8 - PharmaI_Asthma Copy

Anti Asthmatic Agents

Ana Marie R. Morelos, MD, DPPS

Asthma

One of the most common chronic diseases worldwide and the

prevalence is increasing, especially

among children.

Fortunately asthma can be treated and controlled

Asthma

Causes recurrent episodes of

wheezing

breathlessness

chest tightness

nocturnal coughing

Chronic inflammatory disorder of the airways (3 cells)

Asthma

Increased airway responsiveness to various stimuli (risk factors)

leading to widespread but variable airflow obstruction

reversible spontaneously or with treatment.

Asthma

Asthma attacks ( exacerbations) are episodic but airway inflammation is

chronically present.

For many patients, medications must be taken every day

To control symptoms

To improve lung function

To prevent attacks

To relieve acute symptoms: cough, wheezing, chest tightness.

Risk Factors for Asthma

Host factors

Environmental factors

Exposure to allergens & viral infxns

Diet

Tobacco smoke

Socioeconomic status

Family size

Asthma Triggers

Viral infections of the resp. tract

Aeroallergens

Environmental tobacco smoke

Air pollutants

Asthma Triggers

Strong/noxious odors or fumes

Occupational exposure

Cold/Dry air

Exercise

Crying/laughter/hyperventilation

Co-morbid conditions

Asthma Pathogenesis (acute)

Early phase response: within 10-20 min of airway exposure to the trigger -

allergen/antigen binds to the

IgE surface

activation of mast cells/macrophages

release of histamine and leukotrienes

contraction of airway smooth muscles

increased mucous secretion,

vasodilation and increased blood flow

microvascular leakage of plasma

thickening of airway walls

Asthma Pathophysiology (acute)

Late phase response

6-12hrs of allergen exposure

recruitment and activation of cells (infiltration by neutrophils, eosinophils,

basophils, monocytes) cause further

mucus production, inflammation and

bronchospasm more wheezing

Asthma Pathophysiology

Studies on bronchial hyperreactivity:

Release of mediators from mast cells

Activation of neural or humoral pathways leading to exaggeration

of responsiveness

Asthma Pathophysiology

chronic phase failure to interrupt ongoing inflammatory cycle

non specific bronchial hyperresponse leads to airway wall

remodeling :

unless treated early and aggressively, airway remodeling can

cause irreversible reduced

pulmonary function

Asthma major types of drugs

Sympathomimetics

Beta 2 selective drugs

Glucocorticosteroids

Sodium chromoglycate

Methylxanthines

Antileukotrienes

Anticholinergics

Anti-IgE monoclonal antibodies

Routes of Drug Delivery

Inhaled Route

Oral

Parenteral

Asthma Medications

Inhaled medications

High therapeutic ratio :

high concentration of low doses of the drug

delivered directly to the airways

potent therapeutic effects

few systemic side effect

Asthma Medications

Inhaled medications

Devices

Pressurized metered-dose inhaler (pMDI)

Breath-actuated metered-dose inhaler

Dry powder inhaler (DPI)

Nebulizer

Spacer (holding chamber)

MDI & spacer

Nebulizer

Nebulizer - mask

Nebulizer - mouthpiece

Asthma Medications

Oral medications

Higher doses

More systemic side effects

Reserved for patients unable to use inhalers

For drugs that are ineffective via the inhaled route

Parenteral medications

IV for severely ill

More side effects

Bronchodilators

2 Adrenergic agonists (sympathomimetics)

Theophylline (methylxanthine)

Anticholinergic agents (muscarinic receptor antagonists)

2

Adrenergic agonists

Epinephrine non selective agonist

Albuterol/Salbutamol

Terbutaline

Salmeterol

Formoterol

MOA: bind to Beta2 receptors in airway smooth muscle, activate G-

adenylyl cyclase cAMP-PKA pathway-

muscle relaxation, decrease airway

resistance.

2

Adrenergic agonists

Side Effects

Muscle tremor

Tachycardia and palpitations

Hypokalemia

V/Q mismatch

Metabolic effects

2

Adrenergic agonists

Tolerance desensitization or subsensitivity

Relative resistance of airway smooth muscle responses to

desensitization may reflect the

large receptor reserve: >90% of

2 receptors may be lost without any reduction in the relaxation

response.

