Respiratory Module

Part 1
 Bronchial Asthma
Definition: Chronic inflammatory disease characterized by reversible bronchospasm with bronchial hyper reactivity to different
stimuli (triggers). S/S: Wheeze, Dyspnea especially expiratory & cough.

Types of bronchial asthma

1. Type II (atopic or allergic) 1. Non Type II (Non atopic)

• More severe with systemic eosinophilia
• Responsive to corticosteroids
• Include:
✓ Allergic (atopic) Asthma with +ve serum IgE
(Type I hypersensitivity) early in childhood
✓ Exercise induced asthma
✓ Late onset eosinophilic asthma (older age)
• Less severe without systemic eosinophilia
• Less responsive to corticosteroids
• Due ↓ threshold of vagal receptors to
irritants in response to viral infection of
respiratory system.
• Occurs more in older age

Classification of asthma

Intermittent (controlled Asthma) Persistent (Partially controlled or uncontrolled)

Infrequent attacks Mild, Moderate, Severe
Classification depends on:
Number of bronchoconstrictor episodes, Night time symptoms & peak expiratory flow

Treatment outline of bronchial asthma

1. Pharmacological: Reliver & controller drugs
2. Non-pharmacological: smoking cessation, physical activity, Avoid NSAIDS,…

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 Pathogenesis of Allergic Type II Asthma (Type I Hypersensitivity reaction)

Early phase: within 30-60 minutes

① Trigger (pollen) is taken by APC
③② APC Binds to naive TH cell→ TH2 cell
③TH2 cell secretes
• IL-4 → activate B-cells → changed it
to plasma cells secreting IgE ③
• IL-5 → Bind with its receptors on
eosinophils → its activation & ↑its
survival time
• IL-13 → ↑ mucous secretion ①
④ IgE attaches to mast cells (patients
become sensitized) ②
⑤ Subsequent exposure of the trigger →
mast cell degranulation → release of
④
stored mediators mainly histamine &
eosinophils chemotactic factors → ⑤

Bronchospasm + inflammation

Late phase: within 2 to 7 hours

TH2 cells & Mast cells continue to secrete cytokines (IL-5 & eosinophil chemotactic factor) → continue & intensify the local
inflammatory response (Excess eosinophilia → more tissue damage &↑ mucous production)
Tissue damage →activate arachidonic acid pathway with production of PGs & LTS → bronchospasm, ↑ vascular permeability
& chemoattraction for eosinophils.
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 Summary

Triggers
Antigen Non Antigen Virus Aspirin Avoid
❶ ❷
Induced Induced Cold Triggers
Exercise

Clinical Picture Bronchial Hyper reactivity constricts easily to endogenous (Ach &
Bronchial obstruction histamine) & exogenous stimuli
→ wheezes, dyspnea
due to
& cough.
Wall Remodeling Autonomic Disturbance
 Vagal tone &  Epinephrine
Repeated inflammation & healing by fibrosis

Early Phase
antigen-antibody (IgE) interaction at the surface of mast cells 
release of stored chemical mediators:
A. Bronchodilators
Short-term Relievers
• Histamine→ Bronchospasm, ↑ vascular permeability & mucosu
• Eosinophils, neutrophils & monocytes chemotactic factors
B. Anti-inflammatory
Long-term controllers
↓Hyperreactivity. Late Phase
↓ Recurrence. Release of cytokines (IL4, IL5, IL13) from TH2 & mast cells  attraction & activation
↓ mortality rate of eosinophils in bronchial mucosa → Tissue injury  activation of PLA2 → release
of inflammatory mediators (PGs & LTRS)
Inflammation, epithelia damage, wall edema & Sustained bronchospasm

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 DRUGS USED IN BROCNIAL ASTHMA .‫مهم‬
A) Bronchodilator drugs ❷ ❶
Antimuscarinics Short acting β2
❸
Short acting Adenosine Ach EP agonist (SABA)
Theophylline A1 M3
M3
β2 Smooth muscles of bronchioles

PDE
↑Ca++ ↑Ca++ ↑cAMP Degradation
↓ ↓ ↓ ❸
Bronchoconstriction Bronchoconstriction Bronchodilation Short acting
B) Anti-inflammatory drugs Theophylline

