DRUGS IN RESPIRATORY

SYSTEM

Kinanti Narulita D
Pharmacology Department
FACULTY OF MEDICINE UNISSULA

INTRODUCTION
Symptom of respiratory system :
no sputum---antitussives
Cough
sputum --- expectorants
Asthma ----- antiasthmatic drugs

PHYSIOLOGY OF COUGH
Cough is due to activation of sensory receptors in the
larynx and lower respiratory tract, sending impulses to
the brainstem.
There are many varied agents that can evoke cough :
citric acid, bradykinin, distilled water, SO2, capsaicin,
metabisulfite, cigarette smoke and ACE inhibitors.
The sensitivity of the sensory nerve endings, probably
the RARs, that mediate the cough reflex evoked by
tussive agents is increased in asthmatics with cough,
following upper respiratory tract infections in otherwise
healthy individuals and in patients with ACE-inhibitorevoked cough.

PHYSIOLOGY OF COUGH
Cough usually occurs when sensory receptors in the
respiratory tract receive stimuli of sufficient intensity to
evoke an increase in sensory / afferent nerve impulse
activity. Cough reflexes can be provoked easily by
mechanical and chemical stimuli applied to either the
larynx or tracheobronchial tree, for it is here that the
greatest protection against the ingress of foreign
materials is required.
Sensory information from the respiratory tract which
initiates the cough reflex is carried in the vagus nerves.

COUGH IN DISEASE
Clinically, cough is one of the most frequent presenting
symptoms of many diseases affecting the airways and
lungs, and is often an early symptom of disease.
The clinical spectrum of chronic cough has changed
over the years. TB which had been the leading cause of
persistent cough replaced by chronic bronchitis.
The commonest conditions that are associated with a
chronic dry cough, excluding diseases such as
carcinoma of the lung, include postnasal drip associated
with
chronic
sinusitis
/
rhinitis,
asthma,
gastroesophageal reflux, upper respiratory tract virus
infection, smoking, occupational exposures, air
pollution and iatrogenic (ACE inhibitor therapy).

COUGH IN DISEASE
Cough frequently occurs in asthma and during upper
respiratory tract infections that are accompanied by
inflammation of the airways.
The etiology of cough in children differs from that in
adults : viral URTI, protracted bacterial bronchitis and
asthma are frequently the cause of coughin children. So,
the empirical approach commonly used in adults is
unsuitable for children. Clinical evaluation of cough in
children should also include an assessment of
environmental factors.

ANTITUSSIVE
AGENTS

SITE AND MECHANISMS OF ACTION

OF ANTITUSSIVE AGENTS
When cough is associated with excess production of
mucus within the lung, suppression of the cough reflex
is generally undesirable, since mucus retention may
occur which may present serious complications.
When cough is non-productive and becomes a
nuisance, preventing sleep and rest, suppression
becomes desirable, although complete suppression
can be dangerous as the lung is then deprived of an
essential defence mechanism.

SITE AND MECHANISMS OF ACTION

OF ANTITUSSIVE AGENTS
An ideal drug would reduce the increased sensitivity
of the cough reflex to normal, preferably by removing
the disease process or by reducing the
responsiveness of the airway sensory receptors.
The most obvious airway sensory receptors to target
would be the RARs. Drugs that affect cough can also
do so indirectly. For example, drugs that cause
bronchodilatation, such as the receptor agonists and
cholinoceptor antagonists used in asthma, reduce the
cough reflex without having any significant central
effects.

SITE AND MECHANISMS OF ACTION

OF ANTITUSSIVE AGENTS
Drugs with antitussive activity are loosely classified
into two groups : peripheral or central.
Centrally acting antitussive drugs act inside the central
nervous system to depress one or more components
of the central cough pathway.
Peripherally acting agents exert their mode of action
outside the central nervous system, probably by
inhibiting the activation of the airway sensory
receptors responsible for initiating the cough reflex.
The most frequently used cough suppressants are the
opiates, local anesthetics, demulcents, expectorants,
antihistamines and decongestants.

SITE AND MECHANISMS OF ACTION

OF ANTITUSSIVE AGENTS
Antitussive effects of the classical opiates, such as
codeine and morphine, were generally reported to be
mediated centrally.
Opioid receptors on the afferent / sensory neurones of
the vagus nerves.
Codein & morphine with opioid-receptor-mediated
antitussive actions can modulate impulse activity in
airway sensory neurones originating from RARs and Cfibre receptors.
Antitussive activity of drugs such as codeine is not
restricted entirely to the central nervous system, but
that some of its activity is also exerted peripherally.

ANTITUSSIVES
Classification :
A. Central Antitussives / Cough Supressants
1. Dependent Central Antitussives (Opioid)
2. Independent Central Antitussives (Non
Opioid)
B. Peripheral Antitussives
Note : codeine, dextromethorphan and cloperastine are
among the most common central agents that inhibit
cough primarily by their effect on the cough center.

DEPENDENT CENTRAL
ANTITUSSIVES
Centrally acting antitussives opioid /
narcotic alkaloids.
Mechanism : suppressing of cough center.
Morphine is the most effective drug for the
suppression of cough, but have addiction.
Ex : codeine, hydrocodone.

