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Adrenergic (Sympathomimetic) bronchodilators

Clinical indication

General indication:

Relaxation of airway smooth muscle in the presence of airflow obstruction associated with acute and chronic asthma, bronchitis, emphysema, bronchiectasis, CF and other obstructive airway diseases, ex. occupational.

Indication for short-acting agents:

Relief of acute reversible airflow obstruction. Also named "rescue agents".

Indication for long-acting agents:

Maintenance bronchodilation, control of bronchospasm and control of nocturnal symptoms in asthma and other obstructive diseases.

Classes of adrenergic bronchodilators

Ultra-short-acting (<3 hours' duration)

Epinephrine, Isoproterenol, Isoetharine.

Short-acting (4-6 hours duration)

Metaproterenol, Terbutaline, Albuterol, Bitolterol, Pirbuterol, Levalbuterol.

Long-acting (12 hours duration)

Salmeterol, Formoterol

Slight differences in chemical structure lead to significant differences in activity

Catecholamines

Epinephrine

Brand name: Adrenalin Cl

Dosage form: SVN solution 1% and MDI (Primatene Mist)

Adult dosage: .25-.5 ml qid, Primatene Mist (.2 mg/puff) as ordered or needed.

-potent catecholamine bronchodilator

-both beta and alpha stimulation, with strong cardiac side effects

-rapid onset of action

-short half life, because of fast and efficient COMT inactivation

-it could be used SC (1/1000. .3 ml every 15-20 min, up to 1 mg within 2 hrs.)

Racemic epinephrine

Brand names: Micro-Nefrin, Asthma Nefrin,

others.

Dosage form: SVN solution 2.25%

Adult dosage: .25-.5 ml qid

It only has half of the alpha action of Epinephrine.

It is often used either by inhalation or direct

instillation to reduce airway swelling after extubation, for

treatment of epiglottitis and other diseases and to control

bleeding during bronchoscopy.

Isoproterenol

Brand names:Isuprel, SVN solution .5%, .25-.5ml qid

Isuprel Mistometer, MDI 103 μg/puff, 2

puffs qid

-potent catecholamine bronchodilator

-no alpha action; beta unspecific action with

strong cardiac side effects because of beta 1 component

-short half life due to COMT inactivation

Isoetharine

Brand name: Isoetharine HCl

Dosage form: SVN solution 1%

Adult dosage: .25-.5 ml qid

-one of the first β2 specific bronchodilators

-currently considered obsolete as an inhaled bronchodilator

-useful to prevent bronchoconstriction as a side effect and

for "before and after" test

-cardiac side effects are minimal, if any

-half life is short, due to COMT inactivation

Catecholamine metabolism and the "keyhole" theory

All the previously mentioned catecholamines are metabolized by COMT to an inactive compound COMT is very efficient; thus, the half life of catecholamines is 1.5-3 hours.

They are unsuitable for oral administration because they are inactivated in the gastrointestinal tract and the liver.

Catecholamines must be stored in amber bottles because of heat, air and light inactivation (be aware of the pink-tinged residue in the SVN).

The larger the side chain attachment to a catechol base, the greater the β2 specificity.

Resorcinols

They resulted from a modification in the structure of the catechol nucleus (OH group was shifted from C4 to C5, ), which became a resorcinol nucleus, resistant to COMT inactivation).

Advantages:

- Significantly longer half life (4-6 hours), thus

better suited for maintenance therapy.

- They could be taken orally.

Disadvantage:

- They are slower to reach a peak effect.

Metaproterenol

Brand name: Alupent

Dosage form Adult dosage

SVN 5% .3 ml tid-qid

MDI 650 μg/puff 2-3 puffs tid-qid

tablet 10-20 mg 20 mg tid-qid

syrup 10 mg/5 ml 2 tsp tid-qid

Terbutaline

Brand name: Brethaire

Dosage form Adult dosage

MDI 200 μg/puff 2 puffs q4-6h

tablet 2.5-5 mg 5 mg q6h

injection 1 mg/ml .25 mg SC

Saligenins

Saligenins resulted from a different modification of the catechol nucleus (see

Albuterols C3 and Terbutalines C3).

Currently available saligenins are Albuterol, Pirbuterol, Bitolterol and Levalbuterol.

Average half life is 6 hours, up to 8 for Bitolterol and Levalbuterol.

        Albuterol

Brand names: Proventil, Proventil HFA, Ventolin.

Dosage form Adult dosage

SVN .5% .5 ml tid-qid

MDI 90 μg/puff 2 puffs tid-qid

DPI 200 μg/capsule 1 capsule q4-6h

tablet 2 mg 4 mg tid-qid

syrup 2 mg/5 ml 1-2 tsp tid-qid

Pirbuterol

It is faster than Albuterol but less potent.

Similar in both efficacy and toxicity to Metaproterenol.

Brand name: Maxair

Dosage form: MDI 200 μg/puff

Adult dosage: 2 puffs q4-6h

Bitolterol

It is a prodrug, because the administered

form must be converted to the active drug Colterol

in the body This results in a sustained-release effect of up to 8 hours.

Brand name: Tornalate

Dosage forms Adult dosage

SVN .2% 1.25 ml bid-qid

MDI 370 μg/puff 2 puffs q8h

Levalbuterol (R-isomer of Albuterol)

Advantages:

-Less side effects

-Longer half life, up to 8 hours

Brand name: Xopenex

Dosage forms: Adult dosage

SVN .63 mg/3 ml 3 ml tid

1.25 mg/3 ml 3 ml tid

Long-acting β-adrenergic agents

Sustained-release Albuterol

Proventil Repetabs (2-layer tablets)

Volmax (perforated tablet)

Salmeterol

Advantage: 12-hour long half life (less frequent dosing and

protection through the night). Not useful for acute attack

therapy.

Brand name: Serevent

Dosage forms Adult dosage

MDI 25 μg/puff 2 puffs bid

DPI 50 μg/blister 1 blister bid

        Formoterol

Advantage: Same half life, faster onset of action.

Brand name: Foradil

Additional indications:

Prevention of exercise-induced asthma in

adults and children 12 or older.

- Treatment of asthma in adults and children 5 or older.

Dosage form: DPI 12 μg/inhalation

Daily dosing schedule: 12 μg bid

Summary

Group Onset Peak Half life

of action

Catech. 1-3 m 15-20 m 1-3 h

Non-cat. 5-15 m 30-60 m 4-6 h

(except Salmeterol)

Salmet. >20 m 3 h 12 h

Formot. 15 m 30-60 m 12 h

Side effects seen with β-agonist use

-Tremor

-Palpitations and tachycardia

-Headache

-Insomnia

-High blood pressure

-Nervousness

-Dizziness

-Nausea

-Tolerance to bronchodilator effect

-Loss of bronchoprotection

-Decrease in PaO2 (drop in oxygen saturation is minimal)

-Hypokalemia

-Bronchoconstricting reaction to solution additives (SVN) and propellants (MDI)