You are on page 1of 79
Pharmacology of Asthma AZL & YSP Dept. Pharmacology & Therapeutic, School of Medicine Universitas Sumatera Utara
Pharmacology of
Asthma
AZL & YSP
Dept. Pharmacology & Therapeutic,
School of Medicine
Universitas Sumatera Utara

Pathophysiology of Asthma

• Airway inflammation

– Cytokines

• Bronchial hyper-responsiveness

– Hipersensitifity type 1

• Alergen • Antibodi (IgE) • Mast cell • Mediators (Histamin, Lekotrien, etc)

– Slow phase

• Airflow limitation

Pathologic Findings

Pathologic Findings • Bronchoconstriction • Hyperinflation of the lungs • Hyperplasia of the smooth muscle surrounding

• Bronchoconstriction •

Hyperinflation of the lungs

Hyperplasia of the smooth muscle surrounding the bronchial and bronchiolar walls

Thickening of the basement membrane

Mucosal edema

DesJardin, T, Burton, G: Clinical Manifestations and Assessment of Respiratory Disease. St. Louis, Mosby,

1995

Chemicals Involved in Inflammation

IgE • Histamine • Tryptase • Leukotrienes (LTC 4 ) • Platelet activating factor (PAF) • Prostaglandins (PGD 2 )

• Interleukins (IL-4, IL-5) • Granulocyte-macrophage colony stimulating factor (GM-CSF) • Tumor Necrosis Factor (TNF) • Major Basic Proteases (MBP) • Eosinophil Cationic Protein (ECP)

Patho-physio-pharmacology of Asthma

Allergen

Patho-physio-pharmacology of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial
Patho-physio-pharmacology of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial

Macrophage/ dendritic cell

Mast cell

Patho-physio-pharmacology of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial
Patho-physio-pharmacology of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial

Th2 cell

Neutrophil

Eosinophil Mucus plug Epithelial shedding Nerve activation Plasma leak Oedema
Eosinophil
Mucus plug
Epithelial shedding
Nerve activation
Plasma leak
Oedema

Vasodilatation

New vessels

Patho-physio-pharmacology of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial

Subepithelial

fibrosis

Sensory nerve activation

Cholinergic

Mucus

hypersecretion

Hyperplasia

reflex

Bronchoconstriction

Hypertrophy / hyperplasia

Patho-physio-pharmacology of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Mucus plug Epithelial

Barnes PJ

Asthma components Healthy airway Asthmatic airway Aveolar septum Inflammation and oedema Mucus and plasma exudation Smooth
Asthma components
Healthy airway
Asthmatic airway
Aveolar septum
Inflammation
and oedema
Mucus and plasma
exudation
Smooth
Epithelium
muscle
Smooth muscle
contraction
Epithelial shedding /
damage
Barnes PJ

General Goals of Asthma Therapy

• Relief airways tightening / bronchoconstriction immediately.

• Education of asthma management.

• Prevent chronic symptoms and asthma exacerbations during the day and night • Maintain normal activity levels • Have normal or near-normal lung function

• Have no or minimal side effects while receiving optimal medications

Intervention in Asthma

Avoidance of allergens, infections
Avoidance
of allergens, infections
Inhaled corticosteroids
Inhaled
corticosteroids

Inducers

 

Triggers

Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP Exercise induced asthma
Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP Exercise induced asthma
Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP Exercise induced asthma

Inflammation

Airways

eosinophils

Hyper-responsiveness

ECP

Exercise induced asthma

ß2 agonist bronchodilators
ß2 agonist
bronchodilators
Intervention in Asthma Avoidance of allergens, infections Inhaled corticosteroids Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP
Intervention in Asthma Avoidance of allergens, infections Inhaled corticosteroids Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP

Symptoms

Intervention in Asthma Avoidance of allergens, infections Inhaled corticosteroids Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP
Intervention in Asthma Avoidance of allergens, infections Inhaled corticosteroids Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP

