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DRUGS AFFECTING THE

RESPIRATORY SYSTEM

Department of Pharmacology
Medical Faculty Brawijaya University
RESPIRATORY SYSTEM

UPPER RESPIRATORY TRACT  COMON COLD


RESPIRATORY SYSTEM

LOWER RESPIRATORY TRACT  ASTHMA, COPD,


BRONCHITIS, EMPHYSEMA
RESPIRATORY SYSTEM
Understanding the Common Cold
• Rhinitis, pharyngitis, laryngitis
• Most caused by viral infection
(rhinovirus or influenza virusthe “flu”)
• Virus invades tissues (mucosa) of upper
respiratory tract, causing upper
respiratory infection (URI)
• Difficult to identify whether cause is viral
or bacterial
Treatment of the Common Cold
 Treatment is symptomatic only, not curative
 Symptomatic treatment does not eliminate the
causative pathogen
 Involves combined use of antihistamines, nasal
decongestants, antitussives, and expectorants
 Treatment is “empiric therapy,” treating the most
likely cause
 Antivirals and antibiotics may be used, but a definite
viral or bacterial cause may not be easily identified
Antihistamines
Drugs that directly compete with histamine for
specific receptor sites

• Two histamine receptors


• H1 (histamine1)
• H2 (histamine2)

• H1 histamine receptor found on smooth muscle,


endothelium, and central nervous system tissue;

causes vasodilation, bronchoconstriction, smooth muscle


activation, and separation of endothelia cells
(responsible for hives), pain and itching due to
insect stings
Antihistamines

H1 antagonists are commonly referred to as


antihistamines
• Antihistamines have several properties
• Antihistaminic
• Anticholinergic
• Sedative
• H2 blockers or H2 antagonists
• Used to reduce gastric acid in Peptic Ulcer
• Examples: cimetidine, ranitidine, famotidine
Antihistamines:
Mechanism of Action
 Block action of histamine at the H1 receptor sites
 Compete with histamine for binding at unoccupied
receptors
 Cannot push histamine off the receptor if already bound
 The binding of H1 blockers to the histamine receptors
prevents the adverse consequences of histamine
stimulation
• Vasodilation
• Increased GI and respiratory secretions
• Increased capillary permeability
 More effective in preventing the actions of histamine
rather than reversing them
 Should be given early in treatment, before all the
histamine binds to the receptors
Antihistamines: Indications
Management of:
• Nasal allergies
• Seasonal or perennial allergic rhinitis (hay
fever)
• Allergic reactions
• Motion sickness
• Also used to relieve symptoms associated
with the common cold
• Sneezing, runny nose
• Palliative treatment, not curative
Antihistamines: Side effects
• Anticholinergic (drying) effects, most
common
• Dry mouth
• Difficulty urinating
• Constipation
• Changes in vision
• Drowsiness
• Mild drowsiness to deep sleep
Antihistamines: Two Types
Traditional
• Older
• Work both peripherally and centrally
• Have anticholinergic effects, making them more effective
than nonsedating agents in some cases
• Examples: Diphenhydramine (Benadryl, Delladryl)
Chlorpheniramin maleat (ChlorTriMethon=CTM)
Nonsedating/peripherally acting
• Developed to eliminate unwanted side effects, mainly
sedation
• Work peripherally to block the actions of histamine; thus,
fewer CNS side effects
• Longer duration of action (increases compliance)
• Examples: Terfenadin, Loratadin, Citerizine
Side Effects :
Antihistamines

