Respiratory pharmacology

• Pharmacotherapy of bronchial asthma

• Management of COPD

• Treatment of acute & chronic rhinitis

Management of asthma
Nebulizer Inhaler
 Bronchial asthma

• Asthma is a chronic inflammatory disease of bronchial airways

that result in airway obstruction in response to external stimuli

• Clinical symptoms include

– Coughing

– Recurrent wheezing

– Recurrent shortness of breath/dyspnea

– Recurrent chest tightness

– Symptoms occur or worsen at night, awakening the patient

 Etiology

• Exacerbating agents/external stimuli:

– Allergens: Pollen, house dust mite, animal dander, mold, others

– Exercise, viral infection

– Irritants (tobacco or wood smoke, airborne chemicals)

– Strong emotional expression (laughing or crying hard)

– Stress, changes in weather, menstrual cycles

– Drugs: NSAIDs (Aspirin), muscarinic agonists, Beta blockers

 Pathophysiology

• Characteristics and responses of asthmatic airway

– Bronchospasm (constriction of the bronchial muscles causes

narrowing of the airway tube)

– Inflammation: Swelling & thick mucus production.

– Airway hyper-reactivity: abnormal sensitivity of the airways

to wide range of external stimuli.

Summary
Pathophysiology...
Classification of asthma based on its severity
 Anti asthmatic drugs
II. Control /prophylactic
I. Quick relief medications
medications
• Bronchodilators
•Anti-inflammatory Agents
• Treat acute episodic attack
•Reduce the frequency of attacks
of asthma 1. Corticosteroids
1. Short acting 2-agonists 2. Mast cell stabilizers
3. Long acting 2-agonists
( SABA)
4. Leukotrienes antagonists
2. Antimuscarinic 5. Omalizumab
3. Xanthine derivatives
 Goal of therapy

• To decrease the intensity and frequency of asthma

symptoms

 All patients need to have a “quick-relief” medication to treat

acute asthma symptoms due bronchoconstriction.

 Drug therapy for long term control of asthma is designed to

reverse and prevent airway inflammation and hypersensitivity.

 1. 2- adrenoceptor agonists

• Inhaled agonists directly relax airway smooth muscle.

• Used for the quick relief of asthma symptoms (SABA), as well as

adjunctive therapy for long-term control of asthma (LABA).

Mechanism of Action
 Direct 2 receptor activation results in:
– Bronchodilation
– Decreases congestion of mucous in the bronchi
– Decreases histamine releases…which decreases allergy
a. Short-acting β2 agonists (SABAs)

• Salbutamol (albuterol), terbutaline

• Have a rapid onset of action (5 to 30 minutes)

• Provide relief for 4 to 6 hours.

• They are used for symptomatic treatment of

bronchospasm
– Providing quick relief of acute bronchoconstriction.

• All stages of patients with asthmatic symptoms should be

prescribed a SABA inhaler.
 SABAs cont’d…

• They should never be used as the sole therapeutic

agents for patients with persistent asthma.
– Lack anti-inflammatory effects

• Monotherapy with SABAs may be appropriate for

– Intermittent asthma or exercise-induced bronchospasm.

• ADRs: headache, nervousness, dizziness, palpitation,

tachycardia, skeletal muscle tremor, muscle cramp,
paradoxical bronchospasm.
b. Long-acting β2 agonists ( LABAs)

• Salmeterol and formoterol

• Have a slow onset and long duration of action,

providing bronchodilation for at least 12 hours.
• Neither salmeterol nor formoterol should be used for
quick relief of an acute asthma attack.
• Use of LABA monotherapy is contraindicated
– LABAs should be used only in combination with an asthma
controller medication.
 LABAs cont’d…

• Inhaled corticosteroids (ICS) remain the long-term

controllers of choice in asthma
– LABAs are considered to be useful adjunctive therapy for
attaining asthma control.

• Some LABAs are available as a fixed dose combination

product with an ICS
• Adverse effects of LABAs are similar to SABA
c. Non-selective adrenergic agonist (Adrenaline)

• It has a rapid onset but a brief duration of action (due to

rapid degradation)
• Used as quick relief medication with inhalation/IV

• Second/third line bronchodilator of choice owing to its:

– Slow onset and many ADRs

• Associated with many ADRs: Angina pain, cardiac

arrhythmias, hyperglycemia, HTN, gangrene, Anxiety, fear,
tension, headache, others
 2. Cholinergic antagonists
• MOA: Block M-3 receptor in bronchi…causes bronchodilation and
decrease mucous secretion

a. Ipratropium
• Given by aerosol inhalation

• Quaternary derivative of atropine

– Does not diffuse into the systemic circulation, less anticholinergic side effects

• Is not recommended for the routine treatment of acute bronchospasm in

asthma
– As its onset is much slower than inhaled SABAS.
 Ipratropium cont’d..
• Useful in patients:
– Who are unable to tolerate a SABA or

– With concomitant chronic obstructive pulmonary disease (COPD).