INDEPENDENT CENTRAL
ANTITUSSIVES
Non opioid / narcotic alkaloids.
Stereoisomers of opioid molecules that are devoid
of analgesic effects and addiction liability.
Classification :
1) Orphan antitussives : dextromethorphan
2) Amido antitussives : pentoxyverine,
clofedanol
3) Piperidine antitussives : cloperastine
4) Morpholine antitussives : promolate,
fominoben
5) Others : eprazinone, zipeprol

PERIPHERAL ANTITUSSIVES
Inhibiting receptor, afferent nerve, efferent nerve
of cough reflex arc cough suppression.
1. local anesthesia action : narcotine, benzonatate
2. Alleviative action : extractum glycyrrhizae
liquidum

PERIPHERAL ANTITUSSIVES
Levodropropizine is a non-opioid agent whose
peripheral antitussive action may result from its
modulation of sensory neuropeptide levels
within the respiratory tract.
Locally acting agents (throat lozenges, cough
drops) may suppress cough by increasing the
flow of saliva and by containing demulcents or
local anesthetics to decrease irritation of
pharyngeal mucosa.

ANTITUSSIVES
Indication for use of antitussives :
A dry, hacking, nonproductive cough that interferes
with rest and sleep.
It is not desirable to suppress a productive cough
because the secretions need to be removed.
Although antitussives continue to be used and some
people report beneficial effects, some research
studies indicate that cough medicines are no more
effective than placebos in children or adults.

ANTITUSSIVES
Adverse effects
Excessive suppression of the cough reflex with
antitussives (inability to cough effectively when
secretions are present).
This is a potentially serious adverse effect because
retained secretions may lead to atelectasis, pneumonia,
hypoxia, and respiratory failure.
Nausea, vomiting, constipation, dizziness, drowsiness,
pruritus, loss of awareness, insomnia, difficulty in
breathing and drug dependence : associated with
narcotic agents. When narcotics are given for
antitussive effects, however, they are given in relatively
small doses and are unlikely to cause adverse reactions.

ANTITUSSIVES
Drug interactions
Drugs that increase antitussive effects of codeine :
CNS depressants (alcohol, antianxiety agents,
barbiturates, and other sedative-hypnotics) Additive CNS depression. Codeine is given in small
doses for antitussive effects, and risks of significant
interactions are minimal.
Drugs that alter effects of dextromethorphan :
MAO inhibitors This combination is contraindicated. Apnea, muscular rigidity, hyperpyrexia,
laryngospasm, and death may occur.

ANTITUSSIVES
GENERAL PRECAUTION :
Anti cough agents that include codeine,
dextromethorphan,
butamirat
are
not
recommended for using in kids (to 2 years of age),
during pregnancy and lactation.
Agents that include glaucini hydrochloridum may
provoke decreasing of arterial blood pressure in
kids.
Anti cough agents that include dextromethorphan
may cause CNS and breathing depression if using in
hight doses or for a long period.
Anti cough agents that include butamirat,
dextromethorphan
may
cause
weakness,
sleepiness, dizziness.

CODEIN
Codeine phosphate is an opioid analgesic with uses
similar to those of morphine, but is much << potent as
an analgesic & has only mild sedative effects.
Mechanism of Action and Effects :
Selectively suppress cough center in medulla
oblongata. Its primary site of action is at the mu opioid
receptors distributed throughout the central nervous
system.
Codeine phosphate reduces intestinal motility through
both a local and possibly central mechanism of action.
Codeine phosphate also suppresses the cough reflex
by a direct central action, probably in the medulla or
pons.

CODEIN
Potency :
Analgesia : 1/7 of morphine
Suppression of cough : 1/10 of morphine
Respiratory depression, constipation, tolerance,
dependence that of morphine
Clinical Uses :
Dry cough & moderate pain
Pharmacokinetic :
Codeine is readily absorbed from the GI tract &
metabolised by O- and N-demethylation in the liver
morphine & norcodeine which with codeine are
excreted almost entirely by the kidney, mainly as
conjugates with glucuronic acid.

CODEIN
Codeine and its salts are absorbed from the
gastro-intestinal tract and onset of analgesic
action occurs 30 to 45 minutes after
administration, when given orally.
Peak effect is reached within 1 to 2 hours and the
duration of antitussive action is 4 hours and 4 to 6
hours respectively.

CODEIN
Dosage and administration :
Adults = for non-productive cough the usual dose
is 10 mg 20 mg every 4-6 hours to a maximum
total of 120 mg in 24 hours.
Paediatric = for cough children may be given up
to 0.25 mg per kg every 4 - 6 hours.
On the basis of available data, codeine and other
opioid cough suppressants should rarely be
administered to children less than 6 to 12 months
old.
They should not be given in productive cough.

