Pharmacotherapy of Bronchial Asthma

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Beethoven

John F. Kennedy Calvin Coolidge

Elizabeth Taylor

Bob Hope

Charles Dickens

ASTHMA COMPANY!!

8 Marriages7 Men!!2 Oscars

•B.Asthma• ASTHMA IS DEFINED• CHRONIC INFLAMMATORY DISEASE OF AIRWAYS• CHARACTERIZED BY INCREASED

RESPONSIVENESS OF THE TRACHEOBRONCHIAL TREE, MULTIPLICITY OF STIMULI.

• MANIFESTED PHYSIOLOGICALLY• BY WIDESPREAD NARROWING OF THE AIR

PASSAGES• RELIEVED SPONTANEOUSLY OR AS

A RESULT OF THERAPY.• MANIFESTED CLINICALLY• BY PAROXYSMS OF DYSPNEA,

COUGH, AND WHEEZING.

•B.Asthma…..course

B.Asthma…Pathogenesis

The outpouring of mucus from hypertrophied submucosal glands, the bronchoconstriction,

and dehydration ,contribute to the formation of mucus plugs that can block airways in asthmatic

patients.

INSPISSATED MUCUS PLUG

COUGHED UP BY A PATIENT

DURING AN ASTHMATIC ATTACK


Bronchospasm

Bronchospasm

Inflammation

&

HyperactivityInflammation

&

Hyperactivity

Non-Allergens

•Infection

•Exercise

•Cold air

•En.Pollutants

Non-Allergens

•Infection

•Exercise

•Cold air

•En.Pollutants

Allergens

•House

dust

•Cockroach

•Cat dander

•Molds

•Pollens

Allergens

•House

dust

•Cockroach

•Cat dander

•Molds

•Pollens

Neura

lNeura

l

Allergen challenge1h 6h

•Early ReactionType I•Preformed mediator release

•Late ReactionType II•Inflammatory cell recruitment and activation•MAY LAST WEEKS

Early And Late Reaction

B.Asthma…Pathogenesis-Chemical mediators

•Eosinophil Cationic protein

•E.Major Basic Protein

Reversed byβagonists

Theophylline

Neural stimuli

Noxious stimuli[Irritants]


•Pharmacologic stimuliAspirin-Can be fatal [AIA]ß-adrenergic antagonists-Can be

fatalSulfiting agents-Pot.metasulfite

[ pharmaceuticals as preserving agents]

Tartarazine

Allergic inflammation of airways

Pharmacotherapy of Bronchial Asthma

12

3

4


Long Term Control Medications

Quick Relief Medications

1.Short acting ß2 Agonists

2.Methylxanthines3. Anticholinergics[Not alone]

1.Glucocorticoids

2.Long-acting ß2 agonists

3.Combined medications

4.Mast cell stabilizers

5.Leukotrine modifiers

6.Methyl xanthines

Pharmacotherapy of Bronchial Asthma1. BronchodilatorsA. ß2 Agonists-Salbutamol, Bambuterol,Salmeterol,Formoterol, EphedrineB. Methylxanthines-Theophylline,Aminiohylline

,Choline theophyllinate C. Anticholinergics-Ipratropium bromide,

Triotropium bromide2. Leukotrine

modulators

Montelukast, Zafirlukast,

Zileuton

3. Mast cell stabilizers- Nedocromil

Sod. Cromoglycate [Cromonil ]

4. CorticosteroidsA. Systemic-

Hydrocortisone,-- i.v Prednisolone,--oralInhalational:

Beclamethasone5. Anti-IgE Antibody:

Omalizumab

Sympathomimitecis[Bronchodilators]

MOA:

Pharmacological actions:a)Bronchodilatationb)Inhibit mediator release from mast cellsc)Inhibit micro vasc.leakaged)Increase ciliary activity

c) Tachycardiad) Skeletal muscle

tremor

ß2 Selective•Salbutamol[Albuterol],•Terbutaline,•Metaproterenol, •Pirbuterol•Salmeterol, •Formoterol•Non-selective:

•Adrenaline, Ephidrene, Isoproterenol:Not used because of CVS effects

Increase formation

ß2 Selective Sympathomimitics

Salbutamol[Albuterol], Terbutaline, Metaproterenol, Pirbuterol

Route of Admin: • MDI [Inhalation]: Peak15’ To 4-6h• Nebulizer[Inhalation]: For emergency-More

effective,[Less co-ordination required]Larger particles, hence dose is more

• Tablets [Salbutamol & Terbutaline] [Oral]: • Not usually used.• Children, • Severe asthma-Aerosol worsens cough• No advantage, Over inhalation, More

systemic actiono S.C: Terbutaline is availableLong acting, accumulation on repeated

administration

ß2 Selective Sympathomimitics……

• Salmeterol & Formoterol[Long acting]a)Long acting because highly lipid solubleb)Combined with corticosteroids in long term

therapyc) Not used alone

ß2 Selective Sympathomimitics Toxicity:

