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"Respiratory Pharmacology
UNE-MNA
b 2 ADRENERGIC AGONISTS
Dilates the bronchi and inhibits mediator release
Smooth muscle relaxant
Increase 3,5-Cyclic AMP in mast cells and eosinophils by:
Activating adenylate cyclase
Increases the level of c-AMP, from ATP
BETA AGONISTS ® ADENYL
CYCLASE
È
ATP ®
c-AMP
Promotes the release of heparin from mast cells, an anti-inflammatory molecule
-Limits the recruitment of eosinophils into the airway
-Limits damage to the mucosa
Inhibit mast cell degranulation
-Modifies the Early asthmatic response
Inhibit arachidonic aacid metabolite sysnthesis (bronchoconstrictor)
Block the release of:
-Histamine
-Leukotrienes
-Prostaglandins
Postive feedback is quick, compared to slower anti-inflammatory group drugs
The 1st line drugs for rescue treatment of acute asthma symptoms in
all age groups
Most potent/rapid acting bronchodilators in use today
-Bronchodilation is maximal after 30 minutes
-Duration is about 3-4 hours
Considerations:
Asthma control may deteriorate if only b
-2 are used without anti-inflammatory agents. May allow:
-Chronic inflammation of airway wall
-Permanent airway narrowing
May worsen asthma by increasing tolerance (tachyphylaxis) to
the agonists
May inhibit the action of glucocorticoids
May risk of death if usage is
> 1 canister/month
b 2 Adrenergic Agonist usage
Episodic asthma…use b
-agonists as sole therapy
Chronic asthma…use b -agonists
along with anti-inflammatory drugs
Rescue situations…use the combination
Nocturnal asthma…not effective
Not contraindicated in the pre and postoperative periods
Albuterol (Proventil, Ventolin, Volmax, Airet)
Beta2-Adrenergic Agonist
Bronchodilator
Sympathomimetic
Use: Bronchodilator in reversible airway
obstruction due to asthma or COPD
Mechanism of action: Relaxes bronchial
smooth muscle by action on beta2-receptors with little effect on
heart rate.
Pharmacodynamics/Kinetics:
Peak effect:
Oral: 2-3 hours
Nebulization/oral inhalation: Within 0.5-2
hours
Duration of action:
Oral: 4-6 hours
Nebulization/oral inhalation: 3-4 hours
Metabolism: By the liver to an inactive sulfate, with 28% appearing in the urine
as unchanged
drug
Half-life:
Inhalation: 3.8 hours
Oral: 2.7-5 hours
Elimination: 30% appears in urine as unchanged drug
Usual dosage: See Anesthesiology &
Critical Care Drug Handbook, pg. 39
Adverse Reactions: > 10%
Cardiovascular: tachycardia, palpitations, pounding heartbeat
Gastrointestinal: GI upset, nausea
Drug interactions:
Decreased effect with concomitant beta-adrenergic
blockers (eg, propranolol), digoxin serum
levels may be decreased
Increased therapeutic effect: Inhaled Atrovent may increase
duration of bronchodilation,
Nifedipine may increase FEV-1
Increased toxcity: CV effects may be potentiated in patients
already receiving MAO inhibitors,
tricyclic antidepressants; concomitant
administration of sympathomimetic agents (eg,
amphetamine, dopamine, dobutamine) may
result in enhanced CV effects, inhaled
anesthetics (eg, enflurane)
Bitolterol (Tornalate)
Beta2-Adrenergic Agonist
Bronchodilator
Use: Prevention and treatment of bronchial
asthma and bronchospasm
Mechanism of action: Selectively stimulates
beta2-adrenergic receptors in the lungs producing bronchial
smooth muscle relaxation; minor beta1 activity
Pharmacodynamics/Kinetics:
Onset of action: 3-5 min
Duration of effect: 4-8 hours
Metabolism: Is a prodrug, is hydolyzed to colterol (active)
following inhalation
Half-life: 3 hours
Time to peak serum concentration (colterol): Inhalation:
Within 1 hour
Elimination: In urine and feces
Usual dosage: Children > 12 years and
Adults:
Bronchospasm: 2 inhalations at an interval of at least 1-3
minutes, followed by a third inhalation
if needed.
