Transcript Asthma

Asthma & COPD
November 28, 2007
Frank F. Vincenzi
Drug list for asthma & COPD
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* acetylcholine
* adenosine
* albuterol (Proventil®,
Ventolin®)
* aminophylline (theophylline
ethylenediamine)
* beclomethasone
dipropionate (Vanceril®)
* disodium cromoglycate
cromolyn sodium (Intal®)
* epinephrine (Adrenalin®)
* histamine
* ipratropium (Atrovent®)
* isoproterenol (Isuprel®)
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* leukotrienes
* nedocromil (Tilade®)
* prednisone (Deltasone®)
* salmeterol (Serevent®)
* terbutaline (Brethaire®, Brethine®,
Bricanyl®)
* theophylline (Theo-Dur®, SloPhyllin®, Somophyllin-T®, Somophyllin
CRT®, Theobid®)
* triamcinolone acetonide
(Azmacort®)
* zafirlukast (Accolate®)
* zileuton (Zyflo®)
Asthma, a disease of inflammation
• Clinically
intermittent wheezing &/or dyspnea &/or cough
• Physiologically
reversible obstructive airway disease
• Pharmacologically
obstructive airway disease reversed by beta
agonists - or an appropriate course of
anti-inflammatory drug
Some mast cell triggers and products
Drugs used in the treatment of asthma
• Relievers
Sympathomimetic bronchodilators (most)
Injected methylxanthine, e.g., aminophylline
• Controllers
Theophylline (i.e., oral methylxanthine)
Inhibitors of histamine release
Anticholinergics
Corticosteroids
Certain sympathomimetics (e.g., salmeterol)
Leukotriene synthesis inhibitors/antagonists
Sympathomimetics used as relievers in
the treatment of asthma
• albuterol (Proventil®, Ventolin®)
• epinephrine (Adrenalin®)
• isoproterenol (Isuprel®)
• terbutaline (Brethaire®, Brethine®, Bricanyl®)
Beta-agonist bronchodilators compared
Aer = aerosol, Inj. = injection, MDI = metered dose inhaler, PO = oral
Mechanism of action of sympathomimetic
amines in the treatment of asthma
– Activate beta-2 receptors on bronchiolar smooth
muscle
• Beta-2 receptor /G-protein complex increases
cAMP production
• Increased cAMP activates protein kinase A (PKA)
• PKA phosphorylates myosin light chain kinase
(MLCK)
• Phosphorylated MLCK; decreased affinity for
(Ca)ncalmodulin
• Less phosphorylation of myosin light chain
• Decreased activity of smooth muscle actin/myosin
• Bronchodilation
Precautions when using beta-agonists in
the treatment of asthma
• Watch for non-improvement or paradoxical deterioration
• Spacers to improve compliance and reduce systemic side
effects (large droplets deposit in mouth, swallowed)
• Avoid overuse; check number of MDIs used per month
• Instruct patient on maximum number of puffs per day (usually
8-12) and on the number allowed during exacerbation (e.g.,
12-24 over 3-4 hours)
• If a long-acting agent is used, caution patient that frequent
use must be avoided
• “Home updraft nebulizers (pumps) that provide large doses
are rarely needed……”
Contraindication: beta-blockers in asthma
• May precipitate acute attacks in asthmatics
• Antagonize the most effective treatment for an acute
attack
• May precipitate asthma in patients not known to be
asthmatic
• Selectivity of beta-1 selective antagonists (such as
atenolol or metoprolol) is only relative, not absolute
Aminophylline
(ethylenediamine salt of theophylline)
• Soluble form of theophylline can be used for IV
infusion
• Rapid onset of action, can be effective in treating
status asthmaticus - usually as an adjunct to an IV or
inhaled sympathomimetic, typically albuterol or
epinephrine
• Seizures, a major limitation
• ‘Therapeutic monitoring’ typically by nursing staff
following patient symptoms
Controller drugs: prevent asthma attacks
and/or reduce severity
• Methylxanthines (theophylline)
• Inhibitors of histamine release (cromolyn)
• Anticholinergics (ipratropium or tiotropium) [off label]
(tiotropium, also off label)
• Corticosteroids (inhaled or oral)
• Certain sympathomimetics (e.g., salmeterol)
• Leukotriene synthesis inhibitors (zileuton)
• Leukotriene antagonists (zafirlukast)
Methylxanthines (xanthines)
• Theophylline (from Thea sinensis) (tea)
(aminophylline = theophylline
ethylenediamine)
• Theobromine (from Theobroma cacao)
(chocolate)
• Caffeine (from Caffea arabica, etc.) (coffee)
Xanthine pharmacology
• Cellular
