Drugs acting on respiratory system

1. DRUGS ACTING ON
RESPIRATORY
SYSTEM

2. RESPIRATORY DISEASES
Asthma
Allergic rhinitis
Chronic obstructive
pulmonary disease
Cough

3. ASTHMA
Asthma is characterized clinically by
o Recurrent bouts of shortness of
breath
o Chest tightness
o Wheezing
o Reversible narrowing of bronchial
airways
o Marked bronchial responsiveness to
inhaled stimuli

4. PATHOPHSIOLOGY OF ASTHMA
Asthma is a chronic inflammatory
disease of the airways that is
characterized by activation of mast
cells, infiltration of eosinophils, and T
helper 2 (TH2) lymphocytes
Immediate cause of asthmatic
bronchoconstriction is release of
several mediators from the IgE
sensitized mast cells
Chronic inflammation leads to marked
bronchial hyperreactivity to various
inhaled substances

5. o Lymphocytic and eosinophilic inflammation
of bronchial mucosa
o Hyperplasia of secretory, vascular and
smooth muscle cell
o The Th2 cytokines that are released to
promote immunoglobulin (Ig)E synthesis
and responsiveness in some asthmatics. IL-
4 and IL-13 'switch' B cells to IgE synthesis
and cause expression of IgE receptors on
mast cells and eosinophils; they also
enhance adhesion of eosinophils to
endothelium.

8. ANTIBODY RESPONSE
IMAGE: in the antibody
(or humoral) arm of the
the adaptive (acquired)
immune response, the
destruction of invaders is
done by antibodies
(immunolglobulins),
shown as brick red "Y"
shaped molecules at right
of picture. Invading
microorganisms are
shown at top as golden
ovoids. They are engulfed
(phagocytosed) by a
macrophage (green cell at
top). The macrophage
then presents antigens to
a (purple) Helper T-Cell
which in turn activates a
B-Cell causing it to divide
and differentiate into
Plasma Cells (large bluish
cells at lower left). Plasma
cells have a great deal of
rough endoplasmic
reticulum and are devoted
to protein synthesis (of
antibodies). The
antibodies that are
released lock onto their
corresponding antigens
and lead to the
inactivation or destruction
of the invader. A dendritic
cell is shown at upper left.

9. CLASSIFICATION OF DRUGS USED TO
TREAT ASTHMA
Bronchodilators include
oBeta2 Agonist
oMuscarinic antagonist
oMethylxanthines

10. Antiinflammatory drugs
Steroids
Anti IgE antibodies
Leukotriene Antagonist
Lipooxygenase inhibitors
Leukotirene Receptor
inhibitors

11. STRATEGIES OF ASTHMA THERAPY
Acute asthmatic
bronchospasm must be treated
promptly with bronchodilators.
Beta 2 agonist, muscarinic
antagonist, and theophylline
and its derivatives are
available for this indication

12. Long term preventive treatment
requires control of inflammatory
process in airways. Most
important antiinflammatory drugs
are corticosteroids and drugs such
as cromolyn and nedocromil that
inhibit release of mediators from
mast cells and inflammatory cells

13. Long acting beta 2 agonist can
improve the response to
corticosteroids
Anti IgE antibodies also appear
promising for chronic therapy
(Omalizumab)
Leukotriene antaagonists have effects
on both bronchconstriction and
inflammation but are used only for
prophylaxis

14. BRONCHODILATORS
Drugs stimulating both alpha and
beta receptors (adrenaline,
ephedrine)
Drugs stimulating beta receptors
(isoprenaline)
Selective beta 2 stimulants
(salbutamol, terbutaline,
salmeterol, formeterol)

15. EPINEPHRINE
 Effective, rapid acting bronchodilator
 Injected subcutaneously, 0.4ml of 1:1000
solution
 Inhaled as a microaerosol, 320 mcg per puff
 Max. bronchodilation achieved in 15 min
after inhalation and lasts for 60-90 min
 Used in anaphylaxis
 Tachycardias, arrhythmias, worsening of
angina are troublesome effects

16. EPHEDRINE
Alkaloid obtained from ephedra
Acts on both alpha and beta receptors
Has long duration of action
Produces mild stimulation of CNS
Now infrequently used for asthma
because of better therapies

17. ISOPROTERENOL (ISOPRENALINE)
Acts on beta1 and 2 receptors
Potent bronchodilator when
inhaled
80-120 mcg produces max
bronchodilation within 5 min
Has 60-90 min duration of action
Causes cardiac arrhythmias

18. BETA2 ADRENERGIC AGONIST
Albuterol, terbutaline and
metaproterenol are short acting drugs
Salmeterol and formoterol are long
acting drugs
Mechanism of action
Beta adrenoceptor agonist stimulate
adenylyl cyclase and increases cyclic
adenosine monophosphate (cAMP) in
smooth muscle cells

19. The molecular mechanisms by which agonists induce
relaxation of airway smooth muscle include:
 Lowering of concentration by active removal of Ca2+
from the cytosol into intracellular stores and out of
the cell
 Inhibition of myosin light chain kinase activation
 Activation of myosin light chain phosphatase
 Opening of a large conductance Ca2+-activated K+
channel, which repolarizes the smooth muscle cell
and may stimulate the sequestration of Ca2+ into
intracellular stores.