CODEIN
Contra Indications :
Known hypersensitivity to codeine
Acute respiratory depression (cyanosis and excessive
bronchial secretion)
Obstructive airways disease
Acute alcoholism
Head injuries or conditions in which intracranial pressure
Patients at risk of paralytic ileus
Hepatic failure
Acute asthma attack
Heart failure secondary to chronic lung disease
Diarrhoea associated with pseudomembranous colitis or
diarrhoea caused by poisoning
Patients taking MAOI

DEXTROMETHORPHAN
Chemistry :
Dextrorotatory stereoisomers of a methylated
derivative of levorphanol.
Clinical Use :
Dry cough and combined with antihistamine drug.
Dextromethorphan is chemically related to codeine and
acts on the brain to suppress cough, but does not have
the pain-relieving and addictive properties of codeine
Pharmacodynamics :
DMP acts centrally to elevate the threshold for
coughing, and has no significant analgesic / sedative
properties at antitussive doses.

DEXTROMETHORPHAN
It is proposed that DMP is a glutamate and NMDA
antagonist, and blocks the dopamine reuptake site. It
may also increase 5HT 1A activity possibly via NMDA
antagonism.
Pharmacokinetics :
DMP is rapidly absorbed from the gastrointestinal tract
and peak plasma concentrations are reached in
approximately 2.5 hours.
DMP is widely distributed, and is rapidly and extensively
metabolized by the liver. DMP is demethylated to
dextrorphan, an active metabolite, and to 3methoxymorphinan and 3-hydroxymorphinan.

DEXTROMETHORPHAN
It is primarily excreted as unchanged parent drug and
dextrorphan.
Route of Administration : oral.

DEXTROMETHORPHAN
Potency, Purity and Dose :
Adults & children aged 12 years = 60-120 mg daily
in divided doses;
Children aged 6-12 years = 30-60 mg daily in divided
doses;
Children aged 2-6 years = 15-30 mg daily in divided
doses.
Approximate recreational doses are : threshold dose
80-90 mg; light 100-200 mg; common 200-400 mg;
strong 400-600; and heavy dose 600-1500 mg.

PENTOXYVERINE
Suppression of cough : 1/3 of codeine.
Direct suppression of cough center
Atropine like action and local anesthesia action.

CLOPERASTINE
Derivative of diphenhydramine
Suppression of cough center
Blocking H1-receptor

LEVODROPROPIZINE
Mechanism of Action :
Levodropropizine is a non-opioid agent whose
peripheral antitussive action may result from its
modulation of sensory neuropeptide levels within the
respiratory tract.
In particular, levodropropizine exerts its antitussive
effect through an inhibitory action at the level of the
airway sensory nerves and it has been shown to be
able to inhibit in vitro the release of neuropeptides
from C-fibers.
The activity of levodropropizine on airway sensory
units other than the C-fibres has not been investigated.

LEVODROPROPIZINE
Pharmacokinetics :
After oral administration of Levodropropizine, the drug
is rapidly absorbed in the GIT.
The peak plasma concentration can be achieved within
40 minutes after administration of Levodropropizine.
The
plasma
protein-binding
capability
of
Levodropropizine is about 13%.
Precautions :
Levodropropizine is contraindicated in patients with
excessive mucus discharge or limited mucociliary
functions, severe hepatic disorders and allergy to
levodroperizine.
Levodropropizine can cause dizziness.

LEVODROPROPIZINE
Other Drug Interactions :
Levodropropizine may interact with alcohol, sedatives,
hypnotics and sedating anti-histamine drugs.
Dosage :
Adults : consider administration of 60 mg of
Levodropropizine, thrice daily. The duration should not
exceed more than seven days.
Pediatrics : children >2 years, consider administration
of 1 mg/kg, thrice daily. Children >12 years, consider
administration of 60 mg of Levodropropizine, thrice
daily. The duration should not exceed more than seven
days.

LEVODROPROPIZINE
Contra Indications :
USFDA pregnancy category D.
Levodropropizine can harm the
unborn fetus.
Avoid breast feeding.
Furthermore, the efficacy of most
antitussive drugs, particularly those
for URTI, has been challenged
recently; in fact, the American
College of Chest Physicians (ACCP)
advises against the use of antitussive
drugs in URTI.

MUCOACTIVE
AGENTS

1. EXPECTORANTS
DEFINITION :
Expectorants are defined as medications that improve
the ability to expectorate purulent secretions. This
term is now taken to mean medications that increase
airway water or the volume of airway secretions,
including secretagogues that are meant to increase the
hydration of luminal secretions (eg, hypertonic saline
or mannitol) and abhesives that decrease the
adhesivity of secretions and thus unstick them from
the airway (eg, surfactants).
Expectorants are agents given orally to liquefy
respiratory secretions and allow for their easier
removal.

1. EXPECTORANTS
MECHANISM OF ACTIONS :
Increase volume or hydration of airway secretion :
Systemic hydration no clinical effect
Classic expectorant no clinical effect
Modifier of airway water transport (being
investigated)
Expectorants do not alter ciliary beat frequency or
mucociliary clearance. Oral expectorants were once
thought to increase airway mucus secretion by acting
on the gastric mucosa to stimulate the vagus nerve, but
that is probably inaccurate.