• Inhalational-Safe• Oral-Cardiac toxicity,

tremors

ß2 Selective Sympathomimitics…USES

Short acting-• Rescue therapy• Caution-Use of 2 or more cannisters /month

→Marker of risk of long term asthma mortality →Requires anti-inflammatory to prevent loss of

pulmonary functionLong acting• Not for acute• Long term-not controlled by low dose ICS• May carry a risk of arrhythmia


1. BronchodilatorsA.ß2 Agonists-

Salbutamol, Bambuterol, Salmeterol,Formoterol

EphedrineB. METHYLXANTHINES

THEOPHYLLINE, AMINIOHYLLINE, CHOLINE THEOPHYLLINATE

C. Anticholinergics-

2.Leukotrine modulators

3.Mast cell stabilizers-

4. Corticosteroids

5. Anti-IgE Antibody:

Methyl xanthines-Theophylline

Source Alkaloid contentTea leaves

CaffeineTheophylline

50mg1 mg

1cup

Coffee seeds

Caffeine 75 mg 1 Cup

Cocoa, Chocolate

TheobromoineCaffeine

24 mg4mg

1Cup

Cola Caffeine 30 mg 200ml

•Inhibition of PDEs •Accumulation of cyclic AMP and cyclic GMP, •Increasing signal transduction through these pathways

•Competitive antagonist at adenosine receptors

MOA:

Methyl xanthines-TheophyllinePharmacological actions

• CNS;• Low and moderate

doses, caffeine—• Cortical arousal • Increased alertness Deferral of fatigue.• Nervousness and

tremor• Very high doses, • Medullary

Stimulation – convulsions- death;

• CVS:• +ve chronotropic and

inotropic effects LOW Block Adenosine

receptors Mod PDE inhibition-Accu.of

cAMP High Release of Ca at

sarcoplasmic reticulum Increase blood flow-

Pentoxyfiilline

Methyl xanthines-TheophyllinePharmacological actions…..

• GIT: Stimulate secretion of gastric acid

and digestive enzymes. [Coffee . Not caffeine]

• KIDNEY Theophylline—weak diuretic. Not

useful• SMOOTH MUSCLE The bronchodilation Adverse effects, limit the dose Inhibit antigen-induced release of

histamine from lung tissue;

Methyl xanthines-Theophylline

• SKELETAL MUSCLE

• Improves-contractility, reverses fatigue of the diaphragm in patients –COPD

Not the first line therapy in Asthma[ADE]

Only when others fail

S.R. Tab in chronicTDM InexpensiveApnoea in

premature infants• PK?????

USESPharmacological actions

30 μg

25 μg

20 μg

15

10

5 μg5 μg

10 μg

15 μg

20 μg

Theophylline toxicity and plasma concn•Death, •Convulsions, Shock, Arrhythmias•Delirium-Worsening CVS-

•VPBs- ↑ Muscle tone-Flashes of light•Tachypnioea-Agitation

•Tremors-•Restlessness-•Palpitation•Vomiting-Headache-Insomnia

BRONCHODLATION

TherapeuticRange

Toxic

μ g/ml

Theophylline- Drug Interactions• Metabolism Inducers: Smoking, Phenytoin,

Rifampicin, Phenobarbitone• DOSE of Theophylline ?????

• Metabolism inhibitors-Erythro, Cipro, Cimetidine, OCP

• DOSE of Theophylline??????

PreperationsTablets, SR Tabs. Aminophylline-Inj. ,

Why NSAIDs worsen Asthma?

Linoleic acid

Arachidonic acid

Prostaglandins (PG) Leukotrienes (LT)

LipoxygenaseCyclooxygenase

Anti-inflammatory steroidsGlucocorticoids

NSAIDsaspirin

Worsening of Asthma

Zileuton

Cox 1 Specific


3. Mast cell stabilizers-

4. Corticosteroids

5. Anti-IgE Antibody:

1. BronchodilatorsA. ß2 Agonists-Salbutamol, Bambuterol,

Salmeterol,Formoterol, EphedrineB. Methylxanthines-

Theophylline, Aminiohylline, Choline theophyllinate

C. ANTICHOLINERGICS-• IPRATROPIUM

BROMIDE,• TRIOTROPIUM

BROMIDE2.

