Drugs used to treat bronchial asthma

Chládek J, Martínková J
2010
 Asthma: Definition
• Asthma is a chronic inflammatory disorder
of the airways, in which many cells and cellular
elements play a role, in particular, mast cells,
eosinophils, Th2-lymphocytes, macrophages,
neutrophils, and epithelial cells.
 Asthma: Definition
• In susceptible individuals, this inflammation causes
recurrent episodes of wheezing, dyspnoea,
restlessness, chest tightness, and coughing,
particularly at night or early morning.
• These episodes are usually associated with widespread
but variable airflow obstruction (difficulty in breathing
out) that is often reversible either spontaneously or with
treatment.
• The inflammation also causes bronchial
hyperresponsiveness to a variety of stimuli (exposure
to asthma triggers).
 Symptoms of asthma
• In most patients, chronic asthma is characterized by relatively
asymptomatic periods with occasional acute attacks (exacerbations),
characterized by dry cough (at night , after excersise), dyspnoe,
wheezing…

• These episodes may resolve fairly rapidly after pharmacological

intervention.

• Sometimes patients may chronically experienced some degree

of airway resistance.

• A serious condition, status asthmaticus (severe asthma attack), occurs

when significant obstruction persists for extended periods. Status
asthmaticus is defined as a therapeutic emergency.
Asthma prevalence and mortality
Masoli M et al. Allergy 2004
 The prevalence of allergy and asthma:
Czech Repulic

1996 2006
allergy 16,9% 31,8%
allergic rhinitis 5,7% 16,1%
asthma 3,8% 8,2%
 Factors that may trigger an asthmatic
reaction

• Allergens (Airborne pollens, Haus dust mites, Animal

dander,Cockroaches, Fungal spores)
• Occupational Factors
• Respiratory Infection
• Smoking (active and pasive)
• Air pollution
• Exercise
• Emotional Factors
• Drugs (aspirine, NSAID)
 Asthma pathophysiology: influence of atopy
and allergy
• Atopy
– genetically determined disposition for augmented Th2 immune
response with increased production of IgE by B cells and
production of certain interleukins (IL-4,5,13) that induce
expression of IgE receptors on mast cells and eosinophils..)
constitutes the largest risk factor for asthma development
– causes positive wheal-and-flare reactions to intradermal injection
of antigen extracts and is associated with increased levels of
serum IgE
• Allergic asthma
– is associated with a family history (or personal history) of allergic
diseases including urticaria (hives), rhinitis, and/or eczema. It is
characterized by positive bronchial response to specific inhaled
antigen (allergen).
Early and late phase of acute asthmatic
reaction. Chronic asthma.

Asthmatic response: Acute Late Chronic asthma

Exposure to allergen

Lung function
(PEF, FEV1)

Time: min hours days

 Phases of acute asthmatic response
(reaction)
• Early asthmatic response: allergen (antigen) causes
IgE-mediated release of preformed and newly
synthetized mediators from mast cells and T-cells
followed by spasm of the bronchial smooth muscle
(bronchoconstriction, decreased FEV1)
• Effective drugs:
– bronchodilators = „quick relievers“
– most effective are inhaled beta-2 agrenergic agonists
(salbutamol, terbutaline, …)
Mediators of early asthmatic response
 Late asthmatic response
• second phase of bronchoconstriction,
• inflammation due to invasion of inflammatory cells
(eosinophils, T cells, neutrophils, macrophages,..)
and activation of epithelial and endothelial cells
• inflammatory cells and activated structural cells release
various mediators of inflammation
• effective drugs:
– antiinflammatory drugs are used to prevent
the second phase and to suppress chronic
inflammation
– most effective are inhaled glucocorticosteroids
(beclomethsone, budesonide, fluticasone)
– bronchodilators are effective against
bronchoconstriction
 Asthma pathophysiology

Smooth
Airways
muscle
inflammation
dysfunction

Airway
remodelling

Its pathologic features are contraction of airway smooth

muscle, mucosal thickening, oedema and cellular infiltration,
viscid plugs of mucus.
Asthma pathophysiology

Smooth
muscle
dysfunction

• Exaggerated contraction
• Increased smooth muscle mass
• Increase release of
inflammatory mediators
 Asthma pathophysiology

Acute Chronic
inflammation inflammation

• Inflammatory cell
• Increased inflammatory
activation
cell numbers
• Inflammatory mediator
release • Epithelial damage
Asthma pathophysiology: chronic asthma