1. EXPECTORANTS
PREPARAT :
The most commonly used expectorants are simple
hydration, including :
Bland aerosol / fog inhalation (1.8% NaCl, 2% ~ 7.5%
NaHCO3)
Oral hydration
Iodide-containing compounds such as super-saturated
potassium iodide or iodinated glycerol
Ammonium chloride
Glyceryl guaiacolate (guaifenesin)
The more recently developed ion-channel modifiers
such as the P2Y2 purinergic agonists

1. EXPECTORANTS
GUAIFENESIN
Oral expectorant that is believed to increase the
leaking of fluid out of the lung tissue and into the
airways. This action thins (liquefies) the thick mucous
in the airways and facilitates the clearing of the
mucous by coughing. Clearing of mucous from the
airways decreases cough.
Guaifenesin is the most commonly used expectorant. It
is available alone and as an ingredient in many
combination cough and cold remedies, although
research studies do not support its effectiveness and
many authorities do not recommend its use.

1. EXPECTORANTS
OTHER EXPECTORANTS

Hot beverages, potassium iodide, and ipecac

stimulate production of watery mucus.
In the first 2-3 days of reception of expectorants a
cough and separation of sputum can increase : these
phenomena testify to efficiency of preparation.
Plant decoctions and extracts render not only
coughing up action, but also the regenerations of the
damaged mucous membrane of bronchial tubes
promote
due to the contained microelements,
vitamins and biogenic stimulators.

1. EXPECTORANTS
EFFICACY
Expectorants show their clinical efficiency on 6-7 days
of treatment.
At presence of acute inflammatory process herbal
expectorants are preferable.
ADVERSE EFFECTS

At an overdose or prolonged reception of

preparations, containing iodides, the origin of
iodism is possible : rhinitis, somnolence, swelling;
hyperthyroidism - tachicardia, tremor, insomnia,
diarrhea are possible (more frequent at persons
after 40 years).
Dont combine expectorants with drugs that supress
cough reflex.

EXPECTORANTS

2. MUCOLYTICS
MECHANISM OF ACTIONS :
Degrade polymers in secretion
Mucolytics are administered by inhalation to liquefy
mucus in the respiratory tract. Solutions of mucolytic
drugs may be nebulized
into a face mask or
mouthpiece or instilled directly into the respiratory
tract through a tracheostomy.

CLASSIFICATIONS :
A. Thiol with free sulphydryl groups (classic mucolytics)
N Acetyl Cystein (NAC) :
Disrupts disulfide bond making mucus less
resistant.

2. MUCOLYTICS
NAC can be taken orally, inhalation or instillation
Sodium chloride solution and acetylcysteine are the only
agents recommended for use as mucolytics.
Oral acetylcysteine is widely used in the treatment of
acetaminophen overdosage.
Acetylcysteine is effective within 1 minute after
inhalation, and maximal effects occur within 5 to 10
minutes. It is effective immediately after direct
instillation.
Side effects :

GIT irritation (oral)

Burning sensation in airways (inhalation)
Bronchospasm (inhalation)
Sulphorous taste & odor (inhalation)

2. MUCOLYTICS
A. Thiol with free sulphydryl groups (classic mucolytics)
L Cystein ethyl ester hydrochloride :
Given orally
Biotransformed in liver to NAC
Used in COPD
Has no GIT side effects
B. Thiol with blocked sulphydryl group
Preparate : S-caboxymethyl cysteine (SCMC)
Does not break mucin disulfide bonds
Increases nasal mucociliary clearance in chronic sinusitis
(not in chronic bronchitis)
Second generation mucolytic & free radical scavenging
activity (antioxidant) : erdostein

2. MUCOLYTICS
C. Proteolytic enzymes (peptide enzymes)
They increases sputum viscidity

Indications
Indications : all forms of tracheobronchitis,
emphysema with bronchitis pneumoconiosis,
chronic inflammatory pulmonary conditions,
bronchiectasis, bronchitis with bronchospasm
asthma. During acute exacerbations of bronchitis it
should be given with the appropriate antibiotic.
Contraindications : there are no absolute
contraindications but in patients with gastric
ulceration relative caution should be observed.

2. MUCOLYTICS
Precaution
Acetylcysteine may cause pulmonary hemorrage, liver
and kidney function disturbances, may provoke attack
of asthma.

