BRONCHODILATORS: Sympathomimetics and Catecholamines

 β2 adrenergic agonists (sympathomimetics) Actions are classified into:

 Theophylline (methylxanthine)
 Anticholinergic agents (muscarinic receptor antagonists) 1. Peripheral excitatory action on certain types of smooth muscle
- Blood vessels supplying:
o Skin
 Cromolyn sodium (prevents bronchoconstriction) has no direct o Kidney
bronchodilator action. Ineffective once bronchoconstriction has o Mucous membranes
occurred. - Gland cells:
 Anti-leukotrienes have small bronchodilator effect and prevent o Salivary
bronchoconstriction o Sweat glands
 Corticosteroids have no effect on contraction of airway smooth 2. Peripheral inhibitory action on certain types of smooth muscle
muscle and are not considered bronchodilators cells
- Wall of gut
- Bronchial tree
- Blood vessels supplying skeletal muscle
3. Cardiac excitatory action
- Increases HR and force of contraction
4. Metabolic actions
- Increase rate of glycogenolysis in liver and muscle
- Liberation of free fatty acids from adipose tissue
5. Endocrine actions
- Increasing/decreasing secretion of:
o Insulin
o Renin
o Pituitary hormones
6. Actions in CNS
- Respiratory stimulation
- Increase wakefulness and psychomotor activity
- Reduction in appetite
7. Prejunctional actions
- Inhibit/facilitate release of neurotransmitters

Classification of sympathomimetic drugs:

Direct-acting Indirect-acting Mixed-acting

Acts directly in one or more Increase availability of NE Indirectly
adrenergic receptors or E to simulate release NE and
adrenergic receptors directly
activate
receptors
May be
selective/nonselective for a
specific receptor
Selective: Releasing agents: Ephedrine
o α1 – phenylephrine o Amphetamine
o α2- clonidine o Tyramine
o β1- dobutamine
o β2- terbutaline
Nonselective: Uptake inhibitor:
o α1 α2- oxymetazoline o Cocaine
o β1 β2- isoproterenol
o α1α2β1β2- MOA inhibitor
epinephrine o Selegiline
o α1α2β1- NE
COMT inhibitor:
o Entecapone

Physiological basis of adrenergic receptor function:

- Response of any cell or organ to sympathomimetic amines is

related to the density and proportion of α and β adrenergic
receptors
o NE (α1α2β1) has little capacity to increase bronchial
airflow since receptors in bronchial smooth muscle are
largely β2
o Isoproterenol (β1 β2) and epinephrine (α1α2β1β2) are
potent bronchodilators
o Cutaneous blood vessels express almost exclusively α
receptors
 NE and epinephrine cause constriction
 Isoproterenol (β1 β2) has little effect
o Smooth muscle of blood vessels that supply skeletal
muscles has both α and β2 receptors
 β2 activation: vasodilation
 α activation: constriction
- response is also dictated by reflex homeostatic adjustments
o Rise in arterial BP caused by stimulation of vascular α
receptors. This elicits compensatory reflexes mediated
by carotid-aortic baroreceptor system. Results in
slowing of heart
β2 adrenergic agonists
- Inhale β2 adrenergic agonists b ronchodilator treatment of choice
in asthma
- Last resort: isoproterenol (isoprenaline) or metaproterenol
(systemic, short-acting nonselective β agonists)

Chemistry:
- Developed by substituting the catecholamine structure of
norepinephrine and epinephrine. Terminal amine group is
modified to confer β receptor selectivity.
- Exogenous catecholamines are rapidly metabolized by catechol-O-
methyl transferase (COMT) and accounts for short duration of
action of catecholamines.
- Modification of catechol ring (albuterol and terbutaline) prevents
degradation and prolongs effect.