Airway
remodelling

• Cellular proliferation
-smooth muscle cells
-mucous glands
• Increased matrix protein deposition
• Basement membrane thickening
• Angiogenesis
 Antiasthmatics
• Contraction of smooth muscle is reversed by
BRONCHODILATORS = drugs for acute
use = quick relievers
– used on demand, as needed to supress symptoms

• ANTI-INFLAMMATORY AGENTS = drugs

used prophylactically (also in the absence
of symptoms)
– used regularly in long-term therapy
– cause reversal of the oedema and cellular
infiltration, supress activation of structural cells,
prevent exacerbation, decrease bronchial
hyperreactivity, improve lung function…
 Bronchodilators for acute use
• inhaled beta2-agonists with rapid onset of
action (RABA) are drugs of the first choice
– short acting (6 h, SABA) drugs salbutamol
(=albuterol), terbutaline
– long acting (12 h, LABA) drug formoterol
• inhaled antimuscarinic (anticholinergic)
drugs
– ipratropium
• methylxanthines (theophylline) can be used parenterally
(ICU) or orally only if the above effective drugs are
unavailable
 Bronchodilators: mechanisms of action
anticholinergics (parasympahtolytics)
2-agonists ( 2-sympathomimetics) antagonists of acetylcholine on
M receptors
stimulace 2 adrenergních receptorů
acetylcholine

M3

bronchodilation inhibition of
bronchoconstriction
adenylatcyclase phospholipase C
proteinkinase A proteinkinase C

ATP cAMP IP3 + DAG phosphatidylinositol

phosphodiesterases
cGMP
5´AMP
inhibitors:
methylxantines (theofylin)
 Inhaled beta2-selective agonist drugs

are most widely used quick-relief drugs for the treatment

of asthma at the present time
 relax airway smooth muscle
 inhibit release of some mast cell bronchoconstrictive mediators from mast
cells
 inhibit microvascular leakage
 increase mucociliary transport

Salbutamol (albuterol), terbutaline, (SABA, short acting) are

administered by inhalation from simple inhalers.
Bronchodilation begins in 5 minutes, is maximal by 30-60
minutes and persists for 2-4 hours.
Formoterol can also be used as a quick reliever. It is a long-
acting drug (LABA) but with rapid onset of action (7-10 min).
Fenoterol is less beta-2 selective and was associated with
an increased risk of sudden cardiovascular death.
Adverse effects of inhaled beta2 agonists

• inhaled beta2-agonists are well tolerated

• AE result from activation of beta-2 receptors
in other organs or, after very high doses, from
activation of beta1-receptors
• muscle tremor and palpitation: unpleasant but not
risky
• tachycardia, worsening of ischemia, cardiac
arrhythmias (no increase in cardiovascular
mortality and morbidity in large trials with COPD
patients)
• hypokalemia
 Beta2 agonists for systemic use

Adverse effects are more frequent and

bronchodilating effect is less after systemic
administration (oral, i.v.) of rapid acting beta2-
agonists than after inhalation.
Nonselective sympathomimetic adrenaline is
used to treat anaphylaxis and is not suitable for
asthma treatment

Although effective when injected subcutaneously (1:1000

solution) or inhaled as a microaerosol, its effect is of short
duration and adverse effects are worse (tachycardia,
arrhythmias, worsening of angina pectoris) .
DRUGS FOR ACUTE USE
2. Muscarinic antagonists
Muscarinic antagonists competitively inhibit the effect of acetylcholine
at muscarinic receptors.
More selective quaternary ammonium derivative of atropine, ipratropium
bromide, a short-acting drug, is used for patients with heart disease or
thyreotoxicosis in whom beta agonists are unsuitable.
Another derivative is thiotropium (longer duration of action 12 h).

atropine ipratropium

Bronchodilating effect is less compared to beta-2 agonists and

onset of action is delayed (15-30 min), duration of action 4-6 h.
DRUGS FOR ACUTE USE

3. Theophylline
Theophylline is similar to theobromine 3,7- dimethylxanthine , and
caffeine (1,3,7,-trimethylxanthine) (alkaloids from tea, cocoa, and coffee,
respectively).
Theophylline in immediate release oral or i.v. formulations was
largely replaced by beta2-agonists.
Its use is possible if beta2-agonists are unavailable or as a cheap
alternative in less developed countries.
Theophylline in tablets (slow-release) is used in combination with
inhaled CS as ant-iinflammatory therapy.