antagonism of adenosine receptors
inhibition of cyclic nucleotide phosphodiesterase
release of calcium in muscle
• Systemic
CNS stimulation
cardiac stimulation
diuresis
smooth muscle relaxation
Concentration-effect curves for caffeine in
vivo
Cup of coffee
Toxic dose
100
75
Block A2A
Block A1
50
Inhibit PDE
25
Block GABAa
Promote Ca release
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-6
-5
-4
-3
-2
Caffeine (molar)
-1
Adapted from Fredholm (1980)
Theophylline:
Potential mechanisms in asthma
• Antagonism of adenosine receptors
• Inhibition of cyclic nucleotide
phosphodiesterase (could synergize
sympathomimetics by sparing intracellular
cAMP)
• Increased Ca2+ release (increased
contractility of diaghragmatic skeletal muscle)
Increased bronchial smooth muscle
sensitivity to adenosine: association with
human asthma
Adapted from Björck et al. (1991) NY Acad. Sci. 629: 458-459
Theophylline: adverse reactions
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Anorexia
Nausea & vomiting
Anxiety
Fever
Tremors
Dehydration
Seizures
Cardiac arrhythmias
Cardiovascular & respiratory collapse
Theophylline pharmacokinetics
• Half life
children
adult smokers
adult non-smokers
~ 200 min
~ 325 min
~431 min (P < 0.0001)
• Therapeutic monitoring is a must
• Therapeutic range is 10 - 20 µg/ml, t1/2 extremely
variable
• Dosage must be calculated based on ideal body weight
(i.e., lean body mass)
Theophylline as a controller for the treatment
of asthma: trap for the unwary physician
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Rapid absorption
Variable elimination (CYP1A2 and CYP3A4)
Uncertain volume of distribution (ideal body weight)
Interaction with
many other drugs
smoking
viral infections
Symptoms and theophylline levels of
several young patients treated with
theophylline before and during an
influenza outbreak
Adapted from Kraemer et al., Pediatrics 69: 476-480, 1982
Factors that decrease theophylline
clearance
• Minor changes
verapamil, nifedipine, tetracycline,
hydrocortisone, aluminum hydroxide,
magnesium, thiabendazole
• Major changes
hepatic insufficiency, heart failure
cor pulmonale, viral pneumonia,
cimetidine, mexiletine, ciprofloxacin,
allopurinol, erythromycin, propranolol*,
oral contraceptives, zileuton
Precautions when using theophylline
• Initiate with a low dose, then adjust
• Instruct patient to take drug at the same time each
day with respect to meals
• Reduce dose if clearance is likely to be impaired for
ANY reason
• Do not allow additional xanthines
• If symptoms change, acute illness occurs, drugs are
added (or removed), or symptoms suggest toxicity
CHECK SERUM LEVEL
• Aim for 8-12 µg/ml, adjust and follow serum level
Controller drugs: prevent asthma attacks
and/or reduce severity
• Methylxanthines (theophylline)
• Inhibitors of histamine release (cromolyn)
• Anticholinergics (ipratropium or tiotropium) [off
label]
• Corticosteroids (inhaled or oral)
• Certain sympathomimetics (e.g., salmeterol)
• Leukotriene synthesis inhibitors (zileuton)
• Leukotriene antagonists (zafirlukast)
Inhibitors of histamine release
• Chromones
– Disodium cromoglycate (cromolyn sodium, Intal®,
Nasalcrom®)
– Nedocromil (Tilade®)
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Inhaled
Inhibit the release of histamine
Effective in some patients only
Some local irritation, cough, rhinitis,
sneezing, throat irritation
Controller drugs: prevent asthma attacks
and/or reduce severity
• Methylxanthines (theophylline)
• Inhibitors of histamine release (cromolyn)
• Anticholinergics (ipratropium or tiotropium) [off label]
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Corticosteroids (inhaled or oral)
Certain sympathomimetics (e.g., salmeterol)
Leukotriene synthesis inhibitors (zileuton)
Leukotriene antagonists (zafirlukast)
Precautions when using ipratropium as a
controller drug for the (off label) treatment of
asthma or COPD (approved)
• Use a spacer and avoid getting spray in the eyes
• Be prepared to increase dose if necessary from 2-3
puffs 3-4 times per day to 6-8 puffs 3-4 times per day,
if tolerated
• Caution patients that the onset of effect is slow;
additional doses should not be taken for acute relief
of symptoms.