Cough, chest tightness

Intervention in Asthma Avoidance of allergens, infections Inhaled corticosteroids Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP

Wheeze, dyspnea

Intervention in Asthma Avoidance of allergens, infections Inhaled corticosteroids Inducers Triggers Inflammation Airways eosinophils Hyper-responsiveness ECP

Airways obstruction

General Pharmacologic Approach to the Treatment of Asthma

Relievers

• Short-acting bronchodilators

2 -adrenergic agents – Anti-cholinergic (Parasympatholytic) agents

Controllers

• Corticosteroids • Long-Acting bronchodilators

2 -adrenergic agents – Methylxanthines

• Cromolyn sodium • Leukotriene inhibitors • Anti-IgE monoclonal antibodies

“Relievers”

Historical Perspective

Datura stramonium (1802) Epinephrine (1903) Ephedrine (1926) Isoproterenol (1940) Isoetharine (1951) Metaproterenol (1961) Beta 2 -adrenergic agents via MDI (1973) Ipratropium bromide (1987) Salmeterol (1994) Levalbuterol (1999)

Patho-Physio-Pharmacology of Bronchodilators

Patho-Physio-Pharmacology of Bronchodilators

Adrenergic Bronchodilators – Short-Acting Agents

Adrenergic Bronchodilators – Short-Acting Agents • Catecholamines – Epinephrine – Isoproterenol – Isoetharine • Resorcinol agents

• Catecholamines

– Epinephrine – Isoproterenol – Isoetharine

• Resorcinol agents

– Metaproterenol

• Saligenin agents

– Salbutamol

• Pirbuterol • Bitolterol

-Agonists

• Mechanism of Action -relax smooth muscle within the airways, causing bronchodilation.

Short Acting

– Salbutamol (Various Brands) – Levalbuterol (Xopenex) – Biltolterol (Tornalate) – Pirbuterol (Maxair) – Isoproternol (Medihaler-Iso) – Metaproternol (Alupent) – Terbutaline (Brethaire)

Long Acting

– Salmeterol (Serevent) – Formoterol (Foradil)

Classification of agonists

 

Beta Agonists

Short acting

Generic name

Duration of action

2-selectivity

Salbutamol

4-6 h

+++

Levalbuterol

8 h

+++

Metaproterenol

4-6 h

++

Isoproterenol

3-4 h

++

Epinephrine

2-3 h

-

Long acting

Salmeterol

12 + h

+++

Formoterol

12 + h

+++

2 agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in 2 selectivity. The selectivity of 2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure. agonists are generally divided into short (4-6 h) and long (>12 h) acting agents.

Beta-2 Adrenergic Agonists – Short acting agents

• Mode of administration

– Inhaled/Parenteral

• Modes of action

– Relax airway smooth muscle – Enhance mucociliary clearance – Decrease vascular permeability

– May modulate mediator release from mast cells and basophils

Beta-2 Adrenergic Agonists – Short acting agents

• Role in therapy

– Medication of choice for treatment of acute exacerbations of asthma and useful in the pretreatment of exercise-induced bronchospasm (EIB)

– Used to control episodic bronchoconstriction

• Increased used – or even daily use of these agents is a warning of deterioration of asthma and indicates the need to institute or to intensify regular anti-inflammatory therapy.

Beta-2 Adrenergic Agonists – Short acting agents

Side Effects

• Tremor • Papitations and tachycardia • Headache • Insomnia • Rise in blood pressure • Nervousness • Dizziness • Nausea

Salbutamol

• Mainstay of Therapy for Many Years • Characteristics

– Dosing –every 4-6 hours – Dosage Forms

• MDI (HFA), Unit Dose Vials for Nebulizers, Oral Solutions, Oral Tablets

– Advantages- quick action, “rescue therapy” – Side Effects/Problems

• The most common side effects are heart palpitations, irregular, rapid heartbeat, anxiety, and increased blood pressure.

