DRUGS OF

THE
RESPIRATORY
DISEASE

These categories are:

I. Cough preparations.
II. Mucolytics.
III. Drugs used in asthma.
IV. Respiratory stimulants.
V. Drugs used in allergies
and anaphylaxis.

I. COUGH
PREPARATIONS

Typical drugs are weak

opioids :

1.Codein phosphate :
Inhibits the cough reflex
centrally.
Codein is approximately
60% as effectively orally as
parenterally, both as an
analgesic and as respiratory
depressant.

Codeine has a high oral to

parenteral potency ratio.
The greater oral efficacy of
these drugs less first-pass
metabolism in the liver.
Codeine is metabolized by the
liver, its metabolites are
excreted chiefly in the urine,
largely in inactive forms.

A small fraction
(approximately 10%) of
administered codeine is Odemethylated to form
morphine, and both free and
conjugated morphine
found in the urine after
therapeutic doses of
codeine.

Codeine low affinity for

opioid receptors, analgesic
effect of codeine due to
its conversion to morphine.
Its antitussive actions may
involve distinct receptors
that bind codeine.
Half-life of codeine in plasma
is 2-4 hours.

Conversions of codeine to
morphine is effected by the
cytochrome P450 enzyme CYP2D6.
Well-characterized genetic
polymorphisms in CYP2D6 lead to
the inability to convert codeine to
morphine, making codeine in
effective as an analgesic for about
10% of the Caucasian population.

Other polymorphisms
can lead to enhanced
metabolism increased,
sensitivity to codeines
effective.

Morphine and related opioids

produce a wide spectrum of
unwanted effects
respiratory depression,
nausea, vomiting, dizziness,
clouding, dysphoria, pruritus,
constipation, increased
pressure in the biliary tract,
urinary retention and
hypotension.

2.Dextromethorphan
Dextromethorphan (d-3methoxy-N-methylmorphinan)
the d isomer of the codeine
analog methorphan; no
analgesic or addictive
properties and does not act
through opioid receptors.

The drug acts centrally to

elevate the threshold for
coughing.
Its potency is nearly equal
to that of codeine.

Compared with codeine,

dextromethorphan produces
subjective and gastrointestinal
side effects.
In therapeutic dosages, the
drug does not inhibit ciliary
activity, its antitussive effects
persist for 5-6 hours.

Its toxicity is low, but

extremely high doses may
produce CNS depression.
Mechanism my which
dextromethorphan exerts its
antitusive effects is still
unclear.

3.Noscapine
Occuring opium alkaloid of
the except for its antitissive
effect, it has no significant
actions on the CNS in doses
within the therapeutic.
The drug is a potent releaser
of histamine, and large doses
bronchoconstriction and
transient hypotension.

4. Other drugs
As centrally acting
antitussives include
carbetapetane, caramiphen,
chlophedianol,
diphenhydramine, and
glaucine.

Each is a member of a
distinct pharmacological
class unrelated to the
opioids.
The mechanism of action of
diphenhydramine, an
antihistamine unclear.

II. MUCOLYTICS

Mucolytics (e.g.
carbocisteine and methyl
cysteine hydrochloride) are
designed to reduce the
viscosity of sputum, thereby
aiding expectoration.

The indications for use have

been in:
Chronic bronchitis.
Chronic asthma.
Cystic fibrosis.
Bronchiectasis.

The drugs may be of

benefit in treating
acute exacerbations
in COPD.

III. DRUGS USED IN

ASTHMA

Two main categories :

A.Relievers (Bronchodilators).
B.Preventers (corticosteroids,
sodium cromoglycate,
leukotrine receptor
antagonist)

A.Relievers (Bronchodilators)
Bronchodilators can be
split into :
-adrenergic receptor
agonist.
2.Anticholinergics.
3.Xanthines.

1. -adrenergic receptor agonist.

Mechanism of action and use in
asthma
The -adrenergic receptor
agoints for the treatment of
asthma selective for the 2receptor subtype.
The agonists can be classified
as short- and long-acting.

Short-acting -adrenergic
receptor agonists
Drugs in this class include
albuterol (Proventil,
Ventolin), levalbutel
[Xopenex, the (R)enantiomer of albuterol],
metaproterenol (Alupent),
terbutaline (Brethaire), and
pirbuterol (Maxaair).

These drugs are used for

acute inhalation treatment
of broncospasm.
Each of the inhaled drugs
on onset of action within
1-5 minutes and produces a
bronchodilation that lasts
for about 2-6 hours.

In oral dosage forms, the

duration of action in some
what longer (oral
terbutaline, for example,
has a duration of action of
4-8 hours).

The mechanism of the

antiasthmatic action of
short-acting -adrenergic
receptor agonist is
undountedly direct
relaxation of airway smooth
muscle and consequent
bronchodilation.

