GENETIC FACTORS ENVIRONMENTAL FACTORS

-synthesis of specific IgE -poluants (smoking included)

-airways hiper-reactivity -stress factors
-abnormalities of -viral infections
inflammation mediators -respiratory allergens
synthesis regulation -professional milieu related factors
-diet (infants fed with cow milk or
soy protein)
ALTERED IMMUNE RESPONSE
-imbalance of Th1 and Th2, with overexpression of TH2
and underexpression of Th1
-Th2 synthetise cytokines which mediate inflammatory
allergenic response (IL-4, 5, 6, 9 and 13)
-activation of mastocytes located in mucosa,
eosinophils, macrophages, epithelial cells etc.
 Contraction of smooth muscles airways
acute narrowing of airways
 Airways edema
 Mucus hypersecretion local occlusions
 Airways hyperreactivity

variable limitation of airflow as response to

certain stimuli, provoking asthma symptoms
 CLASSIFICATION OF ASTHMA SEVERITY
Severity Intermittent Persistent- Persistent- Persistent-
markers Mild severity Moderate Severe
severity severity
Symptoms ≤2 days/week >2 days/week, but daily Throughout the
not daily day
Nocturnal ≤2 days/month 3-4x/month >1x/week, but not Often 7x/week
awakenings every night

Utilization of short ≤2 days/week >2 days/week, but daily several times

acting ß2-agonists not >1x/zi each day
for symptoms
control
Interferation with absent minor limitation Some limitation extremely limited
normal activity

Lung function Normal FEV1 FEV1≥80% FEV1>60% but <80% FEV1<60%

between predicted; predicted; predicted;
exacerbations; normal FEV1/FVC FEV1/FVC reduced FEV1/FVC
Normal 5% decreased >5%
FEV1/FVC;
FEV1 >80%
predicted

NHLBI Guidelines for the Diagnosis and Management of Asthma (EPR-3). National Heart, Lung and Blood Institute, July 2007.
 LEVELS OF ASTHMA CONTROL

Characteristic Controlled Partially Uncontrolled

(all of the controlled
following) (any measure
present in any
week)
A. Evaluation of the actual level of symptoms control (preferable in the last 4 weeks)

Daytime symptoms None (≤2/week) ≥2/week ≥3 criteria of partly

controlled asthma present
Limitation of activities None Any in any week

Nocturnal None Any

symptoms/awakening
Need for reliever/rescue None(≤2/week) ≥2/week
treatment
Lung function Normal <80% predicted or personal
(PEF or FEV1) best
B. Evaluation of the future risk (of exacerbation, instability, fast decline of lung function, adverse events)
Features associated with an increased risk of adverse events include:
Poor clinical control, frequent exacerbations during the last year, any hospitalization in ITU for asthma symptoms,
reduced FEV1, exposure to smoke, high dose medication

A Pocket Guide for Physicians and Nurses. Global Initiative for Asthma, Updated 2011
ANTIASTHMA DRUGS - BRONCHODILATORS

FIRST LINE TREATMENT

β2 adrenergic agonists
•Relax bronchial smooth muscle
•Decrease mast cell mediators release
•May stimulate muco-ciliary transport due to ciliary
activity increase
•Inhibit neutrophil, eosinophil, and lymphocyte functional
response
•Affect vascular tone and edema formation
ANTIASTHMA DRUGS - BRONCHODILATORS

•If administered inhalatory, they are the treatment of

choice for mild form of asthma, with occasional symptoms
•The majority of this class’ representative agents have fast
onset of action (5-30 min), but their effect lasts 4-6h; there
are also long-acting agents, of minimum 12 h duration
•Because they don’t have anti-inflammatory properties,
they are not recommended as monotherapy in persistent
asthma
•Inhalatory administration decrease very much adverse
events incidence, when compared to systemic
administration
 DRUGS WITH β2 – AGONIST ACTION

 SHORT ACTING BETA-AGONISTS (SABA)

