ANTIASTHMATIC

DRUGS
Latest-1
 ASTHMA

Asthma is a reversible obstruction of airflow through the airway.

The airway resistance is increased and the patient has difficulty
in breathing out. This is manifested as a decrease in the forced
expiratory volume in 1 second (FEV1). Symptoms are:
 Episodic wheezing
 Episodic coughing
 Breathlessness
 Chest tightness
 Rapid respiration

All the above symptoms are due to acute bronchoconstriction, an

increased viscid mucous secretion, inflammation of the
bronchial wall & hyperplasia of smooth muscle cells. The
bronchiole muscles also become hyperactive (hyperreactivity,
hyperresponsiveness) and give an exagerated response to
stimuli. These effects are due to production of leucotrienes,
cytokines, and migration of eosinophils, macrophages and
lymphocytes.
PATHOGENESIS & Tx STRATEGIES

PATHOGENESIS Tx STRATEGIES

Bronchial Mucosal Inflammation

Inflammation -Anti-inflammatory Agents:

-corticosteroids

-Leukotriene
antagonist/inhibitor
-Inhibitor of mast cell
degranulation
Bronchoconstriction Bronchodilatation
(most easily reversed) -Bronchodilators

-Beta
agonists,PDEI,ipratropium
Mucus Get rid of mucus
- Mucolytic & expectorant
 THERAPY FOR ASTHMA

Short-term Long-term
Relievers Controller
(Reduce
symptoms &
-Bronchodilators
prevent attacks)
e.g. Salbutamol
-Anti-inflammatory
e.g. Inhaled
Corticosteroid
 BRONCHODILATORS

 β2 – adrenoceptor agonist

short acting - Salbutamol (Albuterol)

long acting, delayed onset – Salmeterol (not for acute attack)

 Metylxanthine

- Theophylline
- Aminophylline

 Antimuscarinic agents

- Ipratropium bromide
 ANTI-INFLAMMATORY AGENTS
 Corticosteroids

- Prednisolone – oral
- Hydrocortisone – IV
- Beclomethasone – inhalation
- Budesonide - inhalation
 Mast Cell Stabilizer

- Sodium cromoglycate – inhalation or aerosol

 Leucotriene Receptor Antagonist

- Montelukast – oral

 Leucotriene Synthesis Inhibitor

- Zileuton - oral
BRONCHODILATORS
Mechanism of action of bronchodilators

• cause bronchodilatation
• increase ciliary function
• block release of bronchoconstricting
mediators from mast cells.

ATP cAMP 5’- AMP

Adenyl Phosphodiesterase
cyclase

Stimulate bronchial
B2 adrenoceptors

* B2 Agonist Agents &

B2 Agonist Methylxantine are not given
Agent together
 Mechanism of action of PDEI

• cause bronchodilatation (major

effect)
• increase mucociliary
activity(questionable)
• block release of bronchoconstricting
mediators from mast cells.

ATP cAMP 5’- AMP

Adenyl Phosphodiesterase
cyclase

Methylxanthine

* B2 Agonist Agents &

Methylxantine are not given
together
Mechanism of action of PDEI

 Mechanism is unclear.
 One possible mechanism of
inhibition of PDE (see next slide)
 Blocks adenosine at adenosine
receptors.
 May have effect on cGMP
phosphodiesterase.
 β2 – adrenoceptor agonists

 Prototype: Salbutamol (Albuterol): by inhalation for acute

attacks. Fast OOA (effect maximal within 15-30 mins& short
DOA (3-4 hrs).

 Salmeterol. Not for acute attacks. Slow OOA & long DOA (12
hrs). Given b.d.regularly as adjuncts in patients whose asthma
is not controlled by oral glucocorticosteroids.

 Mode of administration
- Inhalation: aerosol, nebulizer
- Oral, parenteral (rare)

 Adverse effects
- CVS: tachycardia, arrhythmia, palpitation (unsubstantiated)
- Tremor: β2 effect on skeletal muscle
 Methylxanthine (PDEI)

Xanthine drugs are theophylline, theobromine and caffeine.

 Only theophylline (oral) was used clinically.

