General Introduction
Respiratory system is subjected
to a lot of injurers and harms because it is nearly the only system which is in
continuous contact with the external environment during the whole life of human
being. As a result respiratory system is subjected to pollution smoke,
chemicals dust, & microorganism which means it is subjected to everything
in the environment.
In particular, I will focus on:
1) Agents used in the treatment
of cough (antitussives and expectorants)
2) Agents used as decongestants
3)Agents used in the treatment
of asthma and4)Agents used in the treatment of chronic obstructive pulmonary disease (COPD).
RELIEF OF COUGH
Two types of cough:
- Productive: leads to removal of sputum from the lungs
- Dry cough: no removal of sputum
Treatment of cough mainly
consists of treating the underlying cause. A productive cough should not be
suppressed except in special circumstances (eg, when it exhausts the patient or
prevents rest and sleep) and generally not until the cause has been identified.
Suppressing a productive cough is
less advisable because sputum needs to be cleared.
Cough remedies are categorized as
antitussives and expectorants.
- Antitussives: Codene, Dextromethorphan
Either centrally or peripherally acting.
Centrally acting antitussives inhibit
or suppress the cough reflex by
depressing the medullary cough center or associated
higher centers through sensory
inputs from afferent nerves that are stimulated by airway irritation and
inflammation. The most commonly used drugs in this group are dextromethorphan
and codeine. Other centrally acting antitussives include chlophedianol,
levopropoxyphene, and noscapine in the non-narcotic group and hydrocodone, hydromorphone,
methadone, and morphine in the narcotic group.
Dextromethorphan is technically
not considered an opiate because it does not bind to traditional opiate
receptors and is not addictive or analgesic. It is the d-isomer
of levorphanol. The l-isomer of levorphanol has
addictive and analgesic properties. It does not depress respiration in usual
doses, extremely high doses may depress respiration. No evidence of tolerance
has been found during long-term use.
Codeine, is methylmorphine; methylation of
morphine significantly improves the oral bioavailability by reducing the
first-pass effect.It has antitussive, analgesic, and slight sedative effects,
is especially useful in relieving painful cough. It also exerts a drying action
on the respiratory mucosa that may be useful (e.g., in bronchorrhea) or
deleterious (e.g., when bronchial secretions are already viscous). At
doses used for cough suppression, codeine has minimal respiratory depressant
effects. Nausea, vomiting, constipation, tolerance as well as analgesic effects
and physical dependence can occur, but potential for abuse is low.
Morphine is an
effective antitussive at doses lower than the doses that produce analgesia and
sedation. It is not commonly used for antitussive activity due to adverse
effects and the potential for abuse and addiction. Morphine has poor oral
bioavailability due to a significant first-pass effect by the liver.
Hydrocodone is
chemically and pharmacologically similar to codeine but more potent. It is
combined with an anticholinergic drug (homatropine) to discourage abuse by
people.
Peripherally acting antitussives
may act by reducing the input of stimuli by acting as a mild analgesic or
anesthetic on the respiratory mucosa, by modifying the output and viscosity of
the respiratory tract fluid, or by relaxing the smooth muscle of the bronchi in
the presence of bronchospasm. Peripherally acting agents are grouped as
demulcents, local anesthetics, and humidifying aerosols and steam inhalations.
Demulcents are useful for
coughs originating above the larynx. They form a protective coating over the
irritated pharyngeal mucosa. They are usually given as syrups or lozenges and
include acacia, licorice, glycerin, honey, and wild cherry syrups.
Local anesthetics (e.g., lidocaine,
benzocaine, hexylcaine hydrochloride, and tetracaine) are used to inhibit the
cough reflex under special circumstances (e.g., before
bronchoscopy or bronchography).
Benzonatate, a congener of tetracaine, is a local
anesthetic; its antitussive
effect may be due to a combination of local anesthesia, depression of pulmonary
stretch receptors, and nonspecific central depression.
Humidifying aerosols and steam inhalations exert an
antitussive effect by acting as a demulcent and by decreasing the viscosity of
bronchial secretions. Inhaling water as an aerosol or as steam, with or without
medicaments (sodium chloride, compound benzoin tincture, eucalyptol), is the
most common method of humidification. The efficacy of added medicaments has not
been clearly proved.
- Mucolytics and Expectorants: Iodides, Guaifenesin
Mucolytic and Expectorant drugs are used to
increase the output of bronchial secretions, enhance the clearance of bronchial
exudate, and promote a productive cough.