Inhaled β2- selective drugs duration of action: 3-6 hours

Long acting inhaled β2- selective drugs duration: >12 hours
 Salmeterol
 Formoterol

Mode of Action:

occupation of β2 receptors

stimulate G protein

activate adenylyl cyclase

increase inctracellular cyclic

AMP

activation of PKA

phosphorylates various substances

phosporylative events:
•↑ Ca-activated K channel activation leads to
hyperpolarization
•↓ phosphoinositide (PI) hydrolysis
•↑ Na/Ca exchange
•↑Na, Ca, ATPase activity
•↓myosin light chain kinase activity

Bronchodilation
 - Improve asthma control (when given BID) compared to SABA (4-
6x a day)
- Formoterol- more rapid onset; almost full agonist
- Salmeterol- slower onset; partial agonist

- In COPD:

o effective bronchodilators with/without

anticholinergics or ICS
o reduce air trapping and exacerbations
- in asthma:
o never used alone because it does not treat underlying
chronic inflammation
o LABA + ICS

Directly stimulates β2 receptors in airway smooth muscle. 3. Combination inhalers

 LABA + corticosteroids
Induces relaxation by: o Fluticasone/salmeterol (Advair)
 Lowering of calcium concentration by active removal of calcium o Budesonide/formoterol (Symbicort)
from cytosol into intracellular stores and out of the cell  Treatment for asthma and COPD
 Inhibition of myosin light chain kinase activation  Advantages:
 Activation of myosin light chain phosphatase o More convenient
 Opening of a large conductance of calcium-activated potassium o Simplifies therapy
channel which repolarize smooth muscle cell and may stimulate o Improves compliance
sequestration of calcium into intracellular stores. o 2 drugs delivered simultaneously to the same cells in
the airways allow beneficial molecular interaction
β2 agonists also inhibits release of bronchoconstrictor mediators from between LABA and corticosteroids to occur
inflammatory cells and bronchoconstrictor neurotransmitters from airway o More effective than used alone
nerves. Mechanisms include:
 Prevention of mediator release from lung mast cells Stereoselective β2 agonists
 Prevention of microvascular leakage (thus prevention of mucosal o Albuterol – racemic mixture of R- and inactive S-
edema) after exposure to mediators such as histamine and isomers
leukotriene D4 o Levalbuterol- R-albuterol; more potent and more
 Increase mucus secretion from submucosal glands and ion expensive (thus no clear clinical advantage)
transport across airway epithelium; these may enhance
mucociliary clearance Side effects: dose-related and due to stimulation of extrapulmonary β
 Reduce neutransmission in human airway cholinergic nerves by receptors. Common with oral or IV administration
action at presynaptic β2 receptors to inhibit acetylcholine release.  Muscle tremor
(reduce reflex cholinergic bronchoconstriction) o Stimulation of β2 receptors in skeletal muscle
 Tachycardia and palpitations
NO ANTI-INFLAMMATORY EFFECT (even though they have inhibitory effect o Reflex cardiac stimulation secondary to peripheral
on mast cell mediator release microvascular leakage) vasodilation from direct stimulation of atrial β2
receptors and from stimulation of myocardial β1