-Albuterol- mixture of racemic isomers- R (levalbuterol) and S, but
R stereoisomer is responsible for bronchodilator properties of the
drug.
-Bitolterol -Metaproterenol -Fenoterol
-Pirbuterol -Terbutaline -Procaterol
 LONG ACTING BETA-AGONISTS (LABA)
-Salmeterol
-Formoterol
-There are also agents with a 24 h duration of action, like
indacaterol, vilanterol, olodanterol, which are presently FDA
approved only for COPD
FENOTEROL 100 μg/dose
-100-200 μg once, maximum 800 μg/day
-approx. 10-30% of the released active substance
from the aerosol reach inferior airways
-after oral administration approx. 60% of the dose is
absorbed, with extensive hepatic metabolism at first
passage, oral bioavailability reach only 1.5%

SALBUTAMOL=ALBUTEROL 100 μg/dose

-100-200 μg once, maximum 800 μg/day
-approx. 10-20% of the inhaled dose reach inferior
airways, the rest is swallowed and extensively
metabolized in liver at the first passage
-most of the inhaled dose is excreted in 72 hours
-clinical effect is observed after 15 min after the
inhalation and has a 3-4 h duration
SALMETEROL 25 μg/dose + FLUTICASONE
PROPIONATE 50 μg/dose
-50 μg salmeterol BID
-salmeterol has a 12h duration of action
-reaches very low plasma concentrations (approx.
200 pg/ml) after inhaled administration, therefore
data about salmoterol pharmacokinetics are
limited
-fluticasone is a synthetic glucocorticoid

FORMOTEROL 12 μg/dose
-12 μg BID, maximum dose 48 μg/zi
-90% of the inhaled dose is swallowed and enter
gastrointestinal tract
-t1/2=5h
 ANTIASTHMA DRUGS -
SECOND LINEBRONCHODILATORS
OF TREATAMENT
Methylxanthines
•Bronchodilator and moderate antiinflammatory actions
•Immunomodulator and bronchoprotector properties

Theophylline is the most widely used methylxanthine in

the asthma therapy.
However, according to the current guidelines these drugs
are not frequently prescribed due to the unfavourable
risks/benefits ratio.
-mechanism of the bronchodilator action is PDE3 inhibition
-antiinflammatory effect is attributed to PDE4 inhibition
and histone-deacethylase activation
 Indications:
-associated maintenance therapy for patients with poor
therapeutic control of asthma with conventional doses of
inhaled glucocoticoids
-can be used instead of beta2-agonists if they didn’t work
properly;
-main long-term therapy if patient doesn’t adhere enough
to inhaled drugs, or if he/she can not administer
him/herself this kind of drugs, especially if montelukast
is not efficient enough;
-as adjunctive treatment in ICU (intensive care units) in
those patients who don’t respond to beta2-
agonists+ipratropium+/-magnesium IV and systemic
glucocorticoids
 Theophylline is no longer recommended by FDA for the
treatment of acute bronchospasm or status asthmaticus
 It is hepatically metabolised, as a substrate for CYP1A2 and
3A4
 It has a good gastrointestinal absorption rate
 Products:
Theotard capsules extended release 200 or 350 mg
Aminophylline (combination of anhydrous theophylline and
ethylendiamine) 24 mg/l inj. Sol.
 ANTIASTHMA DRUGS -
BRONCHODILATORS
Theophylline has a narrow therapeutic index and a high
variability of clearence from one patient to another.