Anticholinergic Bronchodilators

• Tertiary Ammonium Compounds

– Atropine sulfate – Scopalamine

• Quaternary Ammonium Compounds

– Ipratropium – Tiotropium

Anticholinergic Bronchodilators

• Mode of administration

– Inhaled

• Mechanisms of action

– Block the effects of acetylcholine released from cholinergic nerves in the airways (i.e., reduce intrinsic vagal cholinergic tone to the airways).

– Block reflex bronchoconstriction caused by inhaled irritants

– They do not diminish the early and late allergic reactions and have no effect on airway inflammation.

– Less potent bronchodilators than inhaled beta-2 agonists, and in general, have a slower onset of action (30-60 min to maximum action).

Anticholinergic Bronchodilators

• Role in therapy

Additive effect when nebulized together with a rapid-acting beta-2 agonist for exacerbations of asthma

It is recognized that Ipratropium can be used an alternative bronchodilator for patients who experience adverse effects such as tachycardia, arrhythmias, and tremors from beta-2 agonists.

• Side effects

Dryness of the mouth and bitter taste

“Controllers”

Controllers

• Corticosteroids • Long-Acting bronchodilators

2 -adrenergic agents – Methylxanthines

• Cromolyn sodium/Nedrocromil • Leukotriene inhibitors • Anti-IgE monoclonal antibodies

Corticosteroids

Inhaled Glucocorticoids

Beclomethasone

Flunisolide

Fluticasone

Triamcinolone

Budesonide, and

Mometasone

Systemic Glucocorticoids

Prednisone

Methylprednisolone

Prednisolone

Dexamethasone

Inhaled Glucocorticoids

• Mechanisms of action

– Reduces pathologic signs of airway inflammation mediated in part by inhibition of production of inflammatory cytokines

– Airway hyperresponsiveness continues to improve with prolonged treatment

• Role in therapy

– Most effective anti-inflammatory medication for the treatment of asthma

Inhaled Glucocorticoids

Side effects

– Local adverse effects include oropharyngeal candidiasis, dysphonia, and occasional coughing from upper airway irritation. – Because there is some systemic absorption, the risks of systemic adverse effects will depend on the dose and potency of the Glucocorticoids as well as its bioavailability, absorption in the gut, metabolism by the liver, and the half-life of its systemically absorbed fraction.

Contraindication:

– hypersensitivity, nasal infection and haemorrhage, candidiasis orofaring, and patient with recurrent epistaxis.

Inhaled Glucocorticoids

• Beclomethasone dipropionate

– Dosage: 200-1000µg

• Budesonide

– Dosage: 200-800µg

• Flunisolide

– 500-2000µg

• Fluticasone

– 100-500µg

• Triamcinolone acetonide

– 400-2000µg

Systemic Glucocorticoids

Mode of administration

– Oral – Parenteral

Mechanisms of action

– Same as for inhaled Glucocorticoids however systemic Glucocorticoids may reach different target cells than inhaled drugs

Role in therapy

– Long-term oral Glucocorticoids therapy (daily or alternate-day) may be required to control severe persistent asthma.

Systemic Glucocorticoids

side effects

– Osteoporosis – Arterial hypertension – Diabetes – Hypothalamic-pituitary axis suppression – Cataracts – Glaucoma

– Obesity

– Skin thinning leading to cutaneous striae

– Easy bruising – Muscle weakness

– Fatal herpes virus infections have been reported among patients who are exposed to these viruses when they are taking systemic Glucocorticoids

Adrenergic Bronchodilators – Long-Acting Agents

Adrenergic Bronchodilators – Long-Acting Agents • Sustained- released salbutamol • Salmeterol • Formoterol

• Sustained- released salbutamol

• Salmeterol • Formoterol

Adrenergic Bronchodilators – Long-Acting Agents

• Modes of administration

– Inhaled – Oral

• Mechanisms of action

– Same as short-acting beta-2 agonists – Effects persists for at least 12 hours

Adrenergic Bronchodilators – Long-Acting Agents

• Role in therapy

– Long-acting inhaled beta-2 agonists should be considered when standard introductory doses of inhaled Glucocorticoids fail to achieve control of asthma before raising the dose of inhaled Glucocorticoids.

