Drugs used for treatment of Asthma July 2021.ppt

RESPIRATORY SYSTEM PHARMACOLOGY
Daniel chans. M (MPS)
B.Pharm, MScPHA, MPharmClinical
Pharmacy
2/7/2024 Daniel chans MPS 2021 1
Dept of Pharmacology&Therapeutics
MUST
danielchans@must.ac.ug

•Drugs Acting on
Respiratory System
Drugs used in Asthma
Drugs used in COPD
Drugs used in Cough
Drugs used in Allergic
Rhinitis..
e.g. Decongestants…

COURSE OBJECTIVES
By the end of this lecture, students are expected to learn
•Disorders of the respiratory system
•Bronchial asthma i.e. types of asthma and pathophysiology
•Drugs used in management of bronchial asthma and COPD
•The drug targets in asthma, their MOA, PK, ADRs, DIs,
Contraindications
•The drugs used in cough i.e antitussives, expectorants, mucolytics
•Drugs used in Allergic Rhinitis…eg Nasal decongestants
2/7/2024 Daniel chans MPS 2021
3

Main disorders of the respiratory system ar
1. Bronchial asthma
Chronic obstructive pulmonary disease
(COPD, also called emphysema)
2. Cough
3. Allergic rhinitis
4. Others are infections, cancer, pulmonary
emboloic disease, Cystic Fibrosis

BRONCHIAL ASTHMA
• Asthma is a condition in which there is recurrent 'reversible'
obstruction of the airflow in the airways in response to
stimuli which are not in themselves noxious and which do not
affect non-asthmatic subjects.
• The term asthma is derived from the Greek word meaning
difficulty in breathing.
• Asthma may be chronic or acute (exacerbation).
• In chronic asthma, the individual has intermittent attacks of
dyspnoea (difficulty in breathing), wheezing, and cough.
• Acute severe asthma (also known as status asthmaticus) is
not easily reversed.
• It is life threatening and the severest acute asthmatic attack
with compromise of vital pulmonary function and can be fatal
and requires prompt treatment.
5

Characters of airways in asthmatic patients :
 Bronchospasm (constriction of the bronchial muscles).
 Bronchial hyper-reactivity: abnormal sensitivity of the
airways to wide range of external stimuli.
• The term bronchial hyper-reactivity (or hyper-
responsiveness) refers to abnormal sensitivity to a wide
range of stimuli such as irritant chemicals, cold air, stimulant
drugs, etc., all of which can result in bronchoconstriction.
 Inflammation
• Swelling
• Thick mucus production.

http://link.brightcove.com/services/player/bcpid236059233?bctid=347806802

Symptoms of asthma
Asthma produces recurrent episodic attack of
 Shortness of breath
 Chest tightness
 Wheezing
 Rapid respiration
 Cough
Symptoms can happen each time the airways
are irritated by inhaled irritants or allergens.

Triggers of asthmatic attacks
 Allergens (in sensitised individuals) e.g pollen,
food additives, dust mite
 Respiratory Infection (viral or Bacterial)
 Atmospheric pollutants such as sulfurdioxide.
 Emotional conditions e.g. stress
 Exercise (in which the stimulus may be cold air)
 Pets
 Seasonal changes e.g cold weather
 Cigarette smoking
 Some drugs as aspirin, Non Selective β blockers

TYPES OF ASTHMA
1. Extrinsic Asthma (e.g. Allergic asthma)
• Asthma associated with specific allergic reactions. E.G. pollen, dust,
exercise, etc
• It is the commonest and occurs in patients who develop allergy to
inhaled antigenic substances.
• Allergen avoidance is particularly relevant to management of this type
of Asthma.
• Occurs most in children over age 3 years and in most young adults
2. Intrinsic Asthma
• Some patients exhibit wheeze and breathlessness in the absence of
an obvious allergen.
• They are considered to have an intrinsic asthma because of lack an
identifiable allergen.
• More common in patients after the age of 40 years
.
10

Airways Innervations
Afferent nerves (sensory)
 Irritant receptors in upper airways.
 C-fiber receptors in lower airways.
Stimulated by :
Exogenous chemicals
Physical stimuli (cold air)
Endogenous inflammatory mediators

Efferent nerves (motor)
 M3 receptors in smooth muscles and
glands.
 B2 receptors in smooth muscles and glands

Pathophysiology of asthma
• One hypothesis suggests—that Asthmatic bronchospasm
results from a combination of:
– Release of mediators and an exaggeration of responsiveness to
their effects
• Predicts that drugs with different modes of action may
effectively treat asthma.
• In the early (acute) phase there are smooth muscle spasm
leading to Bronchoconstriction&vascular leakage.
• In the late (chronic or delayed) phase, influx of
inflammatory cells and increased bronchial reactivity. (after
3-6hrs)