Failure of an adequate monitoring of theophylline treatment

can lead to drug intoxication with lethal potential
Maximum serum concentration must be maintained between 10 and 20
mg/L (μg/ml), but therapeutic effects may be observed even at 5 mg/L
Dose interval for adults: acute phase- loading regimen 5 mg/kg; maintenance
dose- 5-15 mg/kg/day (greater doses in smokers, lower doses in heart patients); do
not go over 900 mg/day, and for heart patients the upper limit is 400 mg/day
 MAIN SYMPTOMS IN THEOPHYLLINE
INTOXICATION (plasma concentration>30μg/ml)
GASTROINTESTINAL NEUROLOGIC
Vomiting Nervousness
Abdominal pain Tremor
Diarheea Disorientation
Hematemesis Seizures
METABOLIC DEATH
Hypopotassemia
Hyperglycemia
Acid-base imbalance
Rhabdomyolysis
CARDIOVASCULAR
Synus tachycardia
Supraventricular tachycardia
Ventricular extrasystoles
Atrial fibrillation, flutter
Multifocal atrial tachycardia
Ventricular arrhythmia with hemodynamic instability
 THEOPHYLLINE
Drug interactions
T½=8h
T½< T½>
 ENZYME INDUCERS  INHIBITORS CYP450
Phenobarbital Oral contraceptives
Rifampicin Erythromycin
Phenitoin Ciprofloxacin
Carbamazepine Calcium blockers
 SMOKERS Fluconazole
 CHRONIC ALCOHOLISM Cimetidine
LIVER DISEASES
HEART FAILURE
VIRAL INFECTIONS
 Antimuscarinic drugs (Ipratropium,
oxytropium)
 Bronchodilators with fast onset of action, but less
efficient compared to beta2-agonists
 Block smooth muscles contraction in airways and
inhibit mucus secretion- both phenomena have as
explanation vagus nerve blocking
In patients with reversible airway obstruction there is an increased
parasympathetic activity, which leads to bronchoconstriction due to
acetylcholine actions over M2 and M3 bronchial receptors. Antimuscarinic
agents block these receptors.
 Inhaled ipratropium bromide is useful in patients who do
not tolerate adrenergic agonists
 They have slow onset of action, and their systemic
absorption is reduced
 Can not be adminsitered in patients with narrow angle
glaucoma, gastrointestinal or urinary tract obstructions
 May be administered TID or QID
 Especially efficient in old age patients with COPD
 Is more efficient in patients with asthma and COPD
(overlap syndrome)
A measured dose (puff) of BERODUAL N contains ipratropium
bromide (0,020 mg) combined with fenoterol bromhydrate (0,020 mg)

It is recommended to administer in asthma this combination only PRN (as

needed). For an acute asthma attack 2 puffs/day are usually enough, but in
severe cases, the dose may be repeated after 5 min.
 ANTIINFLAMMATORY DRUGS IN ASTHMA

CORTICOSTEROIDS

 Don’t provoke bronchodilatation, but they have a strong anti-

inflammatory action
 The most efficient medication with anti-inflammatory properties
in persistent asthma
 They don’t antagonize immediately a spasmogen, but decrease
bronchial hyperreactivity
 Decrease the risk of tolerance to adrenergic drugs (inhibit down-
regulation of adrenergic receptors) or may even lower these
receptors density
 Decrease frequency and severity of exacerbations in asthma and
also decrease mortality rate in this disease
 ANTIINFLAMMATORY DRUGS IN ASTHMA
Mechanisms of action
At the cellular level
 Reduce the activity of leucocytes
 Decrease mononuclear cells activity
 Reduce blood vessels prolipheration
 Decrease clonal expansion of B and T lymphocites

At the inflammation mediators and immune processes level

 Inhibit COX2 transcription genes, cytokines (interleukins), cellular
adhesion molecules
 Decrease eicosanoids synthesis
 Decrease IgG synthesis
 Modyfies collagene transcription genes
Results:
 Decrease of chronic inflammatory processes
 Decrease the severity of autoimmune processes and reactions
 Reduction of healing processes in wounds
 Reduction of bronchial hyper-reactivity
 Negatively interfere with beta2-adrenergic receptors
desensibilization
 Mode of administration:
 Inhaled –first line;
 Approx. 15-20% of the inhaled dose reach the lungs, the rest is swallowed and
rapidly inactivated by hepatic metabolism;
 At recommended doses don’t suppress HPA axis, but in high doses may inhibit
this axis.

INHALED CORTICOSTEROIDS DON’T CURE ASTHMA!

