Sunday 5/ 4 / 2015
©Ali Kareem 2014-2015
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مكتب اشور لالستنساخ
DRUGS ACTING ON
RESPIRATORY SYSTEM
Lecture 6
Total lectures NO. 51
Dr. Ahmed Al-Zohyri
Pharmacology
Drugs of Respiratory system
1
Dr. Ahmed Al-Zohyri
Lec. 6
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.
Drugs that are used for treatment of respiratory problems include
1. Drugs & air flow obstruction.
2. Oxygen.
3. Respiratory stimulants.
4. Expectorants & cough suppressant.
Drugs & air flow obstruction
The aim of treatment in air flow obstruction is to increase ventilation by reducing
bronchial smooth m. tone with specific agonist & antagonist drugs, by blocking the
mechanisms of allergic response.
Drugs used in the treatment of airways obstruction are:
1. B
2
- Adrenoceptors agonist or stimulants:
The mechanism of action is by increasing cAMP in the bronchial smooth
muscles and mast cell leading to bronchodilation.
2. Theophylline and other xanthine derivatives: they act by blocking the
enzyme phosphodiesterase leading to increase intracellular cAMP.
3. Mast cell membrane stabilizers: as Na cromoglycate [cromolyn], they
prevent the release of broncho constrictor mediators.
4. Corticosteroids: they stabilize mast cell and improve the pulmonary
function in extrinsic and intrinsic asthma by other mechanisms not well
understood.
5. Anti-cholinergic drugs: they act by decreasing muscarinic broncho-
constriction.
Pharmacology
Drugs of Respiratory system
2
Dr. Ahmed Al-Zohyri
Lec. 6
1) B
2
- Adrenoceptors agonists or stimulants:
A. Salbutamol:
Mechanism of action:
Agents as salbutamol, terbutaline and fenoterol are selective stimulants of
B
2
receptors; they act on these receptors in bronchi and small airways and on
mast cells.
They cause fewer side effects on heart than adrenadine or isoprenaline which
are non-selective (obsolete).
Action:
1. Relaxation of bronchial smooth muscles.
2. Stabilization of mast cells.
Route of administration:
Salbutamol is best given by inhalation because:
1. Itpermits direct delivery of the drug to the site of action.
2. It reduces the possibility of general systemic side effect.
3. The total dose administered is very small and this furtherlimit the adverse
effects.
4. It provides large surface area for absorption.
5. Rapid onset of action.
Salbutamol has a relativity long duration of action of about 4 hours or even longer.
Side effect:
1. Tremor due to Stimulation of B
2
receptors.
2. Other does-dependent effects resulting from weak activation of B- receptor
as tachycardia and hypokalemia, these are rare however with higher degree
of selectivity afforded by aerosol route.
Note: Dose dependent means occur or increase when increase in dose.
Pharmacology
Drugs of Respiratory system
3
Dr. Ahmed Al-Zohyri
Lec. 6
Clinical Uses:
1. In asthma.
2. In chronic obstructive airways disease (long-term treatment and
prophylactic), or maintenance therapy (aerosol or oral tablets) orin acute
attacks by nebulizers.
B. Terbutaline & Fenoterol:
They are selective B
2
- 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.
C. Other selective B
2
stimulants:
Isoetharine, rimiterol, and reproterol are either less selective or short acting and
have no clear advantage over salbutamol and terbutaline.
Notes:
• B
2
agonist given as aerosol inhalation result in symptomatic relief with minimum
cardiac adverse effects especially in patient with reversible airways obstruction.
• Response depends on the patient using the aerosol correctly, even with optimal
use only 10% of the drug is inhaled while the remaining 90% is swallowed or
metabolized.
2) Theophylline & other Xanthine derivatives:
Mechanism of the action:
By inhibition of phosphodiesterase and thus increasing cAMP cone. by blocking
the enzyme that breaks down the nucleotide.
Increased cAMP reduce the tone in bronchial smooth m. and stabilizes mast cell
membrane. Xanthine may have wide spread effect on s.m. not only in bronchi but
also in CVS.
Pharmacology
Drugs of Respiratory system
4
Dr. Ahmed Al-Zohyri
Lec. 6
Kinetics:
Theophylline is well absorbed from the gut and it is extensively metabolized in the
liver, difference 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.