Katzung 20th Edition

• Antigens (pollen and house-dust mites) sensitize patients
by eliciting the production of IgE type of antibodies, which
remain either circulating in the blood or become attached to
the mast cells of nasal or bronchial tissues and basophils.
• On re-exposure the same antigen, the resulting antigen-
antibody reaction in the early phase causes degranulation
of the lung mast cells and releasing of the powerful
bronchoconstrictors: histamine, Tryptase, PGD2 and
cysteinyl leukotrienes (LTB4, LTC4 and LTD4).
• Also PAF, PGF2alpha, which promote mucus secretion and
pulmonary edema

NB
•Localised
degranulation
causes asthma or
hay fever
•Systemic mast cell
degranualtion
causes anaphylaxis

• In the late (delayed) phase of asthma, these mediators activate
additional inflammatory cells (eosinophils, basophils, and alveolar
macrophages) which also release LTs and ILs (IL-4, IL-5 and IL-13).
• Other mediators of inflammation, in delayed phase,are: adenosine
(causing bronchconstriction), neuropeptides (SP, causing mucus
secretion and increase in vascular permeability; neurokinin A,
causing bronchoconstriction), PAF etc.
• The normal tone of bronchial smooth muscle is influenced by a
balance between parasympathetic, sympathetic and non-
adrenergic–non-cholinergic (NANC) mediators activity.

• Activation of M3-receptors by the release ACh results in
increase in cGMP levels and leads to
bronchoconstriction and increase in mucus secretion.
• The main NANC inhibitory neurotransmitter is NO.
• The main NANC excitory transmitters are neuropeptides
(neurokinin A and SubstanceP), released from
unmyelinated sensory C-fibres when stimulated by
inflammatory mediators and irritant chemicals (e.g
cigarette smoke).

GOALS OF MANAGEMENT OF ASTHMA
• Prevent chronic (recurrent)and troublesome
symptoms
• Return the pulmonary function to as to near to normal
as possible
• Maintain normal activity levels
• Prevent recurrent exacerbations of asthma and
minimize the need for emergency department visits or
hospitalizations
• Provide optimal pharmacotherapy with minimal or no
adverse effects
21

22

Non pharmacological therapy
• Avoid triggers eg smoking, dust, some drugs,
cold weather (warmup) etc
• Patient education on how to recognize
allergens and avoid them
• Education on how to recognize symptoms
• Education on how to control symptoms, e.g
proper use of medication like the metered dose
inhalers

Antiasthmatic Drugs
I. Bronchodilators
– Sympathomimetics/adrenomimetics (e.g. β2 receptor
agonists, epinephrine, isoprenaline)
– Menthylxanthine drugs e.g. Theophylline, Aminophylline
– Muscarinic antagonists e.g. Ipratropium, Tiotropium
II. Anti-inflammatory agents
– Steroids eg ICS, systemic steroids
III. Mast Cell Stablizers
– e.g Cromolyn and Nedocromyl
IV. Leukotriene Modulators
o 5-Lipoxygenase Inhibitor: Zileuton
o Leukotriene receptor antagonists (LTD4-antgonists): Zafirlukast,
Montelukast
V. H1 receptor blocker

VI. TARGETED (MONOCLONAL ANTIBODY) THERAPY
• Anti-IgE Monoclonal Antibodies
• Anti-IL-5 Therapy
• Anti-IL-4α co-receptor (IL-4 and IL-13)

Classification of antiasthmatic drugs
1. Bronchodilators
A. Sympathomimetics:
i) Selective B2-adrenergic agonists:
salbutamol/albuterol, terbutaline (short acting),
salmeterol, and formoterol (long acting).
ii) Non selective : adrenaline,
isoprenaline/isoproterenol, ephedrine
B. Methylxanthines: theophylline, aminophylline,
etophylline

C. Anticholenergics: Ipratropium bromide, tiotropium bromide,
Oxitropium, aclidinium, and umeclidinium
2. Mast cell stablizers: sodium chromoglycate (cromolyn), nedocromil
sodium (nedcromyl), ketotifen.
3. Glucocorticoids:
Oral: Prednisone, Methylprednisolone
Parenteral: Methylprednisolone, Hydrocortisone
Inhalational: Beclometasone, Budesonide, Fluticasone,
triamcinolone, mometasone, flunisolide, ciclesonide
4. Leukotriene Modulators
• 5-Lipoxygenase Inhibitor: Zileuton
• Leukotriene receptor antagonists (LTD4-antgonists): Zafirlukast,
Montelukast
5. Targeted Monoclonal antibody Therapy
a. Anti-Ig-E monoclonal antibody: omalizumab.
.b. Anti IL-5: Mepolizumab and Reslizumab
c. Anti-IL-4α co-receptor e.g. Dupilumab
6. Miscellaneous: NO-donors, Calcium antagonists
2/7/2024 27