• Monitor for systemic side effects; tachycardia, dry
mouth, urinary retention, glaucoma
Controller drugs: prevent asthma attacks
and/or reduce severity
• Methylxanthines (theophylline)
• Inhibitors of histamine release (cromolyn)
• Anticholinergics (ipratropium or tiotropium) [off label]
• Corticosteroids (inhaled or oral)
• Certain sympathomimetics (e.g., salmeterol)
• Leukotriene synthesis inhibitors (zileuton)
• Leukotriene antagonists (zafirlukast)
Corticosteroids in the treatment of asthma
• Inhaled
beclomethasone dipropionate (Vanceril®)
triamcinolone acetonide (Azmacort®)
• Systemic
prednisone (Deltasone®)
…decrease inflammation and airway responsiveness.
Systemic absorption occurs following inhalation.
Long term steroid dosage is associated with
substantial adverse reactions.
Systemic corticosteroids:
some adverse effects
• Shapiro et al. (1976) J. Allergy Clin. Immunol. 57:
430-439.
Steroid dependent asthmatic children daily
prednisone or methylprednisolone or twice equivalent
alternate-day methylprednisolone:
abnormal growth, bone maturation and cataracts
high incidence of disturbed pituitary and adrenal
function (alternate-day therapy did not alter)
Beclomethasone dipropionate (BDP):
some pharmacokinetics
• BDP has negligible oral and intranasal bioavailability.
Similarly, inhaled BDP is extensively (95%) converted
to B-17-MP [active metabolite] in the lung.
• Bioavailability of B-17-MP is 41%, 44% and 62% for
oral, intranasal and inhaled dosing.
• When given IV, BDP [inactive] is rapidly (t1/2 = 0.5 h)
converted to B-17-MP [active], which is eliminated
more slowly (t 1/2 = 2.7 h) mainly by conversion to
BOH [inactive].
Daley-Yates et al. (2001), Br.J.Clin.Pharmacol. 51: 400-409.
Inhaled corticosteroids:some systemic effects
• Skin thinning (striae)
Skin thinning and purpura are associated
with the use of oral or inhaled high dose
steroids. Low dose inhaled steroids did not
produce significant thinning of skin. Capewell
et al. (1990) BMJ 300: 1548-1551.
Inhaled corticosteroids:some systemic effects
(continued)
• Osteoporosis
Inhaled corticosteroid therapy, unlike oral
corticosteroid therapy may not induce bone loss at
the doses used by our subjects. Wolff et al (1991)
Ann. Allergy 67: 117-121.
Although there was substantial interindividual
variability in the responses, asthmatic patients
receiving high dose inhaled beclomethasone and
intermittent courses of systemic corticosteroids have
reduced vertebral bone density Packe et al. (1992)
Thorax 47: 414-417.
Inhaled corticosteroids:some systemic effects
(continued)
• Cataracts
All inhaled corticosteroid users are at a marginally
increased risk of cataract (RR = 1.3). (Jick et al.
(2001) Epidemiology 12: 229-234).
Inhaled corticosteroid users are at increased risk of
nuclear (RR = 1.5) and posterior subcapsular (RR =
1.9) cataracts. Risk of posterior subcapsular
cataracts is greater (RR = 2.7) among users of
systemic corticosteroids. (Cumming et al. (1997)
NEJM 337: 8-14.)