Adverse effect:
Tachycardia and palpitation at therapeutic doses. Nausea. vomiting and diarrhea at
high therapeutic doses and convulsions are associated with plasma level above
30µg/l.
Clinical Uses: It is used orally in long term treatment of asthma & Chronic
obstructive airways diseases (COAD) especially in patient who show response to
it.
Aminophylline:
It consists of theophylline and ethylene diamine in ratio of 2:1 it is used in:
1. Severe acute attacks of asthma & status asthmatics.
2. Exacerbation of COAD.
3. Acute left ventricular failure with pulmonary edema.
Oral theophylline preparations are useful in long-term treatment of asthma &
reversible (COAD). A useful bronchodilation response can be often achieved with
in the therapeutic range & the S/E can be minimized with the aid of plasma level
measurements.
3) Mast cell membrane stabilizers:
As Na cromoglycate (cromolyn) & Ketotifen.
They are not bronchodilators but they prevent bronchoconstriction in patient
with extrinsic (allergic) asthma which is caused by pollen & allergic agents.
Pharmacology
Drugs of Respiratory system
5
Dr. Ahmed Al-Zohyri
Lec. 6
They stabilize sensitized mast cell and inhibit the release if broncho-
constrictor agent like: histamine, SHT (serotonin) & SRS-A (slow reacting
substances for anaphylaxis) as leukotrines.
Mast cell stabilizers are useful in extrinsic (Allergic) asthma particularly in
children & young adults & can prevent exercise induced asthma.
Response in intrinsic asthma is usually disappointing and these agents have
nothing to offer to patients with (COAD).
Clinical uses:
Na Cromoglycate is administered locally to the lung by inhalation as powder or
from pressurized aerosols or nebulizers.
Ketotifen:
• It is a histamine Hl - receptor blocker which may also has some antiasthmatic
effect.
But it effect or benefit has not been conclusively demonstrated. In common with
other anti-histamine it causes drowsiness.
Ketotifen is given orally as tablets or capsules.
Side effect: sedation & dry mouth that result from additional
antihistamine..... effect of these drugs.
4) Corticosteroids:
The actions on the bronchi is not fully understood, their effect are the result of the
following action:
a. Anti-inflammatory (for any reason).
b. Reduction of mucosal oedema increase airflow.
c. Modification of immune response & stabilization of mast cells.
d. Increase B
2
- receptor responsiveness to agonist
Pharmacology
Drugs of Respiratory system
6
Dr. Ahmed Al-Zohyri
Lec. 6
In the management of airway obstruction they are given by inhalation orally and
IV according to the condition:
A. 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: they are usually very much less than those of systemic
agents but infection of pharynx & larynx with candidiasis may occur
(disadvantage).
Aerosol inhalation corticosteroid should replace long term oral
corticosteroid therapy wherever possible as the benefit can be attained
without adverse effects of long term systemic steroid treatment
B. 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 effectfor this reason Hydrocortisone is not used in case of
emergency in addition to that other measures should be pursued at the same time.
C. oral corticosteroid:
Patients with severe exacerbation of asthma require high doses of prednisolone by
mouth after I.V hydrocortisone.
5) Anti-cholinergic drugs: Ipratropium:
Mechanism of action:
The parasympathetic cholinergic bronchoconstrictor effect can be blocked by the
use of atropine like drugs, usually this effect of anticholinergic on airway
resistance is less than that of sympatheticstimulant agents.
Pharmacology
Drugs of Respiratory system
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Dr. Ahmed Al-Zohyri
Lec. 6
Adverse effect:
The anticholinergic adverse effects of synthetic derivativesipratropium bromide are
much less than those of atropine itself, it is given by pressurized aerosols or from
nebulizers.
Oxygen
When O2 is given to supplement the amount normally present in the inspired
airit should be regarded as drug.
It is given in tow forms:
1. High cone. as possible
2. Low cone. (controlled) (24 %-28%)
1. High O2 cone. :
It should be given to all hypoxic patients except those with established potential
narcosis. Any apparatus which provide O2 flow to the oro-nasal area at a rate of 5
liters/min or more is effective in supplying a high cone. of O2 in the inspired gas.