3. MUCOKINETICS
Mechanism of Action :
Increase mucociliary efficiency or cough efficiency
Agents :
Bronchodilators : they increase cough flow in patients
with airway hyperactivity e.g. B2 agonist &
theophylline cilio-stimulant and bronchodilator
Ipratropium bromide has no anti-mucokinetic
Abhesives : such as surfactants
Pharmacological Action :
Decrease mucus attachment to cilia and epithelium
Increase cough and mucociliaryeffect

4. MUCOREGULATORY AGENT
Mechanism of Action :
Decrease the volume of airway mucus secretion
Effective in hypersecretorystates (bronchorrhea and
bronchial asthma)
Long-term oral administration causes decrease in
water and mucus secretion in airway
Agents :
A. Anti-inflammatory agents : Iidomethacin &
corticosteroids
B. Anticholinergic agents
C. Macrolide antibiotics : erythromycin, clarithromycin,
and azithromycin

5. OTHER MUCO ACTIVE AGENTS

A. Bromohexine & Ambroxol
Bromohexine increases expectoration of sputum in
chronic bronchitis.
Ambroxol stimulates mucus secretion and causes
normalization of mucus viscosity in viscid secretion.
Bromhexine / ambroxole may effectively decrease
viscosity of bronchial secretions.
Ambroxol is a clinically proven systemically active
mucolytic agent. When administered orally onset of
action occurs after about 30 minutes. The breakdown
of acid mucopolysaccharide fibers makes the sputum
thinner and less viscous and therefore more easily
removed by coughing.

5. OTHER MUCO ACTIVE AGENTS

A. Bromohexine & Ambroxol
Although sputum volume eventually decreases, its
viscosity remains low for as long as treatment is
maintained.
Bromhexine and ambroxole stimuly surfactant
synthesis, making better alveolar cells function, and
help clearing of mucous from the airways.

B. Saline solution (isotonic, 0.9%)

Uses :
For routine nebulisation therapy
Hydration of mucus

5. OTHER MUCO ACTIVE AGENTS

C. Sodium bicarbonate (2%) : alkaline environment
causes decrease in mucus elasticity
If mucus secretion increases, viscidity decreases
Therapeutic Uses of Mucoactiveagents :
Respiratory mucostasis e.g. chronic bronchitis, asthma
& cystic fibrosis
Chronic sinusitis (+ antibiotics)
With antibiotics for treatment of airway infections e.g.
bronchiectasis
Prophylaxis of post-operative chest complications
Sputum production for diagnostic purposes e.g. T.B.

2. MUCOLYTICS
Precaution
Ambroxol is contraindicated in first term of pregnancy.
Dont use ambroxol in kids to 3 years age.
Bromhexine and ambroxole may increase liver
transaminase activity. Bromhexine and ambroxole are
not combined with codeine including drugs.

TOPICAL COUGH MEDICATION

Camphor and menthol are topical cough
medications. Camphor and menthol ointments are
rubbed on the throat and the chest as a thick layer.
The anesthetic action of their vapors is believed to
relieve cough. They are also available as products
for steam inhalation. Menthol is also available as
lozenges and compressed tablets.

ASMA BRONCHIALE
Pathophysiology :
Asthma is a disease characterized by airway
inflammation and episodic, reversible
bronchospasm
Two characteristic features :
1) Inflammatory changes in the airway
2) Bronchial hyperreactivity to stimuli
Important mediators : histamine, LTC4, LTD4,
etc.

ASTHMA BRONCHIALE

BASIC PHARMACOLOGY
OF AGENTS USED IN THE
TREATMENT OF ASTHMA

MANAGEMENT OF ACUTE SEVERE

ASTHMA
Assessment of asthma severity
Life-threatening asthma (e.g. silent chest, exhaustion,
cyanosis, peak flow 33% of predicted or best,
saturation 92%) needs urgent treatment with :
High flow oxygen (FiO2 4060% oxygen);
Glucocorticosteroids : hydrocortisone i.v., followed
by prednisolone p.o..
Nebulized 2-agonist (e.g. salbutamol) plus
ipratropium; via oxygen-driven nebulizer.

MANAGEMENT OF ACUTE SEVERE

ASTHMA
If the response to the above bronchodilator
treatment is inadequate or not sustained, consider
intravenous bronchodilator : 2-agonist (e.g.
salbutamol
by
i.v.
infusion),
or
aminophylline/theophylline (by slow i.v. injection).
Antibiotic (co-amoxiclav or clarithromycin), if bacterial
infection is strongly suspected beware potential
interactions with theophylline.

PRINCIPLES OF DRUG USE IN

TREATING CHRONIC ASTHMA
1. Metered dose inhalers (MDIs) of 2-agonists
Convenient and with correct usage little drug enters
the systemic circulation.
Inhalation formulations include :
Metered-dose inhaler aerosol
Aerosol administered via a nebulizer
As a dry powder inhaler
Aerosols are particularly useful for treating an acute
episode of breathlessness.

PRINCIPLES OF DRUG USE IN

TREATING CHRONIC ASTHMA
Long-acting 2-agonist (salmeterol) should be taken
regularly with top-ups of on-demand shorteracting agents.
Oral preparations have a role in young children who
cannot co-ordinate inhalation with activation of a
metered-dose inhaler. Children over five years can
use inhaled drugs with a spacer device. Oral
formulations, including slow-release preparations.

PRINCIPLES OF DRUG USE IN

TREATING CHRONIC ASTHMA
2. Patients should contact their physician promptly if
their clinical state deteriorates or their 2-agonist use
is increasing.
3. Inhaled
glucocorticosteroids
(beclometasone,
fluticasone, budesonide) are initiated when
symptoms are not controlled or when :
regular (rather than occasional, as needed) doses of
short-acting 2-agonist bronchodilator are required
repeated attacks interfere with work or school.