Leukotrine modulators

Antimuscarinic Agents

Effect of Vagal Tone[Ach

Effect of Vagal Tone[Ach]

Effect of Antimuscarinics?????Receptors

•Ipratropium Bromide•Tiotropium Bromide[longer acting]•Inhalation•As Rotacaps• + Salbutamol•More effective in COPD•Not always effective-Other pathways?

Datura a source of ATROPINEWas in India from ages

Pharmacotherapy of Bronchial Asthma1. BronchodilatorsA. ß2 Agonists-Salbutamol, Bambuterol,



C. Anticholinergics-Ipratropium bromide, Triotropium bromide

2. LEUKOTRINE MODULATORSMONTELUKAST, ZAFIRLUKAST,ZILEUTON

3. Mast cell stabilizers-

4. Corticosteroids5. Anti-IgE

Antibody:

:Leukotriene Modifiers: 1. Leukotriene Receptor Antagonists

2. 5-Lipoxygenase Inhibitor

• Arachidonic acid

• 5-Lipoxygenase

• Leukotrines[LTB4, C4, D4]

• LT Receptors

•Food interferes with absorption•Prophylactic•Oral•Safe

•Efficacy and use same as below•Short acting•Hepatotoxic

5-Lipoxygenase Inhibitor

Zileuton

Leukotriene Receptor Antagonists MontelukastZafirlukast

Airway edema,*Smooth muscle*constriction, *Inflammatory process

PRPHYLACTIC





2. Leukotrine modulatorsMontelukast, Zafirlukast,Zileuton

3. MAST CELL STABILIZERS- NEDOCROMIL

SOD. CROMOGLYCATE [CROMONIL ]

4. Corticosteroids5. Anti-IgE

Antibody:

Mast cell stabilizers

•Nedocromil]•Sod. Cromoglycate [Cromonil]•Inhibit degranulation of mast cells•Route-MDI•Uses-Asthma, Allergic rhinitisAllergic conjuctivitis

PRPHYLACTIC





2. Leukotrine modulators

Montelukast, Zafirlukast,

Zileuton

3. Mast cell stabilizers- Nedocromil

Sod. Cromoglycate [Cromonil ]

4. CORTICOSTEROIDSA. SYSTEMIC-

HYDROCORTISONE, PREDNISOLONEINHALATIONAL:

BECLAMETHASONE5. Anti-IgE Antibody:

Glucocorticoids• Asthma

• Airway inflammation,

• Airway hyperreactivity,

• Acute bronchoconstriction

• Glucocorticoids do not directly relax airway smooth

muscle

• No effect on acute bronchoconstriction

• Most effective drugs

• Profound and generalized antiinflammatory action

• Very few mechanisms of inflammation escape the inhibitory effects

1. Modulation of cytokine and chemokine production;

2. ↓ of PG synthesis; 3. ↓ Accumulation of

basophils, eosinophils,4. ↓Vascular permeability 5. Potentiate the effect of ß-

agonists

Inhaled Glucocorticoids[Aerosol therapy]

1. Glucocorticoids are very effective in controlling asthma,

2. Systemic glucocorticoids -serious adverse effects

3. Inhaled glucocorticoids - target drug directly to the site of inflammation-LUNG

4. Enhance the therapeutic index

5. ↓number and degree of side effects

6. Without sacrificing clinical utility

PREPERATIONS• Beclomethasone

dipropionate • Triamcinolone

acetonide • Flunisolide• Fluticasone

propionate• Budesonide• Mometasone• Ciclesonide[Trial]

GlucocorticoidsUses

• Acute asthma • Persistent asthma• ‘Status’-Acute severe• Oral prednisone• COPD-Exacerbations

Glucocorticoids-ADE• ADE[Inhalation]

• Cough, oral candidiasis• Dysphonia• Abolished by rinsing the

mouth after use and• Use of a spacer device.• Systemic effects can

occur [Inhalation] :• Increases with dose• Growth retardation

(children)• Increased bone catabolism

(osteoporosis risk)• Adrenal suppression• Bruising

• ADE:Oral glucocorticoids

• Hypertension• Diabetes• Proximal

myopathy• Osteopenia/

osteonecrosis• Central

adiposity/purple striae/buffalo hump

Glucocorticoids; Some facts

•Steroid phobia•Inhaled is not=systemic Or = Anabolic steroids

•Regular therapy is important•If inadequately controlled, Long-acting Beta agonist can be combined-Combination inhalers•Fluticasone+Salmaterol•Budesonide+Formeterol

Other Drugs OMALIZUMAB•Anti-IgE Monoclonal AB•Prophylactic•Expensive

Future:1.MAB against cytokines2.Antagonists of cell adhesion molecules3. Protease inhibitors4. Immunomodulators5.Macrolides[??Anti Chlamydial]6.PDE4 Specific inhibitorsRoflumilast, Cilomilast, Tofimilast

Pharmacotherapy

Causes of airway narrowing and Tt.• Broncho constriction• Mucosal edema• Cellular infiltration• Hyperplasia of secretory cells• Hyperplasia of vessel wall• Hypertrophy of smooth muscles

Easily reversed

Sustained

Tt with

Anti-infl.

required

Management

[Rescue medication]

?