INN LOW DOSE MEDIUM DOSE HIGH DOSE
(International Non- (μg) (μg) (μg)
proprietary Name)

Beclomethasone 100-200 200-400 >400

Budesonide 200-400 400-800 >800
Fluticasone 100-250 250-500 >500
Ciclesonide 80-160 160-320 320-1280
Doses according to Global Initiative for Asthma Guidelines (GINA 2015)
 ANTIINFLAMMATORY DRUGS IN ASTHMA

CONFIRMED EFFECTS
 Reduce or eliminate the need for systemic corticosteroids
 Decrease symptoms or exacerbations in asthma
 Improve lungs function
 Decrease diurnal variations of the lungs function
 Decrease the need for emergency bronchodilator
 Reduce nocturnal attacks
 Improve quality of life index

OTHER POSSIBLE/PROBABLE EFFECTS

 Decrease the need for hospitalisation and the number of deaths
 Decrease the rhythm of lung function deterioration
 Increase of remission periods duration
 ADVERSE EVENTS OF INHALED
CORTICOSTEROIDS
LOCAL
 Dysphonia
 Oropharyngeal candidiasis
 Throat irritation and cough
SYSTEMIC
 CSR supression
 Negative effects over growing in children
 Weight gain, truncal obesity
 Skin atrophy
 Cataract, glaucoma
 Osteoporosis
 HBP, hyperglycemia
 Peptic ulcer
 Depression, psychosis
 Dissemination of varicella-zoster virus infection
 Mode of administration:
 Oral or IV
- Corticosteroids with systemic administration may be necessary on long term in
several forms of severe asthma, but the clinician must be careful because of the
risks for significant adverse events (osteoporosis, HBP, cortisone diabetes, obesity
immune depression etc.)
- No other drug/class of drugs has the same efficacy as corticosteroids in the control
of long-term asthma in children and adults
- Doses are gradually decreased after the improving of patient’s clinical status

INN Products available in Romania

Prednisone tablets 5 mg
Methylprednisolon vials 40,125, 500, 1000 mg
Hydrocortisone hemisuccinate vials 25 mg, 100 mg, 500 mg
Dexamethasone vials 4 mg/ml
 STRATEGIES FOR DECREASE OF ADVERSE
EVENTS DURING CORTICOSTEROID-THERAPY

 Tissue selectivity
 Mimic the corticosteroids circadian rhythm of secretion
 Alternate day corticotherapy (especially for antiinflammatory
properties)
 decrease the suppression of HHC axis
 the remission of the treated disease is maintained
 severity of other adverse events is also decreased
 but no drug-dependent adverse event is excluded
 Local administration:
 Inhaled (high potency, effect of first passage- low systemic
concentration)
 ADVERSE EVENTS

METABOLIC: glucose intolerance, obesity, dyslipidemia, proteolisis,

inhibition of protein synthesis
BONES: decrease of calcium absorption, osteoporosis, avascular necrosis of
femoral head
CARDIOVASCULAR: hydrosaline retention, HBP, aterosclerosis
IMMUNE SYSTEM SUPPRESSION: vulnerability to infections
SKIN: atrophy
REPRODUCTIVE SYSTEM: hypogonadism
GASTRO-INTESTINAL: peptic ulcer
OPHTALMOLOGIC: cataract
NEURO-PSYCHIATRIC: euphoria, long duration treatment – depression,
insomnia, psychosis
DEVELOPMENTAL IMPAIRMENTS IN CHILDREN: decrease of growth
hormones secretion, especially Insulin-like Growth Factor type 1
DECREASE OF THYROID- STIMULATING HORMONE SECRETION
 ANTIINFLAMMATORY DRUGS IN ASTHMA

ANTILEUCOTRIENES
LTB4 and cysteinyl-leucotrienes (LTC4, LTD4, LTE4) are
synthesized by 5-lipoxygenase starting from arachidonic acid and
are included in the inflammatory cascade.
ZILEUTON is a specific and selective 5-lipoxygenase, therefore
suppresses the above mentioned leucotrienes biosynthesis.
ZAFIRLUKAST and MONTELUKAST are selective and
reversible inhibitors of several leucotrienes receptors.
MONTELUKAST may be administered PO in children aged
above 6 years old. Montelukast is a competitive inhibitor of
LTC4 and LTD4 at Cys-LT1 receptors.
 Antileucotrienes reduce the necessity for glucocorticoids administration
in asthma and improve chronic asthma symptoms.
 These class of drugs has a limited bronchodilator effect, but decreases
bronchial inflammation and exacerbations frequency.
 They are efficient in the prophylaxis of antigen/physical exercises-induced
asthma.
 Montelukast is efficient in aspirin-provoked asthma, being associated
with deviation of arachidonic acid from the cyclooxygenase pathway
(blocked by aspirin), resulting in synthesis of leucotrienes by 5-
lipoxygenase.
 ANTIINFLAMMATORY DRUGS IN ASTHMA