1,3-dimethylxanthine
(theophylline)
 Theophylline
Mechanism of action:
- inhibition of phosphodiesterases (partial and only at hich conc.)
- antagonism on adenosine receptors
- other (antiinflammatory, not yet fully known)

• Effects on smooth muscle vasodilation, bronchodilation

• Central nervous system effects increased alertness, tremor and
nervousness, stimulant effects on respiration
• Cardiovascular effects stimulation of the heart (positive chronotropic
and inotropic actions)
• Effects on the GIT spasmolytic action, increase in HCL secretion
• Effects on kidney weak diuretic effect, involving both increased GF
and reduced reabsorption in the tubules
• narrow threapeutic window

Pharmacokinetics: well absorbed from GIT, metabolised in the liver,

variable kinetics, many PK interactions through cytochrome P450
enzymes,
 DRUGS FOR PROPHYLAXIS
1. Glucocorticosteroids
1.1 Inhaled (ICS)
1.2 Oral
2. Antileukotrienes
3. Anti-IgE antibody
4. Drug combinations
ICS + long-acting beta2-agonist (LABA),
ICS + antileukotrienes
ICS + slow-release oral theophylline
ICS + anti IgE antibody
5. Immunoprophylactic drugs
DRUGS USED FOR PROPHYLAXIS

1.1 Inhaled corticosteroids (ICS)

Mechanism of action:
• increased synthesis of antiinflammatory molecules
• inhibition of proinflammatory cytokine production
• secondary: enhancement of beta-receptor agonist
effects (synergy)
Effects:
• effectively reduce symptoms
• improve pulmonary function
• reduce bronchial hyperreactivity
 Mechanism of action
• binding to cytoplasmatic receptor (GR), this complex moves to the nucleus
• increased transcription of antiinflammatory genes
• supression of transcription of proinflamatory genes
ICS are lipid-soluble corticosteroids with high glucocorticoid
potency but minimum systemic availability if administered
orally (i.e. if swallowed after inhalation):
beclomethasone, budesonide, fluticasone,
mometasone, ciclesonide

An average daily dose ranges from 100-2000 g/day.

It is different for different molecules, inhalers and asthma
severity.

Systemic steroid adverse effects of ICS are negligible if compared

with those of oral CS (prednisone, prednisolone).
Local adverse effects (oropharyngeal candidiasis, horse voice..)
- good inhalation technique and mouthwashes can reduce this problem.
ICS and the growth in children

Long-term and retrospective studies proved that long-term

treatment with ICS (BUD 200-800 g/day) does not
lead to the shorter definitive stature.

Uncontrolled asthma itself leads to growth

deceleration but also to the shorter definitive stature.
 ICS
• are currently the most effective long-term
preventive medications
• early diagnosis and treatment with ICS is important for
prevention of airway remodelling
• initial treatment: dosing guided by asthma severity, more
agressive (higher doses)
• long-term treatment: titration of the lowest effective dose
 TIME for various effects of ICS to occur

symptoms pulmonary function

bronchial
Responses (%)

hyperreactivity

months
 DOSE - RELATED RESPONSES OF ASTHMATICS TO INHALED
CORTICOSTEROIDS (ICS)

supersensitivity
mild asthma
to ICS
Responses (%)

moderate asthma

severe asthma

resistence to ICS

Doses ( g/day)
1.2 Corticosteroids administered orally

1/Because of severe adverse effects of long-term tratment,

oral corticosteroids are generally reserved for patients with
most severe corticosteroid-dependant asthma.
Nevertheless, attempts are performed to reduce or interrupt
dosing of oral ICS with the help of high doses of ICS and
combination therapy.
Dosing: 30-60 mg of prednisone per day or on alternative days

2/ Short-term use to treat asthma exacerbation: 3-10 days

Systemic adverse effects of glucocorticoids
administered orally (long-term therapy several
weeks to months):

• gluconeogenesis (hyperglycemia)
• hypertension
• immunosuppresion
• adrenal suppresion
• osteoporosis
• growth decelaration in children/reduced adult hight
• cataract
• glaucoma
 2. Antileukotrienes

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) were previously

described as a slow-reacting substance of anaphylaxis.

LTC4, LTD4 are most potent bronchoconstrictors.

LTB4 is a chemotaxin that recruits leukocytes into the

bronchial mucosa and then activates them.
2. Antileukotrienes
 2. Antileukotrienes
• Cysteinyl leukotriene-receptor antagonists.

Montelukast prevents antigen-induced and exercise-induced asthma.

It relaxes the airways in mild asthma, its effects are additive with 2
adrenoceptors agonists. It is more effective in the treatment of aspirin-
sensitive asthma. Administered orally once daily.

