Pharmacology of Asthma Farmakologi Compatibility Mode

1

Pharmacology of Asthma

AZL & YSP

Dept. Pharmacology & Therapeutic, School of Medicine

Universitas Sumatera Utara

Mei 2011, KBK, Respirasi, FK USU, Medan

Pathologic Findings

• 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

2

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

Etiology

• Genetic factors

– Atopy

• Environmental factors

– Viruses

– Allergens

– Occupational exposure

3

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

4

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 ofepithelium

Mucus plug

BasementMembranethickening

Neutrophil andeosinophil infiltrationSmooth muscle

Hypertrophy and contraction

Oedema

Hyperplasia ofMucos glands

Barnes PJ

5

Chemicals Involved in Inflammation

• IgE

• Histamine

• Tryptase

• Leukotrienes (LTC4)

• Platelet activating factor (PAF)

• Prostaglandins (PGD2)

• 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

Mucus

hypersecretion

Hyperplasia

Eosinophil

Mast cell

Allergen

Th2 cell

Vasodilatation

New vessels

Plasma leakOedema

Neutrophil

Mucus plug

Macrophage/

dendritic cell

Bronchoconstriction

Hypertrophy / hyperplasia

Cholinergic reflex

Epithelial shedding

Subepithelial

fibrosis

Sensory nerve activation

Nerve activation

Barnes PJ

6

Asthma components

Healthy airway Asthmatic airway

Smooth muscle

Epithelium

Aveolar septum

Smooth muscle

contraction

Epithelial shedding / damage

Inflammation and oedema

Mucus and plasma exudation

Barnes PJ

7

8

SeverityDays with Symptoms

Nights with Symptoms

PEF or FEV1.0

Severe Persistent

Continual Frequent ≤ 60%

Moderate Persistent

Daily ≥ 5/month > 60% < 80%

Mild Persistent

3-6/ week 3-4/month ≥ 80%

Mild Intermittent

≤ 2/week ≤ 2/month ≥ 80%

Classification of Asthma Severity:Clinical Features Before Treatment

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

9

Intervention in Asthma

Inducers Triggers

Inflammation

eosinophils

ECP

Airways

Hyper-responsivenessExercise induced asthma

Symptoms

Cough, chest tightness Wheeze, dyspnea

Airways obstruction

Avoidanceof allergens, infections

Inhaled corticosteroids

ß2 agonist bronchodilators

General Pharmacologic Approach to the Treatment of Asthma

– “Relievers” • Short-acting bronchodilators

– β2-adrenergic agents– Anti-cholinergic (Parasympatholytic) agents

– “Controllers” • Corticosteroids• Long-Acting bronchodilators

– β2-adrenergic agents– Methylxanthines

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

10

“Relievers”

Historical Perspective

• Datura stramonium (1802)

• Epinephrine (1903)

• Ephedrine (1926)

• Isoproterenol (1940)

• Isoetharine (1951)

• Metaproterenol (1961)

• Beta2-adrenergic agents via MDI (1973)

• Ipratropium bromide (1987)

• Salmeterol (1994)

• Levalbuterol (1999)

11

Patho-Physio-Pharmacology of Bronchodilators

Adrenergic Bronchodilators –Short-Acting Agents

• Catecholamines– Epinephrine

– Isoproterenol

– Isoetharine

• Resorcinol agents– Metaproterenol

• Saligenin agents– Salbutamol

• Pirbuterol

• Bitolterol

12

ββββ-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 β−β−β−β−agonists

Beta Agonists

Short acting

Generic name Duration of action β2-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 +++

β2 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 β2 selectivity. The selectivity of β2

agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small

doses to the airways and minimizes systemic exposure. β agonists are generally divided into short

(4-6 h) and long (>12 h) acting agents.

13

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

• 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.


14

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.

15

Anticholinergic Bronchodilators

• Tertiary Ammonium Compounds

– Atropine sulfate

– Scopalamine

• Quaternary Ammonium Compounds

– Ipratropium

– Tiotropium


• 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).

16


• 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”

17

Controllers

• Corticosteroids

• Long-Acting bronchodilators

– β2-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

18

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


• 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.

19


• 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.

20

Systemic Glucocorticoidsside 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

• Sustained-released salbutamol

• Salmeterol

• Formoterol

21

• Modes of administration

– Inhaled

– Oral

• Mechanisms of action

– Same as short-acting beta-2 agonists

– Effects persists for at least 12 hours


• 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®)


22

• 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.

23

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

• 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

24

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

25

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• Advantages:

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

–Dosing QID

–Dosage Forms – MDI or Nebulized solution (Cromolyn)

–Advantages - alternative to steroids/β-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).

26

Leukotriene modifiersZafirlukast, Montelukast, and Zileuton

• 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.

27


• 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.

28


• 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 Antibodies

29

IgE AntibodyOmalizumab

• Used as intravenous or intramuscular anti-asthma.• diminishing the production of IgE through effects on

interleukin 4 or on IgE itself have been evaluated– Soluble recombinant IL-4 receptor that can be delivered by

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

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

30

Routes of Administration

• Inhaled– Metered dose inhalers (MDI)

• “Spacers”

– Dry powder inhalers (DPI)

– Nebulized (“wet”) aerosols

• Oral

• Parenteral– Subcutaneous

– Intramuscular

– Intravenous

31

Pharmacokinetics of anti-asthma

Inhaler Sub-cutane

Venaportae

Bloodflow

Urine

Membranemucous

Oral

Excretion

32

Is there an advantage to using a nebulizer, as

opposed to an MDI, for delivery of medications

for the treatment of asthma?

33

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

34

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

35

• 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

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

Key Points

• Short-acting beta2-agonists: Therapy of choice for relief of acute symptoms and prevention of EIB.

• Anticholinergics: May provide some additive benefit to inhaled beta2-agonists in severe exacerbations. May be an alternative for patients who do not tolerate inhaled beta2-agonists.

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

36

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 beta2-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.

37

Treatment Protocols

38

39

Documents

Pharmacology of Asthma Farmakologi Compatibility Mode