Indications:
a. Pneumonia.
b. Acute pulmonary edema.
c. Pulmonary thrombo-embolism.
d. Fibrosing alveolitis.
e. Status asthmaticus.
f. respiratory failure or arrest due to drug over dose.
g. Acute circulatory failure.
h. Cyanide and CO poisoning.
2. low O2 cone. :
Usually reserved for patients with exacerbation of COPD with respiratory
failure.
Pharmacology
Drugs of Respiratory system
8
Dr. Ahmed Al-Zohyri
Lec. 6
Ventilation is then ineffective because CO
2
excretion is not maintained in
spite of the raised PCO
2
The increaser PCO2 lead to less of sensitivity of respiratory centerto CO
2
,
and. dependence on low arterial PO2 to drive ventilation.
High cone. of O2 administered lead to further suppression of ventilation by
the removal of the hypoxic drive .
Further CO
2
accumulate then rapidly produces narcosis & death. Low con.
May be administered by masks using the ventori principle to supply a
calibrated inspired O
2
conc. Of 24-28%
Respiratory stimulant
Some patients with respiratory failure requires Intubations and artificial
ventilation.
The place of respiratory stimulants is controversial. They may occasionally lead to
improvement in ventilation &obviate the need for assisted respiration.
Nikethamide:
It is a convulsant or analeptic used in sub-convulsive doses.
It's central activity is not selective for the respiratory center
Its effect is transient lasting about 5 minutes.
Adverse effect include vomiting I restlessness and convulsion.
It may be used in respiratory depression following lrappropriate O2 therapy.
\
Doxapram:
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 anesthesia or in chronic respiratory failure with CO2 retention.
Expectorants & cough suppressant
These are two other classes of drugs commonly used in respiratory disease; but
their therapeutic value is doubtful.
Pharmacology
Drugs of Respiratory system
9
Dr. Ahmed Al-Zohyri
Lec. 6
Expectorants:
• Difficulty in bringing up sputum is a common complaint, but there is no evidence
that any agent given by any route specifically promoted expectoration of
bronchialsecretions.
• Agents with expectorant properties as ammonium chloride & guaniphesin are
often included in cough mixtures.
• Agents claimed to possess a mucolytic properties such as acetyl cysteine haven't
been conclusively shown to show any important role in the management of airway
obstruction, their beneficial effect may be attributed to the inhalation of steam or
water by aerosol rather than the pharmacological properties of theconcerned drugs.
Cough suppressant (Antitussive):
• Cough is a frequent complaint or secondary to an upper respiratory tractinfection.
Chronic persistent cough is often caused by cigarette smoking.
• In acute respiratory infection, cough is a useful protective mechanism enabling
the clearing the secretions from trachea and bronchi. Cough usually improves
spontaneously with treatment of any underlying bacterial infection. Patients with
terminal lung cancer with bronchial obstruction or tumor involvement of afferent
(sensory) nerve from the lung and chest wall may develop persistent distressing
cough this is one of few conditions in which the symptomatic treatment of cough
can be completely justified.
• Cough suppressants are opiate agonists & the suppression of cough reflexes is
only part of the narcotic induced depression of the CNS.
• Drugs used of cough suppression are usually given in the form of a sweet syrup
or linctus, although oral or parental opiate will block cough reflexes justified as
effective examples are: Diamorphine, Methadone, and Codeine phosphate.
New Bronchodilotors or leukotriens antagonists:
They are two classes:
Pharmacology
Drugs of Respiratory system
10
Dr. Ahmed Al-Zohyri
Lec. 6
1) Cysteinylleukotrien receptor antagonist:
Zafirlucost:
A potent competitive antagonist at L TD4 receptor.
It prevents aspirin sensitive asthma & antigen induced and exercise induced
bronchospasm.
It relaxes airway in mild asthma with activity of 1/3 than that of salbutamol,
it is better to be used with B2 receptor agonist (additive effect).
2) 5-Lipoxygenase inhibitor:
The act by preventing the production of L TCIY D4, B4 (C4 and D4 are the most
potent).
Zeleulin:
The prototype compound.
It blocks antigen & exercise induced broncrospasm & may inhibit or '
reduce late phase inflammation.
It is taken orally with low potency and short t1/2, so it is used in large dose
3-4 times daily.
Done by
Ali Kareem