20. Other mechanisms of beta2 receptors include
 Prevention of mediator release from isolated human
lung mast cells (via beta2 receptors).
 Prevention of microvascular leakage and thus the
development of bronchial mucosal edema after
exposure to mediators, such as histamine and
leukotriene D4.
 Increase in mucus secretion from submucosal
glands and ion transport across airway epithelium;
these effects may enhance mucociliary clearance,
and thereby reverse the defective clearance found
in asthma.

24. Clinical use
Short-acting beta2 agonists are the
bronchodilators of choice in treating
acute severe asthma.
The nebulized route of administration is
easier and safer than intravenous
administration and just as effective.
Inhalation is preferable to the oral
administration because systemic side
effects are less, and inhalation may be
more effective. Their effect is maximal
in 15 min and lasts for 4 hrs.

25. Long acting drugs are used for prophylaxis.
The long-acting inhaled beta2 agonists
(LABA) salmeterol, formoterol, and
arformoterol have proved to be a significant
advance in asthma and COPD therapy.
These drugs have a bronchodilator action of
>12 hours and also protect against
bronchoconstriction for a similar period.
They improve asthma control (when given
twice daily) compared with regular treatment
with short-acting beta2 agonists (four to six
times daily). They are used in combination
with corticosteroids to improve control .

26. ADVERSE EFFECTS
 Muscle tremor due to stimulation of beta 2 receptors in
skeletal muscle is the most common side effect. It may
be more troublesome with elderly patients and so is a
more frequent problem in COPD patients.
 Tachycardia and palpitations are due to reflex cardiac
stimulation secondary to peripheral vasodilation, from
direct stimulation of atrial beta 2 receptors. These side
effects tend to disappear with continued use of the drug,
reflecting the development of tolerance.
 Hypokalemia is a potentially serious side effect. This is
due to beta2 receptor stimulation of potassium entry into
skeletal muscle, which may be secondary to a rise in
insulin secretion.

27. TOLERANCE
 Continuous treatment with an agonist often leads to
tolerance (desensitization, subsensitivity), which
may be due to down-regulation of the receptor .
 Tolerance of non-airway 2 receptor–mediated
responses, such as tremor and cardiovascular and
metabolic responses, is readily induced in normal
and asthmatic subjects.

28. METHYLXANTHINES
Methylxanthines are purine derivatives
Theophylline found in tea is the only
member used in the treatment of asthma
Mechanism of action
Theophylline inhibits phosphodiesterase
(PDE), the enzyme that degrades cAMP
to AMP and thus increase cAMP
It also block adenosine receptors in CNS
and inhibit sleepiness inducing
adenosine

29.  Effects on gene transcription. Theophylline
prevents the translocation of the pro-inflammatory
transcription factor NF-kappaB into the nucleus,
potentially reducing the expression of inflammatory
genes in asthma and COPD. Inhibition of NF-
kappaB appears to be due to a protective effect
against the degradation of the inhibitory protein.
However, these effects are seen at high
concentrations and may be mediated by inhibition
of PDE.

30.  Histone deacetylase activation. Recruitment of
histone deacetylase-2 (HDAC2) by glucocorticoid
receptors switches off inflammatory genes.
Therapeutic concentrations of theophylline activate
HDAC, thereby enhancing the anti-inflammatory
effects of corticosteroids. This mechanism is
independent of PDE inhibition or adenosine
receptor antagonism and appears to be mediated
by inhibition of PI3-kinase delta, which is activated
by oxidative stress

31.  Major clinical indication is asthma
 They are also used in prophylaxis of mild or moderate
bronchospasm
 Theophylline: It is poorly water soluble, hence not suitable for
injection. It is available for oral administration.
 The main actions of theophylline involve:
 relaxing bronchial smooth muscle
 increasing heart muscle contractility and efficiency; as a
positive inotropic
 increasing heart rate: positive chronotropic
 increasing blood pressure
 increasing renal blood flow
 some anti-inflammatory effects
 Central nervous system stimulatory effect mainly on the
medullary respiratory center.

