1. Drugs used to treat bronchial asthma
J. Chládek
2013

2. 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.

3. 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).

4. 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.

5. Asthma prevalence and mortality Masoli M et al. Allergy 2004

6. The prevalence of allergy and asthma: Czech Repulic
allergy 16,9% ,8%
allergic rhinitis 5,7% ,1%
asthma ,8% ,2%

7. Hygiene hypothesis

8. Factors that may trigger an asthmatic reaction
Allergens (Airborne pollens, House dust mites, Animal dander,Cockroaches, Fungal spores)
Occupational Factors
Viral Respiratory Infection
Smoking (active and pasive)
Air pollution
Exercise
Emotional Factors
Drugs (aspirin, other NSAID)

9. Asthma pathophysiology: influence of atopy and allergy
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).

10. 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

11. 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, …)

12. Mediators of early asthmatic response

13. 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:
Anti-inflammatory drugs are used to prevent the second phase and to suppress chronic inflammation
most effective ones are inhaled glucocorticosteroids (beclomethasone, budesonide, fluticasone …)
bronchodilators are effective against bronchoconstriction

14. Asthma pathophysiology
Smooth
muscle
dysfunction
Airways
inflammation
Airway
remodelling
Its pathologic features are contraction of airway smooth muscle, mucosal thickening, oedema and cellular infiltration, viscid plugs of mucus.

15. Asthma pathophysiology
Smooth
muscle
dysfunction
Exaggerated contraction
Increased smooth muscle mass
Increase release of inflammatory mediators

16. Asthma pathophysiology
Acute
inflammation
Chronic
Increased inflammatory
cell numbers
Epithelial damage
Inflammatory cell
activation
Inflammatory mediator
release

17. Asthma pathophysiology: chronic asthma
Airway
remodelling
Cellular proliferation
-smooth muscle cells
-mucous glands
Increased matrix protein deposition
Basement membrane thickening
Angiogenesis

18. 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…

19. Bronchodilators for acute use
inhaled beta2-agonists with rapid onset of action (RABA) are drugs of the first choice
short acting (6 h, SABA): salbutamol (= albuterol), terbutaline
long acting (12 h, LABA) drug formoterol
inhaled antimuscarinic (anticholinergic) drugs
Ipratropium, thiotropium
methylxanthines (theophylline, aminophylline = theophylline ethylenediamine) can be used parenterally (acute asthma -ICU) or orally (delayed effect) but have weaker effect. Only if the above effective drugs are unavailable or patients shows insuff. response to them

20. Bronchodilators: mechanisms of action
phosphodiesterases
phospholipase C
bronchodilation
cAMP b 2
b2-agonists (b2-sympathomimetics)
5´AMP
inhibitors:
methylxantines (theofylin)
IP3 + DAG M 3
anticholinergics (parasympahtolytics)
acetylcholine
stimulation of b2 adrenoreceptors
adenylate cyclase
antagonists of acetylcholine on M receptors
protein kinase A
phosphatidylinositol
inhibition of bronchoconstriction
protein kinase C
cGMP

21. Bronchodilators: beta2-agonists
terbutaline
cAMP

22. 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 mucocilliary transport
Salbutamol (albuterol), terbutaline, (SABA, short acting) are administered by inhalation from simple inhalers.
Bronchodilation begins in 5 minutes, is maximal by minutes and persists for 4-6 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.

23. 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

24. 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.
clenbuterol, procaterol

25. Nonselective sympathomimetic adrenaline is used to treat anaphylaxis and is not suitable for asthma treatment
Although effective when injected or inhaled as a microaerosol, its effect is of short duration and adverse effects are worse (tachycardia, arrhythmias, worsening of angina pectoris) .