1. Corticosteroids Phospholipids
2. Zileuton
NSAIDs
PLA2
# in BA Lipoxygenase
Cyclooxygenase
Arachidonic Acid
Prostaglandins
Leukotrienes
⑥ 3. Zafirlukast
Montelukast
④ LABA
LT
receptor
⑦ s

• Inflammation
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⑤ Omalizumab • Bronchospasm
OmOmalizumab
 Drug therapy of Bronchial asthma

A. Short term relivers B. Long term controllers

Bronchodilator drugs
to relieve acute bronchospasm (S/S of acute attack)
1. Short acting β2 agonists: 1st choice (SABA)
2.Short acting Antimuscarinics
3. Low dose ICS – Formoterol
Anti -inflammatory drugs
to ↓ bronchial hyper reactivity → ↓ tissue damage & recurrence
1. Corticosteroids: Most effective
2. Long Acting β2 Agonist (LABA) + ICS (not alone)
3. Leukotriene pathway inhibitors
4. Cromolyn & nedocromil
5. Anti-IgE: Omalizumab: /3 weeks (SC) Monoclonal
6. Anti-IL5: Mepolizumab & Reslizumab (SC) antibodies
7. Anti-IL5R: Benralizumab (SC)
8. Anti-IL4: Duplimab (SC)

LABA are the 1st choice (Add-on therapy) to steroids (given in separate or combination inhaler)
Adding LABA & LT antagonists → ↓ the need to increase corticosteroid dose
Short acting theophylline: used as short term reliver. long acting theophylline (SR) used as anti-
inflammatory specially in patients with COPD
Drugs used in different types of Asthma
• Exercise induced (prophylactic) β2 agonists (1st choice) short term reliever. LT inhibitors.
• β blocker & Psychogenic induced Antimuscarinic: Ipratropium or tiotropium ( as bronchodilators)
• Cardiac, thyrotoxic & old patients
• Aspirin induced LTS pathway inhibitors
• Severe uncontrolled allergic asthma Omalizumab and other monoclonal antibodies
• COPD Tiotropium long acting → useful in maintenance therapy
Theophylline: Bronchodilator + ↓diaphragmatic fatigue
Nocturnal Asthma (dyspnea) SR Theophylline: less fluctuation in plasma level and taken once/day
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 5 steps strategy for Management of bronchial Asthma (according to severity):
Initial:
As-needed: Low dose ICS (Budesonide)- Formoterol
Step For controlled (intermittent) asthma
1 Alternative:
Low dose ICS whenever SABA is taken
Initial:
Daily Low dose ICS OR as needed Low dose ICS (Budesonide)-Formoterol
Step

As -needed reliever in all steps

2 Alternative:

Short acting β2 agonist (SABA)

LTRA OR Low dose ICS whenever SABA is taken

Low dose ICS- Formeterol

Initial:
Daily Low dose ICS LABA
Step

Alternative
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Alternative: Low dose ICS LTRA OR Medium dose ICS

Initial: Medium dose ICS LABA

Add-on
Step
Tiotropium( LAMA) or LTRA
4 Alternative: High dose ICS

Initial High dose ICS LABA Add-on

Step
• Tiotropium (≥ 6 y) : Inhalation
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• Anti IgE (Omalizumab): ≥ 6 years

SC
ICS = Inhaled Corticosteroids • Anti- IL5 or Anti- IL5R
LTRA = leukotrienes receptor antagonist • Anti-IL4: ≥12 years
LABA = Long acting β2 agonist
LAMA = Long Acting Muscarinic Antagonist • Oral CS (consider adverse effects)