receptors as doses are increased
Clinical use: o Dose-related prolonged QT interval
 Hypokalemia
1. Short-acting β2 agonists (SABA) o Serious side effect
- Most widely used o β2 receptors stimulation of potassium entry into
- Effective in asthma skeletal muscle secondary to rise in insulin secretion
- Convenient, easy to use, rapid in onset, without significant  ventilation-perfusion (V/Q) mismatch
systemic side effects o due to pulmonary vasodilation in vessels previously
- Bronchodilator of choice for acute severe asthma constricted by hypoxia, resulting in shunting of blood
- Inhalation route preferred to poorly ventilated areas
- Used PRN and not on regular basis for mild asthma; increased use  Metabolic effects
indicates need for more anti-inflammatory therapy o Increase fatty acids
- Resistant to degradation by COMT and MAO (except rimiterol) o Increase insulin
- Duration of action: ~3-4 hours o Increase glucose
o Increase pyruvate
 Albuterol (salbutamol) o Increase lactate
 Levalbuterol
 Metaproterenol Tolerance:
 Terbutaline  Continuous treatment often leads to tolerance which may be due
 Fenoterol to down-regulation of the receptor
 Tulobuterol  However, airway smooth muscle β2 receptors are resistant to
 Rimiterol desensitization because:
 Pirbuterol o Large receptor reserve
o High level of ADRβ2 expression in airway
2. Long-acting inhaled acting β2 agonists (LABA) o GRK2 (inactivates occupied β2 receptors) is very low in
airway
 Salmeterol Long term safety:
 Formoterol  risk of death with fenoterol
 Arformoterol  link between high β2 agonist usage and increased asthma
mortality does not prove causal association
- Duration of action: > 12 hours  LABA should be used with ICS because LABA does not treat
- Also protect from bronchoconstriction underlying chronic inflammation
 Albuterol (Ventolin-HFA, Proventil-HFA)  Muscle cramps
 Flu-like syndrome
Classification: Selective β2 receptor agonist  Conjunctivitis
Administration: inhalation or PO  UTI
Indication: symptomatic relief of bronchospasm  Hypokalemia
 Stevens-johnson syndrome
Action (time):
o Bronchodilation within 15 minutes Monitoring parameters:
o Duration: 3-4 hours  BP
 HR
 Electrolyte and fluid balance
Mechanism of action:  Glucose
Activates adenyl cyclase then stimulates production of cAMP. Increased  Lactate
cAMP leads to activation of protein kinase A (PKA) which inhibits  K levels
phosphorylation of myosin and lowers intracellular ionic calcium
concentrations, resulting in smooth muscle relaxation. Drug interactions:
 Increased risk of hypokalemia with K-depleting agents
Onset: 5 minutes (inhalation), 30 minutes (oral) (corticosteroid, diuretics, xanthines, digoxin)
Duration: 3-6 hours (inhalation), 6 hours (oral)  Increased uterine inertia with halogenated anesthesia
 Increased risk of pulmonary edema with corticosteroids
Absorption: Readily absorbed from GIT  May antagonize effect of anti-diabetics
Metabolism: Undergoes metabolism in liver and gut wall  Increased risk of CV effects with other sympathomimetic agents
Excretion:
 Antagonistic effect with β-blockers
 Via urine (metabolite and unchanged drug)
 Feces (small amounts)