Mucolytic drugs are designed to help loosen/break
up the disulphide bonds on mucoprotein through the free sulfhydryl group they
posses, thus making mucus less viscous/sticky by altering the mucin-containing
components. Expectorants help
expel bronchial secretions from the respiratory tract by increasing the amount
of respiratory tract fluid, thus decreasing their viscosity and facilitating the
removal.
The most common type of mucolytic
is N-acetylcysteine. Another type is dornase alfa (the new highly purified
recombinant human deoxyribonuclease I (rhDNase), seems likely to become
important in the treatment of cystic fibrosis, although its place has not been
defined).
Examples of Expectorants includes
Iodides (Potassium iodide been the most common) and Guaifenesin.
Iodides are used to liquefy tenacious bronchial
secretions (e.g., in late stages of bronchitis, bronchiectasis, and
asthma). A saturated solution of potassium iodide is the least expensive, most
commonly used preparation. Their usefulness is limited by low patient
acceptance because they have an unpleasant taste and because side effects (e.g.,
acneiform skin eruptions, coryza, erythema of face and chest, painful swelling
of the salivary glands) are common. The side effects are reversible and subside
when the drug is stopped. Iodinated glycerol is better tolerated than potassium
iodide solution but is probably less effective. Prolonged use of iodides or
iodinated glycerol can lead to hypothyroidism.
Guaifenesin (glyceryl guaiacolate) is a
centrally acting muscle relaxant that may also have an expectorant effect. It
may stimulate bronchial secretions via vagal pathways. The volume and viscosity
of bronchial secretions does not change, but particle clearance from the
airways may accelerate. It is a common component of human cold remedies in
combination with dextromethorphan. It has no serious adverse effects, but there is no clear
evidence of its efficacy.
Many other traditional expectorants include the volatile oils, such
as eucalyptus oil and oil of lemon. They are believed to directly increase
respiratory tract secretions. Their efficacy is doubtful and not well proven.
DECONGESTANTS
These
agents are all B2-adrenergic agonists and are commonly used in people for
allergic rhinitis. The α-adrenergic agonist drugs cause local vasoconstriction
in mucous membranes, which reduces swelling and edema. They are used topically
as nasal decongestants in allergic and viral rhinitis, or systemically in
combination with antihistamines as respiratory tract decongestants.
- Short-acting (topical) decongestants: Delivered as nasal sprays, these agents have the benefit of avoiding deleterious side-effects of systemic introduction of B2-agonists. The most commonly used short-acting agonist decongestant is phenylephrine. Repeated topical use of these compounds can lead to down-regulation of the receptors, and subsequent rebound hyperemia in the nasal blood vessels.
- Long-acting (systemic) decongestants: Used for prolonged duration of action, with an increased potential for systemic side-effects (hypertension, cardiac stimulation, urinary retention, CNS stimulation, and mydriasis). Systemic administration of antihistamines often causes sedation. Psuedoephedrine is the most commonly used long-acting B2-agonist decongestant. Other agents such as ephedrine and phenylpropanolamine were formerly used, but they have been withdrawn from the OTC market.
TREATMENT OF
ASTHMA
Asthma is
a common chronic inflammatory disease of the airways characterized by variable
and recurring symptoms, reversible airflow obstruction, and bronchospasm. Common
symptoms include wheezing, coughing, chest tightness, and shortness of breath.
Pathophysiology
of Asthma
-Clinically characterized by
recurrent, episodic bouts of coughing, wheezing, and shortness of
breath/dyspnea (quantitated by a reduction in FEV1)
-Physiologically characterized by
increased responsiveness of trachea and bronchi to various stimuli and by
widespread narrowing that changes either spontaneously or in response to
therapy.
-Pathologically characterized by contraction of
airway smooth muscle, mucosal thickening from edema and cellular infiltration.
Pathogenesis
of Asthma
-Mediated by IgE antibodies bound
to mast cells in airway mucosa
-Following an initial exposure to
allergen; which can be by inhalation (of pollen, mold, dust mites etc),
ingestion (swallowing a type of food mostly sea foods, or medication), touch
(with poison ivy, latex or certain metals such as nickel) or by injection
(receiving a medication or being stung by an insect); the body produces IgE
designed specifically for that particular allergen, but wont experience
reaction yet. The IgE binds to special receptors on mast cells, hence the
system is said to be sensitized.
-Re-exposure to allergen/antigen
(pollen, fur, etc.), antigen-antibody reaction triggers the release of mediators
stored in mast cell granules and synthesis and release of other mediators.
-Early mediators include:
histamine, tryptase and other neutral proteases, leukotrienes (LTC4, LTD4) and prostaglandins;
these mediators cause airway smooth muscle contraction and vascular leakage.
