Drugs Used in Asthma

1
Drugs Used in Asthma

• Katzung, Chapter 20

2
Lecture Outline

• Pathophysiology of asthma as it relates to
  pharmacologic management
• Acute and long term therapies
• Drug therapies
• Decrease airway inflammation
• Corticoids
• Chromones
• Leukotriene inhibitors
• Anti-IgE monocolonals
• Decrease bronchoconstriction
• Beta blockers
• Methylxanthines
• Anti-muscarinic drugs
• Clinical Use

3
Study Goals

• Know what drugs are used to treat reactive
  inflammatory events and acute bronchoconstrictive
  events
• Have a basic understanding of the how drugs
  relate to the early and late stages of asthma

4
Asthma Fact Sheet

• Most common chronic disabling disease of
  childhood
• One of the most common chronic conditions in the
  US
• 14.9 million persons in 1995 affected
• causing over 1.5 million emergency department
  visits
• 500,000 hospitalizations, and
• over 5,500 deaths.
• Total cost in 1998 11 billion
• Can be managed effectively with pharmacology if
  diagnosed

5
Asthma Pathogenesis

• What is asthma?
• Hypersensitive immune response of trachea and
  bronchi to stimuli/allergen mediated by T and B
  cells, IgE production, mast cell activation,
  leukotriene and cytokine release, eosinophils
  infiltration, resulting in airway inflammation
  and constriction.

NEJM 344, N5 2001
6
Pathogenesis

• Early and Late reactions
• Early (Mediatedhistamine, perhaps leukotrienes)
• bronchoconstriction
• mucosal thickening from edema and infiltration
• inspissation with thick, viscid plugs of mucus
• Late (Mediated leukotrienes and cytokines)
• Eosinophil infiltration, inflammation
• Scarring (remodelingsubepithelial fibrosis and
  smooth muscle hyperplasia)

7

• Asthma-Treatment
• What are the treatments?
• Drugs that reduce inflammation
• Drugs that reduce bronchoconstriction

8
Asthma - Introduction (Cont.)

• Drug therapy

? Airway Inflammation
? Bronchospasm
b adrenergic receptor agonist
Glucocorticoids
Leukotriene inhibitors
Methylxanthine
Chromones
Muscarinic receptor antagonist
IgE inhibitors
Prophylaxis prevention Long-term (controller
medications)
Symptomatic relief Short-term
9
Drug Delivery

• Factors involved in reducing systemic effects
• Aerosol delivery (topical)
• Particles size
• gt10mm deposited in mouth and oropharynx
• lt0.5mm inhaled but exhaled before deposition
• 1 to 5mm most effective
• Poor oral absorption or high first pass effect
• Proper technique, use of spacers
• Slow deep breath coordinated with device
  activation and held 5-10 seconds

Goodman and Gilmans Pharmacological Basis of
Therapeutics, McGraw Hill fig 27-2
10
Basic PharmacologySympathomimetics- Use in Asthma

• Adrenoceptor agonists (?2-selective agents
  preferred)

Short-acting (2-6 hrs)
Long-acting (gt12 hrs)
Symptomatic relief
Prophylactically in combination with steroid
Salmeterol (Serevent) Formoterol (Foradil)
Albuterol (Proventil, etc.) L-albuterol
(Xopenex) Metaproterenol (Alupent) Terbutaline
(Brethaire) Pirbuterol (Maxair)
11
Short-Acting Beta2-Agonists

• Most effective medication for relief of acute
  bronchospasm
• More than one canister per month suggests
  inadequate asthma control
• Regularly scheduled use is not generally
  recommended
• May lower effectiveness
• May increase airway hyperresponsiveness

12
Long-Acting Beta2-Agonists

• Not a substitute for anti-inflammatory therapy
• Not appropriate for monotherapy (sometimes OK
  with mild asthma)
• Beneficial when added to inhaled corticosteroids
• Not for acute symptoms or exacerbations

13
Basic PharmacologySympathomimetics- Use in Asthma

• Adrenoceptor agonists (?2-selective agents
  preferred)
• Stimulates cAMPi production and PKA activation

b2-R
Gs
AC
NO
cAMP
GC
AMP
PKA
cGMP
P
MLK inhibition
P
Activation site (when P)
14
Basic PharmacologySympathomimetics- Use in Asthma

• ?2-agonist have two important effects involved in
  asthma therapy
• Relax airway smooth muscle
• Somewhat resistant to receptor downregulation and
  desensitization (genetic variability/
  nonresponders)
• Inhibits function of immune cells
• Inhibits cell growth
• Prevents release of inflammatory mediators and
  cytokines
• Susceptible to receptor desensitization and
  downregulation less useful to treat with
  inflammation and why long-duration agonist are
  used in combination with a steroid

