This document discusses neuronal regulation of airways and various drugs used for bronchodilation. It notes that airway tone is mainly controlled by the vagus nerve and parasympathetic nerves. Various receptors like muscarinic, beta-adrenergic, and their roles in airway smooth muscle contraction and relaxation are described. Different classes of bronchodilators like adrenergic agonists, cholinergic antagonists, methylxanthines and their mechanisms and examples like isoproterenol, ipratropium, theophylline are summarized along with their effects, dosages and limitations.

1. DR TULSI RAM SHRESTHA, KMCTH

2. Neuronal Regulation

3. Neuronal Regulation
• Airway tone mainly controlled by the vagus nerve, and the
parasympathetic nerves carried in the vagus nerve are tonically active,
producing a stable, readily reversible baseline tone of the airway
smooth muscle
• Preganglionic parasympathetic nerve fibers project to the airways via
the vagus nerve. They form cholinergic synapses with postganglionic
neurons via airway parasympathetic ganglia.
• Postganglionic parasympathetic cholinergic and nonadrenergic
noncholinergic (NANC) fibers innervate ASM, providing the dominant
control of smooth muscle tone and thus airway caliber, as well as
airway glands and microvasculature in the respiratory tract

4. Muscarinic receptors
▪ ASM contraction induced by ACh is mediated primarily
via the M3 mAChRs
▪ M1 mAChRs: inhibit the opening of K+ channels→
depolarization of parasympathetic ganglion cells
▪ M2 mAChRs couple to adenylyl cyclase via Gi in an
inhibitory manner→ oppose β-AR-mediated increase in
cAMP→attenuation of β-AR-induced relaxation

5. β Adrenergic receptors
▪ β2 AR: localized to ASM (3-4 X
104 per cell), endothelial,
vascular smooth muscles, SM
glands, proinflammatory and
immune cells, including mast
cells, macrophages,
neutrophils, lymphocytes,
eosinophils, type I and type II
alveolar cells
▪ β1 AR: glands, alveoli

6. Bronchodilators
▪ Adrenergic Agonists
▪ Cholinergic Antagonists
▪ Methylxanthines

7. Adrenergic Agonist
▪ β2 Adrenergic agonists produce
effects through interaction with
specific β2-adrenergic receptors
located in the plasma membrane
of cells
▪ Airway smooth muscle relaxation
▪ Bronchial dilatation and
increased airflow

8. Isoproterenol
▪ Potent bronchodilator
▪ Inhaled as a microaerosol from a pressurized canister
▪ 80–120 mcg isoproterenol causes maximal bronchodilation within 5
minutes
▪ 60- to 90-minute duration of action
▪ ready transportation into cells by the uptake process for
catecholamines
▪ converted by catechol-O-methyltransferase to 3-O methyl-isoprenaline
▪ A/E: Tachycardia, dysrhythmias

9. Epinephrine
▪ Rapidly acting bronchodilator
▪ SC (0.4 mL of 1:1000 solution)
▪ Inhaled as a microaerosol from a pressurized canister (320 mcg per puff)
▪ Maximal bronchodilation achieved 15 minutes after
inhalation
▪ A/E: tachycardia, HTN, arrhythmias, and worsening of
angina pectoris
▪ Short duration of action (60–90 minutes)
▪ Cardiovascular effects of epinephrine: in acute vasodilation
and shock as well as the bronchospasm of anaphylaxis

10. Short acting (3-6 hrs)
▪ Levalbuterol
▪ Salbutamol
▪ Metaproterenol
▪ Pirbuterol
Long acting (>12 hrs)
▪ Salmeterol
▪ Formoterol
▪ Arformoterol
β2-Selective Bronchodilators

11. Structure of β-Adrenergic Bronchodilators

12. ▪ Longer acting β2 agonists: highly lipophilic and have a
high affinity for β2 receptor
▪ Salmeterol: side chain binds to a specific site within the
β2 receptor that allows prolonged activation of the
receptor
▪ Formeterol: enter the plasmalemma lipid bilayer,
gradually leaches out and is available over a prolonged
period to stimulate the β2 receptor

13. Short-acting β2 agonist
▪ For rapid relief of wheezing, bronchospasm, airflow
obstruction.
▪ Salbutamol: Max bronchodilation in 15 min of inhalation
▪ Short duration: 4 to 6 hours
▪ Binds weakly to receptor and quickly diffuses back to
microcirculation
▪ Dose: 2-4mg oral, 0.25-0.5mg IM/SC, 100-200 mcg inhal
▪ Presystemic metabolism in the gut wall
▪ Oral bioavailability is 50%, Acts for 4–6 hours

14. ▪ Terbutaline: synthetic sympathomimetic amine
▪ Possess tertiary butyl group on terminal N of side
chain→ greater B2AR specificity
▪ Decrease histamine induced bronchospasm
▪ Dose: 5mg oral, 0.25mg SC, 250-500 mcg inhal

15. Long-acting β2 agonists
▪ Control of symptoms when rescue therapies are
used greater than two times per week.
▪ Combination therapy including a long-acting β2
agonist and inhaled corticosteroid
• Salmeterol: 25 μg per metered dose inhaler; 2
puffs BD
▪ Formeterol: 12–24 μg by inhalation twice daily

16. Adverse effects
▪ Muscular: Tremor
▪ CVS: Tachycardia, Transient ⬇PaO2 > 5mmHg, secondary
to β2-mediated vasodilation in poorly ventilated lung
region
▪ GI: Glycogenolysis and gluconeogenesis→Hyperglycemia
▪ Stimulation of Na+K+ATPase pump→Hypokalemia
▪ Hypomagnesemia