 Aminophylline (theophylline ethylenediamine,(IV)
 Now replaced by beta agonists and corticosteroids. It has a
low therapeutic index. Blood level measurement is necessary.

Side effect on other systems.

 CNS: stimulation causing insomnia, higher blood level -
seizures leading to death.
 CVS: inotropic +ve & chronotrophic +ve (fatal arrhythmias)

 GIT: major side effect is nausea and vomiting, also causes

gastric acid secretion.
 Kidney: mild diuresis.
 Methylxanthine-cont

 Pharmacokinetics

- Oral, IV
- Metabolized
- Narrow therapeutic Index (5-20 mg/l)
- Different individual plasma conc.
- Toxic Effects:
> 20 mg/l - GIT: anorexia, nausea, vomiting
- CNS: headache, anxiety

> 40 mg/l – CNS: convulsion

- CVS: serious arrhythmias
 Muscarinic Receptor Antagonist

 Ipratropium bromide, a quaternary ammonium compound

 ACH + muscarinic receptor (MR) on hyperreactive bronchus

causing bronchoconstriction.

 Mechanism of action
- It binds to ACH receptor (competitively) on the bronchioles,
blocks the effect of ACH and causes bronchodilatation.
Effective only where there is a parasympathetic component
involved in causing the bronchoconstriction.
- does not dry airway secretion and interfere with mucociliary
secretion.
 Pharmacokinetics
- Inhalation (oral – not absorb via GIT)
- Elimination – lung (exhalation)

 Adverse effects
- minimal muscarinic effects since given by inhalation and it is a
quaternary ammonium compound.
ANTI-INFLAMMATORY AGENTS
 ANTIINFLAMMATORY:
CORTICOSTEROIDS

 MECHANISM OF ACTION:
 have antiinflammatory effect by reversing oedema of
bronchiole mucosa, inhibiting release of leucotrines and
decreasing the permeability of capillaries.
 decrease formation of cytokines, contributing in part to
antiinflammatory effect.
 decrease the number and activity of oesinophils, macrophages
and T lymphocytes that are involved in airway inflammation.
This is their most important action.
 Increase effect of beta 2 adrenoceptor agonists.
 Do not cause bronchodilation directly.
 Do not relieve acute asthma.
 Reduce bronchial hyperreactivity when inhaled for several
months.
 Reduce frequency of asthmatic attacks.
ANTIINFLAMMATORY: CORTICO-
STEROIDS.
 Oral steroids cause serious side
effects, so used only when
symptoms of asthma worsen despite
treatment with beta adrenoceptor
agonists + inhaled steroids. Usually
given for 7 to10 days,then tail off
dose.
 Inhalation steroids are used for
regular therapy, best way to avoid
systemic adverse effects. Given for
10- 12 weeks,then withdrawn to see
response.
 Inflammatory mediators

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase Lipoxygenase
Enzyme
Enzyme (COX)

PG LEUCOTRINE
 Inflammatory mediators

PHOSPHOLIPID IN CELL MEMBRANE

Corticosteroids Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase Lipoxygenase
Enzyme
Enzyme (COX)

PG LEUCOTRINE
Adverse effects of corticosteroids
local(inhalation)
- oral candiasis, hoarseness of voice
systemic (oral)
- cataract, glaucoma,osteoporosis,
peripheral myopathy,
depression,infections due to
decreased immunity.
Drugs: beclomethasone,
prednisolone,hydrocortisone,
budesonide.
 ANTIINFLAMMATORY:
CROMOLYN SODIUM,NEDOCROMIL

