AIRWAY PHARMACOLOGY
©2006 ?, updated by Mark Tuttle
ASTHMA DRUGS
Group/Mechanism
Beta-adrenergic agonists
Relax bronchial SM by ↑
cAMP=↓ Ca2+
Adverse effects:
- Tremor/Anxiety
- Nausea/Vomiting
- Sinus tachycardia
o Even β2-selective since β2 are 1050% of heart adrenerg Rs
 Contraindicated w/heart
disease
- Hyopkalemia
- Hyperglycemia
o ↑ liver glycogen breakdown
Drug examples
Short-Acting:
Epinephrine
Isoproterenol
Metaproterenol
Albuterol
inhaled/oral
Terbutaline
Inhaled/oral/IV
Levalbuterol
Long-acting:
Salmeterol
Formoterol
Anticholinergics
Ipratropium
Parasympathetic ACh normally
bronchoconstricts and ↑ mucus by:
↑ Ca2+ BLOCKED
Tiotropium
Quaternary atropine
analog
Quat. scopolamine an.
Glucocorticoids
↓ Inflammatory cell proliferation
↑ β2 Receptors: Bronchodilation
↓ WBC entry into tissue
- ↓Endothelium adhesion LTB4+TNFα
- ↓ Chemotaxis: LTB4, PGD2
- ↓ Vascular perm.: LTC4, LTD4
- ↑ Vasodilation:PGE2, PGD2
Short-term= mod-severe attacks
resort to dilators
Long-term (inhaled) =1st line Tx for
mild-mod asthma
 w/β2 agonists for mod-severe
persistent asthma
Long-term (systemic) for very severe
persistent asthma
Prednisone (prodrug)
Methylprednisolone
Triamcinolone
acetonide
Beclomethasone
Fluticasone
Budesonide
Clinical uses
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All= tachyphylaxis =
Emergencies
↓ effective w/ ↑ use
Severe attacks
Via βARK and PKA phosphorylating
OTC low doses inhaled for mild
adrenergic Rs, downregulation of
No longer used for rescue
adrenergic Rs
because of excess cardiac
Epinephrine
stimulation
Agonist @ all adrenergic Rs
Acute attack
 bad adverse effects
Prevention of exercise-induced
Albuterol
asthma
N/V, sinus tachycardia
Don’t use regularly!
Like albuterol, but is a racemic
mixture
Salmeterol
Long-term tx of mod-severe
↑ risk of respiratory-related death
asthma (w/corticosteroids)
w/monotherapy (especially in AfricanNOT for acute attacks! (b/c
Americans)
slow)
Prophylaxis of exercise-induced
COPD bronchoconstric
**Only works when the agonist is present
Treatment of COPD
TOC for β-blocker bronchoconst. (unlike β-agonists)
Asthma w/excess mucus
Rescue tx if intol to b-agonists
Nasal spray for rhinorrhea
 Mod-severe acute attacks and
used w/β-agonists since don’t
take effect for hours
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Adverse Effects
Only prophylaxis
NOT severe acute attacks
Used w/long-acting β-agonist
Also nasal sprays-allergic rhinitis
>2 wks of systemic treatment:
1) Iatrogenic Cushing’s Syndrome
- Moon facies, Buffalo hymp
- Osteoporosis
- Hyperglycemia  diabetes
- ↓ collagen synthesis
- Glaucoma
- Mineralcorticoid effects
o Edema, hypokalemia, alkalosis, BP↑
2) Hypothalamic-pituitary-adrenal
suppression (pseudo Addison’s Disease)
- B/c of negative feedback loop
3) Inhaled glucocorticoid side effects
- Oral candida infections (thrush)
- Dysphonia, cough
- High doses= systemic effects (↓ growth in
kids, osteoporosis, glaucoma, cataracts)
Pharmacokinetics