Adverse Reactions: > 10%
Neuromuscular & skeletal: Trembling
Drug interactions:
Decreased effect: Beta-adrenergic blockers (eg, propranolol)
Increased effect: Inhaled Atrovent may increase duration of
bronchodilation, nifedipine
may increase FEV-1
Increased toxcity: MAO inhibitors, tricyclic antidepressants,
sympathomimetic agents,
inhaled anesthetics (enflurane)
Epinephrine (Adrenalin, Sus-phrine,Bronkaid, AsthmaNefrin, Racemic
Epinephrine, etc)
Adrenergic Agonist Cardivascular: CO, ¯
TPR, mean BP, ¯ renal
perfusion
Adrenergic Agonist Agent
Bronchodilator
Sympathomimetic
Uses: Treatment of bronchospasms,
anaphylactic reactions, cardiac arrest, management of open-angle
glaucoma; added to local anesthestics to decrease systemic
absorption, increase duration of action,
and decrease toxcity of the local anesthetic
Mechanism of action: Stimulates alpha-, beta1-,
and beta2-adrenergic receptors resulting in relaxation of
Smooth muscle of the bronchial tree, cardiac stimulation, and
dilation of skeletal muscle
Vasculature; small doses produce can cause vasodilation via
beta2-vascular receptors; large doses
May produce constriction of skeletal and vascular smooth
muscle; decreases production of
Aqueous humor and increases aqueous outflow; dilates the pupil
by contracting dilator muscle
Pharmacodynamics/Kinetics:
Onset of bronchodilation:
Subcutaneous: Within 5-10 minutes
Inhalation: Within 1 minute
Metabolism: Following administration, drug is taken up into
the adrenergic neuron and
metabolized by monoamine oxidase and
catechol-o-methyl-transferase; circulating
drug is metabolized in the liver.
Usual dosage: See Anesthesiology &
Critical Care Drug Handbook, pg. 329-330
Adverse Reactions: > 10%:
Cardiovascular: Tachycardia (parenteral), pounding heartbeat
CNS: Nervousness, restlessness
Drug Interactions:
Increased toxcity: Increased cardiac irritability if
administered concurrently with halogenated
inhalational anesthetics, beta-blocking
agents, alpha-blocking agents
Formoterol
Levalbuterol (Sepracor)
Isoetharine (Bronkometer)
Isoproterenol (Isuprel, Mistometer, Medihaler-iso, Norisodrine)
Adrenergic Agonist Agent
Bronchodilator
Sympathomimetic
Use: Parentrally in ventricular
arrhythmias due to A-V nodal block; hemodynamically compromised
Bradyarrthythmias or atropine-resistant bradyarrthymias;
temporary use in third degree A-V block
until pacemaker insertion; low cardiac output;
vasoconstrictive shock states; treatment of
reversible airway obstruction as in asthma or COPD
Mechanism of action: Stimulates beta1-
and beta2 receptors resulting in relaxation of bronchial, GI, and
uterine smooth muscle, increased heart rate and contractility, vasodilation of
peripheral vasculature
Pharmacodynamics/Kinetics:
Onset of bronchodilation:
IV: immediate
Metabolism: By conjugation in many tissues including the liver
and lungs
Half-life: 2.5 5 minutes
Elimination: In urine principally as sulfate conjugates
Usual dosage: See
Anesthesiology & Critical Care Drug Handbook, pg. 505
Adverse Reactions: > 10%
CNS: Insomnia, restlessness
GI: Discoloration of saliva (pinkish-red), xerostomia, dry
throat
Drug Interactions:
Decreased effect with beta-blockers
Increased pressor effects with sympathomimetics, albuterol,
guanethidine, oxytocic agents, TCAs
Arrythmias with bretylium, theophylline
Metaproterenol (Alupent, Metaprel)
Beta2-Adrenergic Agonist Agent
Bronchodilator
Sympathomimetic
Use: Bronchodilator in reversible airway
obstruction due to asthma or COPD; because of its delayed onset
of action (1 hour) and prolonged effect (4 or more hours),
this may not be the drug of choice for
assessing response to a bronchodilator.
Mechanism of action: Beta1- and
beta2-adrenergic stimulation; relaxes bronchial smooth muscle by
action on beta2 receptors with very little effect on heart rate.
