Bronchial asthmaLecture 1

Professor Ahmed ShaabanProfessor of Pharmacology &

Senior Consultant of Endocrinology

Sympathomimetics A) DIRECT

(stimulate α and / or β receptors)

Catecholamines (CA) Non CA

a) Natural a) α1 selective agonists:

1. Epinephrine (α & β).

2.Norepinephrine (NE):

3.Dopamine (DA)

b) Synthetic: b) β2 selective agonists:

1. Isoproterenol 1. Salbutamol (albuterol).

2. Bambuterol.

(isoprenaline) : β 3. Terbutaline. 4. Hexoprenaline.

2. Dobutamine : 5. Fenoterol. 6. Metaproterenol.

7. Salmeterol. 8. Formoterol.

* Short acting: 1- 6

* Long acting: 7 & 8.

A) INDIRECT (non CA) : →

a) rapid release of CA:

1. Ephedrine.

b) ↓ reuptake I of CA: cocaine &…..

B) DUAL ( mixed ) : (non CA)

Ephedrine: 70% indirect & 30% direct.

N.B.

1. Direct & indirect sympathomimetics have rapid & delayed onset

respectively. Accordingly, they are usually used in acute and

chronic cases (or prophylaxis) respectively.

2. CA contain catechol nucleus (dihydroxybenzene). Due to specific

metabolism by MAO & / or COMT they have short duration and

cannot be given orally. They do not pass BBB.

Non CA have longer duration and many of them can be given

orally.

Molecular mechanism α1 adrenoceptors (excitatory) are linked to Gq proteins. They stimulate phospholipase C → ↑ IP3 → ↑ free Ca++ inside cytoplasm.

β receptors (β1,β2 & β3 ) are coupled to Gs proteins . Stimulation activates adenyl cyclase →↑cAMP →

β1 receptors are stimulatory. ↑cAMP →↑free Ca++ inside myocard. m. fibers. β2 receptors are inhibitory. ↑cAMP→:

1. Inactivation of myosin light chain kinase in smooth muscles → relaxation.

2.↑ Ca++ bound to inner side of cell membrane →↓ free Ca++ → relaxation.

3. ↓ release of allergic mediators as histamine by ↑ Ca++ bound to the inner side of mast cell ( & other cells mediating allergic reactions) membrane.

4. ↑ mucociliary transport.

Adrenoceptors & Actions

Epin

Isopr.

Salb.

α 1 β 1 β 2 central Central

1.VC of skin, m. membr.& splanchnic vessels. 2.Mydriasis(contraction of dilator pup.)

1.↑ cardiac properties:….. 2.↑ lipolysis

1. brochodilatation 1. anxiety & 2.↑glycogenolysis in 2. tremors muscles & liver. 3.VD of skeletal, coron.

- CNS stimulation e.g. anxiety (β1) &tremors

1- Epinephrine stimulates : α , β & weak central

2- Isoprenaline stimulates : β & weak central.

3- Salbutamol stimulates : β2 > central & weak β1.

Bronchial asthma

Definition:

A chronic inflammatory condition of reversible airway obstruction with intermittent exacerbation of acute asthmatic attacks causing expiratory dyspnea. Mainly nocturnal, with dry cough (may also sputum) and wheezes.

Pathology Treatment

1. Bronchoconstriction. Bronchodilators

2. Congestion (VD), edema & Decongestants

inflammatory cells in bronchial mucosa.

3. Increase bronchial mucous secretions. Expectorants

& fluids

Causes1) Allergy & inflammation. Antiinflammatory drugs:

1. Corticosteroids

2. Leukotriene inhibitors

3. Mast cell stabilizers

2) Infection. Antimicrobials

3) Psychological. Psychotropic drugs

4) Drug-induced (iatrogenic) Avoid these drugs1. ß blockers.

2. Cholinomimetics.

3. Histamine & histamine releasers as morphine, curare & thiopental.

4. Drugs acting as hapten (incomplete antigen) as penicillin.

5. Aspirin asthma: salicylates inhibit cyclooxygenase leading to increase arachidonic acid which is converted into leukotrienes.

Pathogenesis of bronchial asthmaA) Release of allergic & inflammatory mediators:

B) Release of T lymphocytes mediators:

C) Autonomic imbalance:

Disturbance in intracellular cAMP/IP3 ratio:

Receptors in bronchial muscle are adrenergic β2 (bronchodilator, predominant) & α1 (bronchconstrictor) or cholinergic M3 (bronchconstrictor).

NANC fibers are mainly bronchoconstrictor.

Airway obstruction is usually reversible, but may be irreversible → epithelial damage, subepithelial fibrosis, smooth muscle hypertrophy, ↑mucus secretion (↑no. & size of mucus glands) & ↑vascularity (airway remodeling). This → ↑obstruction & ↓ttt response.

Types of bronchial asthma

Antigenic Cryptogenic

(atopic or specific) (non atopic)

Age < 15 y > 35 y

Causes allergy iatrogenic, infection,

psychological, exercise, cold.

Family history + ve -ve

Seasonal variations + ve -ve

Skin sens. tests + ve -ve

Ig E increased normal

Response to bronchodilators +++ +

,, to leukotriene inhibitors good bad

Bronchodilators used in asthma ↑ cAMP ↓ IP3

By anticholinergics

↑ adenyl cyclase ↓phosphodiestrase e.g. ipratropium

By sympathomimetics by methyl xanthines

Direct (rapid onset) Indirect (delayed onset)

Bronchodilators & corticosteroids attenuate bronchial circad. rhythm.

Normal peak of corticosteroids occurs at noon causing

bronchoconstriction at early morning & night.

corticostr. level

bronch. circ. rhythm

Morning noon night