• Ipratropium also offers additional benefit when used

with a SABA for the treatment of acute asthma
exacerbations in the ED…acts on different receptors
• Adverse effects such as xerostomia and bitter taste are
related to local anticholinergic effects.
 3. Methylxanthines
a. Theophylline, aminophylline

MOA
•Bronchodilation

– Inhibits phosphodiestrase (enzyme which converts cAMP to

AMP)   cAMP
– Adenosine (bronchonstrictor) receptors antagonists
•They may also possess weak anti-inflammatory activity, although
the mechanism of action is unclear.
theophylline, aminophylline cont’d…

• Previously, the mainstay of asthma therapy

• But it has been largely replaced with SABAs and

corticosteroids due to its

– Narrow therapeutic window

– High adverse effect profile, and

– Potential for drug interactions.

theophylline, aminophylline cont’d…

Pharmacological effects :
•Bronchial muscle relaxation
•CVS: ↑ heart rate, ↑ force of contraction, ↑BP
•GIT: ↑ gastric acid secretions
•Kidney: ↑renal blood flow, weak diuretic action
•CNS stimulation
* Decrease fatigue & elevate mood
* Overdose (tremors, nervousness, insomnia, convulsion)
theophylline, aminophylline cont’d…

Pharmacokinetics
•Narrow therapeutic index
•T ½= 8 hours
•Metabolized in the liver and is a CYP1A2 and 3A4
substrate.
•Has many drug interactions

 Enzyme inducers like phenobarbitone, rifampicin →

↑metabolism of theophylline →↓ T ½…therapeutic failure
 Enzyme inhibitors like erythromycin→ ↓ metabolism of
theophylline → ↑T ½…Toxicity
theophylline, aminophylline cont’d…
Uses
• Second line drug in asthma (theophylline)
• For status asthmaticus (aminophylline, as slow infusion)

Side Effects
• Low therapeutic index narrow safety margin
– Monitoring of theophylline blood level is necessary.
• CVS effects: hypertension, arrhythmia.
• GIT effects: nausea & vomiting, ulceration
• CNS side effects: tremors, nervousness, insomnia, convulsion
II. Control medications / prophylactic therapy

• They have Anti- inflammatory effects

a. Glucocorticoids

b. Leukotrienes antagonists

c. Mast cell stabilizers

d. Anti-IgE monoclonal antibody (omalizumab)

 a. Inhalational Corticosteroids (ICs)

• Drug of choice for long-term control in patients with any degree of

persistent asthma.
– No other medications are as effective as ICS in the long-term control
of asthma in children and adults.
• Severe persistent asthma may require the addition of a short course of
systemic glucocorticoid treatment.
• MOA: inhibit the release of arachidonic acid through PL-A2 inhibition,
which in turn reduce leukotriene synthesis
– Producing direct anti-inflammatory properties in the airways

– Bronchodilation and reduces fluid accumulation (mucosal edema)

 Inhalational Corticosteroids (ICs) cont’d..

 Are not used as bronchodilators

 Reduce bronchial inflammation
 Reduce bronchial hyper-reactivity to stimuli
 Have delayed onset of action (effect usually attained after 2-4 wks)
 Maximum action at 9-12 months.
 Given as prophylactic medications, used alone or combined with
LABA.
 Effective in long term management of allergic, exercise, antigen
and irritant-induced asthma.
 Actions on lung
• ICS do not directly affect the airway smooth muscle.

• Instead, ICS therapy directly targets underlying airway

inflammation by decreasing the inflammatory cascade as:
– LTB4 is a potent chemo-attractant for neutrophils & eosinophils

– Cysteinyl LT (LTC4, LTD4, LTE4) cause bronchoconstriction,

increase endothelial permeability & promote mucus secretion.

• After several months of regular use, ICS reduce the hyper-

responsiveness of the airway smooth muscle to a variety of
bronchoconstricting stimuli: allergens, irritants, cold air,
exercise.
 Routes of administration of corticosteroids
• Inhalation:

– The development of ICS has markedly reduced the need for

systemic corticosteroid treatment to achieve asthma control.

– However, as with all inhaled medications, appropriate inhalation

technique is critical to the success of therapy
– Budesonide, fluticasone & beclometasone commonly used as IC

• Oral/systemic:

– Patients with a severe exacerbation of asthma (status asthmaticus)

may require IV methylprednisolone or oral prednisone to reduce
airway inflammation.
 Routes of administration cont’d..
– Oral/IV…

– Due to the increased incidence of adverse effects with systemic

route therapy, chronic maintenance with systemic administration
of corticosteroids should be reserved for patients who are not
controlled on an ICS.

• Orally: Prednisone

• Injection: Hydrocortisone, dexamethasone, methyl prednisolone

 Adverse effects of corticosteroids
• Oral/parenteral glucocorticoids have serious ADRs
– Hyperglycemia ( ↑ protein catabolism)
– Susceptibility to infections (Decrease antibody production)
– Hypertension & Peripheral edema (Sodium/fluid retention)…
aldosterone like effects
– Growth retardation in children (↓calcium absorption into bone
cells)
– Osteoporosis (↓ calcium absorption into bone cells)
– Fat distribution to face & torso…moon face, buffalo hump…
Cushing-like syndrome
– Glaucoma, cataract, Psychosis
 Adverse effects cont’d…

Oral/parenteral glucocorticoids have serious ADRs…

• Sudden D/C of these drugs can be a serious problem if the

patient has suppression of the HPA axis.