Pharmacodynamics/Kinetics:
Oral:
Onset of bronchodilation: Within 15 min
Peak effect: Within 1 hour
Duration of action: ~ 1-5 hours
Inhalation:
Onset of effects: within 60 seconds
Duration of action: Similar (~ 1-5 hours)
regardless of route adminstered
Usual dosage: See Anesthesiology &
Critical Care Drug Handbook, pg. 589
Adverse reactions: > 10%
CNS: Nervousness
Neuromuscular & skeletal: Tremor
Drug interactions:
Decreased effect: Beta-blockers
Increased toxcity: Sympathomimetics, TCAs, MAO Inhibitors
Pirbuterol Acetate (Maxair, Autohaler)
Salmeterol Xinafoate (Serevent)
Adrenergic Agonist Agent
Beta2-Adrenergic Agonist Agent
Bronchodilator
Use: Maintainence and treatment of asthma
and in prevention of bronchospasm in patients > 12 years of
age with reversible obstructive airway disease, including patients with symptoms
of nocturnal asthma, who require regular treatment with inhaled, short-acting
beta2 agonists; prevention of exercise-induced bronchospasm. Not
recommended for acute treatment of bronchospasm.
Mechanism of action: Relaxes bronchial
smooth muscle by selective action on beta2 receptors with little
Effect on heart rate; also inhibits release of inflammatory
mediators from the lung; because
salmeterol acts locally in the lung, therapeutic effect is not
predicted by plasma levels.
Pharmacodyamics/Kinetics:
Onset of action: 5-20 minutes (average 10 minutes)
Peak effect: 2-4 hours
Duration: 12 hours
Protein binding: 94% to 98%
Metabolism: Hydroxylated in liver
Half-life: 3-4 hours
Usual dosage: See Anesthesiology &
Critical Care Drug Handbook, pg. 851
Adverse reactions: > 10%
CNS: Headache
Respiratory: Pharyngitis
Drug interactions: CYP3A3/4 enzyme substrate
Increased effect: Beta-adrenergic blockers (eg, propranolol)
Decreased toxcity (cardiovascular): MAO inhibitors, tricyclic
antidepressants
Terbutaline Sulfate (Brethaire, Brethine, Bricanyl)
Beta2-Adrenergic Agonist Agent
Bronchodilator
Sympathomimetic
Tocolytic agent
Use: Bronchodilator in reversible airway
obstruction and bronchial asthma; inhibition of premature
labor (oral and IV)
Mechanism of action: Selective B2
agonist that relaxes bronchial smooth muscle and peripheral vessels
Pharmacodynamics/Kinetics:
Onset of action:
Oral: 30-60 min
SC: within 6-15 min
Oral inhalation: 5-30 minutes
Peak effect:
Oral: 2-3 hours
SC: 30-60 min
Oral inhalation: 1-2 hours
Protein binding: 25%
Metabolism: In the liver to inactivate sulfate conjugates
Bioavailability: SC doses are more bioavailable than oral
Half-life: 11-16 hours
Elimination: In urine
Usual dosage: See Anesthesiology &
Critical Care Drug Handbook, pg. 912
Adverse reactions: > 10%
CNS: Nervousness, restlessness
Neuromuscular & skeletal: trembling
Drug interactions:
Decreased effect with beta-blockers
Increased toxcity with MAO inhibitors, TCAs
a - and b -
site/selectivity
a
1 a 2 b
1 b 2
TERBUTALINE - - - +
ABUTEROL - - - +
EPHEDRINE + + + +
METAPROTERENOL - - - +
ISOETHARINE - - - +
EPINEPHRINE + + + +
ISOPROTERENOL - - + +
ASTHMA
Reactive airway
New Pathogenesis:
The precise nature of the inflammatory response in asthma has not yet been
defined…
Chronic inflammatory disease of the airways
Inflammatory reactions ® smooth muscle contraction,
swelling of the airway, mucous secretions, structural changes
Becomes chronic if not treated appropriately
Autonomic abnormality:
Disruption of the bronchoconstrictor-bronchodilator
balance-tone imbalance
Excitatory vs inhibitory stability is
altered
Complex interactions between inflammatory mediators and effector cells:
Prostaglandins
Leukotrienes…very potent (upper and lower
airway)
Thromboxanes
Key cellular players in asthma
Central role in seasonal/intermittent asthma:
Mast cells
Eosinophils…major inflammatory cell in the airway mucosa
In severe, steroid dependent asthma:
T-lymphocytes
Origin of Asthma
Anytime…any age