• Cromolyn & nedocromil (rarely used): May be used in long term control of mild persistent asthma ( with ICS). Never alone
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• Theophylline is not recommended by several guidelines especially in children < 12 years
 A. Bronchodilator Drugs
1. Adrenoceptor agonists (selective) 2. Antimuscarinic drugs
• Stimulates β2 receptors → ↑cAMP → Block M3 receptors in bronchial muscles → BD & ↓
Mechanism
a) Bronchodilation + Ө release of mast cell mediators & cytokines
b) ↑ bronchial muco-ciliary clearance
• LABA → ↑ anti-inflammatory effect of cortisone
(↑nuclear localization of steroid receptor)   asthma control.
SABA: Salbutamol (Albuterol), Terbutaline (all routes)
Short (4 hours)/Rapid. Used in children Orally ‫أسهل‬
Members
LABA: Formoterol, Salmeterol (inhalation):
Longer /slower (lipid soluble → dissolve in smooth m. membrane)
NB: LABA should be combined with cortisone to avoid ↑ risk of
mortality (LABA has Bronchodilator effect >>>anti-inflammatory
effect → mask progression of the disease → ↑risk of mortality) ‫مهم‬
1. Tremors (most common), anxiety
2. Tolerance: due to down regulation of β2 receptors
Adverse
effects
3. Tachycardia ((high concentration  stimulate 1 receptors).
4. Hypokalemia & muscle cramps
5. Hypoxemia: Worsen Ventilation/Perfusion ratio (VD>BD)
Short acting (SABA): As short term reliever: as needed in:
• Asthma & COPD.
• Prophylactic in exercise induced asthma 10 min before exercise
Indications
Long acting (LABA): As long term controller in:
• Asthma (with corticosteroids)
• COPD (maintenance therapy)
• Prophylactic in exercise induced asthma: 1 hour before exercise
• Formoterol: (rapid onset) → used also as rescue medication (+ ICS)
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mucous secretion mediated by vagal stimulation
• Atropine substitute, Quaternary compound
• Taken by inhalation with or without β2 agonist
• Less systemic adverse effect than atropine
Short acting: Ipratropium: Non selective → Ө
presynaptic M2 → ↑ release of Ach → tolerance
Long acting: Tiotropium: Selective M3 antagonist → no
tolerance. Used as maintenance therapy in COPD
(Long acting, No tolerance, Maintenance)
‫خد بالك يادكت‬
Disadvantages Of Ipratropium
1. Tolerance: Ө presynaptic M2 → ↑ Ach → ↓ its
effect (unlike Tiotropium)
2. Delayed onset & less effective than β2 agonist
1. Bronchodilator of choice in:
• Asthma due to psychogenic stimulus or β blockers.
• Asthmatic intolerant to other bronchodilators
especially thyrotoxic, elderly & cardiac patients
2. Status asthamticus (adjuvant to β2 agonists)
3. COPD (better than in asthma): Tiotropium
Since vagal- induced bronchospasm is the only
reversible cause of bronchial obstruction in COPD.
• Oral LABAs e.g SR salbutamol, SR terbutaline & bambuterol ( prodrug of terbutaline) may be used as controllers if
additional bronchodilation is needed.
Non-selective Adrenoceptor Agonists
Epinephrine (, β1, 2): Largely replaced by selective 2 agonists Because Epinephrine is
A. Shorter action
B. Non-selectivity  dangerous tachycardia, arrhythmia (β1) & hypertension (ἀ1).
Mainly used in acute attacks of bronchospasm especially in Anaphylaxis (→ rapid 2 bronchodilation, 1 cardio stimulant & α1
VC → support Blood Pressure & decongestant effects).

Ephedrine: Rarely used. Has CNS & addictive adverse effects.

3. Methylxanthines
• Ө Phosphodiesterase enzyme (PDE) → ↑cAMP →
Mechanism of a) Bronchodilatation
action b) Anti-inflammatory: Ө release of mast cell mediators & cytokines (↓ late asthmatic response)
• Block A1 receptors → Bronchodilatation
Absorption: Xanthine basic & their slats are absorbed from GIT
Pharmacokinetics Metabolism: 90% by hepatic cytochrome P450 Many drug interaction
Elimination: saturation kinetics → ↑ risk of toxicity
Factors affecting theophylline clearance
Requiring dose adjustment
↑ t1/2 & serum level → ↓ dose ↓ t1/2 & serum level → ↑ dose
• Neonates & elderly (Extreme of age) • Children
• Hepatic & heart diseases • Heavy smokers
• Viral infections • Heavy drinkers
• Enzyme inhibitors: Erythromycin, OCP, Ciprofloxacin, • Enzyme inducers: Rifampicin, Phenobarbitone,
Zileuton, Zafirlukast Phenytoin, Carbamazepine
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 Pharmacological actions