1st Generation 2nd Generation


• Sedation • Mild sedation
• Dry mouth • Interaction with
• Blurred vision antifungi,
• GI disorder antibiotics,
prokinetic
• Headache
drugs,
• Urine retention
• Heart disorder
Anticholinergic
Drugs Usual Adult Dose Comments
Activity
1st Generation
Dimenhydrinate
Marked sedation;
(salt of
50 mg +++ anti-motion
diphenhydramine)
sickness activity
(Dramamine)
Marked sedation;
Diphenhydramine
25–50 mg +++ anti-motion
(Benadryl, etc)
sickness activity
Slight sedation;
Chlorpheniramine
common
(Chlor-Trimeton, 4–8 mg +
component of OTC
etc)
“cold” medication
2nd Generation
Loratadine
Longer action;
(Claritin), 10 mg (deslorat-
– used at 5 mg
desloratadine adine, 5 mg)
dosage
(Clarinex)
Cetirizine (Zyrtec) 5–10 mg –
Nasal Decongestants
Nasal Congestion
 Excessive nasal secretions
 Caused by dilated and engorged nasal capillaries
 Inflamed and swollen nasal mucosa
 Primary causes  Allergies
Upper respiratory infections (common cold)
Decongestant
 Drugs that constrict these capillaries are effective nasal
decongestants Adrenergic-α agonist
 Constriction blood vessels surrounding nasal sinuses
 Alpha 1 agonists may be given either topically or orally
 Examples of agents: phenylephrine, pseudoephedrine, and
phenylpropanolamine, (administered in drops or mist)

Two dosage forms decongestant


 Oral nasal decongestant
 Inhaled/topically applied to the nasal membranes
Summary of
upper respiratory
drugs
Oral Nasal Decongestants
• Prolonged decongestant effects, but delayed onset
• Effect less potent than topical
• No rebound congestion
• Exclusively adrenergics
• Example: Pseudoephedrine, Phenylpropanolamin (PPA)

Topical Nasal Decongestants


• Topical adrenergics
• Desoxyephedrine
• Phenylephrine
• Prompt onset, Potent
• Sustained use over several days causes rebound
congestion, making the condition worse
• Intranasal steroids
• Beclomethasone dipropionate
• Fluticasone
Nasal Decongestants:
Mechanism of Action
Adrenergics Nasal steroids
 Constrict small blood Work to turn off the
vessels that supply immune system cells
URI structures involved in the
 As a result these inflammatory response
tissues shrink, and nasal Decreased inflammation
secretions in the swollen results in decreased
mucous membranes are congestion
better able to drain Anti-inflammatory
 Nasal stuffiness is effect
relieved Nasal stuffiness is
relieved
Nasal Decongestants:
Indications
 Relief of nasal congestion associated with:
• Acute or chronic rhinitis
• Common cold
• Sinusitis
• Hay fever
• Other allergies
May also be used to reduce swelling of the
nasal passage and facilitate visualization of the
nasal/pharyngeal membranes before surgery or
diagnostic procedures
Nasal Decongestants:
Side Effects

Adrenergics Steroids
Nervousness Local mucosal dryness
Insomnia and irritation
Palpitations
Tremors
(systemic effects due to
adrenergic stimulation of the
heart, blood vessels, and CNS)
Antitussives
Cough Physiology
• Coughing is a complex reflex that depends on
functions in the CNS, the PNS, and the
respiratory muscles.
• It is a defense mechanism that aids the removal
of foreign particles like smoke and dust.
• Respiratory secretions and foreign objects are
naturally removed by the
• Cough reflex 
• Induces coughing and expectoration
• Initiated by irritation of sensory receptors in the
respiratory tract
Coughing
Most of the time, coughing is beneficial
• Removes excessive secretions
• Removes potentially harmful foreign substances
In some situations, coughing can be harmful,
such as after hernia repair surgery
• In general, treating a productive cough is not
appropriate, as it is performing a useful
function.
• An unproductive cough, usually results from an
irritated oropharynx and can be troublesome.
Two basic type of cough
Productive cough
o Congested, removes excessive secretions
Nonproductive cough
o Dry cough (caused by irritation)
Antitussives
Drugs used to stop or reduce coughing
• Opioid and nonopioid (narcotic and non narcotic)
• Used only for nonproductive coughs!
Opioids
• Suppress the cough reflex by direct action on the cough
centre in the medulla (CNS)
Examples:
• Codeine
• Hydrocodone
Non opioids
• Suppress the cough reflex by numbing the stretch
receptors in the respiratory tract and preventing the
cough reflex from being stimulated
Examples:
• Dextromethorphan (DMP), Noskapin
Antitussives: Indications
Used to stop the cough reflex when the cough is
nonproductive and/or harmful

Antitussives: Side Effects


Dextromethorphan
•Dizziness, drowsiness, nausea
Opioids (Codein)
•Sedation, nausea, vomiting, light headedness,
constipation

Antitussives: Contra indications ?