Short acting β2 agonist SOS for symptom relief

ICSLow Dose

ICSLow Dose

ICS High Dose

ICS High Dose

LABA

LABA LABA

OCS

1 MildIntermittent

MildPersistent

SeverePersistent

VerySevere

Persistent

ModeratePersistent

Stepwise approach to asthma therapy

•ICS: Inhaled corticosteroid

•LABA: Long acting β2 agonist

•OCS: Oral corticosteroid

Harrison II Vol. Page 1605

3

4

5

2

Acute Severe asthma1. High flow OXYGEN via mask2. Nebulised high dose beta2-

agonists 3. Intermittent repeated doses

(every 15-30 minutes) to continuous nebulisation

4. +Nebulised ipratropium -5. Steroid therapy - continue

oral prednisolone therapy for 3 days (children) or 5 days

6. Intravenous hydrocortisone -Patients unable to take oral medication.

7. IV fluids where dehydrated 8. Correction of hypokalaemia

9. Bolus IV magnesium sulphate - in those over 5 years with poorly responsive

10. IV[Infusion?] aminophylline - only used in patients with near-fatal or life threatening asthma with poor response

11. Antibiotics are not indicated routinely.

12. May require intubation.

http://www.patient.co.uk/DisplayConcepts.asp?WordId=PREDNISOLONE&MaxResults=50

http://www.patient.co.uk/DisplayConcepts.asp?WordId=HYPOKALAEMIA&MaxResults=50

Aerosol Delivery of Drugs

• Accomplishes topical application• Most of Anti asthma drugs, Otherwise systemically

toxic• Particles >10 mm – deposited in mouth and

oropharynx,• Particles smaller than 0.5 mm are inhaled to the

alveolae and subsequently exhaled without being deposited in the lungs.

• Particles with a diameter of 1 to 5 mm deposited in small airways hence the most effective.

• Unfortunately, no system in use produces particles limited to the appropriate size range.

Metered dose Inhaler

Step1:Shake the inhaler well.

Step 2: Breathe out gently, place the mouthpiece in the mouth with lips curled around it.

Step 3: Begin breathing in slowly but at the same time, press down on the inhaler canister.

Step 4: Continue breathing in slowly and steadily until the lungs are full.

Step 5: Hold your breath for 10 seconds or for as long as comfortable. Breathe out slowly.

MDI

Rotahaler

Step 1: Insert a rotacap, transparent end first, into the raised square hole of the rotahaler

Step 2: Rotate the base of the Rotahaler in order to separate the two halves of the rotacap.

Step 3: Breathe in as deeply as you can*. Hold your breath for 10 seconds. Breathe out slowly.

*Note: If you are breathing correctly, you will hear the soft rattling sound of the rotacap.

How to use the Spacer[Less cordination required]

Step 1: Assemble your Spacer by fitting the two parts together

Step 2: Shake the Inhaler. Fill the inhaler into the slot opposite the mouthpiece.

Step 3: Close your lips firmly around the mouthpiece.

Step 4: Release a dose of medicine into the Spacer and breathe in steadily and deeply through your mouth.

Step 5: Remove the Spacer and hold your breath for as long as comfortable. Breathe out slowly

Zerostat Spacer

Nebulizer

MDI•Drug micronizedAnd under pressure•Sprayed into the mouth•Then pt.inhales

Rotahaler•Powder in a capsule•Pt effort is•Required to draw the drug and inhale

Nebulizer•Drug driven by compressed air/oxygen•Motorized•Less pt effort•Emergencies•Expensive

Bronchial asthma

• Inflammatory disease• NSAIDs not effective! But may worsen.• Inflammation , secretions and

bronchospasm.• Each is targeted by appropriate group

of drugs• Severe asthma may be fatal• Regular medication very important.• Steroid phobia is ill placed.• Children are also not spared

New drugs targeting Th2 lymphocytes in asthma

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2259400 • J Occup Med Toxicol. 2008; 3(Suppl 1): S6.• Gaetano Caramori,1 David Groneberg,2 Kazuhiro

Ito,3 Paolo Casolari,1 Ian M Adcock,3 and Alberto Papi1

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2259400

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2259400

Pharmacotherapy of Bronchial Asthma

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