26. 2. Muscarinic antagonists
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).
Bronchodilating effect is less compared to beta-2 agonists and onset of action is delayed (15-30 min), duration of action 4-6 h.
atropine
ipratropium

27. 3. Theophylline DRUGS FOR ACUTE USE
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)

28. 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,

29. DRUGS FOR PROPHYLAXIS ICS + long-acting beta2-agonist (LABA),
1. Glucocorticosteroids
1.1 Inhaled (ICS)
1.2 Oral
2. Antileukotrienes
3. Anti-IgE antibody (omalizumab)
4. Drug combinations
ICS + long-acting beta2-agonist (LABA),
ICS + antileukotrienes
ICS + slow-release oral theophylline
ICS + anti IgE antibody
5. Allergen immunotherapy
6. Immunoprophylactic drugs-mast cell stabilizers

30. 1.1 Inhaled corticosteroids (ICS)
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

31. 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

32. beclomethasone, budesonide, fluticasone, mometasone, ciclesonide
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 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.

33. ICS and the growth in children
Long-term and retrospective studies proved that long-term
treatment with ICS (BUD g/day) does not
lead to the shorter definitive stature.
Uncontrolled asthma itself leads to growth
deceleration but also to the shorter definitive stature.

34. are currently the most effective long-term
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

35. TIME for various effects of ICS to occur
symptoms
pulmonary function
bronchial
hyperreactivity
Responses (%)
months

36. supersensitivity to ICS mild asthma moderate asthma Responses (%)
DOSE - RELATED RESPONSES OF ASTHMATICS TO INHALED
CORTICOSTEROIDS (ICS)
supersensitivity
to ICS
mild asthma
moderate asthma
Responses (%)
severe asthma
resistence to ICS
Doses (g/day)

37. 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: mg of prednisone per day or on alternative days
2/ Short-term use to treat asthma exacerbation: 3-10 days

38. 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

39. 2. Antileukotrienes
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) were previously described as a slow-reacting substance of anaphylaxis.
LTC4, LTD4 are the most potent bronchoconstrictors.
LTB4 is a chemotaxin that recruits leukocytes into the bronchial mucosa and then activates them.

40. 2. Antileukotrienes

41. 2. Antileukotrienes Cysteinyl leukotriene-receptor antagonists.
Montelukast (zafirlikast, pranlukast) prevent antigen-induced and exercise-induced asthma. They relax the airways in mild asthma, their effects are additive with 2 adrenoceptors agonists. Are more effective in the treatment of aspirin-sensitive asthma. Administered orally once (montelukast) or twice daily.
weak antiinflammatory effects compared to ICS
free of significant adverse effects
5-lipoxygenase inhibitors
Zileuton. These agent prevent the production not only of 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) was recorded.

42. 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

43. 3. Anti-IgE antibody (s.c.)
administered s.c. once in 2-4 weeks
dose according to body weight and IgE concentration
high costs: 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 43

44. 4. DRUG COMBINATIONS
USED FOR PROPHYLAXIS

45. 4.1 ICS + inhaled long-acting beta2-agonists (LABA) = first choice
DRUG COMBINATIONS USED FOR PROPHYLAXIS
4.1 ICS + inhaled long-acting beta2-agonists (LABA) = first choice
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 the absence of anti-inflammatory effects!!!

46. ICS + LABA by inhalation are available
DRUG 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).

47. 4.2 ICS + antileukotrienes p.o.
DRUG COMBINATIONS USED FOR PROPHYLAXIS
4.2 ICS + antileukotrienes p.o.
4.3 ICS + oral sustained-release tablets with
theophylline
4.4. ICS + omalizumab

48. 5. Subcutaneous and sublingual allergen immunotherapy
Specific immunotherapy involves the administration, subcutaneously or sublingually, of increasing doses of the causative allergen, in order to induce clinical and immunologic tolerance.

49. 6. 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.

50. 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)

51. Management of acute asthma exacerbation
Hospital-based management: severe exacerbation nonresponding to the initial therapy at home = 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) – i.v. or i.m. in the case that severe asthma attack is caaused by anaphylaxis
Assessment of asthma management plan (change in prophylactic therapy (increased dosing of ICS / combinations)
The use of other bronchodilators is possible but generally 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).