32. Pharmacokinetics.
 Theophylline is distributed in the extracellular fluid, in
the placenta, in the mother's milk and in the central
nervous system.
 The volume of distribution is 0.5 L/kg.
 The protein binding is 40%.
 The volume of distribution may increase in neonates
and those suffering from cirrhosis or malnutrition,
whereas the volume of distribution may decrease in
those who are obese. Theophylline is metabolized
extensively in the liver (up to 70%). It undergoes N-
demethylation via cytochromeP450
 Theophylline is excreted unchanged in the urine (up to
10%).

33. Aminophylline: It is water soluble but highly irritant. It can
be administered orally. Aminophylline is less potent and
shorter-acting than theophylline. Its most common use is
in the treatment of bronchial asthma.
 Causes bronchodilatation, diuresis, CNS and cardiac
stimulation, and gastric acid secretion by blocking
phosphodiesterase which increases tissue
concentrations of cyclic adenine monophosphate
(cAMP) which in turn promotes catecholamine
stimulation of lipolysis, glycogenolysis, and
gluconeogenesis and induces release of epinephrine
from adrenal medulla cells
 Toxicity
 CNS: restlessness, insomnia, headache, tremors
 GIT: nausea, vomiting, gastritis
 Heart: tachycardia, palpitation, hypotension

34. ANTICHOLINERGICS
 These drugs are now rarely used in bronchial
asthma as they often have unpleasant side effects.
Some of the drugs are ipratropium bromide and
tiotropium bromide. These are atropine substitutes.
 They selectively block the effects of acetylcholine in
bronchial smooth muscle and cause
bronchodilatation. They have slow onset of action
and less effective than sympathomimetic drugs in
bronchial asthma.

35. The anticholinergics are preferred bronchodilators in
COPD and often used in combination with beta2
agonists. These drugs increase air flow, alleviate
symptoms and decrease exacerbation of disease.
They are contraindicated in patient s with glaucoma
and urinary retention.
Pharmacokinetics
 The ipratropium is poorly absorbed after oral
administration. The drug is rapidly cleared by
kidney and excreted in bile. The dose is 18 – 36
mcg (1-2 puffs) 3-4 times daily.

36. LEUKOTRIENE ANTAGONISTS
 Leukotrienes result from action of lipooxygenase
on arachidonic acid. LTC4 and LTD4 exert many
effects known to occur in bronchial asthma
including bronchoconstriction, increased bronchial
reactivity, mucosal edema and mucus
hypersecretion. Leukotriene antagonists are used
to treat these diseases by inhibiting the production
or activity of leukotrienes. These drugs
competitively block the effects leukotrienes.

37.  Two approaches have been pursued
 Inhibition of lipooxygenase, thereby preventing
leukotriene synthesis like zileuton.
 Inhibition of binding of leukotriene to its receptor on
target tissues, thereby preventing its action like
montelukast and zafirlukast

38. Montelukast
 Montelukast is a leukotriene receptor antagonist
(LTRA) used for the maintenance treatment of
asthma and to relieve symptoms of seasonal
allergies. It is usually administered orally.
Montelukast is a CysLT1 antagonist; that is it blocks
the action of leukotrienes (and secondary ligands
LTC4 and LTE4) on the cysteinyl leukotriene
receptor CysLT1 in the lungs and bronchial tubes by
binding to it. This reduces the bronchoconstriction
otherwise caused by the leukotriene and results in
less inflammation.

39.  Clinical uses
 Montelukast is used for the treatment of asthma
and seasonal allergic rhinitis. Montelukast begins
working after 3 to 14 days of therapy. Therefore, it
should not be used for the treatment of an acute
asthmatic attack.
 Side effects
 The most common side effects with montelukast
are headache, dizziness, abdominal pain, sore
throat, and rhinitis (inflammation of the inner lining
of the nose). These side effects occur in 1 in 50 to 1
in 7 persons who take montelukast. Rarely, patients
may experience nose bleeds.

40. Zafirlukast
 Zafirlukast is an oral leukotriene receptor antagonist
(LTD4) for the maintenance treatment of asthma, often
used in conjunction with an inhaled steroid and/or long-
acting bronchodilator. It is available as a tablet and is
usually dosed twice daily.
 Zafirlukast blocks the action of the cysteinyl leukotrienes
on the CysLT1 receptors, thus reducing constriction of
the airways, build-up of mucus in the lungs and
inflammation of the breathing passages.
 A single oral dose of 40 mg of zafirlukast attaining peak
plasma concentrations of about 607 μg/L at 3.4 hours.
The elimination half-life ranged from 12 to 20 hours.