Expectorants
• Drugs that aid in the expectoration (removal)
of mucus
• Reduce the viscosity of secretions
• Disintegrate and thin secretions

By loosening and thinning sputum and bronchial


secretions, the tendency to cough is indirectly
diminished
Expectorants:
Mechanisms of Action
• Reflex stimulation
• Agent causes irritation of the GI tract
• Loosening and thinning of respiratory tract
secretions occur in response to this irritation
• Example: ipekak, guaifenesin, glyceril guaicolate
• Direct stimulation
• The secretory glands are stimulated directly to
increase their production of respiratory tract fluids
• Examples: iodine-containing products such as
iodinated glycerol and potassium iodide
• Final result: thinner mucus that is easier to
remove
Expectorants:
Indications
Used for the relief of productive coughs
associated with:
Common cold  Influenza
Bronchitis
Laryngitis
Pharyngitis
Pertussis
Measles
Coughs caused by chronic paranasal sinusitis

EXPECTORANTS:
CONTRAINDICATIONS ?
Mucolytic

• Mechanisme of action Mucolytic  to


degrade mucoprotein  lysis
•  thiny mucus  easier to remove
• Mucolytic :
bromhexin
ambroxol
acetyl cystein
Pharmacotherapy of common cold

• A man 66 years old, Pak Miftah, came to the clinic. He


complained about his common cold, nasal congestion. His
blood pressure is 160/90.
• Problem : nasal congestion with high blood pressure
• Therapeutical Objective : remove nasal congestion
• P-treatment : advise, drug
• P-drug : Drugs Efficacy Safety Suitability Cost

• choose drugs between pseudoephedrine and PPA  with


blood pressure case we choose PSEUDOEPHEDRINE
Prescription :
Dr. Cika
Jl.Watumujur no. ab Malang,(0341) xxxxx
SIP : 1234567
Malang 10-10-2013
R/
Pseudoephedrine tab No. X
∫ 3dd 1tab pc

Pro : Pak Miftah


Communication :
• Information : common cold isn't
dangerous, but your BP is high so I give
you this pseudoephedrine. It’s safe for
you.
• Instruction : drink it 3 times daily, one
tablet each.
• Warning : if there is any dizziness,
comeback to my place.
• Recalling : for patient’s data

MONITORING & EVALUATION:


Drugs use in
Bronchial Asthma
Clinical features of bronchial asthma

1. Acute attacks of dyspnea associated with


acute airway obstruction due to contraction
of airway smooth muscle
2. Mucus hypersecretion, which may lead to
mucus plugging
3. Airway inflammation
4. Bronchial hyperresponsiveness
Normal airway Asthmatic airway
Early Response
Muc us hy pe rs e c re tio n

Go blet cell Alle rge n Co lumnar


cell

Ede ma

Alle rge n binds to Ma s t c e ll Infla mma to ry me dia to rs


IgE o n ma s t c e ll de gra nula tio n Che mo ta c tic fa c to rs

Eo sino phils

Bro nc ho -
PMN c o ns tric tio n
Smo o th muscle
Late Response

Muc us hy pe rs e c re tio n
Cilia ry
func tio n

Epithe lia l
da ma ge

Effe re nt (va ga l)
ne rve dis c ha rge
Affe re nt ne rve
dis c ha rge

Bro nc ho -
c o ns tric tio n
Ag (polutan, alergen)

Ag-Ab/IgE di mast cell

MEDIATOR

Early response : Late response :


Bronchoconstriction Inflamation

Symptom Hyperreactivity
THERAPY
Ag (polutan, alergen)
avoid
Ag-Ab/IgE di mast cell
cromolin, steroid
MEDIATOR
agonist, steroid
theophyllin,
anti cholinergic
Early response : Late response :
Bronchoconstriction Inflamation

Symptom Hyperreactivity
Pharmacotherapy of Bronchial Asthma :
1. Bronchodilator
2. Anti inflamatory drug
3. (Prophilactic drugs)
Bronchodilators
Bronchodilators
• Adrenergic agonists
• Methylxanthines
• Anticholinergics