PRINCIPLES OF DRUG USE IN

TREATING CHRONIC ASTHMA
4. Leukotriene receptor antagonists (e.g. montelukast)
are used in adults and children for long-term
maintenance
therapy
and
can
reduce
glucocorticosteroid requirements.
5. In moderate to severe steroid-dependent chronic
asthma, the anti-IgE monoclonal antibody omalizumab
can improve asthmatic control and reduce the need for
glucocorticosteroids.

ANTI ASTHMATIC DRUGS

I. Bronchodilators
1. receptor agonists
2. Theophylline
3. Muscarinic antagonists
II. Anti-inflammatory agents
1. Steroids
2. Anti-leukotriene agents
III. Anti-allergic agents
1. Stabilizer of inflammatory cell membrane
2. H1 receptor blocker
3. Anti IgE antibody

BRONCHODILATORS

BETA-ADRENOCEPTOR AGONISTS
A. Prototypes and Pharmacokinetics
Adrenaline : , agonist
Ephedrine : , agonist
Isoprenaline : 1 ,2 agonist
2-selective agonists
Salbutamol
short / intermediate Terbutaline
acting
Clenbuterol
Formoterol
long-acting
Salmeterol
Bambuterol

BETA-ADRENOCEPTOR AGONISTS
A. Prototypes and Pharmacokinetics
The most important sympathomimetics used to reverse
asthmatic bronchoconstriction direct-acting 2-selective
agonists.
Short-acting agents : albuterol, terbutaline, metaproterenol
(durations of action of 6 h or less).
Long-acting 2-selective agonists : salmeterol, formoterol,
and indacaterol (act for 1224 h), but indacaterol is currently
approved only for COPD.
Given by inhalation, usually from pressurized aerosol
canisters but occasionally by nebulizer decreases the
systemic dose ( adverse effects) & delivering an effective
dose locally to the airway smooth muscle.

B. Mechanism and Effects

Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the
2-adrenoceptorGs-coupling
protein-adenylyl
cyclase
pathway) and increase cyclic adenosine monophosphate
(cAMP) in smooth muscle cells results in a powerful
bronchodilator response.
C. Clinical Use
Shorter acting (albuterol, metaproterenol, terbutaline) DOC
for acute episodes of bronchospasm. Their effects last for 4 h
or less not effective for prophylaxis.
Long-acting agents (salmeterol) used for prophylaxis (12-h
duration of action is useful). They should not be used for acute
episodes onset of action is too slow.
Furthermore, used alone increase asthma mortality,
whereas in combination with corticosteroids improve
control.

 Shorter-acting agonists :

most effective bronchodilators available

life-saving for acute asthma.
chronic obstructive pulmonary disease (COPD) also
benefit
D. Toxicity
Skeletal muscle : tremor is a common adverse 2 effect.
CV : beta2 selectivity is relative at high clinical dosage,
these agents have significant 1 effects. Even when they
are given by inhalation, some cardiac effect (tachycardia) is
common. Excessively arrhythmias may occur. Loss of
responsiveness (tolerance, tachyphylaxis) is an unwanted
effect of excessive use of the short-acting
sympathomimetics.
Metabolism disturbance : ketone bodies, acidosis

METHYLXANTHINES
A. Prototypes and Pharmacokinetics
The methylxanthines are purine derivatives. 3 major
methylxanthines are found in plants and provide the
stimulant effects of 3 common beverages: caffeine (in
coffee), theophylline (tea), and theobromine (cocoa).
Theophylline is the only member of this group that is
important in the treatment of asthma.
This drug and several analogs are orally active and available
as various salts and as the base. Theophylline is available in
both prompt-release and slow-release forms, eliminated by
P450 drug-metabolizing enzymes in the liver.
Clearance varies with age (highest in young adolescents),
smoking status (higher in smokers), and concurrent use of
other drugs that inhibit or induce hepatic enzymes.

B. Mechanism of Action and Effects

Methylxanthines inhibit phosphodiesterase (PDE), enzyme
that degrades cAMP to AMP cAMP accumulation.
Block adenosine receptors
Increase endogenous catecholamine (CA) releasing
Interfere with receptor-operated Ca2+ channels [Ca2+]i
Anti-inflammatory action
C. Clinical Use
Slow-release theophylline (for control of nocturnal asthma).
Aminophylline is a salt of theophylline that is sometimes
prescribed.

D. Toxicity
Narrow margin of safety. Toxic effects are related to its
plasma concentrations.
The common adverse effects : GI distress, tremor,
insomnia.
Overdosage : severe nausea and vomiting,
hypotension, cardiac arrhythmias, and seizures.
Very large overdoses (eg, in suicide attempts) :
potentially lethal because of arrhythmias and seizures.
Beta blockers are useful in reversing severe
cardiovascular toxicity from theophylline.