– Because long-term treatment with these agents does not appear to influence the persistent inflammatory changes in asthma, this therapy should be combined with inhaled Glucocorticoids

• Fluticosone propionate – salmeterol and bedesonide- formoterol inhalers (Advair®)

Adrenergic Bronchodilators – Long-Acting Agents

• Side effects

– Inhaled beta-2 agonists cause fewer systemic adverse effect (e.g., cardiovascular stimulation, skeletal muscle tremors, and hypokalemia) than oral therapy particularly if the oral regimen includes theophylline.

Salmeterol

• Dosing - every 12 hours • Dosage Forms

MDI, Discus (powder), combination with steroid

• Advantages

long acting, less tolerance to effects than salbutamol- decreases need to increase corticosteroid dose

• Side Effects/Problems

Slow onset of effect Headache, tremor, palpitations, and nervousness are the most frequent side effects.

Formoterol

Dosing every 12 hours Dosage Forms –aerosolized powder

– Similar to Spinhaler (drug in gelatin capsule)

Advantages

– has both a rapid-onset bronchodilator is long- acting but not as a rescue medicine

Side Effects/Problems

– The most common side effects are headache, palpitations, and tremor.

– Less common side effects include agitation, restlessness, sleep disturbance, muscle cramps, and increased heart rate

Xanthine Agents

Naturally Occurring Agents

– Caffeine (Coffee and kola beans; tea leaves) – Theophylline (Tea leaves) – Theobromine (Cocoa seeds or beans)

Synthetic Derivatives

– Dyphylline – Proxyphylline – Enprophylline

Xanthine Agents • Naturally Occurring Agents – Caffeine (Coffee and kola beans; tea leaves) – Theophylline

Methylxanthines

Mode of administration

– Oral or Parenteral

Mechanisms of action

– The bronchodilator effect may be related to phosphodiesterase inhibition (>10mg/L);

– anti-inflammatory effect is due to an unknown mechanism and may occur at lower concentrations (5-10mg/L).

This latter mechanism may involve the inhibition of cell surface receptors for adenosine, which modulate adenylyl cyclase activity (contraction of isolated smooth muscle and to provoke histamine release from mast cells.

– Most studies show little or no effect on airway hyperresponsiveness

Role in therapy

– Sustained release theophylline is effective in controlling asthma symptoms and improving lung function (i.e., nocturnal symptoms; may be used as an add-on therapy to low or high doses of glucocorticoids)

Methylxanthines

• Side effects (serum concentrations > 15µg/mL)* – Gastrointestinal symptoms – nausea, vomiting – CNS – Seizures – Cardiovascular – tachycardia, arrhythmias

– Pulmonary – stimulation of the respiratory center

*Monitoring theophylline levels is advised when high-dose therapy (>10mg/kg body weight is used or when a patient develops an adverse effect on the usual dosage

Mast Cell Stabilizing Agents

Mechanism of Action:

– inhibit the activation of mast cells within the airway, thereby preventing release of mediators that provoke asthma symptoms. – alter the function of delayed chloride channels in the cell membrane – considered by some as a type of NSAID.

Used for preventing asthma attack

– As the prophylaxis of asthma attack caused by allergen, exercise,

Advantages:

aspirin, and working.

– Used for long term medication

Disadvantages:

– Using dosage four times a day – Expensive – Less effectivity than inhaled corticosteroid

– side effects: throat iritation, cough, dry mouth, and bad taste of tongue.

Cromolyn & Nedocromil

Cromolyn & Nedocromil –Dosing –Dosage Forms – MDI or Nebulized solution (Cromolyn) –Advantages - alternative to

–Dosing QID –Dosage Forms – MDI or Nebulized solution (Cromolyn) –Advantages - alternative to steroids/-agonists –Side Effects/Problems

• Daily dosing required (works prophylactically)

• Cromolyn (throat irritation or dryness, wheezing, nausea, coughing, and a bad taste in the mouth).