 Can’t take orally
 Rapidly metabolized by COMT
 β-selective
 Slow inactivation by COMT
 ↑ selectivity for β2 Rs
 ↑ half-life: Slow inactivation
(COMT), ↑ DOA
 Rapid onset
 R-enantiomer of albuterol= 100X
higher affinity than S (inert!) LOL
 Longer DOA (>12hrs)
Lipophillic, sits in membrane
 2x/day dosing
 Slower onset
 β2-selective
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Minimal absorption/distribution
Inhaled, slow onset
No GI/CNS (Quaternary)
M3 and M1-selective
Longer DOA
No GI/CNS (Quaternary)
Oral
 Topical use (inhalation)
 Triamcinolone-systemically (oral)
 Topical use (inhalation)
 Slow onset of action (3 weeks)
 Low oral bioavailability helps
but still 20-30% enter systemic
 Rapidly inactivated in liver
 Double bond in quinoline group
increases specificity for
glucocorticoid R over
mineralcorticoid R
AIRWAY PHARMACOLOGY
©2006 ?, updated by Mark Tuttle
ASTHMA DRUGS continued
Prophylaxis, NOT acute
Block Leukotrienes which:
1) Bronchoconstrict
2) ↑ mucus secretion
3) Inhibit cilia
4) ↑ Vascular permeability
Mast Cell Stabilizers
Inhibit histamine release from
Mast cells in lung
- Block entry of Ca2+ into Mast
-does NOT bronchodilate
Methylxanthines
Kids > 5yo
LT receptor
antagonist
Anti-Leukotrienes
Drug examples
Zafirlukast
Montelukast
Once per day
Kids > 2yo
(better)
Cause (or reveal) Churg-Strauss
(↑ asthma, eosinophilia, vasculitis)
 Prophylaxis, NOT acute
 and exercise bronchoconstric
 Only mild persistent asthma
as alternative to GCs
 Few AEs, but low efficacy since
partition coefficient is low
Theophylline
 Prophylaxis, NOT acute
 Alt to low dose GCs for mild
persistent asthma
 Alternative to long-acting βagonists w/GCs for moderate
asthma, but GCs are
preferred
 CNS= nervous, insomnia, headache
 GI= ↑ acid secreted
Heartburn, N/V, anorexia
Omalizumab
Pharmacokinetics
 Oral admin
 Slow onset of action
 Metabolized by CytP450 but does not
inhibit
Cromolyn Sodium
Nedocromil
Pemirolast
- Induces bronchodilation
-↓ PDE = ↑cAMP
-↓adenosine receps =↑cAMP
-↓activation of inflamm. Cells
via Ca2+ ↓
Prevent IgE binding to mast cell
receptor
Adverse Effects
 Liver toxicity
 Inhibit CytP450 2C9 and 3A4
 Inhibits synthesis of all LTs, not just
the asthma-related ones
Zileuton
Ex. caffeine
Ab’s against IgE
Clinical uses
 Alternative to GCs for mild
persistent asthma
 Used w/GCs for moderate
persistent asthma
 Allergic rhinitis
 Prophylaxis, NOT acute
 Used w/β-agonists
5-LO inhibitor
Group/Mechanism
 Moderate-severe allergic
asthma
 Allergic rhinitis (possibly)
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Oral
High first-pass metabolism
Short half-life
Inhibits metabolism of:
Theophylline, warfarin and
propranolol
 Inhaled dry powder
 Little GI absorption
 Low partition coefficient
 Oral or IV
 Slow release preparations
reduce dosing frequency
Heartburn can exacerbate asthma
 Toxicities at high levels
o Arrhythmias (SV tachycardia)
o Seizures, tremor
o Hypotension (peripheral vasodilat.)