MUSCARINIC ANTAGONISTS
A. Prototypes and Pharmacokinetics
There are M1, M2, M3 receptor subtype in the airway.
Selectively blocking M1, M3 receptor is resulted in
bronchodilating effect.
Ipratropium bromide binds to all M-R subtypes (M1, M2
and M3 ), and inhibits acetylcholine-mediated
bronchospasm.
Atropine & other naturally belladonna alkaloids have
been replaced by ipratropium, a quaternary
antimuscarinic agent designed for aerosol use.
Ipratropium is delivered to the airways by pressurized
aerosol little systemic action. Tiotropium is a longeracting analog.

MUSCARINIC ANTAGONISTS
B. Mechanism of Action and Effects
Ipratropium & tiotropium competitively block muscarinic
receptors in the airways effectively prevent bronchoconstriction mediated by vagal discharge.
Muscarinic antagonists reverse bronchoconstriction
especially children and in many patients with COPD.
They have no effect on the chronic inflammatory aspects
of asthma.
C. Clinical Use
Ipratropium and tiotropium are useful in one third to two
thirds of asthmatic patients.
For acute bronchospasm, the agonists are usually
preferred than muscarinic antagonists.

 In COPD, which is often associated with acute episodes

of bronchospasm, the antimuscarinic agents may be
more effective and less toxic than agonists.
D. Toxicity
Ipratropium and tiotropium are delivered directly to the
airway and are minimally absorbed, systemic effects are
small.
Excessive dosage minor atropine-like toxic effects.
In contrast to the 2 agonists, muscarinic antagonists do
not cause tremor or arrhythmias.

ANTIINFLAMMATORY
AGENTS

GLUCOCORTICOIDS 319 343 346

A. Prototypes and Pharmacokinetics
All the corticosteroids are potentially beneficial in severe
asthma. However, because of their toxicity, systemic (oral)
corticosteroids (usually prednisone) are used chronically
only when other therapies are unsuccessful.
In contrast, local aerosol administration of surface-active
corticosteroids
(eg,
beclomethasone,
budesonide,
dexamethasone, flunisolide, fluticasone, mometasone) is
relatively safe, and inhaled corticosteroids have become
common first-line therapy for individuals with moderate to
severe asthma.
Important intravenous corticosteroids for status asthmaticus
include prednisolone (the active metabolite of prednisone) and
hydrocortisone.

B. Mechanism of Action & Effects

Corticosteroids reduce the synthesis of arachidonic acid by
phospholipase A2 and inhibit the expression of COX-2, the
inducible form of cyclooxygenase. It has also been suggested
that corticosteroids increase the responsiveness of
adrenoceptors in the airway and they probably act by other
mechanisms as well.
Glucocorticoids bind to intracellular receptors and activate
glucocorticoid response elements (GREs) in the nucleus,
resulting in synthesis of substances that prevent the full
expression of inflammation and allergy.
Reduced activity of phospholipase A2 is thought to be particularly
important in asthma because the leukotrienes that result from
eicosanoid synthesis are extremely potent bronchoconstrictors
and may also participate in the late inflammatory response.

C. Clinical Use and Toxicity

Inhaled glucocorticoids are now considered appropriate
(even for children) in most cases of moderate asthma that
are not fully responsive to aerosol agonists.
It is believed that such early use may prevent the severe,
progressive inflammatory changes characteristic of longstanding asthma. This is a shift from earlier beliefs that
steroids should be used only in severe refractory asthma.
In such cases of severe asthma, patients are usually
hospitalized and stabilized on daily systemic prednisone and
then switched to inhaled or alternate-day oral therapy
before discharge.
In status asthmaticus, parenteral steroids are lifesaving.
Patients with COPD tend to be more resistant to the
beneficial effects of steroids.

 Frequent aerosol administration of glucocorticoids can

occasionally result in a very small degree of adrenal
suppression, but this is rarely significant. More commonly,
changes in oropharyngeal flora result in candidiasis. If oral
therapy is required, adrenal suppression can be reduced by
using alternate-day therapy (ie, giving the drug in slightly
higher dosage every other day rather than smaller doses
every day).
The major systemic toxicities of the glucocorticoids are much
more likely to occur when systemic treatment is required for
more than 2 weeks, as in severe refractory asthma. Regular
use of inhaled steroids does cause mild growth retardation
in children, but these children eventually reach full predicted
adult stature.

LEUKOTRIENE ANTAGONISTS
A. Leukotriene Receptor Blockers
Mechanism of Action :
Cysteinyl leukotrienes is a important
inflammatory
mediator of bronchoconstriction, increased bronchial
reactivity, mucosal edema, mucus hypersecretion, etc.
These drugs interfere with the synthesis or the action of
the leukotrienes. Although their value has been
established, they are not as effective as corticosteroids in
severe asthma.
Prototypes :
Zafirlukast and montelukast are antagonists at the LTD4
leukotriene receptor. The LTE4 receptor is also blocked.
Orally active and effective in preventing exercise, antigen
& aspirin-induced bronchospasm.

 Toxicity :
They are not recommended for acute episodes of asthma.
Toxicity is generally low. Rare reports of allergic
granulomatous angiitis, have appeared, but an
association with these drugs has not been established.