Anti asthmatic effect

• Bronchodilation → relieve acute bronchospasm Adverse effects & Precautions (① to ④)
• Anti-inflammatory ( Modest) → control chronic asthma

CNS: Stimulatory
• Headache.
• Alertness- insomnia – nervousness. • Insomnia- Anxiety. ①
• Tremors - convulsions (high dose). • Convulsions. # epilepsy
• Respiratory stimulant.

CVS • Sinus Tachycardia & arrhythmias. # ISHD

• Cardiac arrest ( ⊕ CIC) if given rapidly →given
②
• +ve inotropic & chronotropic
• VD (except cerebral BV) in high doses  hypotension slowly IV.
• VC of cerebral blood vessels. • Hypotension.

GIT: Stimulatory
• Anorexia- nausea &vomiting (given with meals):
•  HCl & gastric irritation # peptic ulcer. ③
• Proctitis (with suppositories). Avoid long term use
Kidney: Weak diuretic action.

Skeletal muscle  Risk of toxicity

• ↑ contractility & reverse fatigue of diaphragm in COPD • Narrow safety margin → monitor serum level
→ ↓ dyspnea (therapeutic level 10-20 mg/L). ④
• Saturation kinetics→ adjust dose according to
clearance rate (see kinetics) ‫إكتبهم في السؤال‬
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 1. Aminophylline: High solubility → given by many routes: oral, rectal & slowly IV
2. SR theophylline: less fluctuation of plasma level → effective as control medication & in nocturnal asthma
Preparations
3. Low dose theophylline: Provide full anti-inflammatory effect. Less side effect & no need to monitor its
plasma level
1. BA (2nd or 3rd choice):
• Short term relief of acute asthma
• Long term control esp. nocturnal asthma (SR theophylline)
Indications • Acute severe asthma
2. COPD (bronchodilator & reverses diaphragmatic fatigue)
3. Respiratory stimulant in neonatal apnea (caffeine)

Advantages 1. Cheap
2. Can be given by many routes (except inhalation)
Disadvantages 1. Saturation kinetics requiring drug monitoring.
2. Narrow safety margin.
3.  Risk of drug interactions.

Contraindications of methyl xanthine

1. Peptic ulcer
2. ISHD
3. Epilepsy

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 B. Anti-inflammatory drugs
1. Glucocorticoids Leukotrienes Pathway Inhibitors Cromolyn & Nedocromil
1. Immunosuppressive & anti-inflammatory Zileuton: Ө 5lipooxygenase (LOX) → Weak anti-inflammatory
Ө PLA2 & cytokines → ↓ mediators release & ↓ LTs synthesis. Not commonly used • Ө mast cell degranulation → Ө
Mechanism

reflux of inflammatory cells→ ↓
inflammation & hyper reactivity → ↓
recurrence of attacks
2. potentiate β2 agonists: ↓ tolerance to β2
agonists by ↓ down regulation of receptors
1. Control medication:
• ICS: All steps of persistent asthma, Start by
small doses & ↑ gradually
Indications
due to its hepatic toxicity.
Zafirlukast & Monetlukast:
LTS receptor antagonist →
Bronchodilation + anti-inflammatory
effect.
1. Control medication
• Alternative: to ICS in mild persistent
(Intolerant to steroid or inhaler)
release of mediators (Ө early
response)
• Ө eosinophil activation → Ө late
inflammatory response to antigen
1. Prophylactic: Inhalation
2. Ө (Unavoidable) antigenic &
exercise induced asthma