o Treat:
 Whole-bowel irrigat, NOT Ipecac
 β-blocker, diazepam, dialysis
 NARROW THERAPEUTIC WINDOW
 $100k/year price tag
 SC injection
AIRWAY PHARMACOLOGY
©2006 ?, updated by Mark Tuttle
PULMONARY HYPERTENSION DRUGS
Group/Mechanism
Prostaglandins
Drugs
Epoprostenol
Clinical Uses
Pulmonary HTN (1° + scleroderma)
↑ Exercise capacity + ↓Mortality
Abrupt discontinuation:
rebound hypertension
Treprostinil
 Pulmonary arterial HTN
Adverse effects
 Flushing
 Hypotension
 GI: Nausea, vomiting, diarrhea
 Infusion site pain & rxn
Pharmacokinetics
 Very short t½
 Continuous IV
 t½: 2-4 hrs
 Continuous SC
 t½: 20-30 min
 Inhaled
Iloprost
Endothelin Antagonists
-Antags at ET receps (ETA +ETB)
-In endothelium & vascular sm.
 Vasodilation
 Bronchodilation
Bosentan
Abrisentan
 SEVERE pulmonary
hypertension
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 Antitussive
 Effects on GI motility
 Antagonized by naloxone
 t½: 5 hrs
 Oral admin
 Induces own metabolism by
CYP3A4/2C9
Shared w/ grapefruit juice &
cyclosporin
 takes longer than 4-5 t½’s to
reach steady state
Hepatotoxicity: ↑serum ALT
Potentiated by cyrosporine &
ketokonazole
 Major birth defects
Drug interactions:
- Hormonal birth control pills fail
- Satins less effective
ANTITUSSIVES (COUGH SUPPRESSANTS)
Opioid Agonists
Codeine
Act in CNS to ↑ cough
threshold
(agonist at opioid
receptors)
Contraindicated w/asthma,
emphysema, smoking b/c in
that case it is good to cough up
shit
Dextromorphan
Expectorants
Guaifenesin
↑ respiratory secretions
↓ phlegm viscosity
↑ ciliary action
(antag at NMDA
receptors)
 Antitussive effect at <
analgesic doses
 Metabolized by CytP450 2D6 to
form morphine
 Metab by CYP 2D6 =
dextrophan
 Oral admin
 T1/2= 11hrs, DOA- 5-6
 Interacts w/fluoexetine, paroxetine
 Antitussive
 Blocks Serotonin uptake
 Overdose= excitation,
hallucinations abuse
 NOT antagonized by naloxone
 Interacts w/fluoexetine, paroxetine
 Do NOT use w/MAO inhibitors
 Tx of dry, unproductive coughs
due to colds and URTIs
 In many OTC drugs
 Makes cough more productive
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AIRWAY PHARMACOLOGY
©2006 ?, updated by Mark Tuttle
DRUGS FOR ALLERGIC RHINITIS
Beclomethasone
Glucocorticoids
Fluticasone
Triamcinolone
Cromolyn Sodium
Sympathomimetics
(decongestants)
Phenylephrine
Pseudoephrine
 >effective than antihistamines

used prophylactically
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GCs>CS>antihists
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Used prophylactically
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Decongestion
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Clinical Uses
Decongestion
-act at a1 receps or
release NEP from nerve
terminals
=vasoconstric
Group/Mech
Anticholinergics
-inhibit mucus secretion
Antileukotrienes
Antihistamines
Drugs
Ipatropium
Older antihists
Montelukast
 Seasonal allergic
rhinitis
 relieve itching,
sneezing, rhinorrhea (but
not congestion)
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admin as nasal spray
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admin as nasal spray
 Topical= rebound
congestion
 Systemic= vasocontric
and ↑ HR= ↑BP/CNS effects
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Topical or systemic
Adverse effects
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 sedation and
antimuscarinic effects (older
generation)
Metab/P-kinetics
 Ipatropium= nasal
spray
Other
-older antihists have
antimusc effects, but
newer ones don’t
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most= oral admin

azelastine= nasal spray
-drugs most frequently
used to treat allergic
rhinitis