41. ZILEUTON
 Zileuton is an orally active inhibitor of 5-lipoxygenase,
and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and
LTE4) formation. Zileuton is used for the maintenance
treatment of asthma.
 Pharmacokinetics
 Following oral administration zileuton is rapidly
absorbed with a mean time to peak serum concentration
of 1.7 hours and an average half-life elimination of 2.5
hours.
 The apparent volume of distribution of zileuton is
approximately 1.2 L/kg. Zileuton is 93% bound to
plasma proteins, primarily to albumin.
 Elimination of zileuton is primarily through metabolites in
the urine (~95%). The drug is metabolized by the
cytochrome P450 enzymes

42.  Clinical uses
 Zileuton is indicated for the prophylaxis and chronic
treatment of asthma in adults and children 12 years of
age and older. Zileuton is not indicated for use in the
reversal of bronchospasm in acute asthma attacks.
Therapy with zileuton can be continued during acute
exacerbations of asthma.
 The recommended dose of 600 mg tablet, four times per
day. The tablets may be split in half to make them easier
to swallow. The recommended dose extended-release
tablets is 2400 mg twice daily.
 Research on mice suggests that Zileuton used alone or
in combination with imatinib may inhibit chronic myeloid
leukemia (CML).

43.  Side effects
 The most common adverse reactions reported by
patients treated with zileuton were sinusitis and
nausea
 The most serious side effect zileuton is potential
elevation of liver enzymes (in 2% of patients).
Therefore, zileuton is contraindicated in patients
with active liver disease or persistent hepatic
function enzymes elevations
 Neuropsychiatric events, including sleep disorders
and behavioral changes, may occur.

44.  Drug interactions
 Zileuton is a weak inhibitor of cytochrome P450 and
thus has three clinically important drug interactions,
which include increasing warfarin, theophylline, and
propranolol levels.
 It has been shown to lower theophylline clearance
significantly, doubling the AUC and prolonging half-
life by nearly 25%.
 Warfarin metabolism and clearance is mainly
affected by zileuton. This can lead to an increase in
prothrombin time.

45. CORTICOSTEROIDS
 All corticosteroids are potentially beneficial in
severe asthma; however, because of their toxicity
systemic (oral) corticosteroids are used chronically
only when other therapies are unsuccessful.
 Local aerosol administration of corticosteroids (e.g
beclomathasone, dexamethasone, fluticasone,
mometasone) is relatively safe, and inhaled
corticosteroids have become first line therapy for
individuals with moderate to severe asthma.
 Important intravenous corticosteroids for status
asthamaticus include prednisolone and
hydrocortisone.

46. Mechanism of action
 Corticosteroids reduce the synthesis of arachidonic acid by
phospholipase A2, and inhibit the expression of COX -2. It has
been suggested that corticosteroids increase the
responsiveness of beta adrenoceptors in the airway.
Effects
 Glucocorticoids bind to intracellular receptors and activate
glucocorticoid response elements in the nucleus, resulting in
the 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 bronchoconstrictiors and may also
participate in the inflammatory response

47. Clinical uses
 Inhaled glucocorticoids are now considered appropriate (even
for children) in most cases of moderate asthma that are not
fully responsive to aerosol β agonists.
 In 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 and
apparently act more promptly than in ordinary asthma
 Intravenous steroids are indicated in acute asthma if lung
function is <30% predicted and in patients who show no
significant improvement with nebulized 2 agonist.
Hydrocortisone is the steroid of choice because it has the
most rapid onset (5-6 hours after administration).

49.  Toxicity
 Life threatening toxicities include metabolic effects
(diabetes, osteoporosis), salt retention and psychosis.
 Changes in oropharyngeal flora result in candidiasis
 Frequent aerosol administration can cause a very small
degree of adrenal suppression. In case of oral therapy
adrenal suppression can be reduced by using alternate-
day therapy.
 Inhaled corticosteroids may have local side effects due
to the deposition of inhaled steroid in the oropharynx.
The most common problem is hoarseness and
weakness of the voice (dysphonia) due to atrophy of the
vocal cords following laryngeal deposition of steroid

50. CROMOLYN AND NEDOCROMIL (MAST CELL
STABILIZERS)
 Cromolyn (disodium cromoglycate) and nedocromil
are unusually insoluble chemicals.
 They are given by aerosol for asthma. Cromolyn is
the prototype of this group.
 Mechanism of action
 It involves a decrease in the release of mediators
(such as leukotrienes and histamine) from the mast
cells. The drugs donot have bronchodilator action
but can prevent bronchoconstriction caused by
antigen to which the patient is allergic

51.  Effects
 They are not absorbed from the site of
administration, cromolyn and nedocromil have only
local effects.
 When administered orally, cromolyn has some
efficacy in preventing food allergy.
 Similar actions were noted after local application in
conjunctiva and nasopharynx for allergic IgE
mediated reactions in these tissues.