• Oral: added to ICS in severe cases
2. Rescue medication (oral: for 7 days ‫ )صباحا‬in
acute exacerbation not responding to β2 agonists
3. Status asthamticus (Acute severe asthma):
Oral or IV.
4. ICS + Formoterol: in acute attack as needed
❖ Inhaled CS
• Avoided by gargling & spitting after inhalation
Adverse effect
• Add on: to ICS in moderate or 3. Chronic use: (4 doses /day) in mild
severe Persistent asthma persistent asthma (+ICS) → ↓
2. 1st choice in aspirin induced recurrence
asthma (why?) NOT IN ACUTE ATTACK
3. Prophylactic in: exercise induced 4. Allergic rhino- conjunctivitis (drops)
asthma
Well tolerated: 1. Throat irritation, cough &
1. Headache Bronchospasm (with powder form:

• Use Spacer device 2. Dyspepsia avoid by Prior inhalation of β2

1. Oropharyngeal candidiasis 3. Zafirlukast: Enzyme inhibitor → agonists)
2. Hoarseness of voice drug interaction 2. Stinging in the eye
❖ Systemic CS ad. Effects see box below 4. Zafirlukast & Zileuton → ↑ liver
enzyme

Systemic adverse effects of corticosteroids: ↓by using inhalation route

1. Osteoporosis 2. Cataract, glaucoma 3. Growth retardation 4. Hypertension
5. Diabetes Mellitus 6. Cushing syndrome 7. Adrenal suppression 8. Hypokalemia
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 Inhalation preparations:
Beclomethasone, Fluticasone, Mometasone,
Budesonide
Ciclesonoide: Prodrug activated by bronchial
Others
Advantages of LTs pathway Ketotifen: related to cromolyn:
inhibitors: • Mast cell stabilizer
1. Oral therapy (easier than inhalation • Antihistamines
especially in children)

esterases. High FPM & high plasma protein 2. Long duration of action
binding → - less systemic side effects. 3. Minimal side effects (well
- Less frequent candidiasis. tolerated)
Oral: Prednisone, Prednisolone
Parenteral: Methyl prednisolone,
Hydrocortisone

Monoclonal Antibody (Mab) Drugs

Used as Add on therapy in severe Uncontrolled Asthma
❶ Omalizumab
• Mechanism: Humanized monoclonal antibody. Binds to circulating IgE → inhibits its binding to mast cells
• Uses: Add-on therapy: in severe uncontrolled allergic asthma (Excess serum IgE) → ↓ frequency & severity of exacerbation
• Adverse effects: ↑ risk of anaphylaxis and reaction at the site of injection.
❷ Mepolizumab & Reslizumab
• Mechanism: Anti IL-5 Mab → Binds with IL-5 and prevent activation of the inflammatory cells (eosinophils)
• Uses: Add-on therapy: in severe uncontrolled allergic asthma (not controlled by high dose ICS/LABA)
• Adverse effect: Headache & reaction at site of injection
❸ Benralizumab
• Mechanism: Binds with IL-5 receptors on the surface of eosinophils → prevent its activation & also attracts natural killer
cells → removal of circulating eosinophils
• Uses & adverse effects: as ❷
❹ Dupliumab:
• Mechanism: Anti ITL-4 monoclonal antibody
• Uses: as ❷ & atopic dermatitis
• Adverse effects: as ❷ & blood eosinophilia
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 Management of Acute exacerbation

1. Mild or Moderate Acute exacerbation

• Short acting β2 agonist (SABA) by Inhalation. Salbutamol can be given IV
• Oral Prednisone; 40-50 mg
• Oxygen (95%)

2. Severe Acute asthma (status asthmaticus)

• Refractory to the usual treatment due to down regulation of  receptors, mucus plug and acidosis.
• Precipitated by Infection, emotion or allergy

A. Hospitalization: B. Drug therapy:

• Endotracheal intubation and suction of secretion
• Humidified oxygen inhalation
• IV fluids: for correction of dehydration,
electrolytes & acidosis
• Antibiotics for infections
Avoid sedatives → Respiratory Depression
1. SABA e.g Salbutamol (inhalation) ± Ipratropium (inhalation)
2.Systemic glucocorticoids:
• Oral Prednisone: for 7 days (if the patient can swallow)
• IV Methylprednisolone (switch to oral when possible)
3. Aminophylline IV infusion in severe cases (slowly to avoid
cardiac arrest)
4. Artificial respiration

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 Drug Therapy of Cough
• It occurs due to stimulation of irritant cough receptors in respiratory passages or outside (esophagus, heart or ears).
• Cough reflex is controlled by cough center in the medulla.
Treatment of cough:

Specific Treatment
If persist & → Insomnia,…
1. Bronchodilators Non specific treatment
• Β2 agonists (Salbutamol, Terbutaline) Or during eye surgery
• Theophylline
2. Decongestants (vasoconstrictors)
• Ephedrine Dry cough Productive cough
• Pseudoephedrine Antitussive • Mucolytic
• Phenylephrine (Cough suppressants) • Expectorants

Antitussive
(Cough suppressants)
❶ Central Antitussives ❶ ❷ Peripheral Antitussives
Ө cough Center in medulla
CC Mild to Moderate dry cough e.g. Sore throat
Moderate to Severe dry cough Volatile oil: (Menthol)
A. Opioid Antitussives • Mechanism: Demulcent: Protect irritant
↓ adverse

• Codeine receptors by layer of mucin (used as lozenges or

effect

• Pholcodine ❷ in hot steam) ‫بخار مياه أو أقراص لالستحالب‬

• Dextromethorphan Irritant • Adverse effect: Seizure, coma, Death (serious)
B. Antihistamines BS & receptors
• Diphenhydramine stimulate Diaphragm
• Carbinoxamine
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 Central Antitussives

A. Opioid Antitussives
1. Codeine: (Moderate analgesic + Strong Antitussive)
Adverse effects:
• Drowsiness in adult But paradoxical excitement in children
• Mild dependence in abuse
• Constipation (chronic use)
• Respiratory depression (in large analgesic doses)
2. Pholcodine:
• Mechanism: Direct depression of cough center in the medulla → suppress cough reflex
• semisynthetic opioid with less adverse effects than codeine (replace codeine)
• Adverse effect: Sputum retention
3. Dextromethorphan: 1st choice:
• Mechanism: Cross BBB → Sigma-1 opioid receptor agonist & NMDA receptor antagonist on cough center
→ suppress cough reflex
• Adverse effects: Hallucination (serious)
• Preferred to codeine: Less liability to constipation, respiratory depression and dependence than codeine
(In antitussive doses)

B. Antihistamines:
• Members: Diphenhydramine, Carbinoxamine
• Mechanism: H1 receptor antagonist → suppress central cough mechanism and ↑threshold for afferent cough impulse
• Adverse effects: Anticholinergic adverse effects: dryness of secretion, constipation, urine retention, ↑ IOP,…

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 Treatment of Productive cough
❶ Mucolytics
↓ viscosity of bronchial secretion

1. Carbocysteine & Acetylcysteine

• Mechanism: 1. Break disulfide bonds of thick mucous 2. Antioxidant 3. Anti inflammatory
• Adverse effect: Angioedema, Pruritis & peripheral edema
Therapeutic uses of Mucolytics
2. Ambroxol
• Mechanism: Breakdown acid mucopolysaccharide fibers → 1. Productive cough
make sputum less viscus and easy to expectorate → promote clearance 2. Asthmatic bronchitis
• Adverse effect: Difficulty in breathing and allergic reaction 3. COPD
3. Bromhexine 4. Pulmonary cystic fibrosis
5. Bronchiectasis
• Mechanism: as Ambroxol
6. Care of tracheostomy tube
• Adverse effect: GIT upset (pain in the upper part of the stomach) 7. Acetylcysteine: Antidote in
paracetamol toxicity
❷ Expectorants
Used in productive cough
1. Guaifenesin
• Mechanism: ↑ Volume & ↓ Viscosity of bronchial secretion → Allow
ciliary movement to carry secretion upwards
• Adverse effects: Dizziness, Drowsiness, Headache & stomach pain Cough therapy contraindicated in children
2. Menthol 1. Dextromethorphan & pholcodine
• Mechanism: Aromatic substance opens airway to help reduce cough 2. Antihistamines: Diphenhydramine,
and congestion doxylamine, Promethazine,..
• Adverse effect: Seizure, coma, Death (serious) 3. Guaifenesin
❸ Bronchodilators: Discussed before 4. Pseudoephedrine & Phenylephrine
❹ Decongestant: Discussed before

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