Anti asthmatic drugs
Bronchodilators
(Quick relief medications)
treat acute episodic attack of
asthma
• Short acting 2-agonists
• Antimuscarinics
• Xanthine preparations
Anti-inflammatory Agents and
others
(control medications or
prophylactic therapy)
reduce the frequency of attacks
• Corticosteroids (Esp ICS)
• Mast cell stabilizers
• Leukotrienes antagonists
• Anti-IgE monoclonal antibody
• Long acting ß2-agonists

Sympathomimetics
- adrenoceptor agonists
Mechanism of Action
 Direct 2 stimulation  stimulate adenyl
cyclase  increase cAmp 
bronchodilation
 Inhibit mediators release from mast cells.
 Increase mucus clearance by (increasing
ciliary activity).

Daniel chans MPS 2021 30
Cc:Katzung

Epinephrine/adrenaline
• is an effective, rapidly acting bronchodilator when injected
subcutaneously (0.2-0.5 mL of 1:1000 solution) or inhaled as a
microaerosol from a pressurized canister (320 mcg per puff) by acting
on β2 adrenergic receptors
• Maximal bronchodilation is achieved 15 minutes after inhalation
(aerosol or nebulizer) and lasts 60–90 minutes.
• Adverse effects epinephrine stimulates and α1 , β1 as well as β2
receptors leading to tachycardia, arrhythmias,muscle tremors and
worsening of angina pectoris
• It increases HR and FC. Also causes anxiety
• The cardiovascular effects of epinephrine are of value for treating the
acute vasodilation and shock as well as the bronchospasm of
anaphylaxis, but its use in asthma has been displaced by other, more
β2-selective agents.
• Drug of choice for acute anaphylaxis (hypersensitivity
reactions).

Ephedrine
• Ephedrine was used in China for more than 2000 years
before its introduction into Western medicine in 1924.
• Compared with epinephrine, ephedrine has a longer
duration, oral activity, more pronounced central effects,
and much lower potency.
• Because of the development of more efficacious and β2 -
selective agonists, ephedrine is now used infrequently in
treating asthma.

Isoproterenol
• Isoproterenol is a potent bronchodilator; when inhaled
as a microaerosol from a pressurized canister, 80–120
mcg isoproterenol causes maximal bronchodilation
within 5 minutes.
• Isoproterenol has a 60- to 90-minute duration of action.
• An increase in the asthma mortality rate that occurred
in the United Kingdom in the mid 1960s was attributed to
cardiac arrhythmias resulting from the use of high
doses of inhaled isoproterenol.
• It increases HR and FC
• It is now not used in asthma.

β2-adrenoceptor agonists
• Short-acting agents e.g. Salbutamol (albuterol),
terbutaline, metaproterenol , fenoterol, rimiterol and
reproterol.
• Long- acting agents e.g. Salmeterol, formoterol
• Ultra-long-acting β agonists, such as indacaterol,
olodaterol, vilanterol, and bambuterol, need to be
taken only once a day
• Bambuterol, a pro-drug of terbutaline.
• Can be given by Inhalational, oral, IV routes
35

…
• They are most widely used e.g. albuterol, the treatment of acute
bronchoconstriction.
• They are effective after inhaled or oral administration and have a
longer duration of action than epinephrine or isoproterenol.
• Albuterol, terbutaline, metaproterenol, and pirbuterol are
available as metered-dose inhalers.
• Bronchodilation is maximal within 15 minutes and persists for 3–4
hours.
• All can be diluted in saline for administration from a hand-held
nebulizer.
• Particles generated by a nebulizer are much larger than those from
a metered-dose inhaler, much higher doses must be given (2.5–5.0
mg vs 100– 400 mcg) but are no more effective.
• Reserve nebulized therapy for patients unable to use MDIs well

Nebulizer Inhaler

Short acting ß2 agonists
Salbutamol, inhalation, orally, i.v.
Terbutaline, inhalation, orally, s.c.
 Have rapid onset of action (15-30 min).
 short duration of action (4-6 hr)
 used for symptomatic treatment of acute
episodic attack of asthma.
They are usually used on an 'as needed' basis to
control symptoms.

