Montelukast

Introduction
Montelukast :
Effective in prophylaxis and treatment
of Bronchial asthma and seasonal
allergic rhinitis.

Epidemiology, incidence and family

burden of asthma and allergic rhinitis.
WHO has recently declared that about
60-80% of patients with asthma
also suffer from allergic rhinitis.

Researchers have labeled the 2

conditions as (United Airway Disease)
or (Asthmarhinitis disorder).
Both diseases have a great impact on
the national economic statistics.

Huge numbers of missed days of work

and days of school absence have been
recorded.

Many millions of pounds are spent on

asthma related costs including direct
medical costs and indirect costs
related to caregiver missed days of
work.
 Synthesis
Nature.
of
Nomenclature.

Synthesis : steps & site.

Metabolism.
Conclusion :
Ability of cells to synthesize
leukotrienes depends upon :

1- Their enzymatic capacity to cleave

arachidonic
acid from their membrane
phospholipids.
2- Their enzymatic capacity for synthesis of
LTA4.

Lungs contains cells that have full

 Leukotriene receptors
Types.

Chemistry of each.

Genetics and expression of each.

Mechanism (Transduction).
Leukotriene B4 receptors
(BLTRs)
G-protein coupled.

7 transmembrane protein subunits

(heptahelical).

expressed on leukocytes, spleen

and thymus .
Cysteinyl-Leukotriene
receptors
( Cys-LTRs )
Glycosylated G-protein coupled.

Cys_LTR 1 is expressed more than

Cys-LTR 2
in lung , spleen and leukocytes.
Mechanism:
Binding of leukotrienes to their
receptors changes the target cell
function.

the mechanisms are poorly

understood.

suggested possibility that

leukotrienes act by control of the
adenylate cyclase enzyme.
Effects of leukotrienes:
LTB4 :
a powerful chemotactic effect.
regulation of immune response
by
-activation of natural killer cells
-proliferation and differentiation of T-
cells
into helper and suppressor T-cells
-modulate production of tumor necrosis
Cys-LTs

Mediator of type I hyper sensitivity reaction.

Responsible for properties of slow reacting

substance of anaphylaxis (SRS-A).

Released by mast cells in response to

allergen.
Role of LTs in Asthma
Secreted from leukocytes in the airways in
response to allergens, irritants or even
exercise.

Effects include:
-bronchoconstriction .
-increased mucous secretions.
-increased permeability of
microvasculature.
-inflammatory cell infiltration.
Role of LTs in Allergic
Rhinitis
Secreted from mast cells in response to
allergens.

Effects include:
-vasodilatation.
-mucosal swelling and congestion.
-increase mucous secretion.
-stimulate sensory nerves causing sneezing.
Role of leukotrienes in
Localized in tropical and subtropical regions.
kwashiorkor
Occurs when achildis weaned onto a diet
deficient in proteins.

In the Ga language of Ghana, Kwashiorkor

means
“ Sickness of the baby displaced from the
breast “ .
3 sudanese children with severely swollen
bulging abdomens which is a characteristic
symptom of Kwashiorkor.
It is characterized by high levels of Cys-LTs
(LTC4, LTD4 & LTE4) and deficient LTB4.

The high levels of serum Cys-LTs increase

vascular permeability and increase escape of
fluid to extravascular tissues causing edema.

On the other hand, deficiency of LTB4 causes

inadequate chemotaxis and recruitment of
neutrophils and overall inadequate
inflammatory response to diseases.
Control of cascade of
leukotrienes
Leukotriene modifiers are the most recent class
of medication for asthma and allergic rhinitis
since inhaled corticosteroids were first
approved in 1972.

Corticosteroids inhibit phospholipase A2

thereby decrease production of all leukotrienes.
There are two approaches to
block action of leukotrienes :
1. Inhibition of 5-Lipoxygenase pathway
:

ex. Zileuton (Zyflo).

2. Antagonism of cysteinyl-leukotriene
receptors :

ex. Zafirlukast & Montelukast.

Leukotriene receptor
antagonists
Ø Zafirlukast :

-Indications.

-Dose.

-Side effects.

-Contraindications.
ØMontelukast:

-It is the main highlighted topic of this assay.

-Importance.
Dosage, Pharmacokinetics
and drugDosage
interactions
10 mg tabletforms
: <<<<< 15 years age
or older.
5 mg chewable tablet : <<<<< 6-14 years
age.
4 mg oral granules or chewable tablet :
<<<<< 2-5 years.
4 mg oral granules : <<<<< 6-24 months.
All once daily
 Pharmacokinetics
Absorption :
- Rapidly & oral.
Distribution :
- The steady state volume of distribution = 8-11 L.
- Don’t cross BBB.
Metabolism :
- In liver by cytochrome P450.
Elimination :
- Plasme clearance = 45ml/min.
- Exclusively excreted in bile.
 Drug interactions
Routine medications for treatment of
asthma ” theophylline” .

No effecrt on drugs as prednisone,

prednisolone, terfenadine, and digoxin.

It may affect patients on therapy with

warfarin by prolongation of prothrombine
time.
 Pharmacological actions

Selective leukotriene receptor antagonist .

Rapid onset and long duration of action.

Therapeutic uses of Montelukast
with associated regimens of
2. Management of chronic bronchial asthma
and prophylaxis against exercise induced
asthma.

“Not indicated for acute asthma”

4. Management of allergic rhinitis.

 Asthma
Chronic inflammatory disease.

May be intrinsic due to genetic factors

( Atopy ) or extrinsic due to exposure to
allergens.

Symptoms & pathogenesis.

 Management of Asthma
Prophylaxis against any inflammation.

“avoid exposure to allergens”

Standard drugs as :

- Inhaled B agonists and corticosteroids

(aerosols).
- Leukotriene receptor anatagonists as
Montelukast. (as long term medication)
 Allergic rhinitis

Type I hypersensitivity reaction.

Symptoms & pathogenesis.

Management of Allergic
1. Anti-histaminics, as mezolastine.
rhinitis
2. Topical corticosteroids (intranasal).

3. Mast cell stabilizers, as ketotifen.

4. Intranasal sympathomimetics ,
as phenylephrine.

5. Leukotriene receptor antagonist,

Montelukast.
 Side effects
Side effects include :

1- GIT disturbances.

2-Sleep disorders.

3- Increase bleeding
tendency.
 Adverse effects
Adverse effects include :

1- psychiatric disorders as aggressive

behavior, anxiety,
insomnia, restlessness and tremors.

2- Cardiac disorders as palpitations.

3- Rarely cholestatic hepatitis.

Contraindicat Overdosage
ions : toxicity :
Hypersensitivity to It occurs with
montelukast. administration at
least 150 mg/day.

It is accompanied by
thirst, mydriasis,
hyperkinesia and
some abdominal
pains.