Long-acting -adrenergic
receptor agonists
Salmeterol xinafoate longlasting adrenergic agonists
with very selectivity for the 2receptor subtype.
Inhalation of salmeterol
provides persistent
bronchodilation lasting over
12 hours.

The mechanism
underlying the
therapeutic effect of
salmeterol not yet fully.
Extended side chain on
salmeterol renders it
10,000 times more
lipophilic than albuterol.

Long-acting -adrenergic
receptor agonists relax
airway smooth muscle and
cause bronchodilation by the
same mechanisms as do
short-duration agonists.

 2-adrenergic receptors
inhibits the function of
numerous inflammatory cells
including mast cells,
basophils, eosinophils,
neutrophils, and lymphocytes.

Chronic treatment with longacting 2-adrenergic receptor

agonists shown to improve
lung function, decrease
asthma symptoms, decrease
use of short-acting inhaled 2adrenergic agonists, and
decrease nocturnal asthma.

Toxicity
Higher doses increased
heart rate, and central
nervous system effects.

Oral therapy with 2-adrenergic

receptor agonists
Use of orally administered
adrenergic agonists for
bronchodilation has not gained
wide acceptance, largely because
of the greater risk of producing
side effects, especially
tremulousness, muscle cramps,
cardiac tachyarrhythmias and
metabolic disturbances.

2. Anticholinergics.
Anticholinergic are competitive
antagonists of muscarinic
acetylcholine receptors.
They therefore block the vagal
control of bronchial smooth
muscle tone in response to
irritants and reduce the reflex
bronchocontriction.

Ipratropium bromide and

oxitropium bromide are both
anticholinergics; they have two
mechanisms of action :
Reduction of reflex
bronchocontriction (e.g.
from dust or pollen).
Reduction of mucous
secretions.

These drugs reach their

maximum effect within 6090 minutes and act for
between 4-6 hours.
They are poorly absorbed
orally; they must, therefore,
be given by aerosol.

As anticholinergics only
affect the vagally mediated
element of
bronchoconstriction, they
are bot the first choice
bronchodilator in asthma
treatment.

There is some evidence that

these drugs are effective
when given together with a 2
agonist in severe asthma.
However, their main use is in
COPD that does not respond
to 2 agonists.

Side effecst are rare, but

include :
Dry mouth.
Urinary retention.
Constipation.

3. Xanthines.
Theophylline, caffeine and
theobromie methylated
xanthines.
Xanthines itself a
dioxypurine and structurally
related to uric acid.

Caffeine 1,3,6 trimethylxanthine.

Theophylline 1,3 dimethylxanthine.
Theobromine 3,7 dimethylxanthine.

Mechanisme of action :
Xanthines appear to work
by inhibiting
phosphadiesterase, thereby
preventing the breakdown
of cAMP.

The amount of cAMP

within the bronchial
smooth muscle cells is
therefore increased,
which causes
bronchodilation in similar
way to 2 agonists.

There drugs are metabolized

in the liver and there is
considerable variation in half
life between individuals.
This has important
implications because there is
a small therapeutic window.

Factors altering theophylline

clearance are shown in :
Factor altering theophylline clearance
---------------------------------------------------------------------------Increased clearance
Decrease clearance
---------------------------------------------------------------------------Smoking
Liver disease
Alcohol
Pneumonia
Rifampicin
Cimetidine
Clarythromycin
(erythromycin etc.)
Childhood
Old age
i.e.P450 enzyme
i.e.P450 enzyme inhibition
induction

Theophylline can be given

intravenously in the form of
aminophylline (theophylline
with ethylenediamine), but
must be administrated very
slowly (over 20 minutes to
administer dose).
Attack that do not respond to
2 agonists and in acute
asthma.

Use in asthma :
Theophylline has proven
efficacy as a bronchodilator
is asthma and formerly was
considered fisrt-line
therapy.

Therapy initiated by the

administration of 12-16
mg/kg/d of theophylline up to
a maximum of 400 mg/d for at
least 3 days.
Children <1 y.o. require
considerably less; dose in
mg/kg/d may be calculated as
0,3 X (age in weeks) + 5,0.

Starting with these low doses

minimizes the early side
effects of nausea, vomiting,
nervousness, and insomnia,
which often subside with
continued therapy, and
virtually eliminated the
possibility of exceeding
concentrations of 20 g/ml in
the plasma of patients over the
age of 1 year.

Dosage is increased in two

successive stages to between
16-20 and, subsequently, 1822 mg/kd/d (up to a
maximum of 800 mg/d),
depending on the age and
clinical response of the
patient, allowing at least 3
days between adjustments.

B. Preventers
(corticosteroids, sodium cromoglycate,
leukotrine receptor antagonist)

1. Corticosteroid
Steroid reduce the formation,
release, and action of many
different chemicals involved
in inflammation.