Precautions when using inhaled steroids
• Confirm objective evidence of the value of this
therapy which tends to decrease compliance with
other aerosol usage
• Standard dosing (2-4 puffs, 2-4 times per day) should
not be exceeded
• Use a spacer; monitor to minimize oral thrush and
laryngeal dysfunction
• Watch for systemic side effects
• If replacing oral steroids, taper oral dosage
Toxic effects of chronic glucocorticoids
gluconeogenesis (liver)--hyperglycemia
release of amino acids-catabolism (muscle)--muscle weakness
release of fatty acids-lipolysis (fat)--together with increase in
insulin, leads to inappropriate fat deposition, obesity
insulin secretion (pancreas-in response to glucose)
bone resorption--leading to osteoporosis, fractures
fibroblast proliferation--thin skin, bruising, poor wound healing
collagen synthesis
growth (in children)
changes in mood and excitability--euphoria, restlessness
altered leukocyte functions (anti-inflammatory)--may
mask underlying symptoms
suppression of the HPA axis: acute withdrawal can lead to death
Precautions when using oral steroids
• Reduce to lowest daily or alternate day
dosage as soon as symptoms allow
• Monitor for hypertension, diabetes, weight
gain, mental changes, infections, central
polar cataracts, skin thinning, purpura,
osteoporsis and osteonecrosis - administer
prophylactic calcium
• Monitor FEV1 for 2 weeks to establish
objective evidence of benefit
• Repeatedly evaluate patient to determine if
steroid therapy can be discontinued…..
November 17, 1998: Joint Public
Statement
• American Academy of Allergy Asthma and
Immunology
• American College of Allergy
• American College of Chest Physicians
• American Thoracic Society
• American Academy of Pediatrics
“Patients are advised not to stop using their inhaled
or intranasal corticosteroids without first speaking to
their health care providers about the benefits of these
drugs compared to their risks.”
(Prompted by new FDA warnings on rate of growth)
Controller drugs: prevent asthma attacks
and/or reduce severity
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Methylxanthines (theophylline)
Inhibitors of histamine release (cromolyn)
Anticholinergics (ipratropium or tiotropium) [off label]
Corticosteroids (inhaled or oral)
• Certain sympathomimetics (e.g., salmeterol)
• Leukotriene synthesis inhibitors (zileuton)
• Leukotriene antagonists (zafirlukast)
Salmeterol: a unique beta-agonist with a very
long duration of action (longer than plasma half
life)
(Probably works by an alternate or additional mechanism)
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NOT for acute symptoms
NOT for deteriorating asthma
NOT a substitute for inhaled or oral corticosteroids
Do not exceed recommended dosage
Watch for:
increasing use of short-acting beta agonists
paradoxical bronchospasm
immediate hypersensitivity (urticaria, angioedema, etc.)
upper airway symptoms (laryngeal spasm, irritation)
Salmeterol: an alternative and/or
additonal mechanism?
• Jeffery et al. (2002) Eur. Respir. J. 20: 1378-1385
A novel antineutrophilic effect of salmeterol?
reduced numbers of neutrophils in bronchial lavage fluid
Fluticasone decreased CD3+ T-lymphocytes, (CD4+) T-helper
cells,CD45RO+) activated T-helper cells and eosinophils.
Chronic clinical efficacy of salmeterol in two studies
Controller drugs: prevent asthma attacks
and/or reduce severity
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Methylxanthines (theophylline)
Inhibitors of histamine release (cromolyn)
Anticholinergics (ipratropium or tiotropium) [off label]
Corticosteroids (inhaled or oral)
Certain sympathomimetics (e.g., salmeterol)
• Leukotriene synthesis inhibitors (zileuton)
• Leukotriene antagonists (zafirlukast)
Arachidonic acid metabolism
NSAIDS
cyclooxygenase
thromboxanes
prostaglandins
lipoxygenase
Zileuton: Mechanism of Action
• Zileuton (Zyflo®) is a highly selective inhibitor
of 5-lipoxygenase
• Inhibits the synthesis of leukotrienes (LTB4,
LTC4*, LTD4* and LTE4) - potential for
application in a variety of inflammatory
diseases (e.g., colitis, rheumatoid arthritis) but currently only approved for asthma
• Very short half life (~1-2 hours), given QID
*Slow reacting substance of anaphylaxis, “SRS-A”,
is a mixture of LTC4 and LTD4
Leukotrienes and asthma
Arachidonic acid
Zileuton (Zyflo®)
5-HPETE
5-lipoxygenase
Leukotriene A4
Leukotriene B4
LTB4 receptor
chemotaxis, immunomodulation
Leukotriene C4
Leukotriene D4
Leukotriene E4
LT receptor (CYSLT1)
bronchoconstriction, mucus secretion,
hyperresponsiveness, eosinophilia
Zileuton (Zyflo®)
• Indicated for chronic treatment of asthma. Should be
taken even during symptom-free periods. Zileuton is
NOT a bronchodilator - it should NOT be used to treat
acute episodes of asthma.