• 5-lipoxygenase inhibitors

Zileuton. These agents prevent the production not only cysteinyl LT

(LTC4 and LTD4) but also LTB4 (a chemotaxin that recruits leukocytes
into the bronchial mucosa and then activates them). Administered orally
4-times daily. Hepatotoxicity (elevation of liver enzymes).

• weak antiinflammatory effects compared to ICS

3. Anti-IgE antibody (s.c.)
• omalizumab,
humanized recombinant
anti IgE antibody
• binds to circulating free
IgE
• reduces expression of
high-affinity receptors
for IgE on mast cells
and basophils
 3. Anti-IgE antibody (s.c.)

• administered s.c. once in 2-4 weeks

• dose according to body weight and IgE concentration
• high costs: 1500 USD/month

Effects:
• decreases the intensity of allergic inflammation
• reduces eosinophilia in the airways
• improves lung function
• bronchial hyperesponsivness is influenced less

Indication:
• severe allergic asthma not responding insufficiently
to the combination of ICS+ long-acting beta2 agonists
4. DRUGS COMBINATIONS
USED FOR PROPHYLAXIS
DRUGS COMBINATIONS USED FOR PROPHYLAXIS

4.1 ICS + inhaled long-acting beta2-agonists

(LABA)

The most effective antiinflammatory and prophylactic therapy.

LABA have increased duration of action (12–24h) compared
with older beta2-agonists (4-6 h) and include:
formoterol, salmeterol (for inhalation)
clenbuterol, procaterol (per os, more adverse effects)
As a monotherapy, LABA can be used to eleviate/protect
from bronchoconstriction (nocturnal asthma, exercise-
induced asthma).

LABA must not be used long-term as a monotherapy for

persistant asthma because of absence of anti-
inflammatory effects!!!
DRUGS COMBINATIONS USED FOR PROPHYLAXIS

ICS + LABA by inhalation are available

also as fixed-combinations (both drugs in one inhaler):

Fluticasone/Salmeterol
Budesonide/Formoterol

The most effective (also expensive) inhalation therapy

because of synergy and complementary mechanisms
of action.
Used in moderate-severe and severe asthma.
Daily dose of inhalation corticosteroid can be reduced and
effect is better (less adverse effects of ICS).
DRUGS USED FOR PROPHYLAXIS

4.2 ICS + antileukotrienes p.o.

4.3 ICS + oral sustained-release tablets with

theophylline

4.4. ICS + omalizumab

 3. Immunoprophylactic drugs
(Mast cell stabilizers)

Sodium cromoglycate and nedocromil administered by inhalation.

• reduce histamine and other mediators release from mast cells and
possibly other cells.
• partially inhibit early and late asthmatic reaction and reduce
bronchial hyperreactivity.
• no effect on airway smooth muscle tone - are ineffective in reversing
bronchospasm
• they are only of value when taken prophylactically: 4 to 6 weeks
of treatment for the effect to develop
• week antiinflammatory effect (if any)
• used in some countries to treat children with intermittent asthma.
 Management of acute asthma exacerbation

• At home: according to a written asthma

management plan:
– Bronchodilators: repeated administrations of rapid-acting inhaled
beta2-agonists (2 to 4 puffs every 20 minutes for the first hour)
using MDI+spacer
– Thereafter more all less frequent administration of inhaled
beta2-agonists based on severity and response of exacerbation
– Oral CS once daily for 3 days (up to 1 mg/kg prednisolone or
equivalent) in all but mildest exacerbations
– Assessment of asthma management plan (change in
prophylactic therapy (increased dosing of ICS / combinations)
 Management of acute asthma exacerbation

• Hospital-based management: severe exacerbation nonresponding

to the above therapy:
– Life-threatening medical emergency
– Oxygen
– Bronchodilators (beta2-agonists) by nebulization, however MDI +
spacer/face mask also work. If unavailable, i.v. and oral
formulations work.
– Severe asthma exacerbation nonresponding to inhaled beta-2: i.v.
beta-2, adrenaline
– Adrenaline (epinephrine) – s.c. or i.m. for treatment of anaphylaxis
and angioedema.
– Assessment of asthma management plan (change in prophylactic
therapy (increased dosing of ICS / combinations)
– Other bronchodilators less effective (ipratropium, methylxanthines)
– Systemic CS: oral, i.v., i.m. all work, route of admin. depends on the
situation (0.5 – 1 mg/kg prednisolone or equivalent for 3-10 days).