Their mode of action is

complex and involves
genemodulation after
binding to steroid receptors
in the cytoplasm of cells.

This has a number of effects

including :
Down-regulation of proinflammatory cytokine.
Production of antiinflammatory proteins.

One of these antiinflammatory proteins is

thought to reduce the
activity of phospholipase
A2 which itself plays a role
in the production of
arachidonic acid.

Steroid in treatment of
asthma may be topical
(inhaled) or systemic
(oral parenteral).

Inhaled steroids
These include:
Beclomethasone.
budesonide.
Fluticasone.

Side effects of inhaled

steroids in adults are
relatively minor (primarily
hoarseness and oral
candidiasis).
They may have a short-term
effect on growth in children.

Oral steroids
The primary oral steroid is
prednisolone.
Side effects of systemic
steroids include :
Adrenal suppression.
Effects on bones (including
growth retardation)
DM.

 Increased susceptibility to
infecton.
Weight gain.
Effects on skin (e.g.
bruising and atrophy).
Mood changes.

2. Sodium cromoglycate &

Nedocromil sodium
Cromolyn synthesized in
1965 as part of an attempt
to improve on the
bronchodilator activity.
Nedocromil, a compound
with similar chemical and
biological properties.

Mechanism of action
Cromolyn & nedocromil have
been reported to have a variety
of activities that may relate to
their therapeutic effect in
asthma inhibiting mediator
release from bronchial mast
cells to reverse increase
functional activation in
leukocytes obtained from to
blood of asthmatic patients.

Pharmacokinetics
For asthma, cromolyn is given
by inhalation, using either
solutions (delivered by aerosol
spray or nebulizer), powdered
drug.
The pharmacological effects
are from the topical deposition
of the drug in the lung.

Only about 1% of an oral

dose of cromolyn
absorbed.
Once absorbed, the drug is
excreted unchanged in the
urine and bile in about equal
proportions.

Peak concentrations in plasma

occur within 15 minutes of
inhalation, and excretion
begins after some delay, such
that the biological half-life
range from 45-100 minutes.
The terminal half-time of
elimination following
intravenous administration is
about 20 minutes.

Toxicty
Cromolyn and nedocromil
generally well tolerated by
patients.
Adverse reactions are infrequent
and minor; bronchospasm,
cough or wheezing, laryngeal
edema, joint swelling & pain,
angioedema, headache, rash, &
nausea.

Use in asthma
The main use of cromolyn
and nedocromil treatment
to mild to moderate
bronchial asthma to prevent
asthmatic attacks.

Inhaled several times daily,

cromolyn will inhibit both the
immediate and the late
asthmatic responses to
antigenic challenge or to
exercise.
With regular use for more than
2-3 months, there is evidence
of reduced bronchial
hyperreactivity.

IV. RESPIRATORY
STIMULANTS

A respiratory stimulant
(analeptic) such as
doxapram can be used for
patients with chronic
obstructive pulmonary
disease in type II
respiratory failure.

However, mechanical
ventilation and a high
incidence of side effects have
reduced their use.
Doxapram stimulates carotid
body chemoreceptors and
must be given intravenously.

Side effects of doxapram are:

Tachycardia.
Palpitations.
Nausea.
Sweating.
Tremor.

Contraindications of
doxapram are:
Epilepsy.
Hypertension.
Hyperthyroidism.

V. DRUGS USED IN
ALLERGIES &
ANAPHYLAXIS

These drugs are used in

the treatment of allergies,
such as hayfever.
Examples of these drugs
are :
Promethazine.
Trimeprazine.

The mechanism of action is

to block H1 receptors.
The drugs cross the bloodbrain barrier and have a
general depressant action
(sedative); in high doses, this
actions can cause respiratory
depression.

Newer drugs such as

terfenadine do not
readily cross the bloodbrain barrier and
therefore do not cause
respiratory depression.

Anaphylaxis
Anaphylactic shock is
a systemic allergic
reaction which is a lifethreatening condition.

The features of anaphylactic

shock are:
Severe hypotension.
Laryngeal spasm.
Bronchoconstriction.

The treatment of anaphylaxis

must therefore be rapid:
Secure the airway.
Maintain blood pressure
by lying the patient flat
and raising his or her
legs.

Drug therapy is a follows:

Intramuscular adrenaline
(epinephrine) (0.5 - 1.0 mg,
0.5 - 1.0 mL of adrenaline
injection 1:1000), repeated
at 10-minute intervals
depending on the blood
pressure.
100% oxygen.

 Chlorpheniramine
(antihistamine) 10-20 mg
intravenously, continued 24-48
hours.
Salbutamol can be given
intravenously for those patients
not responsive to adrenaline.
Hydrocorticosteroid 200-300 mg
intravenously may be given as a
second-line drug to reduce
further deterioration.