52.  Clinical uses
 It is used in asthma especially in children
 Nasal and eye drop formulations are available for
hay fever
 Oral formulation is used for food allergy
 Toxicity
 Cromolyn and nedocromil may cause cough and
irritation of the airway when given by aerosol.
 Rare instances of drug allergy have been reported.

53. ANTI- IGE ANTIBODY
 Omalizumab
 It is a recombinant DNA- derived monoclonal
antibody that selectively binds to human IgE.
 It binds to the IgE on sensitized mast cells and
prevents activation by asthma triggers and
subsequent release of inflammatory mediators.
 Omalizumab may be particularly useful for the
treatment of moderate to severe allergic asthma in
patients who are poorly controlled with conventional
therapy.
 It was approved in 2003 for the prophylactic
management of asthma. It is very expensive and
must be administered parenterally.

54. DRUGS USED TO TREART CHRONIC
OBSTRUCTIVE PULMONARY DISEASE
 Chronic obstructive pulmonary disease (COPD) is a
chronic, irreversible obstruction of air flow. Smoking
is the greatest risk factor for COPD and is directly
linked to the progressive decline of the lung
function.
 In COPD, there is a predominance of neutrophils,
macrophages, and cytotoxic T-lymphocytes (Tc1
cells). The inflammation predominantly affects small
airways, resulting in progressive small airway
narrowing and fibrosis (chronic obstructive
bronchiolitis) and destruction of the lung
parenchyma with destruction of the alveolar walls
(emphysema)

55.  Emphysema is a pathological condition sometimes
associated with COPD, in which lung parenchyma
is destroyed and replaced by air spaces that
coalesce to form bullae-blister-like air-filled spaces
in the lung tissue.
 These pathological changes result in airway closure
on expiration, leading to air trapping and
hyperinflation. This accounts for shortness of breath
on exertion and exercise limitation that are
characteristic symptoms of COPD.

56.  Inhaled bronchodilators, such as anticholinergic
agents (ipratropium and tiotropium) and beta2
adrenergic agonists are the foundation of therapy
for COPD.
 Longer acting drugs such as salmeterol and
tiotropium have the advantage of less frequent
dosing and together provide synergistic effect. They
improve the lung function and provide a better relief
in COPD.

57.  Theophylline can be given by mouth but is of
uncertain benefit. Its respiratory stimulant effect
may be useful for patients who tend to retain CO2.
Other respiratory stimulants (e.g. doxapram; are
sometimes used briefly in acute respiratory failure
(e.g. postoperatively) but have largely been
replaced by ventilatory support

58. SURFACTANTS
 Pulmonary surfactants act as a result of their
physicochemical properties within the airways
rather than by binding to specific receptors. They
are effective in the prophylaxis and management of
respiratory distress syndrome in newborn babies,
especially if premature. Examples include
beractant and poractant alpha which are
derivatives of the physiological pulmonary
surfactant protein. They are administered directly
into the tracheobronchial tree via an endotracheal
tube

59. ALLERGIC RHINITIS
 Hay fever; Nasal allergies
 Rhinitis is characterized by sneezing, itchy nose/eyes,
watery rhinorrhea and nasal congestion
 Allergic rhinitis is a group of symptoms affecting the
nose. These symptoms occur when you breathe in
something you are allergic to, such as dust, dander,
insect venom, or pollen.
 When a person with allergic rhinitis breathes in an
allergen such as pollen or dust, the body releases
chemicals, including histamine. This causes allergy
symptoms.
 Hay fever involves an allergic reaction to pollen. A
similar reaction occurs with allergy to mold, animal
dander, dust, and other allergens that you breathe in.

60. Symptoms that occur shortly after you come into contact with the
substance you are allergic to may include:
 Itchy nose, mouth, eyes, throat, skin, or any area
 Problems with smell
 Runny nose
 Sneezing
Symptoms that may develop later include:
 Stuffy nose (nasal congestion)
 Coughing
 Clogged ears and decreased sense of smell
 Sore throat
 Dark circles under the eyes
 Puffiness under the eyes
 Fatigue and irritability
 Headache

61.  Antihistamines
 Over-the-counter antihistamines -- Include
diphenhydramine, chlorpheniramine, clemastine.
These older antihistamines can cause sleepiness.
Loratadine, cetrizine, and fexofenadine do not
cause as much drowsiness as older antihistamines.
 Long acting drugs: These medications are longer-
acting than over-the-counter antihistamines and are
usually taken once a day. They include
desloratadine

62.  H1 receptor blockers have major application in
allergies of the immediate type. These conditions
include hay fever and urticaria. The side effects
include dry mouth/ eyes, difficult urinating and
defecating. These effects are transient and may
resolve in 7 -10 days

63.  Corticosteroids
 These prescription sprays reduce inflammation of
the nose and help relieve sneezing, itching, and
runny nose. It may take a few days to a week to
see improvement in symptoms.
 Beclomethasone
 Fluticasone
 Mometasone
 Triacinolone

64. Cromolyn sodium
 This over-the-counter nasal spray prevents the
release of histamine and helps relieve swelling and
runny nose. It works best when taken before
symptoms start and may needed to be used several
times a day.
Nasal atropine
 Ipratropium bromide is a prescription nasal spray
that can help relieve a very runny nose. People with
glaucoma should not use this.

