles
increased basement membrane thickness
From Katzung, 11th edition
Stimuli / Other Factors
allergens exercise
not all atopic have asthma industrial chemicals and
dust mites, pollen byproducts
pollutants aluminum smelters
SOx cedar dust
food additives lung infection
bisulfite antioxidants predisposing before age of
cold air two
drugs genetic predisposition
more boys than girls in
aspirin childhood
more women than men
from 2nd decade onwards
Familial risk of allergies
Control of Airway Diameter

Parasympathetic
ACh is the neurotransmitter at airway smooth muscle
it acts at M3 receptors- activation causes formation of IP3
(increasing Ca2+) and diacylglycerol tension is the result
No sympathetic innervation
2 adrenoceptors are present in airway smooth muscle
normally epinephrine released from adrenal medulla
activates
Other nerves - bradykinin, neurokinins
From Katzung, et al., 11th edition
Sensory afferents
sensory endings in the mucosal lining
stimulation by irritants leads to local reflex
stimulation of tissue
induce smooth muscle contraction can
induce mucus release
causes local inflammatory response
vasodilatation
These nerve endings are exposed more
when airway epithelium damaged
Mast Cells

Present in or near airway tissues: smooth

muscle (both airway and vascular) and
epithelium (both surface and glands)
Mast cell sensitized by IgE for specific
antigen will then release stored substance
on subsequent exposure to that antigen and
synthesize other factors
From Brodys Human Pharmacology, 4th edition
Inflammatory Response
After release of chemotactic agents from mast cells,
platelets, etc. eosinophils, neutrophils and other
leukocytes invade mucosa
This occurs hours after the initial inflammatory
response - the late phase of an asthma attack
Eosinophils release many agents
Leukotrienes
Platelet activating factor
Chemotactic factor
Cytotoxic substances
From Rang and Dales, 6th edition
Therapies for Asthma

Treatments that mitigate an asthma attack

Treatments that relax airway smooth muscle
Treatments that mitigate chronic inflammation
Relaxing airway contraction

Inhibition of Bronchoconstriction
Phosphodiesterase Inhibitors
Muscarinic receptor antagonists
2-adrenoceptor agonists
From Katzung et al., 11th edition
Phosphodiesterase Inhibitors

Methylxanthine (caffeine is in this group)

Theophylline (aminophylline is the ethylenediamine complex)
The therapeutic index of Theophylline is low
Causing severe toxicity (the conc. > 20 g/mL in blood)
Inhibits the breakdown of cyclic AMP by inhibiting
phosphodiesterase
cAMP produced by 2-adrenoceptor activation initiates a
phosphorylation cascade causing relaxation of airway
smooth muscle
They are adenosine receptor antagonists
Clinical Use of
Phosphodiesterase Inhibitors
Given orally
Sustained release preparations are available
Blood levels should be controlled
therapeutic range 5-20 mg/L
below 5 no therapeutic effect
above 20 side effects become a problem
anorexia, headache, abdominal discomfort,
anxiety
seizures and arrhythmias occur at high
concentrations (>40 mg/L)
Muscarinic antagonists


e.g. Ipratropium
-adrenergic agonists
Atropine is not used now
dries mucus membranes, too many side effects
doesnt reverse bronchoconstriction
in asthma bronchoconstriction is mostly due to
leukotrienes and other substances not muscarinic
receptor stimulation
can cause viscid mucus plugs to form
Ipratropium
Quaternary muscarinic antagonist
Given by nebulization () so effects
limited to airway
Not routinely used as the only drug in the
treatment of asthma
Has definite value in the treatment of acute
asthma exacerbation when used in addition
to -agonists
Used in the treatment of chronic obstructive
pulmonary disease - COPD
Adrenergic agonists

2-adrenergic agonist


Short and long acting drugs
Short acting drugs
15-30 min, 4 6 hours


Metaproterenol, albuterol, salbutamol, terbutaline,
bitolterol, pirbuterol
all can be given by inhalation nebulization
metaproterenol, terbutaline, albuterol can be given orally
terbutaline injectable subcutaneous


Long acting drugs

Salmeterol, formoterol
long acting - 12 hours or more
forms slow release depot in tissue (lipid soluble)
long duration of action used to treat nocturnal
asthma
not used as monotherapy always with inhaled
steroids