Long acting selective ß2 agonists (LABAs)
 Salmeterol, formoterol, bambuterol
 Long acting bronchodilators (12 hours)
 Have high lipid solubility (creates depot effect)
 Are given by inhalation
 Are not used to relieve acute episodes of asthma
 Used for nocturnal asthma (long acting relievers).
 Combined with inhaled corticosteroids to control asthma
(decreases the number and severity of asthma
attacks). E.G symbicort (budenoside/formoterol)

LABAs
• These drugs appear to interact with inhaled corticosteroids to
improve asthma control.
• Because they have no anti-inflammatory action, they should
not be used as monotherapy for asthma
• Ultra-long-acting β agonists, such as indacaterol, olodaterol,
vilanterol, and bambuterol, need to be taken only once a day
• Their prolonged bronchodilation masks symptoms of
bronchial inflammation, thus they should be used only in
combination with an ICS for asthma.
• However, they may be used as monotherapy for treatment of
COPD

Beta 2 agonists
15-30
41

Clinical uses
• Used in acute asthmatic attacks (short acting)
• Used for prophylaxis and maintenance therapy in
asthma (long acting)
• Used to improve respiratory function in chronic
obstructive lung disease
• Used to arrest premature labour
Tachyphylaxis and Tolerance
• There is some evidence that β2-agonist tolerance can
occur in asthmatic airways and that steroids can
reduce the development of tolerance because they
inhibit β2-adrenoceptor down regulation.

Selective β2-adrenomimetics with tocolytic effect
•Fenoterol (Partusisten: tab. 5 mg)
•Salbutamol (Salbupart)
•Terbutaline
Also have an effect on
On K+
Increase movt of
potassium into the
cell>>>Hypokalemia

Side effects
• Muscle tremor, which results from a direct stimulation of β2-
adrenoceptors in skeletal muscle.
• β2-Agonists also cause tachycardia and palpitations in some
patients because of their effect on the heart through β1.
• When used by intravenous infusion for premature labor, β2-
agonists have been re-ported to produce tachycardia and
pulmonary edema in the mother and hypoglycemia in the baby
N.B:
• The β2-adrenoceptor antagonists, such as propranolol, though
having no effect on airway function in normal individuals, cause
wheezing in asthmatics and can precipitate a potentially serious
acute asthmatic attack by blocking the compensatory effect of
endogenous adrenaline
44

Patient education on inhaler use
Inhaler and spacer
Spacers can help patients who
have difficulty with inhaler use and
can reduce potential for adverse
effects from medication.

Nebulizer
• Machine produces a mist
of the medication
• Used for small children or
for severe asthma
episodes
• No evidence that it is
more effective than an
inhaler used with a
spacer

…
• β-adrenoceptor agonists are best delivered by inhalation.
• This results in the greatest local effect on airway smooth muscle with the
least systemic toxicity.
• Aerosol deposition depends on the particle size, the pattern of breathing,
and the geometry of the airways.
• Even with particles in the optimal size range of 2–5 μm, 80–90% of the
total dose of aerosol is deposited in the mouth or pharynx.
• Particles under 1–2 μm remain suspended and may be exhaled.
• Bronchial deposition of an aerosol is increased byslow inhalation of a
nearly full breath and by 5 or more seconds of breath-holding at the end
of inspiration

2. Muscarinic antagonists
Ipratropium – Tiotropium
 Act by blocking muscarinic receptors (M3).
 Given by aerosol inhalation
 Quaternary derivatives of atropine
 Do not enter CNS, minimal systemic side effects.
 Ipratropium has short duration of action 3-5 hr
 Tiotropium has longer duration of action (24 h).

ANTIMUSCARINIC AGENTS
• Ipratropium appears to be as effective as albuterol in
patients with COPD who have at least partially reversible
obstruction.
• Longer-acting antimuscarinic agents, including tiotropium,
aclidinium, and umeclidinium, are approved for
maintenance therapy of COPD.
• They are taken by inhalation
• Their use is of clinical value, especially for patients
intolerant of inhaled β agonists

MOA
Prototype: Ipratropium
• Ipratropium competitively relieves bronchoconstriction
by reducing the effects of acetylcholine in the
bronchioles through blocking muscarinic receptors
in the lungs (M3) and the increase in secretion of
mucus that occurs in response to vagal activity in
asthma
• In the airways, acetylcholine is released from efferent
endings of the vagus nerves.
51

Clinical use
 Main choice in chronic obstructive pulmonary diseases (COPD).
Daily inhalation of tiotropium has been shown not only to improve functional capacity of
patients with COPD, but also to reduce the frequency of exacerbations of their condition.
 In acute severe asthma combined with β2-agonists & steroids.
Although antimuscarinic drugs appear to be slightly less effective than –beta
agonist agents in reversing asthmatic bronchospasm, the addition of
ipratropium enhances the bronchodilation produced by nebulized albuterol
in acute severe asthma.
• As a bronchodilator in some patients with chronic bronchitis, and in
bronchospasm precipitated by β2-adrenoceptor antagonists.
Adverse Effects
• Peripheral side effects: dry mouth, headache,
nervousness, dizziness, nausea, and cough.
• Other anticholinergic effects
52