SODIUM CROMOGLYCATE AND NEDOCROMIL

 Prevention of asthma attacks induced by physical exercise

 Have prophylactic action for allergic asthma in children
 Are safe in children and during pregnancy
 Prevent bronchospasm, inflammation and bronchial
hyperreactivity
 Don’t have efficacy during asthma attack
 Inhibition of mediators from mast cells which are sensitized in
vitro and decrease C fibers firing as response to tachykinins, but
their mechanisms of action are insufficiently clear
 Cromoglycate has a very short duration of action (1.3 h) and a
bioavailability of 1% (after inhaled administration)
 Must be administered several times during the day
 ANTIINFLAMMATORY DRUGS IN ASTHMA
 A period of 4-6 weeks is necessary in order to evaluate these
agents efficacy
 Systemic absorption is very low after it is inhaled
 They are non-toxic products, very rare induce headache and
dizziness, and nedocromil has a bitter taste
 OMALIZUMAB is a monoclonal antibody obtained through
recombined ADN technique, which attaches itself to human
IgE.
 It is used as adjunctive therapy in severe persistent forms of
asthma induced by IgE mediated sensitization to inhaled
antigens with insufficient control by use of corticosteroids
plus long action beta2-agonists (LABA).
 It is not anaphylactogenic because it doesn’t connect to IgE
already attached to mast cells or basophils
 Useful in moderate and severe forms of allergic asthma in
which the disease is insufficiently controlled with
conventional therapy
 Half-time= 20-30 days
 Elimination through reticulo-endothelial system
 Adverse events: rash, pruritus, sinusitis, gastro-intestinal
discomfort, reactions at the injection site
 Is a very expensive therapy
 ADHERENCE TO ANTIASTHMA DRUGS
ADMINISTRATION
Treatment adherence decreases as symptoms improve
 Allow patient to express his/her preferences for specific medications
and discuss them
 Improve patients’ perception over the asthma and its treatment
This objective is not usually realised in one visit!
 Explain to the patient the treatment plan and objectives
Adherence increases if the treatment objectives correspond to the
patients expectations
 A treatment as simple as possible:
•As few as possible drugs
•As few as possible administrations per day
•As few as possible adverse events, explain these events to the patients
•Establish daily administration habits (for prophylactic medication)
 Patient family should be involved in the treatment monitoring
process
Maintain therapeutic alliance with the patient
 LEVEL 1
 Education
 Control of risk factors
 SABA when needed (PRN)