Late mediators include: GM-CSF, interleukins (IL4, IL5); these late mediators
attract and activate eosinophiles and stimulate IgE production. Released mediators
also activate neural pathways that can result in the release of compounds such
as ACh at smooth muscle by vagal efferents resulting in contraction.
Therapeutic
Approach to Asthma
From the various steps involved
in the process, there are several points of attack:
-preventing mast cell degranulation
-reducing bronchial
responsiveness
-relax airway smooth muscle
All three approaches are in
current use.
- Mast cell stabilizers: Cromolyn & Nedocromil
-Since chloride channels are involved in the
process of mast cell activation. Cromolyn sodium and nedocromil sodium are
chloride-channel blockers that modulate mast cell mediator release and
eosinophil recruitment.
-Effective only when used
prophylactically
-Cannot reverse bronchospasm or
alter bronchial tone
-Poorly absorbed from the gut, so
delivered topically by inhalation of a microfine powder or aerosolized
solution.
-Can also be used as a nasal
spray to reduce symptoms of allergic rhinitis
-Very few side effects,
presumably due in part to the localized application of the drugs
- Methylxanthines: Theophylline, Aminophylline
-They act by reducing the
breakdown of cAMP through the inhibition of phosphodiesterases
-cAMP has bronchodilator activity
through increasing the rate in inactivation of MLCK, an important component in
smooth muscle contraction.
-Methylxanthines are taken orally, and this
can lead to a number of side-effects due to increases in [cAMP] in a number of
other systems: CNS (nervousness and tremor), Cardiovascular (tachycardia and palpitation),
GIT (nausea, vomiting, and diarrhoea), and Renal (diuretic activity)
- Theophylline is well absorbed
from the gut and it is extensively metabolized in the liver; differences in the
hepatic metabolism are the principle reason for the wide variation in kinetics
both between individuals and within the same individual during the course of
illness.
-Average t1/2 in adult is about
8-12hr so it is given 2-3 times daily
-No longer used as a first-line
therapy
- Sympathomimetic Agents: B2 Adrenoceptors agonists or stimulants
Salbutamol:
- Agents as salbutamol,
terbutaline and fenoterol are selective stimulants of B2 receptors; they act on these receptors in bronchi and
small airways and on mast cells resulting in relaxation of bronchial smooth
muscles and stabilization of mast cells. They cause fewer side effects on heart
than adrenadine or isoprenaline which are non-selective (obsolete).
- Salbutamol is best given by
inhalation because: It permits direct delivery of the drug to the site of
action, it reduces the possibility of general systemic side effect, and it
provides large surface area for absorption and rapid onset of action.
- Salbutamol has a relativity
long duration of action of about 4 hours or even longer
- Tremor may occur due to
Stimulation of B2
receptors.
Terbutaline
& Fenoterol:
-They are selective B2 - receptor stimulants
(Agonist) with actions similar to salbutamol they are available as oral,
parenteral & inhalation preparations and their adverse effects and
indications are similar to those of salbutamol.
Other selective
B2 stimulants:
Albuterol (Ventolin),
metoproterenol (Alupent), isoetharine, rimiterol, and reproterol
- Corticosteroids: Beclomethasone, Hydrocortisone, Prednisolone
-
The mechanism of actions on the bronchi are not fully understood but
are thought to work mainly via inhibition of the production of cytokines
-They
have anti-inflammatory action (through inhibition of the release of
inflammatory mediators from macrophages and eosinophils), so reduce the
responsiveness of airways.
-They
do not reverse bronchospasm
-
Reduction of mucosal oedema resulting in increase airflow.
-Increase
B2 - receptor responsiveness to agonist
-Modification
of immune response & stabilization of mast cells.
-
In the management of airway obstruction they are given by
inhalation orally and
IV
according to the condition:
Inhalation:
-Steroid
inhalation represent a significant advance in the management of bronchospasm
because of the adverse effect associated with systemic steroid are minimized
(steroids are highly toxic drugs).
-Beclomethasone
& betamethasone & administered by aerosol inhalant
-Adverse
effects are usually very much less than those of systemic agents but infection
of pharynx & larynx with candidiasis may occur.
I.V corticosteroids:
-When
there is sever unresponsive asthma, especially when there is respiratory failure.
Hydrocortisone (cortisol) is given I.V.
-
There is a delay in the onset of any steroid-induced
bronchodilation & this occurs because the receptors of steroid are found
inside cytoplasm and thus they need more time to exert their effect for this
reason Hydrocortisone is not used in case of emergency in addition to that
other measures should be pursued at the same time.