 Other -Agonists
Epinephrine
good bronchodilator - not selective (all and )
short lived
used in emergencies, subcutaneous injection - severe asthma,
hypersensitivity reactions, anaphylaxis
Available OTC (Over-The-Counter)
Ephedrine ()
long history of use in China
2 selective, not used much in asthma now
Not as easily now available since methamphetamine can be made
from this drug
CNS stimulant, amphetamine look-alike, truck stop pharmacology
Side Effects of -agonists
Not completely selective
Can increase heart rate
Can cause arrhythmias
Headache - vasodilation
Anti-allergy agents
- Omalizumab [oh-mah-lye-ZOO-mab]
Recombinant humanized antibody against the C3
domain of IgE
Complexes IgE preventing activation of mast cells
and basophils thus prevents the release of
inflammatory mediators
Market name: Xolair
Used only after primary treatments have failed
The drug is administered subcutaneously in 1 to 3
injections every 2 or 4 weeks
Not recommended when living in environments
where the presence of parasites is common
Inhibition of Leukotrienes
Inhibition of the formation of leukotrienes
5-lipoxygenase inhibitor
Zileuton
Increases the lifetime of theophylline and drugs
metabolized by CYP3A4

Inhibition of the action of leukotrienes

leukotriene receptor antagonists (LTRA)
Zafirlukast (LTD4), montelukast (LTD4)
Zafirlukast (po), montelukast (po)
 Arachidonic acid
Zileuton
-
5-Lipoxygenase Cyclooxygenase

Leukotrienes Prostaglandins
LTB4 LTC4
LTD4
LTE4

LTC4 + CystLT1 Contraction of airway

LTD4 smooth muscle cells

-
Zafirlukast
(CystLT1 antagonists)
Montelukast
 Properties Leukotriene receptor antagonists
Not all patients respond
Aspirin sensitivity results from LTD4 release
Aspirin (or NSAID) sensitivity may be caused by
inhibiting cyclooxygenase and shunting of arachidonic
acid metabolism into the leukotriene pathway
Takes 3-14 days to work - used for chronic
therapy
Contraindications - liver disease, pregnancy
(crosses placenta), breast feeding (excreted)
Fewer of the above concerns with montelukast as
compared to zafirlukast or zileuton
Steroids

Systemic steroids
glucocorticoids (e.g., prednisone, prednisolone)
used to treat severe persistent asthma
significant side effects
water retention - moon face (Cushingoid features)
Immunosuppression
Steroids reverse inflammation and reduce
sensitivity of airway smooth muscle to stimulation
adrenal suppression-must taper dose when discontinuing after
prolonged therapy
Inhaled Steroids

Beclomethasone, Budesonide, Flunisolide,

Fluticasone, Mometasone and Triamcinolone
given by inhaled route
minimal systemic effects (better topical:systemic ratio)
reduces need for oral steroids
Used as first line therapy for newly diagnosed cases -
decreases chronic inflammation and might reverse
remodeling of the airways
Oral candidiasis - thrush - gargle and spit, use a spacer
Pharmacokinetics
of inhaled
glucocorticoids

From Lippincotts 4th edition

Glucocorticoids Actions

Decrease the following

Secretion from, and numbers of eosinophils
Cytokines from T-lymphocytes
Number of mast cells
Secretion and production of cytokines by
macrophages
Leakiness of endothelia (vasoconstriction)
Mucus secretion and hypertrophy of mucus cells
Upregulation of -adrenergic receptors
Glucocorticoids

2
adrenergic agonists
glucocorticoids

glucocorticoids
Glucocorticoids on lung

Steroids
glucocorticoides
T

steroids


Side effects of glucocorticoids

From Lippincotts 4th edition

Cromolyn/Nedocromil
Mechanism
inhibits the degranulation of mast cells - by
inhibiting chloride conductance channels in the
mast cell membranes which reduces
intracellular calcium increases
works only prophylactically ()
cannot terminate an attack
can reduce late phase response when given
after an initial attack - inhibits eosinophil
degranulation
Treatments by
Cromolyn/Nedocromil
Given by nebulization
solution that is nebulized
Microfine powder - Spinhaler
Few side effects because it is poorly absorbed and
not metabolized
side effects primarily in airway
can induce bronchoconstriction, chest tightness, coughing,
xerostomia ()
effects minimized by taking 2-agonist concomitantly
Used to treat allergic rhinitis
available OTC
Cromolyn and nedocromil




Treatment of Asthma

From Lippincotts 4th edition

Asthma

(COPD)


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