65. DECONGESTANTS
 Oral and nasal decongestants –
 Decongestants help to shrink the blood vessels in
the nasal membranes and allow the air passages to
open up. Decongestants are chemically related to
adrenaline, the natural decongestant, which is also
a type of stimulant. Therefore, the side effect of
decongestants taken as a pill or liquid is a jittery or
nervous feeling, causing difficulty in going to sleep
and elevating blood pressure and pulse rate.

66.  Some decongestants may contain
pseudoephedrine, which can raise blood pressure.
People with high blood pressure should not take
drugs containing pseudoephedrine. Using nasal
decongestant sprays for more than 3 days can
cause "rebound congestion," which makes
congestion worse. Do not use them if emphysema
or chronic bronchitis is present.

67. PHENYLEPHRINE
 Phenylephrine is an alpha 1 receptor agonist. It
causes vasoconstriction of the vessels of the nose
and helps decreasing the mucus formation in the
nasal cavity.
 Phenylephrine is used to relieve nasal discomfort
caused by colds, allergies, and hay fever. It is also
used to relieve sinus congestion and pressure.
Phenylephrine will relieve symptoms but will not
treat the cause of the symptoms or speed recovery.

68. COUGH
 Cough is a protective reflex that removes foreign
material and secretions from the bronchi and
bronchioles.
 Cough can be triggered by inflammation in the
respiratory tract, for example by undiagnosed
asthma or chronic reflux with aspiration, or by
neoplasia or by any bacterial infection.
Types of cough
1. Unproductive (dry cough)
2. Productive (associated with large amounts of
sputum)

69. DRY COUGH
 Stimulation of mechanoreceptors in the
tracheobronchial tree and the lung and
chemoreceptors from the lung generate impulses
which are carried via the glossopharyngeal and
vagus nerve as afferent impulse to cough center
and efferent impulses are carried via the
parasympathetic and motor nerves to the
diaphragm intercostal muscles and lungs. Irritation
to the bronchial tract generate these impulses and
trigger cough center to produce dry cough.

70.  In these cases, cough suppressant (antitussive)
drugs are sometimes useful, for example for the dry
painful cough associated with bronchial carcinoma.
 Antitussives should be avoided in cases of chronic
pulmonary infection, as they can cause undesirable
thickening and retention of sputum, and in asthma
because of the risk of respiratory depression.

71.  Dry cough is a very common adverse effect of
angiotensin-converting enzyme inhibitors, in which
case the treatment is usually to substitute an
alternative drug, notably an angiotensin receptor
antagonist which less likely cause this adverse
effect.

72. PRODUCTIVE COUGH
A classic symptom of productive cough is coughing
with sputum or phlegm production. Phlegm usually
contains mucus with bacteria, debris or dead tissue,
and sloughed-off cells. Other symptoms include
heaviness in the chest, slight to severe
breathlessness. In some cases a person may even
have fever, runny nose and drainage of mucus into
the throat.

73.  The airway mucosa responds to infection and
inflammation in a variety of ways. This response
often includes surface mucous (goblet) cell and
submucosal gland hyperplasia and hypertrophy,
with mucus hypersecretion.
 Products of inflammation, including neutrophil-
derived deoxyribonucleic acid (DNA), bacteria, and
cell debris all contribute to mucus purulence.
Expectorated mucus is called sputum. Mucus is
usually cleared by ciliary movement, and sputum is
cleared by cough.

74.  Productive cough can be caused due to a number
of factors. Some of them include viral or bacterial
lung infections like in the case of a common cold.
Other more serious diseases like asthma,
pneumonia, chronic obstructive pulmonary disease
(COPD), lung abscesses or other conditions like
bronchiectasis could manifest as productive cough.

75. MUCOACTIVE MEDICATIONS
 The general term for medications that are meant to
affect mucus properties and promote secretion
clearance is “mucoactive.”
 Mucoactive medications include expectorants,
mucolytics, and mucokinetic drugs.
1. Expectorants are defined as medications that improve
the ability to expectorate purulent secretions.
2. Mucolytics are medications that change the biophysical
properties of secretions by degrading the mucin
polymers, DNA and fibrin in airway secretions,
generally decreasing viscosity.
3. A mucokinetic medication is a drug that increases
mucociliary clearance, generally by acting on the cilia.