Oral corticosteroid:
-Patients
with severe exacerbation of asthma require high doses of prednisolone by mouth
after I.V hydrocortisone.
-Treatment with oral
corticosteroids is usually for a fixed period only 7-10 days
- Leukotriene Pathway Inhibitors: Zileuton, Zafirlukasts
-Leukotrienes
(in particular LTC4 and LTD4) are involved in the inflammatory response, so
blocking their production or action can be a useful form of treatment
-Leukotrienes
are synthesized from arachidonic acid via 5-lipoxygenase, and bind to receptors
on target tissues to initiate inflammatory responses along with other mediators
-Blocking
production with 5-lipoxygenase inhibitors has been shown to be effective in both
blocking response to antigen challenge. Currently used orally-active compounds include
zileuton; which possesses a short half-life; blocks antigen and exercise
induced bronchospasm.
-Blocking
actions of LTD4 at its receptor also reduces inflammatory response. Currently used
orally active compounds include zafirlukast, montelukast. Zafirlukast prevents
aspirin sensitive asthma and antigen induced and exercise induced bronchospasm
and better to be used with B2 receptor agonist (additive effect).
- Anti-cholinergic drugs: Ipratropium
-Cholinergic
stimulation causes bronchoconstriction; asthmatic individuals appear to have
excessive stimulation of cholinergic receptors. The anticholinergic
(parasympatholytic) drugs are effective bronchodilators that act by reducing
the sensitivity of irritant receptors and by inhibiting vagally mediated
cholinergic smooth muscle tone in the respiratory tract.
-
The parasympathetic cholinergic bronchoconstrictor effect can be
blocked by the use of atropine like drugs such as Ipatropium bromide; a
synthetic derivative of atropine with less anticholinergic adverse effect than
atropine itself.
-
It is given by pressurized aerosols or from nebulizers.
- Oxygen: High and Low cone
-When
oxygen is given to supplement the amount normally present in the inspired air
it should be regarded as drug.
-It
is given in two forms: High cone and Low cone (Controlled: 24 %-28%)
-High
cone is given to all hypoxic patients except those with established potential narcosis.
It is usually delivered at the rate of 5 litres/ min or more.
-Low
cone is usually reserved for patients with exacerbation of COPD with
respiratory failure and may be administered by using the ventori principle to
supply a calibrated inspired oxygen conc. of 24-28%.
- Respiratory stimulants: Nikethamide, Ooxapram
-Some
patients with respiratory failure require intubations and artificial ventilation.
The
place of respiratory stimulants is controversial. They may occasionally lead to
improvement in ventilation and obviate the need for assisted respiration.
Nikethamide:
-It
is a convulsant or analeptic used in sub-convulsive doses.
-Its
central activity is not selective for the respiratory centre
-Its
effect is transient lasting about 5 minutes.
-Adverse
effects include vomiting, restlessness and convulsion.
-It
may be used in respiratory depression following inappropriate oxygen therapy.
Ooxapram:
-It
acts like nikethamide but it is given by continuous IV infusion
-It
is used to stimulate respiration in patients who fail to ventilate spontaneously
after general anaesthesia or in chronic respiratory failure with CO2
retention.
TREATMENT OF COPD
-COPD
is characterized by persistent, partially or non-reversible airflow limitation,
dyspnea, cough and expectoration.
-Cigarette
smoking is the most important risk factor.
-Manifests
as one of three pathological entities:
a.)
chronic bronchitis
b.)
chronic obstructive bronchitis
c.)
emphysema
-No drug
treatment can affect the natural history of COPD; treatment is designed toward
correction of symptoms, maintenance of lung function, and improvement of
quality of life.
-Since
obstruction to airflow is the most typical characteristic of COPD,
bronchodilators are drugs of first choice.
-In mild
forms, a short-acting B2 agonist such as albuterol followed by the muscarinic antagonist
ipratropium are used on as “as needed” basis or before exercise.
-For
more severe cases, short-acting B2
agonists with ipratropium are prescribed on a
regular basis (like 3-4 times per day)
-Theophylilline
is used when B2 agonists and ipratropium are ineffective; however, due to systemic
effects of theophylline; its use is declining.
-The
efficacy of corticosteroids in the treatment of COPD is still under debate, but
recent evidence suggests that inhaled corticosteroids, either alone or in combination
with
salmeterol,
can result in a significant increase in FEV1 in COPD patients. Chronic use of oral
or systemic corticosteroids should be avoided.
-Leukotriene
synthesis inhibitors or leukotriene receptor antagonists have not been adequately
tested in COPD patients, so their use cannot be recommended at present.