LEVEL 2
• Add low-dose inhaled corticosteroids (ICS)
to the previous medication
•Alternative medication- leucotrienes
antagonists
 LEVEL 3
 Education
 Control of risk factors
 SABA when needed
 Inhaled corticosteroids (ICS) plus LABA
 Alternative medication for symptoms control:
-ICS medium/high dose;
-ICS low dose plus leucotrienes antagonists;
-ICS low dose plus extended release
theophylline.
 LEVEL 4
 Education
 Control of risk factors
 SABA when needed
 Medium/high dose ICS + LABA
 Alternative medication for symptoms control:
-leucotrienes antagonists;
-extended release theophylline.
 LEVEL 5
 Education
 Control of risk factors
 SABA when needed
 Medium/high dose ICS + LABA
 Alternative medication for symptoms control:
-leucotrienes antagonists;
-extended release theophylline;
-oral corticosteroids- the lowest dose that
works;
-omalizumab.
 Monthly evaluation by the GP
 Every 3 months a specialized evaluation, if asthma is well
controlled and stabilized
 At 2 weeks after an exacerbation
 Maximum efficacy of a treatment is obtained after 3-4
months of administration
 After a symptomatic control is obtained a decrease of
doses/number of drugs is analised
 Any deterioration of clinical status that persist after removal
of the causal factors necessitates treatment intensification
(d.e. increase of ICS doses, systemic administration of
corticoids etc)
 Male patient, aged 24, resides in Prahova county,
diagnosed with atopic dermatitis in childhood, is
hospitalized for severe dyspnea and wheezing,
coughing and chest tightness
 Onset of symptoms was suddenly in the morning of
hospitalization, in his second day of presence in
Bucharest, where he has to participate in an exam
 Patient has an BMI of 30.5 kg/m2 and smokes 5 packs
year (meaning one pack each day for 5 years)
 Risk factors
-changing of environment (air pollution)
-exam-related stress
-atopic vulnerability (atopic dermatitis)
-obesity
-smoking
 Chest radiograph
- hyperinflated lungs
 Spirometry detects:
-FEV1reduced to 72%,
-FEV1/FVC ratio (Tiffenau Index) diminished to 0.62
 Somatic evaluation:
-HR=100 bpm, BP= 130/80 mmHg
-respiratory frequency= 25/min
 Laboratory tests:
-total cholesterol=240 mg/dl, HDL-cholesterol= 30
mg/dl, triglycerides= 200 mg/dl
 Treatament:
-Supplemental oxygen by mask delivery- the flow
is titrated to maintain the pulse oxygen saturation
SpO2 ≥ 90%;
-β2-agonist with short duration of action (SABA)
d.e. salbutamol PRN
-indications regarding weight loss (hypocaloric, low
fat diet), psychologic counselling regarding smoke
cessation
-an allergological evaluation is recommended
 Patient returned to ER after one week for dyspnea and
wheezing, stating he had 5 asthma attacks since his
first presentation to hospital.
 He used inhaled salbutamol on each occasion, but the
therapeutic response gradually decreased
 The next level of treatment is initiated:
-Inhaled corticosteroids are considered the most
efficient medication in adults and adolescents for
symptoms amelioration, lung functioning and
exacerbations prevention
-Inhaled corticosteroids are administered initially in
low dose; this patient received 200μg/day
beclomethasone dipropionate (low dose)
 In patients who smoke, the inhaled corticosteroids
have a smaller efficacy, therefore a gradually
increase of beclomethasone dipropionate dose to 300
μg/day (medium dose) was implemented
-Salbutamol was maintained as inhaler in emergency
situations
-A discussion about diet, stress factors management
and smoke cessation was conducted and new
recommendations were formulated
 Re-evaluation after 4 weeks:
-frequency of asthma attacks was 2/week;
-patient didn’t quit smoking;
-diet program leaded to a BMI decrease of 29.2
kg/m2.
 After an analysis of the disease evolution following
recommendation have been made:
-inhaled corticosteroid dose increased to 400 μg/day
(medium to high dose) in order to compensate for
smoking;
-an inhaled β2-agonist with long duration of action
(LABA)- salmeterol 2 x 25 μg/day, with possibility
to further increase the dose to 4 x 25 μg/day if
symptoms persist
 The reasons for choosing a LABA were:
-theophylline add-on in asthma which is insufficiently
controlled with inhaled corticosteroids is less efficient
than LABA, and the risk of adverse events is higher
with theophylline;
-a simple increase of inhaled corticosteroid dose is a
lesser efficient alternative than an add-on;
-ICS plus LABA is the first option in patients who
don’t respond well to low doses of inhaled
corticosteroids;
-there is also a possibility for administration in the
same inhaler of both ICS and LABA
 Reevaluation after one month:
-FEV1 80%, FEV1/FVC= 0.7
-only 2 asthma attacks were reported in the last 4
weeks, but they rapidly subsided with inhaled SABA
administered PRN;
-no over-the-night asthma;
-no negative influence over the daily activities;
- actual status of this patient is satisfactory, he has a
well controlled asthma and therapeutic decision is to
maintain current treatment;
-BMI decreased to 28.7 kg/m2;
-total daily number of cigarettes decreased to 5;
-patient passed his exams and participated in several
events which he previously considered to stressful.
 Patient aged 42, male, diagnosed with asthma for 18
years, is currently treated with combined ICS and
LABA in the same inhaler (fluticasone/salmeterol
250/25 μg/puff) for 2 years;
 He came to see his doctor because although he
correctly follows his treatment, several asthma attacks
appear every week and he has to administer himself an
inhaled SABA (fenoterol 200 μg/puff).
 Self-evaluation of PEF using a portable peak flow
meter indicates a 30-35% diurnal variation at least 3
days in a week;

