Bez nadpisu

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Drugs used to treat asthma Martínková J 2005
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ASTHMA Asthma is defined as a syndrom in which
there is recurrent reversible obstruction of the
airways in response to stimuli. The patient has
intermittent attacks of dyspnoea, wheezing, and
cough and disorder of breathing out. Its
pathologic features are . contraction of
airway smooth muscle, . mucosal thickening from
edema and . cellular infiltration, viscid
plugs of mucus. Of these causes of airway
obstruction, contraction of smooth muscle is
most easily reversed by BRONCHODILATORS,
reversal of the edema and cellular infiltration
requires sustained treatment with
ANTI-INFLAMMATORY AGENTS.
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Antiasthmatic agents are often used by

inhalation Inhalation methods are
metered dose Inhaler-aerosol, aerosol
administered via a nebulizer, and a dry powder
administered by Rotahaler or Diskhaler.

orally


i.v.
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glucocorticoids
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Schematic diagram of a cross-section of a
bronchiole showing the changes that can occur
with severe chronic asthma.
Dilated blood vessels
Submucosa
Eosinophil
Epithelium
Mucosa
Thickened basement membrane
Infiltration of inflammatory cells, (mononuclear
cells, eosinophils etc.)
Mucus plug with eosinophils and desquamated epithe
lial cells
Hypertrophied smooth muscle
Mast cell
Mononuclear cell
Oedema
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Two phases of asthma
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BRONCHIAL REACTIONS

Exposure to allergen
control
Early phase bronchoconstriction
Late phase inflammation
hours
corticoids
bronchodilation
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DRUGS FOR ACUTE USE
quick relief DRUGS USED FOR PROPHYLAXIS
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DRUGS FOR ACUTE USE
quick relief BRONCHODILATORS GLUCOCORTICOIDS
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DRUGS FOR ACUTE USE
quick relief BRONCHODILATORS 1.
Methylxanthines 2. Sympathomimetic agents 3.
Muscarinic antagonists 4. New bronchodilators GLU
COCORTICOIDS
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(No Transcript)
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DRUGS FOR ACUTE USE quick relief 1.
Methylxanthines Theophylline, theobromine,
and caffeine (alkaloids from tea, cocoa,
and coffee, respectively). Pharmacodynamics
of methylxanthines Central nervous system
effects Cardiovascular effects Effects on
the GIT Effects on kidney Effects on smooth
muscle
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DRUGS FOR ACUTE USE quick relief
Pharmacodynamics of methylxanthines 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 Effects on
smooth muscle vasodilation, bronchodilation
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DRUGS FOR ACUTE USE quick relief Clinical use
of methylxanthines Theophylline is used as a
theophylline salt - aminophylline, which
contains 86 theophylline by weight and
ethylenediamine. Improvements in theophylline
preparations anhydrous theophylline in a
microcrystalline form in which the increased
surface area facilitates solubilization for
complete and rapid absorption after oral
administration.
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DRUGS FOR ACUTE USE quick relief Theophylline
blood level should be m o n i t o r e d.
Therapeutic and toxic effect of theophylline are
related to the plasma concentrations of the
drug. Improvement in pulmonary function is well
correlated with plasma concentration in the
range of 5-20 mg/L. Anorexia, nausea, vomiting,
abdominal discomfort, headache, and anxiety
begin to occur at concentrations of 15 mg/L in
some patients and become common at
concentrations greated than 20 mg/L. Higher
levels (gt 40 mg/L) may cause seizures or
arrhythmias, these may not be preceded by
gastrointestinal or neurologic warning symptoms.
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Rational administration of theophylline,
therefore, requires knowledge of its
pharmacokinetics. plasma clearance and factors
with impact on it (adults, the mean plasma
clearance is 0.69 mL/kg/min - 0,041 L/kg/h).
? changes in hepatic function (cirrhosis
or decrease in hepatic blood flow caused by
heart failure may decrease plasma clearance,
viral infection). ? induction of hepatic
enzymes by cigarette smoking may increase plasma
clearance and cause inadequate concentrations of
drug (the dose is usually increased by 30)
Age children appear to clear theophylline
faster than adults (1-1.5 mL/kg/min 0.06-0.09
L/kg/h). Neonates and young infants have the
slowest clearance.
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DRUGS FOR ACUTE USE quick relief Drug-drug
interaction the half-life of theophylline . is
increased by erythromycin, cimetidine (but not
ranitidine), ciprofloxacin, oral
contraceptives . is decreased by concurrent use
of phenytoin, carbamazepine, rifampicin and
phenobarbital. Intravenous
maintenance therapy is now given only in unusual
circumstances, an infusion rate of 0.7 mg/kg/h
may be used in stable patients. For oral
therapy, an initial dose equivalent to 3-4 mg/kg
of theophylline in 1-2 days, so the dose may be
increased at intervals of 2-3 days until
therapeutic plasma concentrations are achieved
(10-20 mg/L) or until adverse effects develop.
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DRUGS FOR ACUTE USE quick relief 2.
Sympathomimetic agents Nonselective Adrenaline
is an effective, rapidly acting bronchodilator
when injected subcutaneously (11000 solution)
or inhaled as a microaerosol. Maximal
bronchodilation is achieved 15 minutes after
inhalation and lasts for 60-90 minutes. Adverse
effects tachycardia,
arrhythmias, and
worsening of angina pectoris
are troublesome adverse
effects.
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Beta2-selective agonist drugs are the most
widely used sympathomimetics for the treatment
of asthma at the present time. Salbutamol
(albuterol), terbutaline, fenoterol are
available as metered-dose inhalers.
Bronchodilation begins in 5 minutes, is maximal
by 30-60 minutes and persists for 2 hours.
Bronchial deposition depends on the particle
size. Even with particles in the optimal size
range of 2-5 ?m, 70-50 of the total dose is
deposited in the mouth or pharynx. Particles
under 1-2 ?m in size remain suspended and may be
exhaled. Terbutaline is also prepared in
tablet form. One tablet 3 times daily is the
usual regimen.
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• DRUGS FOR ACUTE USE quick relief
• Adverse effects of beta agonists.
• Cardiac arrhythmias from ß1-adrenoceptor
  stimulation,
• hypoxemia
• muscle tremor
• headache and insomnia
• flushing
• hypokalemia