–Abrupt removal of corticosteroids can cause acute adrenal

insufficiency that can be fatal.

–By Negative feed back mechanism

–Dose must be tapered down slowly

 Adverse effects cont’d…

• ICS, particularly if used with a spacer, have few systemic effects.

• ICS deposition on the oral and laryngeal mucosa

– Can cause oropharyngeal candidiasis (due to local immune

suppression) and hoarseness.

– Patients should ben instructed to rinse the mouth in a “swish-and-spit”

method with water following use of the inhaler

 b. Leukotriene modifiers
• Leukotrienes (LT): LTB4, LTC4, LTD4,and LTE4,

• Are products of the 5-lipoxygenase pathway of AA metabolism

and part of the inflammatory cascade.
• 5-Lipoxygenase enzyme is found in mast cells, basophils,
eosinophils, and neutrophils.
• Cysteinyl leukotrienes are bronchoconstrictors, increase
endothelial permeability, and promote mucus secretion.
• LTB4 is a potent chemo-attractant for neutrophils & eosinophils

• LOX inhibitors (Zileuton) & LT receptor blockers (Zafirlukast and

montelukast) are LT modifiers
 Leukotriene modifiers cont’d…
• Zileuton is a selective and specific inhibitor of 5-lipoxygenase,

• Zafirlukast and montelukast are selective antagonists of the

cysteinyl leukotriene-1 receptor
• All three drugs are approved for the prevention of asthma
symptoms.
• Leukotriene receptor antagonists have also shown efficacy for
the prevention of exercise induced bronchospasm.
• They should not be used in situations where immediate
bronchodilation is required…slow onset
 Leukotriene modifiers cont’d…

• Are selective, reversible antagonists of LOX or LT receptors

• Taken orally

• Are not effective to relieve acute attack of asthma.

• Prophylaxis of mild to moderate asthma.

– Less effective than inhaled corticosteroids

• Can be combined with glucocorticoids

– Additive effects, low dose of glucocorticoids

 Pharmacokinetics

• All three drugs are orally active

• All three drugs are highly protein bound.

• Food impairs the absorption of zafirlukast.

• The drugs are metabolized extensively by the liver.

• Zileuton and its metabolites are excreted in urine

• Zafirlukast, montelukast, and their metabolites undergo biliary

excretion.
 Adverse effects

• Elevations in serum hepatic enzymes have occurred with all

three agents

– Requiring periodic monitoring and D/C when enzymes

exceed three to five times the upper limit of normal.

•
Other effects include headache and dyspepsia.
• Zafirlukast, Zileuton are inhibitors cytochrome P450
 c. Cromolyn (cromoglycate) – Nedocromil
• Is a prophylactic anti-inflammatory agent

• MOA: Blocks CCB important for degranulation of mast cells, prevents

inflammatory mediator release

• Alternative therapy for mild persistent asthma.

• It’s main effect is not bronchodilator

– Shouldn’t be use for acute asthma attack

• Due to its short duration of action, this agent requires dosing 3-4 X daily

– Which may affect adherence and limits its use.

• Children respond better than adults

• ADRs: Nasal congestion, respiratory mucosa irritation, unpleasant taste

 d. Omalizumab

• MOA

– Recombinant DNA-derived monoclonal antibody that

selectively binds to human IgE.

– This leads to decreased binding of IgE to its receptor on the

surface of mast cells and basophils.

– Reduction in surface-bound IgE limits the release of

mediators of the allergic response.

 Omalizumab cont’d..
• It is indicated for the treatment of moderate to severe persistent

asthma in patients who are poorly controlled with conventional

therapy.

• Its use is limited by the high cost, route of administration

(subcutaneous), and adverse effect profile.

• Adverse effects include serious anaphylactic reaction (rare),
arthralgias, fever, and rash, immunosupression, etc…
• Secondary malignancies have been reported.
Summary
 Study Questions
A 12-year-old girl with a childhood history of asthma
complained of cough, dyspnea, and wheezing. Her symptoms
became so severe that her parents brought her to the
emergency room. Which of the following is the most
appropriate drug to rapidly reverse her bronchoconstriction?
A. Inhaled fluticasone
B. Inhaled beclometasone
C. Inhaled albuterol
D. Intravenous propranolol
E. Oral theophylline
 Study Questions cont’d….
A 9-year-old girl has severe asthma, which required
three hospitalizations in the last year. She is now
receiving therapy that has greatly reduced the
frequency of these severe attacks. Which of the
following therapies is most likely responsible for this
benefit?
A. Inhaled albuterol
B. Inhaled ipratropium
C. Inhaled fluticasone
D. Oral theophylline
THANK YOU