 This variability is not correlated with stress factors,

environmental factors (either professional or familial),
or with any other investigated possible causes.
 Does your asthma awakened you during the night or early in the
morning?
A: Yes, at least once a week.
 How often do you need to use emergency medication in order to
free yourself from symptoms like coughing, shortness of breath
or chest tightness?
A: At least twice a week lately. But I’m feeling worse almost
every day, even if I try not to use fenoterol very often.
 Have you been to ER of a hospital, did you call for emergency
intervention at home, or have you visited a pneumologist for an
emergency situation related to your asthma?
A: Twice in the last month, because I felt very sick and I didn’t
know what to do… I had to call an ER service…
 Have you been able to participate in daily chores, job-
related tasks and free time activities, as you wished to?
A: I avoid to go out of my house. I just go to my job and
this is all. I don’t want to feel sick on the street.
 Which are your PEF values recorded in the last few weeks?
A: I didn’t reach the green line for quite a while. I usually
stay in the yellow zone and many times I even reached the
red one.
 Did you have any adverse events to your asthma
medication?
R: No, at least not until now…
 Patient has a persistent moderate asthma, with daily
activities and sleep impairment, nocturnal symptoms at
least once/week.
 PEF1 determined in the hospital was 60% of the
predicted value
 PEF Variability over 30%, as document analysis
showed
 FEV1/FVC decreased with 5%
 Asthma is partially controlled by his current
medication and necessitates a change of therapeutic
strategy
 We need to choose of the following options:
-ICS dose increase;
-add-on of an agent that modify leucotrienes, either a
cysLT1 receptors antagonist (montelukast, zafirlukast),
or an 5-lipooxygenase inhibitor (zileuton)
-add-on of an extended release methylxanthine
(theophylline)
-add-on of an oral glucocorticoid.
 Extended release methylxantines 600-800 mg daily
dose may be used as add-on to ICS+LABA, but this
drug has a narrow therapeutic index;
 Corticosteroids with oral administration (d.e.
Methylprednisolone 32, 16, 4 mg tablets) are preferred
in severe cases of asthma as long-term treatment, but
their adverse events become more and more severe in
time.
 The decision in this case was to increase the inhaled
corticosteroid dose- fluticasone/salmeterol 500/50
μg/puff BID and montelukast 10 mg QD as add-on
agent
 Leucotrienes antagonists have a moderate
bronchodilator effect, reduce symptoms, improve
lung function, decrease exacerbations frequency.
 Adverse events are very rare for montelukast, but
still can be observed: drowsiness, paresthesias,
headache, dyspepsia, fatigue.
 SABA was maintained for emergency situations
 Repeated, monthly evaluations detected a better
symptom control and at 6 months a decision has been
made to decrease ICS+LABA dosage to 250/25 μg/day.
 Variations of PEF were not greater than 15%, and
FEV1/FCV didn’t decrease below 70% after 9 months.
 Daily activities were accomplished with a greater rate
of success than previously, and a larger variety of free-
time activities was developed, as patient became less
symptomatic and more confident in his physical
capacities.
 Patient aged 53, male, diagnosed with asthma for 25 years,
came to ER for dyspnea, coughing and wheezing with
acute onset (2 hours ago), progressively aggravated;
 Patient has a poor adherence to asthma treatment, he takes
budesonide/formoterol 80/4.5 μg/puff (combination of ICS
and LABA) and has frequently respiratory tract infections;
 Patient smokes 8 packs year (1/2 pack each day for 16
years) and drinks alcohol chronically.
 CRITERIAS ASTHMA COPD
ONSET In young patients, dyspnea Frequently after 40 years old,
attacks prolonged expectoration,
possible dyspnea in late
stages
DYSPNEA Paroxysmal Progressive
COUGH During attacks Prolonged
EXPECTORATION Rarely, at the end of attack Chronic