For acute reversible bronchospasm


A. Adrenergic agonists
(2 receptor agonists)
Clinical Effects:
Mechanism of Action:
a. 1 receptor
- increases heart rate
- increases contractile force
b. 2 receptor
- relaxes bronchial smooth muscle
- relaxes vascular smooth muscle
- relaxes uterine smooth muscle
 Adrenergic non selective
- adrenalin/ epinefrin
- efedrin
 2 receptor agonists
- isoproterenol, isoprenalin

 2 receptor agonist selective


- Terbutalin (Allupent)
- Albuterol (Salbutamol)
- Metaproterenol
- Fenoterol
- Formoterol Long acting
- Salmetrol
Molecular actions of β2 agonists to induce
relaxation of airway smooth muscle cells
Bronchodilation is promoted by cAMP
A. Adrenergic agonists
(2 receptor agonists)
Kinetics - measured by forced expiratory flow rate
a. isoproterenol - approximately 30 minutes
b. short acting; albuterol, terbutaline – half-life;
2-3 hours
c. long acting agonists; salmeterol, formoterol;
up to 15 hours

Adverse effects
tremor, hypokalemia, tachycardia
Preparation
• Albuterol (generic, Proventil, Ventolin)
Inhalant: 90 mcg/puff aerosol; 0.021, 0.042, 0.083, 0.5,
0.63% solution for nebulization
Oral: 2, 4 mg tablets; 2 mg/5 mL syrup
Oral sustained-release: 4, 8 mg tablets
• Metaproterenol (Alupent, generic)
Inhalant: 0.65 mg/puff aerosol in 7, 14 g containers; 0.4,
0.6, 5% for nebulization
• Terbutaline (generic, Brethine)
Oral: 2.5, 5 mg tablets
Parenteral: 1 mg/mL for injection
• Formoterol (Foradil)
Inhalant: 12 mcg/unit inhalant powder; 1% solution for
nebulization
• Salmeterol (Serevent)
Inhalant powder: 50 mcg/unit
B. Methylxanthines
Mechanism of Action
a. Phosphodiesterase inhibitor, therefore,
increased cAMP  relaxation
b. blocks the action of adenosine

Indication
Dilation of airways in asthma, chronic bronchitis,
and emphysema
Mild to moderate cases of acute asthma
Adjunct agent in the management of COPD
Theophylline affects multiple cell types in the
airway.
B. Methylxanthines
Kinetics
Administration: usually given orally; IV
– short biological half-life;
‘slow-release’ preparations

Side effects:
narrow therapeutic window
generally safe; nausea, cardiac
arrhythmias and convulsions.
B. Methylxanthines
Drug interactions
the serum theophylline concentration can be
decreased by (enzyme inducer)
barbiturates
benzodiazepines
cigarete smoke
increased by
cimetidine
erythromycin; M. peumoniae
ciprofloxacin; Gram -
allopurinol
Drugs
• Theophylline (generic, Elixophyllin, Slo-Phyllin,
Uniphyl, Theo-Dur, Theo-24, others)
Oral: 50 mg/5 mL elixirs
Oral extended-release, 12 hours: 100, 200, 300, 450 mg
tablets
Oral extended-release, 24 hours: 100, 200, 300 mg
tablets and capsules;
400, 600 mg tablets
Parenteral: 0.08, 1.6, 2.0, 3.2, 4 mg/mL, theophylline
and 5% dextrose for injection
• Aminophylline (theophylline ethylenediamine, 79%
theophylline) (generic)
Oral: 100, 200 mg tablets
Parenteral: 250 mg/10 mL for injection
C. Anticholinergics
• Anticholinergic
drugs inhibit
vagally
mediated airway
tone
C. Anticholinergics;
muscarinic receptor antagonists
1. Atropine sulfate – not used today in treatment of asthma
because of too many side effects (urinary retention,
tachycardia, loss of visual accommodation, and agitation)
2. New Agents: ipratropium bromide, oxitropium bromide
poorly absorbed from the lung and do not cross blood-brain
barrier; less systemic adverse effects.
DRUGs
• Ipratropium (generic, Atrovent)
Aerosol: 17 (freon-free), 18 mcg/puff in 200 metered-
dose inhaler; 0.02% (500 mcg/vial) for nebulization
Nasal spray: 21, 42 mcg/spray
• Tiotropium (Spiriva)
Aerosol: 18 mcg/puff in 6 packs
Inhalation of drugs
ANTI-INFLAMATORY DRUGS
Anti-inflammatory and
prophylactic drugs