3. Methylxanthines (xanthines)
• Theophylline (from Thea sinensis) (tea)
(aminophylline = theophylline ethylenediamine)
• Theobromine (from Theobroma cacao) (cocoa)
• Caffeine (from Caffea arabica, etc.) (coffee)
• Theophylline has bronchodilator action, though it is
rather less effective than the β2-adrenoceptor
agonists

MOA
1.Inhibit phosphodiesterase III (present in airway muscle)
and IV (involved in chemokine and cytokine release), the
two specific isoenzymes responsible for the degradation
of cAMP
2.Block the adenosine-1-receptors on airway muscle and
adenosine-3-receptors, present on mast cells.
3. Enhancement of histone deacetylation (low dose
reduces for activation of inflammatory gene transcription
4. Increase diaphragmatic contraction

XANTHINES: MOA

Pharmacological effects :
Bronchial muscle relaxation
contraction of diaphragm improve ventilation
CVS: ↑ heart rate, ↑ force of contraction
GIT: ↑ gastric acid secretions&enzymes
Kidney: ↑renal blood flow, weak diuretic action
CNS stimulation
*increased alertness, decrease fatigue & elevate mood.
• overdose (tremors, nervousness, insomnia, convulsions,
death)
• SKMs: Improved Skeletal muscle contractility,
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PK
• Administered orally and by slow intravenous injection of a
loading dose followed by intravenous infusion.
•Well absorbed from GIT, metabolised in the liver (CYP1A2 and
CYP3A4) and has a half-life of is about 8 hours.
•Its half-life is increased in liver disease, cardiac failure and is
decreased in heavy cigarette smokers and drinkers.
•Clearance may be increased through the induction of hepatic
enzymes by cigarette smoking or by changes in diet.
•Children clear theophylline faster than adults (1–1.5 mL/kg/min).
•Neonates and young infants have the slowest clearance

PK
• Theophylline: poorly water soluble, hence not
suitable for injection, available for oral administration.
• Aminophylline: water soluble but highly irritant.
Administered orally or slow i.v.
• Etophylline: given by oral, i.m., i.v. routes.

Adverse effects of methylxanthine

TDM
• Theophylline should be used only where methods to measure
theophylline blood levels are available because it has a
narrow therapeutic window, and its therapeutic and toxic
effects are related to its blood level.
• Improvement in pulmonary function is correlated with plasma
concentration in the range of 5–20 mg/L.
• Anorexia, nausea, vomiting, abdominal discomfort, headache,
and anxiety occur at concentrations of 15 mg/L in some
patients and become common at concentrations greater than
20 mg/L.
• Higher levels (> 40 mg/L) may cause seizures or arrhythmias;
these may not be preceded by gastrointestinal or neurologic
warning symptoms.

Drug interactions
 Enzyme inducers: as rifampicin, phenobarbital,
phenytoin and carbamazepine → ↑metabolism of
theophylline → ↓ T ½.
 Enzyme inhibitors: oral contraceptives,
erythromycin, ciprofloxacin, calcium-channel
blockers, fluconazole cimetidine (but not ranitidine)
and zileuton→
↓ metabolism of theophylline → ↑T ½.

Factors that decrease theophylline clearance
• Minor changes
verapamil, nifedipine, tetracycline,
hydrocortisone, aluminum hydroxide,
magnesium, thiabendazole
• Major changes
hepatic insufficiency, heart failure
cor pulmonale, viral pneumonia,
cimetidine, mexiletine, ciprofloxacin,
allopurinol, erythromycin, propranolol*,
oral contraceptives, zileuton

SELECTIVE PDE4 INHIBITORS
• In an effort to reduce toxicity while maintaining
therapeutic efficacy, selective inhibitors of PDE4 have
been developed.
• Many were abandoned after clinical trials showed that
they induced unacceptably frequent side effects of
nausea, headache, and diarrhea.
• However, one, roflumilast, has been shown to be
effective for reducing the frequency of exacerbations of
COPD and is approved by the US Food and Drug
Administration (FDA) as a treatment for COPD, although
not for asthma.

ANTIINFLAMMATORY DRUGS
 Glucocorticoids
 Leukotrienes antagonists
OTHER DRUGS
 Mast cell stabilizers
 Targeted monoclonal antibody

Anti - inflammatory Agents:
(control medications / prophylactic therapy)
• Reduce the number of inflammatory cells in the
airways and prevent blood vessels from leaking
fluid into the airway tissues.
• By reducing inflammation, they reduce the spasm of
airways & bronchial hyper-reactivity.

