Download DRUGS AFFECTING THE RESPIRATORY SYSTEM

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
Decongestants
Nasal Congestion
• Excessive nasal secretions
• Inflamed and swollen nasal mucosa
• Primary causes
• Allergies
• Upper respiratory infections (common cold)
Decongestant
 Adrenergic-α agonist
 Constriction blood vessels surrounding nasal sinuses
Two dosage forms decongestant
 Oral
 Inhaled/topically applied to the nasal membranes
Oral 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
 Constrict small blood
vessels that supply
URI structures
 As a result these
tissues shrink, and nasal
secretions in the swollen
mucous membranes are
better able to drain
 Nasal stuffiness is
relieved
Nasal steroids
Work to turn off the
immune system cells
involved in the
inflammatory response
Decreased inflammation
results in decreased
congestion
Anti-inflammatory
effect
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
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
Two basic type of cough
Productive cough
o Congested, removes excessive secretions
Nonproductive cough
o Dry cough
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
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, lightheadedness,
constipation
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
Mucolytic
• Mechanisme of action Mucolytic  to
degrade mucoprotein  lysis
•  thiny mucus  easier to remove
• Mucolytic :
bromhexin
ambroxol
acetyl cystein
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
IgE o n ma s t c e ll
Ma s t c e ll
de gra nula tio n
Infla mma to ry me dia to rs
Che mo ta c tic fa c to rs
Eo sino phils
Bro nc ho c o ns tric tio n
PMN
Smo o th muscle
Late Response
Cilia ry
func tio n
Muc us hy pe rs e c re 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 :
Bronchoconstriction
Symptom
Late response :
Inflamation
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)
1. Clinical Effects:
2. 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
- Salmetrol
Adrenergic (Symphatomimetic) Drugs
Β Adrenergic
Agonist
Mechanism
of Action
Β-Adrenergic
Receptor
Agonist
Mechanism of Action β2 Adrenergic
Receptors
Bronchodilation is promoted by cAMP
A. Adrenergic agonists
(2 receptor agonists)
4. Kinetics - measured by forced expiratory flow
rate
a. isoproterenol - approximately 30 minutes
b. short acting; albuterol, terbutaline – half-life; 23 hours
c. long acting agonists; salmeterol, formoterol; up
to 15 hours
5. Adverse effects
tremor, hypokalemia, tachycardia
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
Xanthine &
Derivates
B. Methylxanthines
4. Administration: usually given orally; IV
5. Kinetics – short biological half-life;
‘slow-release’ preparations
6. 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
C. Anticholinergics
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.
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
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
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
Headache
Nausea
Diarrhea
Liver dysfunction
montelukast has fewer
side effects
Pharmacotherapy of common cold
• A man 66 years old, Pak Miftah, come to the
clinic with complain of common cold, nasal
congestion. His blood pressure is 160/90.
• Problem : nasal congestion
• Therapeutical Objective : remove nasal
congestion
• P-treatment : advise, drug, reveral
• P-drug : 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
R/
Pseudoephedrine tab
∫ 3dd 1tab pc
Pro : Pak Miftah
No. X
Communication :
• Information : common cold isn't
dangerous, but your BP is high so I give
you this ephedrine. It’s safe for you.
• Instruction : drink it 3 times daily, one
tablet each.
• Warning : But if there is any dizziness,
comeback to my place.
• Recalling : for patient’s data
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.