Methylxanthines

Theophylline

Doxofylline

Aminophylline

Methylxanthines

MOA

Phosphodiesterase inhibition

Adenosine receptor antagonism

Interleukin-10 release

Reduce expression of inflammatory genes during gene transcription

Promotion of apoptosis in eosinophils and neutrophils

Histone deacetylase activation

Methylxanthines

Theophylline side effects

Nausea and vomiting

Headaches

Gastric discomfort

Diuresis

Cardiac arrhythmias

Epileptic seizures

Behavioral disturbance and learning difficulties in children

Methylxanthines

Clinical Uses

IV aminophylline for those non-responders/intolerant of 2 agonists

Theophylline added to agonist for more adequate bronchodilation

Theophylline added to inhaled corticosteroid for better symptom

control and lung function (vs doubling

the dose of inhaled steroid)

Muscarinic Cholinergic Antagonists

Atropine

Ipratropium bromide


MOA

Inhibit the effect of acetylcholine at muscarinic

receptors

Relax airway smooth muscle

Decrease mucus secretion


Clinical Use as bronchodilator

Atropine IV Bronchodilation > tachycardia

Ipratropium bromide - inhalation

Can be delivered in high doses

Poorly absorbed into the circulation

Does not readily enter the CNS

For pt intolerant of inhaled 2 agonists

Combined with salbutamol enhanced bronchodilation for acute

severe asthma


Side Effects

Very few because generally well tolerated

Systemic side effects uncommon

Bitter taste of inhaled Ipratropium

May precipitate glaucoma in elderly: direct effect of nebulized drug on

eye, therefore should nebulize with

mouthpiece not face mask.

Urinary retention in elderly

Corticosteroids

Prednisone

Prednisolone

Hydrocortisone

Methylprednisolone

Beclomethasone

Budesonide

Fluticasone

Triamcinolone

Corticosteroids

MOA

Enter target cells and bind to GR (glucocorticoid receptors) in the

cytoplasm

Steroid-GR complex enters the nucleus and repress transcription factors that

activate inflammatory genes anti inflammatory effect of steroids

Corticosteroids

Anti-inflammatory effects in asthma

Inhibit the formation of cytokines IL, TNF, GM-CSF (secreted by T lymphocytes,

macrophages, mast cells)

Decrease eosinophil survival apoptosis

Prevent and reverse the increase in vascular permeability due to inflammatory

mediators resolution of edema

Inhibit mucus secretion by airway submucosal glands

Corticosteroids

Inhaled steroids

Act locally on the airway mucosa

May be absorbed from airway and alveolar surface

May be deposited in oropharynx, swallowed, absorbed from the gut

Use of spacer chamber; mouth rinsing and discarding the rinse reduce oropharyngeal deposition and

absorption

Corticosteroids

Systemic Steroids

IV steroids - acute asthma, if lung function is

Corticosteroids

Local side effects (inhaled steroids) Dysphonia

Oropharyngeal candidiasis

Cough

Systemic side effects Adrenal suppression/insufficiency

Growth suppression, Bruising, Osteoporosis, Cataracts, Glaucoma

Metabolic abnormalities

Psychiatric disturbances

Pneumonia

Leukotriene Pathway Inhibitors

Montelukast

Pranlukast

Zafirlukast

Zileuton


MOA

inhibition of 5-lipoxygenase, thereby preventing leukotriene

synthesis zileuton

inhibition of the binding of LTD4 to its receptor on target tissues,

thereby preventing its action Zafirlukast

Montelukast


Clinical Uses

Inhibit bronchoconstrictor effects of LTD4. allergens, exercise, cold air,

aspirin

Add-on therapy for pts poorly controlled by ICS

Prevent exercise induced asthma

Effective in tablet form

Most prescribed: Montelukast OD dosing, taken without regard to meals,

approved for 2yrs & above


Adverse Events

Liver toxicity Zileuton

Churg-Strauss syndrome ?

rare vasculitis that affects the heart, peripheral nerves, and kidney and is

associated with increased circulating

eosinophils and asthma.