THE GLUCOCORTICOIDS
Systemic: hydrocortisone,prednisolone, methylprednisolone
Inhalational: beclometasone, budesonide, ciclesonide,
flunisolide, mometasone and fluticasone.
• They are main anti-inflammatory drugs used in treatment of
asthma.
• They are effective in the management of chronic asthma
and their effects take several hours to days to develop, so
they cannot be used for quick relief of acute episodes of
bronchospasm.
• They are usually given by inhalational route, but in acute
severe asthma can be given by I.V e.g. Hydrocortisone, as
well as orally (prednsolone)
66

Glucocosteroids
• Their broad anti-inflammatory efficacy, mediated in part by
inhibition of production of inflammatory cytokines
• They do not relax airway smooth muscle directly but reduce
bronchial hyperreactivity and reduce the frequency of asthma
exacerbations if taken regularly.
• Their effect on airway obstruction is due in part to their
contraction of engorged vessels in the bronchial mucosa and
their potentiation of the effects of β-receptor agonists
• Their most important action is inhibition of the infiltration of
asthmatic airways by lymphocytes, eosinophils, and mast cells.

MOA of Glucocorticoid in Asthma
• Glucocorticoids secrete lipicortin which inhibits phospholipase A2
and thereby prevent formation of various mediators such as PGs,
TXA2
• Have antiallergic, antiinflammatory and immunosuppressant effects.
 Decrease formation of cytokines
 By virtue of inducing lipocortin, they inhibit the synthesis of
archidonic acid from membrane phospholipids which is a
precursor for Leukotrienes, inhibiting production of the LTC4 and
LTD4 and decrease the synthesis of the leucocyte chemotaxins
LTB4 and platelet-activating factor, thus reducing recruitment and
activation of inflammatory cells.
 Corticosteroids also act by recruiting histone deacetylactylases
reducing activation of inflammatory gene transcription
68

The anti-inflammatory actions of glucocorticoids are
mediated by stimulation of synthesis of lipocortin,which
inhibits pathways for production of PGs, LTs and PAF.
These mediators would normally contribute to increased
Vascular permeability and subsequent changes including
oedema, leukocyte migration, fibrin deposition.

• Glucocorticoids can upregulate β2-adrenoceptors, decrease
microvascular permeability and reduce mediator release from
eosinophils.
• The reduction in the synthesis of IL-3 (the cytokine that
regulates mast cell production) may explain why long-term
steroid treatment eventually reduces the early-phase response
to allergens and prevents exercise-induced asthma.
Clinical use of glucocorticoids in asthma
• Used prophylactically to control asthma rather than acutely to
reverse asthma symptoms
• IV for severe acute asthmatic attacks
70

Pharmacological actions of glucocorticoids
 Anti-inflammatory actions
 Immunosuppressant effects
 Metabolic effects
– Hyperglycemia
– ↑ protein catabolism, ↓ protein anabolism
– Stimulation of lipolysis - fat redistribution

 Behavioral changes: depression
 Bone loss (osteoporosis) due to
– Inhibit bone formation
– ↓ calcium absorption.

Routes of administration
 Inhalation (ICS):
e.g. beclomethasone, budesonide, ciclesonide, flunisolide,
fluticasone, mometasone, and triamcinolone
– Given by inhalation, given by metered-dose inhaler
– Best choice in asthma, less side effects
 Orally: Prednisone, methyl prednisolone
 IV: Hydrocortisone, methyprednsolone

Glucocorticoids in asthma
o Are not bronchodilators
o Reduce bronchial inflammation
o Reduce bronchial hyper-reactivity to stimuli
o Have delayed onset of action (effect usually attained after 2-4
weeks).
o Given as prophylactic medications, used alone or combined
with beta-agonists.
o Effective in allergic, exercise, antigen and irritant-induced
asthma,

• Because of the efficacy and safety of inhaled
corticosteroids, they are recommended patients
with persistent asthma who require more than
occasional inhalations of a β agonist for relief of
symptoms.
• This therapy is continued for 10–12 weeks and then
withdrawn to determine whether more prolonged
therapy is needed; inhaled corticosteroids are not
curative.
Glucocorticoids…

Side effects due to systemic corticosteroids
– Adrenal suppression
– Growth retardation in children
– Osteoporosis
– Fluid retention, weight gain, hypertension
– Hyperglycemia
– Susceptibility to infections
– Glaucoma
– Cataract
– Fat distribution, wasting of the muscles
– Psychosis
– ulcers

Inhalation has very less side effects:
– Oropharyngeal candidiasis (thrush).
• Use topical clotrimazole
• Gargle with water after inhalation or expectorate
• Ciclesonide (less thrush)
– Dysphonia (voice hoarseness).
• Local effects on the vocal cords
Withdrawal
– Abrupt stop of corticosteroids should be avoided and
dose should be tapered (adrenal insufficiency
syndrome).