CYANOSIS Rarely Frequently

ICS EFFICACY Very Limited
EVOLUTION Episodic Progressive
ECG Rare elements of CPHD CPHD frequently met
(chronic pulmonary heart
disease)
OBSTRUCTION High degree of reversibility Mild or not at all reversible,
progressive
 Based on clinical evaluations, spirometry, chest
radiographs, medical history, patient is diagnosed with
severe asthma attack, his symptoms are not associated
with COPD.
 Severity of the attack is based on:
-incapacity of finishing his sentences, dyspnea after
very short duration physical activities;
-psychomotor restlessness, wheezing;
-respiratory frequency 28/min;
-HR=120/min
-PEF 35% of personal best
-SaO2= 90%
 Emergency intervention:
-O2 administered on nasal tube, in order to
maintain SaO2 over 94%;
-beta2 agonist with short duration (SABA),
nebulization with O2 (salbutamol 5 mg)
-methylprednisolon IV 1 mg/kg
-add-on of ipratropium 0.5 mg in nebulizer because
of insufficient response to previous treatment
algorhythm.
 Patient was admitted to ICU for continuous
surveillance
 Response still incomplete after 60 min, so magnesium
sulphate 1.2 mg IV in 20 min is administered
 Salbutamol continuous infusion- 10 mg/h, under ECG
monitorization
 After 120 min, global clinical status began to improve,
and SaO2 reached 95%
 The clinician decides to switch on oral prednison 40 mg
daily dose;
 Beta2 adrenergic medication administered IV is
discontinued, and a switch on ICS+LABA
(budesonid/formoterol) has been made;
 After 6 ore, patient is transferred in a Pneumology
department where he is still under continuous cardiac and
respiratory monitorization;
 Concomitant therapy for alcohol withdrawal (GGT= 1200
UI/ml, GOT=330, GPT=230) includes IV rehydration,
class B vitamin therapy, short action benzodiazepines
(lorazepam 1 mg TID)
 Discharge recommendations :
-smoking cessation therapy: nicotine replacement with
a transdermic patch;
-treatment with nalmefene 18 mg PRN, for treatment
of ethanol addiction;
-psychotherapy focused on adherence increase to
asthma treatment;
-prescription for influenza vaccine, to decrease
respiratory tract infections during cold season.
-continuation of ICS+LABA therapy
-mentaining oral prednison at least a week, with
dietary precautions related to salt use during
treatment;
-a SABA combined with an antimuscarinic drug
for emergency situations (Fenoterol/Ipratropium
50/20 μg/puff)
 Notes:
-theophylline has a lower degree of recommendation by
actual guidelines in emergency due to its unfavourable
tolerability profile, but in patients hospitalized and
monitored in ICU, theophylline could be a useful
alternative;
-in order to be discharged, patient has to be compensated
under treatment for at least 24 h, to have a PEF at least
75% of the anticipated value, to be on oral corticosteroid
medication, ICS and bronchodilator(s), to establish a re-
evaluation after 7 days and to verify the patient technique
of drug administration (Oxford Guidelines, 2014)
MULTIPLE-CHOICE SINGLE-ANSWER
QUESTIONS
 In a patient diagnosed with asthma, who is currently
treated with an inhaled corticosteroid and a short
acting beta2-agonist, but still has asthma attacks and
impairment of daily activities, the most probable
recommendation is for:
A. an oral corticosteroid
B. theophylline
C. omalizumab
D. a long acting beta2 agonist
E. aspirin
 In a patient with intermittent asthma decision is
made to administer a short acting beta2 agonist in
case of emergency. Which of the following drugs
has no indication in this case:
A. albuterol
B. fenoterol
C. pirbuterol
D. terbutaline
E. indacaterol
 In case of insufficiently controlled symptoms of
asthma under treatment with short acting beta2
agonist, the clinician recommends an inhaled
corticosteroid. Which of the following drugs is not a
correct choice:
A. beclomethasone
B. budesonide
C. fluticasone
D. prednisone
E. ciclesonide
 What do you usually recommend for symptoms
control in a patient diagnosed with aspirin induced
asthma, besides beta2- agonists:
A. high dose of theophylline
B. montelukast
C. nalmefene
D. omalizumab
E. admission in ICU
 In case of a patient with an asthma attack in which a
rapid control of symptoms is needed you recommend
as first line:
A. a long acting beta2 agonist
B. an antileukotrienes agent
C. a short acting beta2 agonist
D. a mast cells stabilizer
E. an oral corticosteroid