• Reassess therapy if short-acting bronchodilators are
needed more often than usual
• Monitor patients on a regular basis - the most serious
adverse reaction is elevation of liver enzymes.
Zileuton: potential drug interactions
• Zileuton decreases clearance of theophylline
and increases AUC and Cmax. More
adverse reactions to theophylline with
zileuton.
• Zileuton decreases clearance of propranolol
and increases AUC and Cmax. There is
increased beta-blockade and a greater
decrease in heart rate when these drugs are
combined.
(Why is this a combination that should not happen??)
Controller drugs: prevent asthma attacks
and/or reduce severity
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Methylxanthines (theophylline)
Inhibitors of histamine release (cromolyn)
Anticholinergics (ipratropium or tiotropium) [off label]
Corticosteroids (inhaled or oral)
Certain sympathomimetics (e.g., salmeterol)
Leukotriene synthesis inhibitors (zileuton)
• Leukotriene antagonists (zafirlukast)
Zafirlukast: Mechanism of Action
• Zafirlukast (Accolate®) is a selective and
competitive receptor antagonist of
leukotrienes D4 and E4 (components of slowreacting substance of anaphylaxis [SRS-A])
Leukotrienes and asthma
Arachidonic acid
5-HPETE
5-lipoxygenase
Leukotriene A4
Leukotriene B4
Leukotriene C4
Leukotriene D4
Leukotriene E4
Zafirlukast (Accolate®)
LTB4 receptor
chemotaxis, immunomodulation
LT receptor (CYSLT1)
bronchoconstriction, mucus secretion,
hyperresponsiveness, eosinophilia
Zafirlukast: Selected adverse reactions
Zafirlukast: potential drug interactions
• Both terfenadine and erythromycin were
reported to decrease bioavailability of
zafirlukast, mechanism unknown
• Zafirlukast inhibits CYP2C9 and CYP3A4
• No studies of interactions between zafirlukast
and other CYP2C9 or CYP3A4 drugs
(dihydropyridine Ca channel blkrs,
cyclosporine, astemizole, etc.), but clearly
best to avoid.
• Reasonable to use therapeutic drug
monitoring as appropriate….
COPD (often misdiagnosed as
asthma): Approaches to treatment
• Cessation of smoking !!
• Oxygen therapy
• Lung volume reduction surgery
COPD (seventh most common reason for
hospital admission in Canada):
Physicians and patients view COPD differently. A 2002
study that showed that because combined therapy
with inhaled corticosteroids and long-acting ßagonists produced a larger benefit than either
therapy alone, it was easier to notice the difference
in lung function and symptoms.
• Each of these studies showed that the combination
inhaler significantly reduced shortness of breath,
reduced night awakenings, was associated with less
use of ß-agonist reliever medications, and decreased
symptom scores
COPD
• Mucolytics and combination inhaled
corticosteroids/long acting beta-agonists
• There may be a modest effect for some COPD
patients - but the evidence is not strong
• On the other hand, NNT was as low as 2.1 -2.4 for
COPD patients treated with formoterol/budesonide to
avoid one severe exacerbation over the course of
one year.
Tiotropium bromide (Spiriva®)
HandiHaler
• Recently approved for COPD
• Six different phase 3 trials, over 2600 pts.
• >40 y/0, >10 pack years, FEV1 < 60%
predicted.
• Overall, tiotropium once daily improved lung
function, peak effect at about 3 hours after
first dose
Summary of mechanisms of drugs
for asthma & COPD
Limitations of drugs for asthma & COPD