76. ANTITUSSIVES
 Antitussives are drugs that are used to suppress
the cough center in the medulla and are given for
symptomatic relief
Antitussives are classified as
 Centrally acting drugs
 They act directly in the medulla on the cough
center. These include
Narcotics: these are controlled substances, because
they are drugs of abuse
 Morphine: It is an effective antitussive but is liable
to prooduce depression of respiratory center. It can
relieve cough but is not used due to its addictive
properties

77. CODEINE
 Codeine or 3-methylmorphine is a natural isomer of
methylated morphine. Codeine is the second mos
predominant alkaloid in opium i.e upto 3%. It is a
moderate agonist of mu receptors
 It has antitussive and sedative action. It is analgesic
but in higher doses.
 Common adverse effects include euphoria, itching,
nausea, vomiting, drowsiness, dry mouth, urinary
retention, constipation, miosis and orthostatic
hypotension.

78.  Chronic use of codeine can cause withdrawal
symptoms as it causes physical dependence. When
physical dependence ha developed withdrawal
symptoms may occur if a person suddenly stops
the medication.
 Withdrawal symptoms include drug craving,
cramps, nausea, vomiting, diarrhea, muscle
spasms, chills, irritability and pain.

79. PHOLCODINE
 It is a semisynthetic derivative of codeine. The
antitussive effect of 10 mg of pholcodine is
comparable to 15mg of codeine. The cough of any
origin can be suppressed effectively.
 The onset of action is 15 minutes after parenteral
dose and 30 minutes after oral dose remain for n4
hrs.
 Nausea and drowsiness can occur

80. DEXTROMETHORPHAN HYDROBROMIDE
 It is a semisynthetic compound with minimum
addiction properties. It is used for dry and painful
cough. It has no analgesic properties.
 It s given in dose of 10-30 mg 3-4 times daily.
 At therapeutic doses, dextromethorphan acts
centrally and elevates the threshold of the
stimulation of cough center.
 It is rapidly absorbed from gastrointestinal tract and
converted into active metabolite dextrophan in the
liver.
 It causes drowsiness, mental confusion, nausea,
body rash and itching.

81. NOSCAPINE
 The opium alkaloid belonging to the
benzylisoquinoline group antitussive action equal to
that of codeine.
 It doesn’t produce constipation and drowsiness.
The common side effect includes nausea.
 Antitussive dose is 15-30 mg 3-4 times daily.
LEVOPROPOXYPHENE
o The levo isomer of propoxyphene has antitussive
action in a dose of 50-100 mg. It is a centrally
acting agent and depresses the cough center to
relieve dry cough.

82. NON NARCOTIC ANTITUSSIVES
Antihistamines
 These include promethazine, chlorpheniramine,
diphenhydramine. Anithistamines suppress cough by
suppressing the cough center but they dry the
secretions. They are mostly given in cough associated
with cold systems.
Carbetapentane (pentoxyverine)
It acts peripherally on the mucous membrane of the
respiratory tract and exert a local anesthetic action.
It acts centrally as well by suppressing the cough center
therefore also therefore also classified under non
narcotic
It has atropine like effects causing dry mouth, blurred
vision.

83. Benzonatate
 Benzonatate acys as local anesthetic, decreasing
the sensitivity of stretch receptors in the lower
airway and lung, thereby reducing the drive to
cough after taking a deep breath.
 Benzonatate is employed to reduce coughing in
various respiratory conditions such as bronchitis,
emphysema, influenza and pneumonia.
 It should never be used to suppress a productive
cough or cough associated with asthma.
 Side effects include drowsiness and dizziness.

84. EXPECTORANTS
 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
1. Secretagogues, that are meant to increase the
hydration of luminal secretions (eg, hypertonic
saline or mannitol)
2. Abhesives that decrease the adhesivity of
secretions and thus unstick them from the airway
(eg, surfactants).

85. The most commonly used expectorants are simple
hydration, including
 bland aerosol
 oral hydration
 iodide-containing compounds such as super-
saturated potassium iodide or iodinated glycerol,
 glyceryl guaiacolate (guaifenesin)
 and the more recently developed ion-channel
modifiers such as the purinergic agonists.

86.  Dehydration might increase the tenacity of
secretions by increasing adhesivity. The more
secretions adhere to the epithelium, the more
difficult they are to cough up. If there was an
effective way to rehydrate the surface of dry
secretions, this would be of benefit. Most of these
medications and maneuvers are ineffective at
adding water to the airway, and those that are
effective are also mucus secretagogues that
increase the volume of both mucus and water in the
airways.