• Glucocorticosteroids
• Cromolyn sodium and nedocromil
sodium

Resolve existing bronchial inflammation


Prevent subsequent inflammation in asthma
Not recommended for acute asthma attacks
Glucocorticoids

1. Inhaled glucocorticosteroids:
triamcinolon, beclomethasone, budesonide
and fluticasone
2. Oral glucocorticosteroids for severe asthma:
prednisone, or prednisolone
3. Metabolized in liver by hydroxylation
4. Side effects
- suppression of the hypothalamus-pituitary
axis
- shunting of growth in children
Glucocorticoids

Mechanism of action
- inhibit inflammatory cell
infiltration into the airways
- reduce edema formation by acting
on the vascular endothelium
Mechanism of anti-inflammatory action of
corticosteroids in asthma
Effect of corticosteroids on inflammatory
and structural cells in the airways
Glucocorticoid : Clinical use
• Treatment of adrenal insufficiency
• Decrease inflammation
• Asthma & COPD
• Allergic reactions & rashes
• Other inflammatory processes
• Suppression of immune response
• Autoimmune processes
• Prevent transplant rejection

• Start with high dose then taper down to prevent


adrenal crisis
• Steroids may be given for up to 5 days without taper
• po, im, iv, topical

• Interaction w aspirin, AINS


insulin, OAD
Cromolyn
Cromolyn

1. Anti-allergic drugs used


prophylactically
2. Route of administration; poor
absorption from GI tract, thus, must
be inhaled as a microfine powder or
aerosolized solution.
3. Ketotifen; orally active form
4. Side effects : rare
Cromolyn

Mechanism of action;
not clearly understood
1. Prevents mast cell degranulation; ‘mast
cell stabilizer’; prevent the release of
inflammatory mediators including
histamine.
2. Also probably suppress the response of
exposed irritant nerves; effective for the
treatment of ‘asthmatic cough’.
Leukotriene pathway inhibitors
Antileukotrienes

Also called leukotriene receptor antagonists


(LRTAs)
Newer class of asthma medications
Three subcategories of agents
Currently available agents:
Montelukast (sold as Singulair®)
Zafirlukast (sold as Accolate®)
Antileukotrienes:
Mechanism of Action
• Leukotrienes are substances released when a
trigger, such as cat hair or dust, starts a series
of chemical reactions in the body
• Leukotrienes cause inflammation,
bronchoconstriction, and mucus production
• Result: coughing, wheezing, shortness of breath
• Antileukotriene agents prevent leukotrienes from
attaching to receptors on cells in the lungs and in
circulation
• Inflammation in the lungs is blocked, and asthma
symptoms are relieved
X

X
Effects of
cysteinyl-
leukotrienes on
the airways and
their inhibition
by anti-
leukotrienes
Antileukotrienes: Drug Effects

By blocking leukotrienes:
• Prevent smooth muscle contraction of the
bronchial airways
• Decrease mucus secretion
• Prevent vascular permeability
• Decrease neutrophil and leukocyte infiltration
to the lungs, preventing inflammation
Antileukotrienes: Indications
• Prophylaxis and chronic treatment of
asthma in adults and children older
than age 12
• NOT meant for management of acute
asthmatic attacks
• Montelukast is approved for use in
children ages 6 and older
Antileukotrienes: Side
Effects
zafirlukast montelukast has fewer
• Headache side effects
• Nausea
• Diarrhea
• Liver dysfunction
Pharmacotherapy Asthma Bronchiale

• Girl, 3 years. Brought in with a severe acute


asthmatic attack, probably precipitated by a viral
infection. She has great difficulty in breathing
(expiratory wheeze, no viscid sputum), little
coughing and a slight temperature (38.2oC).
Further history and physical examination reveal
nothing. Apart from minor childhood infections
she has never been ill before and she takes no
drugs.

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