Dose:

Inhalation IV
Severe A: 2.5-5 mg up to QID A: 50 mcg/ml solution:
bronchospasm 250 mcg (4mcg/kg)
C: >4 yrs old same as injected slowly
adult
IM/SC: 500 mcg
repeated every 4 hours

C: >12 yrs old same as

adult
Acute bronchospasm A: (90-100 A: 2-4 mg TID or QID
mcg/actuation) 1-2
inhalations up to QID.
Max 800 mcg daily

C: 6-12 yrs, 1-2

inhalations. Max 400
mcg daily
Prophylaxis of A: (90-100
exercise-induced mcg/actuation) 2
bronchospasm inhalations 10-15 mins
prior

C: 6-12 yrs, 10-15 mins

prior

Special precautions:
 Hyperthyroidism
 Myocardial insufficiency
 Arrhythmias
 Susceptibility to QT-interval prolongation
 HTN
 DM
 Glaucoma
 Hypokalemia
 Seizure disorder
 Renal impairment
 Elderly
 Pregnancy and lactation

Adverse drug reactions:

 Tremor
 Nervousness
 Nausea and vomiting
 Tachycardia
 Palpitations
 Chest pain
 Shakiness
 Dizziness
 Headache
 Insomnia
 Inhalation site sensation
 Hyperactivity
 HTN
 Hypotension
 Increased swearing
 Allergic reactions
 DM
 Methylxanthines  Phenytoin, phenobarbital, rifampin
o Reduced clearance (reduce to half the dose)
 Theophylline  Liver disease
 Related to caffeine  Pneumonia
 Reduced use because of :  Heart failure
o Frequency of side effects  Erythromycin
o Low efficacy  Quinolone
 Allopurinol
 Cimetidine
 Fluvoxamine
 5’-lipoxygenase inhibitor zileuton
 Zafirlukast
 Viral infection
 Vaccination

Preparations and Routes:

 IV:
o 6 mg/kg over 20-30 minutes, maintenance dose of
Mechanism of action: 0.5mg/kg/hour
 Inhibition of phosphodiesterases  Oral:
o Nonselective PDE inhibitor (minimal) o Immediate-release:
o Leads to increase cAMP and cyclic guanosine  Rapidly absorbed, wide fluctuations
monophosphate (cGMP)  Not recommended
o Results in bronchodilation o Sustained-release:
 Absorbed at a constant rate
 Adenosine receptor antagonisms  Steady plasma concentration over 12-24
o Adenosine causes bronchoconstriction by releasing hours
histamine and leukotrienes
o Responsible for side effects by antagonizing A1 Clinical use:
receptors - In acute asthma, IV aminophylline is less effective than β2
 Cardiac arrhythmias agonists, thus they are used in patients intolerant to β2 agonists
 Seizures - Not added to β2 agonists because it may increase side effects
 Interleukin-10 release - If adequate bronchodilation NOT achieved, it may be given with
o Broad spectrum anti-inflammatory effect β2 agonists as maintenance
o IL-10 is reduced in asthma - Useful in nocturnal asthma (slow release)
- Less expensive, thus an affordable add-on treatment
 Effects of gene transcription - May be given in COPD but not preferred
o Prevents translocation of pro-inflammatory
transcription NF-κB into nucleus Side effects:
o Reduces expression of inflammatory genes - Tend to occur at >15mg/L
- Headache
 Effects on apoptosis - Nausea and vomiting (inhibition of PDE4)
o Prolonged survival of granulocytes due to reduction of - Abdominal discomfort
apoptosis may perpetuate chronic inflammation - Restlessness
 Eosinophils: asthma - Increased acid secretion
 Neutrophils: COPD - Diuresis
o Also induces apoptosis in T lymphocytes - Behavioral disturbance ad learning difficulties
- Cardiac arrhythmias
 Histone deacetylase activation - Seizures
o Recruitment of histone deacetylase-2 (HDAC) by
glucocorticoid receptors switche off inflammatory
genes

 Other effects:
o Increase catecholamines
o Inhibition of calcium influx into inflammatory cells
o Inhibition of prostaglandin effect
o Antagonism of tumor necrosis factor

Nonbronchodilator effects:

 Inhibits late response to inhaled allergen

 Reduces infiltration of eosinophil and CD4 lymphocytes into
airways

Pharmacokinetics and Metabolism:

Below 10 mg/L: bronchodilation effect is small

Above 20 mg/L: benefits are outweighed by side effects

Therapeutic range: 5-15 mg/L (10-20 may be effective but toxicity may still
be observed)