• Nedocromil (bad taste, nausea, abdominal pain, and vomiting).

Leukotriene modifiers

Zafirlukast, Montelukast, and Zileuton

Leukotriene modifiers Zafirlukast, Montelukast, and Zileuton • A relatively new class of anti-asthma drugs that include

• A relatively new class of anti-asthma drugs that include

– cysteinyl leukotriene 1 (CysL T1) receptor antagonists

• (montelukast, zafirlukast) and

– 5-lipoxeygenase inhibitor

• (zileuton)

Leukotriene modifiers

• Mode of administration

Oral Using dosage four times a day (Zileuton)

• Mechanism of action

Receptor antagonists block the CysLT1 receptors on airway smooth muscle and thus inhibit the effects of cysteinyl leukotrienes that are release from mast cells and eosinophils

5-lipoxygenase inhibitors block synthesis of leukotrienes.

Leukotriene modifiers

Role in therapy

– These agents have a small and variable bronchodilator effect, reduce symptoms, improve lung function, and reduce asthma exacerbations.

– Effect of these drugs is less than that of low- doses of inhaled glucocorticoids. There is evidence that the use of these drugs as an add- on may reduce the dose of inhaled glucocorticoid required by patients with moderate to severe asthma.

Note that leukotriene modifiers are less effective than long-acting inhaled beta-2 agonists as an add-on therapy.

Leukotriene modifiers

Side effects

– These drugs are usually well tolerated, and few if any class-related effects have been recognized.

Zileuton has been associated with liver toxicity and monitoring liver test is recommended

There are several reports of Churg-Strauss syndrome associated with the leukotriene modifier therapy (typically associated with a reduction of systemic glucocorticoids)

Contraindication:

patients with coronary heart disease, and cardiac arrhythmias.

IgE Antibody

Omalizumab

Used as intravenous or intramuscular anti-asthma.

– Soluble recombinant IL-4 receptor that can be delivered by

diminishing the production of IgE through effects on

interleukin 4 or on IgE itself have been evaluated

aerosol – Recombinant human monoclonal antibody that forms complexes with free IgE (rhuMAb or omalizumab blocks the interaction of IgE with mast cells and basophils.

• Attenuates the early-phase and late phase airway obstruction response to allergen and suppressed the accumulation of eosinophils in the airways

Advantages:

  • - Decreasing the degrees of asthma

  • - Reducing the used of corticosteroid

  • - Repaired nasal symptoms for patients with allergic rhinitis.

Disadvantage:

very expensive

Routes of Administration

• Inhaled

– Metered dose inhalers (MDI)

• “Spacers”

– Dry powder inhalers (DPI) – Nebulized (“wet”) aerosols

• Oral • Parenteral

– Subcutaneous – Intramuscular – Intravenous

Pharmacokinetics of anti-asthma

Oral
Oral
Inhaler
Inhaler

Sub-cutane

Pharmacokinetics of anti-asthma Oral Inhaler Sub-cutane Vena portae Membrane mucous Blood flow Excretion Urine
Vena portae
Vena
portae

Membrane

mucous

Blood flow
Blood
flow
Excretion
Excretion

Urine

Is there an advantage to using a nebulizer, as opposed to an MDI, for delivery of medications for the treatment of asthma?

Studies comparing Nebulizers to MDIs with Spacers

Chou KJ, et al. Metered-Dose Inhalers with Spacers vs Nebulizers for Pediatric Asthma. Arch Ped Adol Med 149:201-5,1995.

Nebulized beta-agonist therapy had been the standard of care for patients with acute asthma exacerbations. Several studies in adults, however, have found metered dose inhaler (MDI) administration to be as effective.

Use of the MDI instead of nebulizer administration would be economically beneficial and easier for both patients and clinicians.

(MDI+ spacer) vs Nebulizer

(MDI+ spacer) vs Nebulizer

Are antihistamines useful in the prophylaxis and/or treatment of asthma?

