Drugs used in asthma
& COPD
By Dr.
Mahmoud A. Naga
Bronchial Asthma
• Asthma is an chronic inflammatory disease of the airways with
hyper-reactivity
characterized
by
episodes
of
acute
bronchoconstriction causing shortness of breath, cough, chest
tightness, wheezing, and rapid respiration.
* Types & causes →
1- Antigenic (Extrinsic) asthma →
2. Non-antigenic (Intrinsic) asthma →
1- Exercise-induced asthma.
2. Emotional factors
3- Infections
4- Irritants AS dust
5- Drugs → Parasympathomimetics, non selective β.β & may
selective β.β (by large dose), Histamine releasers, PGF2α, Aspirin &
NSAIDs → ↑leukotriens & ACEIs → ↑ kinins
* Pathogenesis & pathology
1- First Exposure → antigenic or non-antigenic stimuli stimulates
inflammatory cells → air way obstruction by
1- Bronchospasm in s.m.f. of bronchi
2- Congestion and edema of mucosa.
3- Infiltration mucosa by inflammatory cells.
4- Increased mucus secretion that is difficult to expel.
2- Recurrent exposure → chronic inflammation → hyperreactive airway with exaggerated response to usual stimuli &
mediators
Treatment
1- Prevention of exposure to precipitating factors (causes)
2- ttt of bronchospasm → Bronchodilators
3- ↓ mucosal inflammation & hyper-reactivity→ anti-inflammatory
drugs
4- Prevent recurrence (Prophylactic ttt) → Mast cell stabilizers
* enough alone in mild asthma
* In moderate & severe asthma may need prophylactic
bronchodilators & steroids
A. Bronchodilators
1. Selective Beta 2 agonist
•
Short acting: Salbutamol = Albuterol, terbutaline,
(duration of action less than 6hrs )
Given by inhalation in acute B.A.
•
Long acting: salmetrol, formoterol
(duration of action more than 12hrs)
Given oral in chronic B.A.
Mechanism of action
Stimulate adenylate cyclase which increases the cAMP
resulting in powerful brochodilator response
Clinical uses:
• Asthma
– First line therapy in the treatment of asthma, the
short acting are used in the acute attacks
– Short act in acute & The long acting are used as
prophylaxis in chronic BA and not used in acute as
onset of action is too slow.
COPD
second line as affect heart (tachycardia)
Adverse effects
• usual dose (beta 2 effect)
Tremors, hypotension (with reflex tachycardia)
• At high dose
stimulate beta 1 and cause tachycardia
• Tolerance and tachyphylaxis develop with excessive use
of the inhaler (by receptor down regulation)
• Patients with COPD usually have concurrent heart
disease, arrhythmia may develop even with normal doses
2. Muscarinic antagonists
• Ipratropium,
short act given by inhalation (aerosol), & also oral
• Tiotropium
longer acting, given oral or inhalation
• Mechanism of action:
competitively block muscarinic receptors (M3) in the
airways and effectively prevent the braonchoconstriction
caused by vagal discharge. It has no effect on the
inflammatory aspect of asthma
Use
1. B.A.: it is 2nd choice after B2 agonist & better to be
combined with B2 agonist
2. COPD: it is 1st choice as no cardiac S.E.
Adverse effects:
•
therapeutic dose
Minimal because the drug is directly delivered to
the airway
•
Overdose causes
3. Methylxanthines
• Three major methylxanthines are found in the plants,
caffeine (coffee) theophylline (tea) & theobromine
(cocoa = Cacao).
• Theophylline is the only one used in B.A.
• given orally (chronic) and injection (slow I.V. in acute)
• Eliminated by CYP 450 in the liver
• Clearance varies with age (highest in young adolescent
& lower in old, neonate), smoking status (higher in
smokers), and drugs that induce liver enzymes
(increase clearance) or inhibit liver enzymes (decrease
clearance)
• Narrow therapeutic window
Mechanism of action
• Inhibit phosphodiestrase, the enzyme that degrades
cAMP leading to incraese cAMP & bronchodilation
• They also block the adenosine receptors in the CNS
Effects:
• CNS stimulation
• Bronchodilator
• Cardiac stimulation (increase contractility & HR)
• Slight increase in blood pressure by increase C. OP
• peripheral Vasodilation (increase renal bl. Flow, diuresis)
• GIT: may Increase GIT motility & HCL by irritative effect
& may cause relaxation by cAMP (as beta2 effect)
Clinical uses
1. B.A. : last choice due to dangerous cardiac S.E.
Aminophylline is a salt of theophylline used in B.A.
2. COPD:
also last choice due to dangerous cardiac
S.E.
3. Cardiac asthma (as increase C. op)
4. Pentoxifylline is Dimethylxanthine for intermittent
claudication (leg ischemia, ttt it by V.D.)
Adverse effects
• CNS: tremor, insomnia, seizure
B. Mast cell stabilizers:
Cromolyn and Nedocromil
• They are insoluble drugs, so even massive doses given
orally or by aerosol result in minimal side effects
• Given by aerosol for asthma
• Cromolyn is the prototype in this group
Mechanism of action
• Decrease the release of mediators from mast cells
(leukotrienes and histamine)
Clinical uses
• Local acting drugs
• inhalation
not bronchiodiltors but they prevent B.A. caused by
reaction to an antigen which the patient is allergic to it
• orally can prevent some food allergy
• Nasal and eye drops are available for hay fever and
conjunctivitis
Adverse effects
• May cause irritation of airways and cough when given by
C. Anti-inflammatory drugs
1. Corticosteroids
• Inhaled
steroids
(beclomethasone,
budesonide,
fluticasone ) are used in moderate to severe asthma that
are not fully responsive to beta agonist.
• Early use may prevent the severe, progressive
inflammatory changes that are characteristic for asthma .
• Local administration of steroids by aerosol is relatively safe
and inhaled steroids has become the first line
management of moderate to severe asthma
• IV steroids (Hydrocortisone and prednsilone ) are used
for status asthmaticus and their mechanism of action in
this condition is not fully understood
Mechanism of action & effects
• Inhibit phospholipase A2 leading to decrease
arachdonic acid, PGs & Leucotriens which are
mediators of bronchospasm & inflammatory
response
• It is also suggested that steroids increase the
responsiveness of beta receptors in the airways
• Glucocorticoids binds to glucocorticoids response
elements in the nucleus resulting in the synthesis of
substances that prevent the full expression of
Toxicity
• Inhaled
Changes in oropharyngeal flora can result in oral
candidiasis
• systemic toxicity of steroids include?
1. Small degree of adrenal suppression & if stopped
suddenly will cause addesonian crisis
2. Cushing with long use
3. Regular use of steroids in children can result in
2. Leukotriene antagonist
Leukotriene synthesis
inhibitors
e.g. →
Leukotriene receptor inhibitors
e.g. →
Zileuton
inhibit 5- Lipoxygenase enzyme
Zafirlukast → twice /d
Montelukast → once /d
due to longer t 1/2
* inhibit Leukotriene receptors
* used in ttt of B.A.
orally active and have been shown to be effective in preventing
exercise induced asthma, antigen- and aspirin induced asthma
Toxicity: elevation of liver enzymes
Toxicity is generally low
Rarely Churg-Strauss syndrome have
been reported
3. Anti Ig E antibody =
Omalizumab
• Omalizumab is monoclonal antibody to human
IgE
• It binds to IgE & prevent it from binding to its
receptor on sensitized mast cells and prevent
activation by antigens and subsequent release of
inflammatory mediators
• Approved for prophylactic management of
asthma