B. Lipoxygenase Inhibitor
Mechanism of Action :
Leukotrienes resulte from the action of 5-lipoxygenase on
arachidonic acid.
Zileuton (5-lipoxygenase inhibitor) is an orally active
drug that selectively inhibits 5-lipoxygenase, a key
enzyme in the conversion of arachidonic acid to
leukotrienes.

 The drug is effective in preventing both exercise and

antigen-induced bronchospasm. It is also effective against
aspirin allergy, the bronchospasm that results from
ingestion of aspirin by individuals who apparently divert
all eicosanoid production to leukotrienes when the
cyclooxygenase pathway is blocked.
Toxicity :
Elevation of liver enzymes, and this drug is therefore less
popular than the receptor blockers.

ANTI-ALLERGIC
AGENTS

DISODIUM CROMOGLYCATE
A. Prototypes and Pharmacokinetics
Madiators release inhibitors & no bronchodilator
action.
Cromolyn (disodium cromoglycate) and nedocromil are
unusually insoluble chemicals, so that even massive
doses given orally or by aerosol result in minimal
systemic blood levels.
They are given by aerosol for asthma but are now rarely
used in the United States.
Cromolyn is the prototype of this group.

B. Mechanism of Action and Effects

The mechanism of action of these drugs is poorly
understood but may involve IgE-mediated reactions in
these tissues.
Stabilizer of mass cell membrane : decrease the
release of mediators from mast cells (histamine).
Inhibit the function of sensory nerve ending and
neurogenic inflammation in airway.
Decrease bronchial hyperreactivity.
The drugs have no bronchodilator action but can
prevent bronchoconstriction caused by a challenge with
antigen to which the patient is allergic.
Cromolyn and nedocromil are capable of preventing
both early and late responses to challenge.

 Because they are not absorbed from the site of

administration, cromolyn and nedocromil have only local
effects.
C. Clinical Uses and Toxicity
Asthma (especially in children) was the most important
use for cromolyn and nedocromil. Nasal and eyedrop
formulations of cromolyn are available for hay fever.
When administered orally, cromolyn has some efficacy in
preventing food allergy. Similar actions have been
demonstrated after local application in the conjunctiva
and the nasopharynx for allergic.
D. Toxicity
Cromolyn and nedocromil may cause cough and irritation
of the airway when given by aerosol. Rare instances of
drug allergy have been reported.

H1 RECEPTOR BLOCKER
A. Effects
H1 receptorThis Gq-coupled receptor is important in
smooth muscle effects, especially those caused by IgEmediated responses. Inositol trisphosphate (IP3) and
diacylglycerol (DAG) are the second messengers.
Typical responses include pain and itching in the skin,
bronchoconstriction, and vasodilation, the latter caused
by release of nitric oxide.
Capillary endothelial cells, in addition to releasing nitric
oxide (NO) and other vasodilating substances, also
contract, opening gaps in the permeability barrier and
leading to the formation of local edema. These effects
occur in allergic reactions.

B. Mechanism and Effects

H1 blockers are competitive pharmacologic antagonists at
the H1 receptor; these drugs have no effect on histamine
release from storage sites. They are more effective if given
before histamine release occurs.
As noted, most older first-generation agents are sedating.
C. Clinical Use
H1 blockers have major applications in allergies of the
immediate type (ie, those caused by antigens acting on IgE
antibody sensitized mast cells). These conditions include
hay fever and urticaria.
Adverse effects of the first-generation H1 blockers are
sometimes exploited therapeutically (eg, in their use as
hypnotics in over-the-counter sleep aids).

D. Toxicity and Interactions

Sedation is common, especially with diphenhydramine.
It is much less common with second-generation agents,
which do not enter the CNS readily.
Antimuscarinic effects such as dry mouth and blurred
vision occur with some first generation drugs in some
patients.
Alpha-adrenoceptor blockade, which is significant with
phenothiazine derivatives such as promethazine, may
cause orthostatic hypotension.
Interactions occur between older antihistamines and
other drugs with sedative effects (benzodiazepines and
alcohol).

D. Toxicity and Interactions

Drugs that inhibit hepatic metabolism may result in
dangerously high levels of certain antihistaminic drugs
that are taken concurrently. For example, azole
antifungal drugs and certain other CYP3A4 inhibitors
interfere with the metabolism of astemizole and
terfenadine, 2 second-generation agents that have been
withdrawn from the US market because high plasma
concentrations of either antihistamine can precipitate
lethal arrhythmias.

ANTI-IgE ANTIBODY
Omalizumab is a humanized murine monoclonal
antibody to human IgE. It binds to the IgE on sensitized
mast cells and prevents activation by asthma triggers
and subsequent release of inflammatory mediators.
Although approved in 2003 for the prophylactic
management of asthma, experience with this drug is
limited because it is very expensive and must be
administered parenterally.

Salbutamol nebule 2,5 mg amp No. I

Adult nebulizer mask
No. I
S imm

Combivent nebule amp

Adult nebulizer mask
S imm

No. I
No. I

Symbicort turbuhaler / MDI No. I

S 2 dd puff I

Thank you!
QUESTIONS?!