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DRUGS FOR ACUTE USE quick relief 3. Muscarinic
antagonists Muscarinic antagonists
competitively inhibit the effect of
acetylcholine at muscarinic receptors. More
selective quaternary ammonium derivative of
atropine, ipratropium bromide, short-acting drug
is used for patients with heart disease or
thyreotoxicosis in whom beta agonists are
unsuitable.
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DRUGS FOR ACUTE USE quick relief 4. New
bronchodilators Cysteinyl leukotriene-receptor
antagonists. Montelucast prevents antigen-induced
and exercise- induced asthma. It relaxes the
airways in mild asthma, its effects are additive
with ?2 adrenoceptors agonists. 5-lipoxygenase
inhibitors-zileutin These agents prevent the
production not only LTC4 and LTD4but also LTB4 a
chemotaxin that recruits leukocytes into the
bronchial mucosa and then activates them.
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DRUGS FOR PROPHYLAXIS BRONCHODILATORS GLUCOCORTIC
OIDS
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DRUGS FOR PROPHYLAXIS BRONCHODILATORS GLUCOCORTIC
OIDS
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BRONCHODILATORS 1. beta2-selective agonists 2.
aminophylline and theophylline 3.
corticosteroids 4. cromolyn and nedocromil
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DRUGS USED FOR PROPHYLAXIS 1. Newer
beta2-selective agonists developed for an
increased duration of action
(12 hours or more) compared with the older
beta2 agonists (4-6 hours) include f o r m o t
e r o l , s a l m e t e r o l (for inhalation)
c l e n b u t e r o l , p r o c a t e r o l
(per os) They appear to achieve their long
duration of action as a result of high lipid
solubility. Their high lipid solubility permits
them to dissolve in the smooth muscle cell
membrane and reach high concentration "slow
release depot" that provides the drug available
to beta receptors over a long period.
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DRUGS USED FOR PROPHYLAXIS 2. In addition,
several sustained-release preparations with
aminophylline and theophylline (Theo-Dur) are
available and can produce therapeutic blood
levels of theophylline for up to 12 or 24
hours. These preparations offer the advantages
of - less frequent drug administration,
- less fluctuation of theophylline blood
levels, - and, in many cases, more
effective treatment of
nocturnal bronchospasm.
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DRUGS USED FOR PROPHYLAXIS 3. Corticosteroids
work by inhibiting or
otherwise modifying the inflammatory response in
airways
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• DRUGS USED FOR PROPHYLAXIS
• Corticosteroids
• administered orally or i.v.
• Because of severe adverse effects when given
  chronically, oral corticosteroids (or i.v.) are
  generally reserved for patients
• who do not improve adequately with
  bronchodilators or
• who experience worsening symptoms despite
  maintenance
• 
  bronchodilator therapy
• Treatment oral dose of 30-60 mg of prednisone
  per day.
• In most patients, corticosteroid therapy can be
  discontinued
• in a week or 10 days, but in other patients
  symptoms may
• worsen as the dose is decreased to lower
  levels.

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• DRUGS USED FOR PROPHYLAXIS
• Systemic adverse effects of glucocorticoids
• administered orally or i.v.
• Gluconeogenesis (hyperglycemia)
• hypertension
• immunosuppresion
• adrenal suppresion
• osteoporosis
• growth decelaration in children
• cataract
• glaucoma

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DRUGS USED FOR PROPHYLAXIS Corticosteroids
administered by inhalation. The most effective
method of decreasing systemic adverse effects
due to corticosteroid therapy is to administer
the drug as an aerosol or powder by inhalation.
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• DRUGS USED FOR PROPHYLAXIS
• Inhaled corticosteroids (ICS)
• are currently the most effective long-term
• preventive medications
• early diagnosis and treatment are important
• prevention of airway remodelling
• long-term treatment with minimal daily doses of
• ICS

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RESPONSES TO INHALED CORTICOSTEROIDS
bronchial hyperreactivity
symptoms
pulmonary function
Responses ()
months
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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)
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• DRUGS USED FOR PROPHYLAXIS
• lipid-soluble corticosteroids for inhalations
  are
• beclomethasone, budesonide, and fluticasone
• with minimal systemic absorption and reduced
  adverse effects.
• An average daily dose ranges from 100-2000
  ?g/day
• inhalation according to asthma severity.
• Systemic steroid effects are still negligible if
  compared
• with those of the oral prednisone
• oropharyngeal candidiasis-
• mouthwashes can alleviate this problem

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DRUGS USED FOR PROPHYLAXIS ICS and the growth
in children Long-term and retrospective studies
proved that treatment with ICS (BUD 200-800
?g/day) does not lead to the shorter definitive
stature. Noncontrolled asthma itself leads to
the growth deceleration but also to the shorter
definitive stature.
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DRUGS USED FOR PROPHYLAXIS Chronic use of
inhaled corticosteroids - effectively
reduces symptoms and - improves pulmonary
function in patients - reduces bronchial
hyperreactivity (unlike beta-stimulant
agents and theophylline), - the maximal
reduction may not be achieved until the
ninth to twelfth months of therapy.