17. Inhaled Cholinergic Antagonists
▪ Act on muscarinic receptors in the airway to reduce
bronchomuscular tone
▪ M1 and M3 receptors are responsible for
bronchoconstriction and mucus production and are the
targets of inhaled anticholinergic therapy
▪ Reduce smooth muscle tone by decreasing release of
calcium from intracellular stores

18. ▪ Ipratropium: short-acting anticholinergic
▪ Used as maintenance therapy for COPD, as rescue therapy for
both COPD and asthmatic exacerbations.
▪ Max bronchodilation with 1-1.5 mg Nebulization
▪ Peak 40-60min, lasts for 6hrs
▪ Tiotropium: long-acting anticholinergic available for
COPD maintenance therapy, 18mcg, peak in 5 min, for 24
hrs
▪ Reduce COPD exacerbations, respiratory failure, and all-cause
mortality

19. Adverse effects
▪ Poorly absorbed, serious side effects are uncommon.
▪ Dry mouth, urinary retention, mydriasis and blurred
vision

20. Systemic cholinergic Antagonists
▪ Atropine and glycopyrrolate
▪ Atropine: Tertiary ammonium structure
▪ Maximum bronchodilation seems to be achieved by
nebulization of 1 to 1.5 mg of the drug; its peak effect is
▪ seen at 40 to 60 min and lasts for up to 6 h
▪ Tachycardia, gastrointestinal upset, blurred vision, dry
mouth, and CNS effects secondary to its ability to cross
BBB

21. ▪ Theophylline: a naturally occurring methylated xanthine
alkaloids
▪ MOA
▪ Release of Ca2+ from sarcoplasmic reticulum, esp in skeletal and
cardiac muscle
▪ Inhibition of PDE which degrades cyclic nucleotides
intracellularly
▪ Blockade of adenosine receptors
Methylxanthine

22. Theophylline
▪ Well absorbed orally, rapidly
▪ Distributed in all tissues—crosses placenta and is
secreted in milk
▪ 50% protein bound, Extensively metabolized in liver by
demethylation and oxidation (P450)
▪ Only 10% excreted unchanged in urine
▪ t½ in adults 7–12 hours, children t½ 3–5 hours and
elderly more slowly
▪ Oral dose: 3–4 mg/kg of theophylline every 6 hours

23. ▪ Dose reduction
▪ Age > 60 yr (× 0.6)
▪ CHF (× 0.6)
▪ Pneumonia (× 0.4)
▪ Liver failure (× 0.2–0.4)

24. Interactions
▪ Inducers
▪ Smoking, phenytoin, rifampicin, phenobarbitone, charcoal
broiled meat meal
▪ Inhibitors
▪ Erythromycin, ciprofloxacin, cimetidine, oral contraceptives,
allopurinol
▪ Theophylline enhances the effects of—furosemide,
sympathomimetics, digitalis, oral anticoagulants,
hypoglycaemics

25. Pharmacodynamics
▪ CNS: arousal, alertness—nervousness, tremor
▪ CVS: ⬆HR, ⬆CO--Arrhythmia
▪ GI: ⬆gastric acid, digestive enzymes secretion
▪ Kidney: Weak diuretic (⬆GFR and ⬇Na reabsorption)
▪ Smooth muscles: Bronchodilation, ⬇ Ag induced release
of histamine
▪ Skeletal muscles: ⬆Contractions of skeletal
muscles→improve contractility and reverse fatigue of
diaphragm

26. Adverse effects
▪ Narrow margin of safety

27. Aminophyllines
▪ Ethylenediamine salt of theophylline with higher
solubility at a neutral pH
▪ Acute bronchodilator effect in patients with asthma that
is most likely to be due to relaxant effect on ASM
▪ Also increases diaphragmatic contractility and reverses
diaphragm fatigue
▪ Dose: 250-500 mg oral or slow IV, children 7.5 mg/kg i.v

29. Anesthetic Bronchodilators
▪ Volatile anesthetics reduce bronchomotor tone and
induce bronchodilation
▪ Isoflurane, Halothane, Sevoflurane
▪ Decrease intracellular calcium mediated by an increase
in intracellular cAMP
▪ Decrease sensitivity of calcium mediated by protein
kinase C

30. Anesthetic Bronchodilators
▪ IV anesthetics reduce bronchomotor tone→relaxant
▪ Ketamine: direct relaxant effect on smooth muscle
▪ Propofol: reduce vagal tone→direct effect on muscarinic
receptors by interfering with cellular signaling and
inhibiting calcium mobilization

31. Adjunctive Agents
▪ Antihistamines: Not standard therapy for asthma, but
the use can diminish the early and late responses to
allergens
▪ Magnesium sulfate: Produces additional bronchodilation
when given in conjunction with standard therapy for
asthma exacerbations.

32. References
▪ Stoelting’s Pharmacology and Physiology in
Anesthetic Practice, 5th edn
▪ Basic & Clinical Pharmacology, 12th edn
▪ Cazzola M, Page CP, Calzetta L, Matera M
G. Pharmacology and therapeutics of
bronchodilators. Pharmacol
Rev 2012;64:450–504.
▪ Nelson HS. β-Adrenergic Bronchodilators.
New England Journal of Medicine.
1995;333(8):499-507.