 MECHANISM OF ACTION:
- ORIGINALLY THOUGHT TO PREVENT HISTAMINE RELEASE
FROM MAST CELLS.
- ALTERS FUNCTION OF DELAYED CHLORIDE CHANNELS
RESULTING IN INHIBITION OF CELL ACTIVATION AND
PRODUCTION OF INFLAMMATORY MEDIATORS.
EFFECTS:
NOT A BRONCHODILATOR, NOT USED FOR IMMEDIATE
EFFECTS
USED AS A PROPHYLACTIC DRUG ( INHALATION OR
AEROSOL )TO DECREASE FREQUENCY/PREVENT
ASTHMATIC ATTACKS.
 ADVERSE EFFECTS:
 NOT ABSORBED AT ALVEOLI, SO MINOR ADVERSE EFFECTS
- THROAT IRRITATION, DRY MOUTH, BRONCHOSPASM,
BITTER TASTE.
ANTIINFLAMMATORY:
LEUCOTRIENE
 LTB4 is a potent neutrophil and eosinophil
chemoattractants whose products
proteases,platelet activating factor(PAF), eosinophil
cationic protein (ECP) and major basic protein
(MBP) are responsible for the symptoms of asthma.
 LTC4 & LTD4 produce
bronchoconstriction,bronchial
hyperreactivity,mucosal oedema and mucus
hypersecretion.
 2 ways to decrease production of leucotriene is by
inhibition of 5-lipooxygenase thereby preventing its
synthesis (zileuton) and by blocking the leucotriene
receptors (montelukast,zafirlukast).
 Zileuton prevents the formation of LTB4 and the
cysteinyl leukotrienes (LTC4 & LTD4 & LTE4).
 Montelukast and zafirlukast blocks cysteinyl
leukotriene receptors reversibly.
 Leukotriene Receptor Antagonist

 Montelukast
 Zafirlukast

 Blocks LT cysteinyl type

receptors

LT Effects LT Antagonism

Bronchus Bronchus
inflammation inflammation
Mucus secretion Mucus secretion

Bronchoconstriction Bronchodilatation
Leukotriene Receptor Antagonists

- not used for immediate bronchodilator effect.

- ability to cause bronchodilatation is lower than beta-

agonist

- very useful for aspirin induced asthma

- not used alone but in addition to beta agonists and

corticosteroids.
MONTELUKAST/ZAFIRLUKAST

 Pharmacokinetics
- oral administration
- Metabolism – liver
- Excretion – biliary

 Adverse effects
- occasional liver toxicity ( especially with
zileuton)
- headache
- dyspepsia
 LEUKOTRIENE SYNTHESIS INHIBITOR

 Zileuton

 Pharmacokinetics

- oral, good absorption

- metabolism – liver
- excretion – urine

 Adverse effects

- headache
- dyspepsia
- hepatotoxic (rare)
LEUKOTRIENE SYNTHESIS INHIBITOR

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase Lipoxygenase
Enzyme
Enzyme (COX)

PG LEUCOTRINE

Given Orally – 4 times a day

LEUKOTRIENE SYNTHESIS INHIBITOR
• Zileuton

PHOSPHOLIPID IN CELL MEMBRANE

Phospholipase Enzyme

ARACHIDONIC ACID

Cyclooxygenase Lipoxygenase
Enzyme
Enzyme (COX)

PG LEUKOTRINE

Given Orally – 4 times a day

STATUS ASTHMATICUS
(bronchospasm not reversed by
usual measures)
 THIS CONDITION IS A MEDICAL
EMERGENCY AND CAN BE FATAL.
PATIENT MUST BE ADMITTED TO
HOSPITAL.
 TREATMENT CONSISTS OF
MECHANICAL INTERVENTION,
SALBUTAMOL IN OXYGEN GIVEN
BY NEBULISER AND I/V
HYDROCORTISONE. THIS IS
FOLLOWED BY A COURSE OF
ORAL PREDNISOLONE.
OTHER DRUGS: ANTI-IgE
MONOCLONAL ANTIBODIES
OMALIZUMAB
INHIBITS BINDING OF IgE TO MAST
CELLS.
MAY ALSO INHIBIT IgE SYNTHESIS BY B
LYMPHOCYTES.
REDUCES THE FREQUENCY AND
SEVERITY OF ASTHMATIC ATTACKS.
DECREASE CORTICOSTEROID
REQUIREMENTS.
SEVERE ASTHMATICS RESPOND WELL.
FOR SELECTED INDIVIDUALS BECAUSE
OF HIGH COST.
 HAPPY STUDYING.
 REF: KATZUNG,LIPPINCOTT’S