Absorption:
- Rapidly and completely absorbed

Metabolism:
- In the liver, by CYP1A2
- Hepatic metabolism influenced by:
o Increased clearance in: (due to induction of CYP1A2
and increase activity) (higher doses needed)
 Children (1-16 years)
 Cigarette and marijuana smokers
 MUSCARINIC CHOLINERGIC ANTAGONISTS - Less likely to antagonize M2-mediated inhibition of Ach
release
- Chemical antagonism of the effects of acetylcholine at muscarinic - More effective than ipratropium QID without loss of
receptors in the lung for relief of asthma efficacy over 1 year treatment period
- Datura stramonium (jimson weed) and related species of
nightshade family contains muscarinic antagonists and were Adverse effects:
smoked for relief of asthma  Unpleasant bitter taste of inhaled ipratropium
o Atropine  Nebulized ipratropium may precipitate glaucoma
o Hyoscyamine o Direct effect of nebulized drug on eyes
o Scopolamine o Use nebulization with a mouthpiece rather than face
- Purified plant alkaloid atropine was introduced but side effect mask
was  Paradoxical bronchoconstriction
o Drying of secretions o Due to additives
 Dryness of the mouth
- Atropine methylnitrate  Urinary retention in elderly
- Ipratropium bromide  Xerostomia
 Blurred vision
 Dyspepsia
Mode of action:  Cognitive impairment
- Competitive antagonists of Ach binding to muscarinic cholinergic Pharmacological Effects: (Atropine)
receptors
- Block effects of endogenous Ach at muscarinic receptors, 1. Cardiovascular
including direct constrictor effect on bronchial smooth muscle - Tachycardia
mediated via the M3-Gq-PLC-IP3-Calcium pathway - No changes I BP or cardiac output
- Dilate cutaneous blood vessels (Atropine flush)
Effect of acetylcholine: (thus antagonists affect these also) 2. Respiratory
 Bronchoconstriction - Bronchodilation
 Increased secretion - Decrease in tracheobronchial secretion
 Stimulation of chemoreceptors of carotid and aortic bodies - Inhibit bronchoconstriction caused by
i. Histamine
Bronchoconstriction is due to: ii. Bradykinin
 Vagal nerve iii. Eicosanoids
 Cholinergic pathways 3. Eye
 Parasympathetic nervous system - Mydriasis (pupil dilation)
- Cycloplegia (paralyze accommodation)
- Photophobia
Only inhibits the reflex Ach-mediated bronchoconstriction - Lens
- Protective against: i. Fixed for far visions
o Sulfur dioxide ii. Near objects are blurred
o Inert dusts iii. Objects may appear smaller than they are
o Cold air - (-) PERRLA
o Emotional factors 4. GIT
- Antispasmodic agents for GI disorders and treatment
No blocking effect on the DIRECT effects of inflammatory mediators of peptic ulcer disease
(histamine, leukotrienes) on bronchial muscle. - Dry mouth
- No/little effect on: - Reduced gastric secretion
o Antigen challenge - Reduce tone and frequency and amplitude of
o Exercise peristalsis
o Fog 5. Urinary tract
o Mast cells - Decrease tone and amplitude of contractions of ureter
o Miscrovascular leak and bladder
o Chronic inflammatory response 6. Biliary tract
- Mild antispasmodic action on gallbladder
7. Sweat glands and temperature
Clinical use: - Inhibition
 Asthma (less effective than β2 agonists) - Hot and dry skin
 Additional bronchodilator in asthmatic patients not controlled on - Sweating may be depressed enough to raise body
LABA temperature
 In COPD, it may be as effective or even superior to β2 agonists 8. CNS
o Due to effect on vagal tone which is the only - Mild in normal doses
reversible element of airway obstruction in COPD - Toxic doses:
 Reduce air trapping and improve exercise tolerance in COPD i. Restlessness
ii. Irritability
iii. Disorientation
Therapeutic choices: iv. Hallucinations
v. Delirium
1. Ipratropium bromide
- Atrovent Contraindications:
- Available as: pMDI and nebulized  Urinary tract obstruction
- Onset: 30-60 minutes  GI obstruction
- Persist: 6-8 hours  Uncontrolled angle-closure glaucoma
- Given MDI 3-4x daily (not given intermittently because
of slow onset) Therapeutic uses:
2. Oxitropium bromide  Respiratory tract
- Quaternary anticholinergic bronchodilator o COPD
- Available in higher doses and therefore have more o Asthma (less effective)
prolonged effect o Rhinorrhea associated with common cold or
- Useful in nocturnal asthma allergic/nonallergic perennial rhinitis
3. Combination inhalers: Ipratropium/albuterol  GUT
- Anticholinergic plus β2 agonist o Overactive urinary bladder
- For COPD o Enuresis in children
4. Tiotropium bromide  GIT
- Long-acting anticholinergic drug o Peptic ulcer
- Once-daily dosing o Reduce gastric motility and secretion of gastric acid
- Binds to all muscarinic receptor subtypes but  Eye
dissociates very slowly from M3 and M1 receptors o Mydriatic
 o Cycloplegia (for measurement of refractive errors) IPRATROPIUM
 CV
o Initial treatment with acute MI in whom excessive Mode of action:
vagal tone causes sinus bradycardia or AV nodal block
 CNS Block all subtypes of muscarinic receptors
o Prevent motion sickness
o Anesthesia Antagonizes the inhibition of Ach release by presynaptic M2 receptors on
 Anticholinesterase poisoning parasympathetic postganglionic nerve terminals in the lung; increase in Ach
o Atropine release may counteract its blockade of M3 receptor-mediated
bronchoconstriction.