Clin Exp Allergy. 29 Suppl 3:98-104,1999.

• Effectiveness of H1 antagonists in adults with “seasonal” asthma

Clin Exp Allergy. 29 Suppl 3:98-104,1999. • Effectiveness of H1 antagonists in adults with “seasonal” asthma

Clin Exp Allergy. 29 Suppl 3:98-104,1999.

Conclusions of Analyses severe persistent asthma

– no significant clinical effect

moderate persistent asthma

– clinical benefits of H1 antagonists are apparent but require higher-than-usual doses and are not worth the risk to patient

mild seasonal asthma and allergic rhinitis coexistant

– significant improvement in asthma symptoms at usual dosing

Key Points

• Short-acting beta 2 -agonists: Therapy of choice for relief of acute symptoms and prevention of EIB.

• Anticholinergics: May provide some additive benefit to inhaled beta 2 -agonists in severe exacerbations. May be an alternative for patients who do not tolerate inhaled beta 2 -agonists.

• Systemic corticosteroids: Used for moderate-to- severe exacerbations to speed and prevent recurrence of exacerbations.

Key Points

• Corticosteroids: Most potent and effective anti- inflammatory medication currently available

• Cromolyn sodium and nedrocromil: Mild-to- moderate anti-inflammatory medication.

• Leukotriene inhibitors: May be considered an alternative therapy to low dose inhaled corticosteroids or cromolyn sodium or nedrocromil for patients >12 years of age with mild persistent asthma.

Key Points

• Long-acting beta 2 -agonists: These drugs are typically used concurrently with anti- inflammatory medications for long-term control of symptoms, especially nocturnal symptoms.

• Methylxanthines: Sustained release theophylline is a mild-to-moderate bronchodilator used principally as an adjuvant to inhaled corticosteroids for prevention of

nocturnal asthma symptoms.

Treatment Protocols

Etiology

Etiology • Genetic factors – Atopy • Environmental factors – Viruses – Allergens – Occupational exposure

Genetic factors

– Atopy

Environmental factors

– Viruses – Allergens – Occupational exposure

Factors that Influence Asthma Development and Expression

Host Factors Genetic

Atopy Airway hyperresponsiveness

Gender Obesity

Environmental Factors

Indoor allergens

Outdoor allergens

Occupational

sensitizers Tobacco smoke

Air Pollution

Respiratory Infections

Diet

Factors that Exacerbate Asthma

Allergens Respiratory infections Exercise and hyperventilation Weather changes Sulfur dioxide Food, additives, drugs

Major Cells Implicated in Inflammatory Response

Mast cells an important cell type in the asthmatic lung. These cells produce numerous mediators that contribute to the development of asthma, including:

• histamine, • cysteinyl leukotrienes, • tryptase, • tumor necrosis factor-alpha, • prostaglandin D2, and • cytokines including IL4, IL-5 and IL-13

Lymphocytes

Eosinophils

Neutrophils

Inflammatory processes

Desquamation of epithelium Hyperplasia of Mucos glands Mucus plug Basement Membrane thickening Oedema Smooth muscle Hypertrophy
Desquamation of
epithelium
Hyperplasia of
Mucos glands
Mucus plug
Basement
Membrane
thickening
Oedema
Smooth muscle
Hypertrophy and contraction
Neutrophil and
eosinophil infiltration

Barnes PJ

Classification of Asthma Severity:

Clinical Features Before Treatment

Severity

Days with Symptoms

Nights with Symptoms

PEF or FEV 1.0

Severe

Continual

Frequent

60%

Persistent

Moderate

Daily

5/month

> 60%

Persistent

< 80%

Mild

3-6/ week

3-4/month

80%

Persistent

Mild

2/week

2/month

80%

Intermittent

IgE Antibodies

Busse, WW, Lemanske, RF: NEJM 344:350-362, 2001

Busse, WW, Lemanske, RF: NEJM 344:350-362, 2001