If present in childhood, peak prevalence…6 to 11 years of age
Diagnosis is confirmed by treating with b 2-agonists
for 5 to 10 days
Classification/precipitants of Asthma
Allergen induced:
Associated with allergic rhinitis
Inhaled or ingested:
Antigens, irritants, metabolites
Nocturnal:
Reflux of gastric fluid into the lower
esophagus
Drug induced:
Aspirin or Non-steroidals
Occupational:
Dusts
Strenuous exercise
Viral:
Upper respiratory tract infections
Adenylcyclase deficiencies:
Increases cyclic AMP…bronchodilator
Temperature-induced:
Cold may evoke symptoms
Psycholgical:
Violence
Stress
Anxiety
Signs and Symptoms of Asthma
Symptoms appear with:
Airflow limitation
Increased airway responsiveness to stimuli
Wheezing:
66% do not wheeze when they are obstructed
- Concentric bronchoconstriction…no
turbulent flow
Secretions may cause turbulence
Cough
Dypsnea/tachycardia:
Correlates with the degree of expiratory
airflow obstruction
Optimizing the Asthmatic
FEV1 measurement is the "gold standard"
-80% of predicted
-20% increase is expected after
bronchodilator use
Eosinophil count:
Parallels the degree of:
-inflammation
-Hyper reactivity
Steroid therapy is provided according to the results
-3 day pretreatment regimen for scheduled
surgery is beneficial
Patients are experts about themselves…and their condition
Patient’s knowledge base…some better than others:
-Bronchodilators…acute situations…symptom
relievers
-Anti-inflammatories…prophylaxis…preventors
Treatment
Economic, cultural, pharmaceutical influences play a role
Aerosol delivery and deposition
Developed in 1950’s
Attempts to deliver to lower airways vs
upper
Mass median aerodynamic diameter (MMAD)
-Particle size is best between 1-5m
m
Available delivery systems:
Delivery device….particle size
Jet nebulizers…….3-8m m
Metered dose…….1-4m m
Ultrasonic nebulizers (home/portable use)
Dry powder inhalers
Spacers
-Permit aerosol to "mature"…big droplets fall out
-Slow the flow…less deposition in large airways
-Minimize "cold Freon" effect…evaporation of Freon
-Serve as reservoir for meds
Aerosolized medications
Anesthetics…usually 4% Lidocaine
Anticholinergics/Antimuscarinics…Atropine
Bronchodilators…b -agonists
Corticosteroids…Antiinflammatory
Others (See Handout)
Aerosol Advantages vs Systemic
Specific to the site of action…minimal systemic side effects
Smaller doses needed
More effective drug response
-averts the 1st pass effect
Rapid therapeutic onset of action
Painless
Self-administered
Aerosol disadvantages
Shorter duration of action in acute asthma
Mastering technique is difficult
-Insufficient knowledge
-Lack of control over delivery variables
Unsupervised…and self medicated
Underdosing
Overdosage
Factors affecting aerosol delivery and deposition
Particle size-optimal size is 4m
m
-5-10m
m--------first 6 airway generations
-2-5m
m---------proximal alveolar deposition
-1-2m
m---------alveoli with 95-100% deposition
80-90%-------------------deposited in mouth and pharynx
10%-----------------------reaches site of action
Inertial impaction…WARP 10…can’t get around corners
>5m
m-----impact against:
-Pharynx
-Lateral walls of the first few bronchial
generations
-Bifurcations
Gravitational sedimentation
with:
-Reduced particle velocity and slow airflow
Airway configuration
-Wide diameter: less premature impaction
Better delivery in males…more
difficult in females and children
Incline
Distortion…malignancies
Edema…mucus
Coordination:
-50% of patient population are technique handicapped
Inspiratory hold or expiratory pause
-5-10 seconds is better
Treatment of Asthmatics
Bronchodilators
-Beta-2 agonists…drugs of choice in acute
asthma
-Methylxanthines
-Anticholinergics
Anti-inflammatory Drugs
-Corticosterids
-Non-steroidals
Others
-Anti-leukotrienes
Go To Respiratory Pharmacology Page 2
Last Updated 09/06/01 08:53:10 PM
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