87.  Saline Expectorants
 7% hypertonic saline increases the volume of the
secretions and hydration.
 Ammonium salts and sodium bicarbonate have also
been used as saline expectorants. They increase
the hydration.
 Ammonium chloride causes gastric irritation and
may cause nausea, vomiting , thirst and headache.
The dose is 300mg 3-4 times daily.
 Sodium bicarbonate s used for tracheal irrigation or
as an aerosol.
 Dry mannitol powder also increases mucus
secretion.

88.  Potassim salts of iodide and iodinated glycerol
 These are directly acting exprectorants . After
absorption they reach the bronchial mucus
membrane and stimulate the bronchial glands to
secrete mucus.
 Use of potassium iodide leads to unpleasant
hypersecretions in the eyes, nose and mouth. Skin
rashes may appear.
 The dose is 0.3g 3-4 times daily.

89.  Surfactant can reduce sputum adhesivity and
increase the efficiency of energy transfer from the
cilia to the mucus layer.
 Ambroxol has been thought to stimulate surfactant
secretion, and has been used for many years in
Europe for the management of chronic bronchitis,
but it has never been approved in the United States
or Canada.

90. VOLATILE OILS
 Volatile oils like oil of eucalyptus, oil of anise and
lemon oil are taken on the form of steam. All are
mild respiratory antiseptic and act directly on the
secretory cells of the respiratory tract and increase
the secretions.
 Terpenes portion of camphor, thymol and menthol
also cause mild reversible anesthesia of the
respiratory tract.

91. MUCOLYTICS
 Mucolytics are medications that change the
biophysical properties of secretions by degrading
the mucin polymers, DNA, fibrin, or F-actin in
airway secretions, generally decreasing viscosity.
Classic Mucolytics
 Classic mucolytics depolymerize the mucin
glycoprotein oligomers by hydrolyzing the disulfide
bonds that link the mucin monomers. This is usually
accomplished by free thiol (sulfhydryl) groups,
which hydrolyze disulfide bonds attached to
cysteine residues of the protein core.

92. N ACETYL CYSTEINE
 This is a derivative of naturally occuring aminoacid,
1-cysteine
 It improves the ability to expectorate mucus.
Acetylcysteine can decrease mucus viscosity in
vitro, but, because oral acetylcysteine is rapidly
inactivated and does not appear in airway
secretions, it is ineffective in vivo. It is given by
inhalation as aerosol.
 It depolymerises the mucin glycoprotein oligomers
by hydrolyzing disulfide polymers that link mucin
polymers.

93.  Published evidence suggests that oral
acetylcysteine may improve pulmonary function in
selected patients with chronic lung disease,
including chronic obstructive pulmonary disease
(COPD), but the clinical benefit observed is
probably due to antioxidant properties.
 Daily use of acetylcysteine reduces the risk of re-
hospitalization for COPD exacerbation by
approximately 30%
 It may cause fever, gastric irritation, nausea,
urticaria and rhinorrhea

94. PEPTIDE MUCOLYTICS
 The mucin polymer network is essential for normal
mucus clearance. It may be that the classic
mucolytics are generally ineffective because they
depolymerize essential components of the mucus
gel. With airway inflammation and inflammatory cell
necrosis, a secondary polymer network of DNA and
F-actin develops in purulent secretions. In contrast
to the mucin network, this pathologic polymer gel
serves no obvious purpose in airway protection or
mucus clearance.

95.  The peptide mucolytics are designed specifically to
depolymerize the DNA polymer (dornase alfa) or
the F-actin network (eg, gelsolin, thymosin 4) and
are most effective when sputum is rich in DNA pus.

96. MUCOKINETIC AGENTS
 A mucokinetic medication is a drug that increases
mucociliary clearance, generally by acting on the
cilia. Although a variety of medications, such as
tricyclic nucleotides, beta agonist bronchodilators,
and methylxanthine bronchodilators, all increase
ciliary beat frequency, these agents have only a
minimal effect on mucociliary clearance in patients
with lung disease

97. BROMOHEXINE (BISOLVON)
 Bromohexine is a mucolytic agent used in the treatment of
respiratory disorders associated with viscid or excessive
mucus. It has antioxidant properties as well.
 It is a synthetic derivative of the herbal active ingriedient
vasicine from the plant Adhatoda vasica.
 It has been shown to increase the proportion of serous
bronchial secretions, making it more easily expectorated.
 Bromohexine also enhances mucus transport by reducing
mucus viscosity and by activating the ciliated epithelium.
 Bromohexine showed secretolytic and secretomotoric effects
in bronchial tract area which facilitates expectoration and
eases cough.
 It is usually administered in dose of 8-16 mg 3-4 times daily.