• Cushing’s syndrome
• Osteoporosis
• Tendency to hyperglycaemia
• Negative nitrogen balance
• Increased appetite
• Increased susceptibility
to infections
• Obesity etc.
Adverse
effects
of GCS
Cushing’s
syndrome

• Because of severe adverse effects when given chronically,
oral and parenteral corticosteroids are reserved for
patients who require urgent treatment,
– ie, those who have not improved adequately with
bronchodilators or who experience worsening symptoms
despite high-dose maintenance therapy
• Inhalational treatment is the most effective way to avoid
the systemic adverse effects of corticosteroid therapy.
• Inhalational dose reduces systemic dose
• Gradually tapper chronic oral therapy to ICS to avoid
precipitation of adrenal insufficiency

LEUKOTRIENE pathway inhibitors
• Leukotrienes result from the action of 5-lipoxygenase on
arachidonic acid and are synthesized by a variety of
inflammatory cells in the airways.
 Leukotriene B4: chemotaxis of neutrophils
 Cysteinyl leukotrienes C4, D4:
– bronchoconstriction
– increase bronchial hyper-reactivity
– mucosal edema, mucus hyper-secretion
Two approaches to interrupting the leukotriene pathway:
1. Inhibition of 5-lipoxygenase, thereby preventing leukotriene
synthesis .
2. Inhibition of the binding of LTD4 to its receptor on target tissues,
thereby preventing its action.
81

Thus leukotriene antagonists are classified into two:
Lipoxygenase enzyme Inhibitors e.g. zileuton
Leukotriene receptor blockers e.g. montelukast and zafirlukast
Lipoxygenase enzyme Inhibitors MOA
• Zileuton suppresses synthesis of the leukotrienes by inhibiting
5-lipoxygenase, a key enzyme in conversion of arachidonic
acid to the leukotrienes.
Leukotriene receptor antagonists MOA
• Montelukast and zafirlukast suppress biological actions of
leukotrienes by competitively blocking leukotriene receptors .
82

Arachidonic acid
5-Lipoxigenase
Leukotrienes (LTs)
LTC4-
receptor
LTD4-
receptor
LTE4-
receptor
Montelukast, Zafirlukast
(–)
(–)
(–)
zileuton
(–)

Leukotriene receptor antagonists
e.g. zafirlukast, montelukast, pranlukast
 are selective, reversible antagonists of cysteinyl
leukotriene receptors (CysLT1receptors).
 Taken orally.
 Are bronchodilators
 Have anti-inflammatory action
 Less effective than inhaled corticosteroids

Clinical uses
• Improve asthma control and reduce frequency of
exacerbations
• They are not as effective as even low-dose ICS therapy in
inducing and maintaining asthma control, but are
preferred by many patients, especially by the parents of
asthmatic children, because of often exaggerated
concerns over the toxicities of corticosteroids.
• They have the additional advantage of being effective
when taken orally, which is an easier route of
administration than aerosol inhalation in young children,
and montelukast is approved for children as young as 12
months of age

Clinical uses
 Prevent aspirin-sensitive asthma and Aspirin Exacerbated Respiratory
Disease
 Inhibit exercise-induced asthma and decrease both early and late
responses to inhaled allergen.
 They relax the airways in mild asthma, their action is additive with β2-
adrenoceptor agonists.
 Can be combined with glucocorticoids (additive effects, low dose of
glucocorticoids can be used).
 They also reduce sputum eosinophilia
 Can be combined with AntiHTs eg monteluekast/levocetrizine
Unwanted effects
 Mainly headache and gastrointestinal disturbances eg dyspepsia
 A few subjects have developed Churg-Strauss syndrome (a systemic
vasculitis accompanied by worsening asthma, pulmonary infiltrates, and
eosinophilia) possibly precipitated by withdrawal of the concomitant
corticosteroid.
87

…
• Of these agents, montelukast is by far the most
prescribed, because it may be taken without regard to
meals, is taken once daily, and does not require periodic
monitoring of liver function, as zileuton does.
• Although not considered first-line therapy, the leukotriene-
modifying agents are sometimes given in lieu of inhaled
corticosteroids for mild asthma when prescription of an
ICS meets patient resistance

OTHER THERAPIES
• Cromolyn sodium and nedocromil
sodium (mast cell stabilizers)
• Targeted (monoclonal antibody)
therapy
89