Asthma Medications

Reliever (Rescue)

Work quickly to treat attacks or relieve symptoms

Beta 2 agonists, anticholinergics, theophylline, epinephrine

Controller

Keep sx and attacks from starting

Steroids, cromolyn, long acting Beta 2 agonists, sustained release theophylline,

antileukotrienes, omalizumab

Controller Medications

Glucocorticoids

Inhaled: Budesonide, Fluticasone, Beclomethasone, Triamcinolone

Tab/Syrup:Hydrocortisone,Methyl- prednisolone, Prednisolone, Prednisone

Sodium cromoglycate

Cromolyn

Sustained-release Methylxanthines

Theophylline, Aminophylline

Controller Medications

Long-acting 2-agonists

(-adrenergics/sympathomimetics)

Inhaled: Formoterol, Salmeterol

Sustained-release tabs: Salbutamol, Terbutaline

Antileukotrienes

Montelukast, Pranlukast, Zafirlukast, Zileuton

Controllers: Glucocorticoids

Inhaled steroids

Beginning dose depends on severity titrated down over 2-3mos

Side effects:( high doses)

Potential but small risk of side effects is well balanced by efficacy

Prevent oral candidiasis

Controllers: Glucocorticoids

Tablets/Syrups

Daily control: lowest effective dose 5-40mg prednisone equivalent in am

Acute attacks: 40-60mg daily in 1-2divided doses young

children: 1-2mg/kg/day

Long-term use: SE/coexisting conditions worsened by oral steroids

alternate day a.m. dosing less toxic

Short-term use: 3-10day bursts prompt control

Controllers: Cromolyn

MDI 2-4 inhalations tid/qid nebulizer 20mg tid/qid

Minimal side effects coughing on inhalation

May take 4-6 wks for maximum effects

Controllers:

Sustained-release Methylxanthines

10mg/kg/day in 2 divided doses max: 800mg

Nausea and vomiting higher doses: seizure, tachycardia,

arrhythmia

Requires theophylline level monitoring

Controllers:

Long-acting 2 Agonist

Inhaled

1-2 puffs bid

Fewer/less significant side effects

Adjunct to anti-inflammatory tx

Best combined with low-medium doses of inhaled glucocorticosteroids

Controllers:

Long-acting 2 Agonist

Sustained-release tablets

For adolescents

Salbutamol 3-6mg/kg/day

Terbutaline 10mg q 12h

SE: tachycardia, anxiety, tremors, headache, hypokalemia

Controllers: Antileukotrienes

Bronchodilator and anti-inflammatory

Reduce exercise induced, aspirin induced and allergen induced

bronchoconstriction

No significant adverse effects

Reliever Medications

Short-acting 2-agonist

Inhaled/tab/syrup: Albuterol, Fenoterol, Metaproterenol,Salbutamol, Terbutaline

Anticholinergics

Ipratropium bromide

Short-acting theophylline

Aminophylline

Epinephrine injection

Relievers:

Short-acting 2 agonist

Prn symptomatic use and pretx before exercise: 2puffs MDI

Asthma attack: 4-8puffs q 2-4h

may administer q 20min x 3

SE: tachycardia, tremor, headache, irritability, hyperglycemia, hypoK

(inhaled less SE)

DOC for acute bronchospasm

Overuse

Relievers: anticholinergics

4-6 puffs MDI q 6h or nebulize q 20 min x 3

SE: minimal mouth dryness or bad taste in mouth

May provide additive effects to 2 agonist but slower onset of action

Alternative for those intolerant to 2 agonists

Relievers: Aminophylline

7mg/kg loading dose over 20min then 0.4mg/kg/hr continuous infusion

SE: nausea, vomiting headache higher doses: seizure, tachycardia,

arrhythmia

Requires theophylline level monitoring

Relievers: Epinephrine

1:1000 solution ( 1mg/ml) 0.01mg/kg up to 0.3-0.5mg q 20min x 3

Similar effects as 2 agonists

SE: hypertension, fever, vomiting, hallucinations

In general, not recommended for treating asthma attacks if selective

2 agonists are available

Have a nice day!

Documents

8 - PharmaI_Asthma Copy