Absorption:
- Via inhalation: 90% is swallowed then appears in feces
- Maximal response: 30-90 mins
- Duration: 4-6 hours

Distribution
- Plasma protein binding: < 9% (oral)
- <20% (nasal)

Metabolism
- Via ester hydrolysis (41%) and conjugation (36%)

Excretion:
- urine and feces
- T ½: 2 hours (oral); 1.6 hour (nasal)

Dose: (Inhalation)

Asthma, COPD
 Adult:
 MDI: 20-40 mcg 3-4x daily
 Nebulization: 250-500 mcg 3-4x daily
 Child
 <6 yr: 20 mcg TID
 6-12 yes: 20-40 mcg TID

Acute asthma:
 <6 years: 125-250 mcg no more than 6 hourly up to a total dose of
1 mg

 6-12: 250 mcg up to a total dose of 1 mg

 Tiotropium bromide

Mechanism of action: antagonizes the cholinergic effects of acetylcholine by

reversibly and competitively binding to type 3 muscarinic receptors (M3),
resulting in bronchial smooth muscle relaxation

Absorption:
- Systemically absorbed from lungs
- Bioavailability:
- Dry powder inhalation: 20%
- Inhalation solution: 33%
- Tmax:
- Dry powder inhalation: 5 minutes
- Inhalation solution: 5-7 minutes

Distribution:
- Plasma protein binding: 72%

Metabolism:
- Undergoes minimal hepatic metabolism by non-enzymatic
cleavage and by CYP2D6 and CYP3A4 isoenzymes
Excretion:
- Via urine as unchanged
- T ½ : 5-6 days (dry powder inhalation)

Dosage:

Asthma, COPD:
 Adult:
o Inhalation cap: 1 cap (18mcg) daily via inhaler device at
same time each day
o Inhalation solution: 2 inhalations (5mcg) daily at same
time each day

Contraindications: Hypersensitivity to tiotropium, atropine

Special precautions:
 Narrow-angle glaucoma
 Prostatic hyperplasia/bladder neck obstruction
 Cystic fibrosis
 History of MI or life-threatening cardiac arrhythmia within the
past year
 Not for initial treatment for acute bronchospasm
 Moderate to severe renal impairment
 Pregnancy and lactation

Adverse drug reactions:

 Dry mouth
 RTI
 Pharyngitis, sinusitis, rhinitis
 Epistaxis
 Non-specific chest pain
 UTI
 Dyspepsia
 Hypersensitivity reactions
 Dizziness
 Dysphagia
 Hoarseness
 Intestinal obstruction
 Increased intraocular pressure
 Palpitations
 Tachycardia
 Application site irritation (glossitis, mouth ulceration)

Drug interactions:
 Additive effect with other anticholinergic drugs

Patient counseling: May cause dizziness and blurred vision, if affected, do

not drive or operate machinery