Mast cell stabilizers
• Prevent transmembrane influx of calcium ions, provoked by
antigen-IgE antibody reaction on the mast cell membrane.
• They prevent degranulation and release of histamine
and Other autacoids from mast cells.
•They also inhibit leukocyte activation and chemotaxis.
Indications:
•Cromolyn solution is also useful in reducing symptoms of
allergic rhinoconjunctivitis (eye drops).
•Oral cromolyn used in mastocytosis

Mechanism

Mast cell stabilizers
• Sodium cromoglycate (cromolyn), nedocromil sodium (
nedcromil), kitotefen.
• They are not bronchodlators.
• Inhibits release of various mediators-histamine, LTs,
PGs PAF etc.
• Stabilizes the mast cell membrane.
Sodium cromoglycate: is not effective orally as it poorly
absorbed from gut, given by inhalation route.

• When taken regularly (2–4 puffs 2–4 times daily), these
agents modestly but significantly reduce symptomatic
severity and the need for bronchodilator
medications, particularly in young patients with allergic
asthma.
• Because the drugs are so poorly absorbed, adverse
effects of cromolyn and nedocromil are minor and are
localized to the sites of deposition.
• These include such minor symptoms as throat irritation,
cough, and mouth dryness, and, rarely, chest tightness,
and wheezing.

ASSIGNMENT
• Read and make notes about Targeted
Monoclonal Antibody Therapy
• Management of Status Asthimaticus

Katzung 20th Edition

Omalizumab
 is a monoclonal antibody directed against
human IgE.
 prevents IgE binding with its receptors on
mast cells & basophils.
 ↓ release of allergic mediators.
 used for treatment of allergic asthma.
 Expensive-not first line therapy.

Monoclonal antibody
• Clinical trials have shown that repeated intravenous or
subcutaneous injection of anti-IgE MAb lessens asthma
severity and reduces the corticosteroid requirement in
patients with moderate to severe disease, especially those with
a clear environmental antigen precipitating factor, and
improves nasal and conjunctival symptoms in patients with
perennial or seasonal allergic rhinitis.
• Omalizumab's most important effect is reduction of the
frequency and severity of asthma exacerbations, even while
enabling a reduction in corticosteroid requirements.
• Combined analysis of several clinical trials has shown that the
patients most likely to respond are, fortunately, those with the
greatest need, ie, patients with a history of repeated
exacerbations, a high requirement for corticosteroid
treatment, and poor pulmonary function.

Status asthmaticus
• It is a potentially life-threatening acute attack of severe
• asthma needing immediate treatment. Most often
• hospitalization is necessary.
(1) A high concentration (40–60%) of O2 is administered.
(2) High doses of inhaled short acting beta-2-agonist.
(3) High doses of systemic glucocorticoids (i.v. then p.o)
(4) Ipratropium through inhalation.

Treatment…
• Humidified oxygen (40–60%) of O2 is administered
• Nebulized β2- adrenergic agonist (salbutamol 5
mg/terbutaline 10 mg) + anticholinergic agents
(ipratropium bromide 0.5 mg).
• Systemic glucocorticoids: i.v. hydrocortisone 200 mg
stat followed by 30-60 mg prednisolone/day.
• I.V. fluid to correct dehydration.
• Antibiotics.
• IV Salbutamol or IVaminophyline can also be used

Dugs to be avoided in asthma
• NSAIDs
• β-adrenergic blockers.
• Cholinergic agents.
• WHY????

READING ASSIGNMENT
• COPD AND ITS MGT
• HOW ITS DIFF FROM ASTHMA
• How is status asthimaticus managed? As per
UCG?

Summary

Drugs
Adenyl
cyclase
 cAMP
– Short acting
– main choice in acute
attack of asthma
– Inhalation
B2 agonists
Salbutamol, terbutaline
Long acting, Prophylaxis
Nocturnal asthma
Salmeterol, formoterol
Blocks M
receprtors
Main drugs For COPD
Inhalation
Inhalation
Antimuscarinics
Ipratropium (Short)
Tiotropium (long)
•Inhibits
phosphodi
esterase
cAMP
(orally)
(parenterally)
Xanthine derivatives
Theophylline
Aminophylline
Bronchodilators (relievers for bronchospasm)

Inhalation
Corticosteroids
(Inhibits phospholipase A2)
Dexamethasone, Fluticasone, budesonide
Orally
prednisolone
parenterally
Hydrocortisone
Inhalation,
prophylaxis
Mast stabilizers
Cromoglycate (Cromolyn), Nedocromil
orally
Cysteinyl antagonists (CyLT1 antagoist)
Zafirlukast
Injection, SC
Omalizumab (Anti IgE antibody)
Anti-inflammatory drugs (prophylactic)

END

Drugs used for treatment of Asthma July 2021.ppt

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