15
Basic Pharmacology- Sympathomimetics (Cont.)

• Toxicity
• Inhaled (low)
• ? heart rate
• Cardiac arrhythmias
• CNS effects
• Tremulousness
• Muscle cramps
• Metabolic disturbances
• Oral (greater risk)
• Still used in patients
• who can not use MDI (small children)
• with severe asthma exacerbations induced by
  aerosols

16
Basic Pharmacology- Sympathomimetics (Cont.)

• Other less favorable sympathomimetics used in
  asthma
• Epinephrine
• Rapid, effective bronchodilation
• s.c. or microaerosol
• maximal at 15 min, lasts for 60-90 min
• ?1 effects tachycardia, arrhythmia, angina p.
• Ephedrine - first drug for asthma, now rarely
  used
• orally active
• longer duration, but less potent than epinephrine
• Isoproterenol - potent bronchodilator
• microaerosol max effect in 5 min., for 60-90 min
• arrhythmias attributed to high doses

17
Basic Pharmacology- Methylxanthine Drugs
Clinical Use Mild to moderate asthma if poor
control with b-agonist/steroid comb, most
effective bronchodilator theophylline

• Caffeine (1,3,7-trimethylxanthine)
• Theobromine (3,7-dimethylxanthine)
• Theophylline (1,3-dimethylxanthine), aminophylline

CH3
O
N
N
Xanthine core in white
N
N
H
CH3
O
18
Basic Pharmacology- Methylxanthine Drugs, contd

• Mechanism of action
• block adenosine receptors (involved in
  bronchoconstriction and mast cell mediator
  release)
• nonselective inhibitor of phosphodiesterase (cGMP
  and cAMP) subtypes

b2-R
Gs
AC
NO
GC
cAMP
AMP
cGMP
PKA
P
MLK inhibition
GMP
P
Activation site (when P)
19
Basic Pharmacology- Methylxanthine Drugs (Cont.)

• Pharmacodynamics
• CNS Effects
• mild cortical arousal, alertness, deferral of
  fatigue (esp. caffeine 100 mg/cup)
• may cause nervousness, insomnia, in higher
  doses convulsions
• side effects of aminophylline nervousness,
  tremor
• Cardiovascular positive inotropic and
  chronotropic
• increase catecholamines through inhibition of
  presynapt. adenosine receptors (slight ?blood
  pressr)
• direct effect mediated by cAMP-induced Ca
  influx
• decrease blood viscosity (pentoxifylline in
  claudication)

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Basic Pharmacology- Methylxanthine Drugs (Cont.)

• Pharmacodynamics (cont.)
• Kidney weak diuretics, no therapeutic
  significance
• Smooth muscle - Lung
• Major therapeutic action- Bronchodilation No
  tolerance
• Inhibit histamine release from lung
• Skeletal muscle
• Diaphragm improves contractility, reverses
  fatigue improves ventilation in obstructive lung
  disease

21
Basic Pharmacology- Methylxanthine Drugs (Cont.)

• Pharmacokinetics
• Given as different salts good oral absorption
• microcrystals, sustained release, other preps
• Clearance by liver, rate varies widely
• fastest in children,
• slowest infants and neonates
• dose correction needed in liver disease

22
Basic Pharmacology- Methylxanthine Drugs (Cont.)

• Clinical Use (Cont.)
• Pharmacokinetics (cont.)
• plasma concentration should be measured
• 5-20 mg/ml improved pulmonary function
• gt 20 mg/ml anorexia, nausea, vomiting ,
  headache, anxiety
• gt40 mg/ml seizures, arrhythmias
• Advantages inexpensive, oral
• Disadvantages needs measurement of plasma
  level insomnia, serious toxicity of overdose

23
Older Adults Special Considerations (continued)

• Theophylline
• Theophylline clearance is reduced, causing
  increased blood levels
• Age is independent factor for developinglife-thre
  atening events from iatrogenic chronic
  theophylline overdose
• Potential for drug interactions (e.g., with
  epinephrine, antibiotics, H2-histamine
  antagonists)

http//www.nhlbi.nih.gov/health/prof/lung/index.ht
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Basic Pharm. Antimuscarinic Agents

• Vagal mechanism of bronchoconstriction

Ach
N
Vagal preganglionic neuron (cholinergic)
NE
Postganglionic neuron (cholinergic)
M3-R
Gq
a1-R
PLC
Gq
Ip3 and DAG
Ca
Smooth muscle cell
MLK activation
Ca
Not shown but also important is the vagal
stimulation of mucous secretion
contraction
CAM-Kinase
25
Basic Pharm.- Antimuscarinic Agents

• Mechanism of action competitively inhibit ACh
  released from vagus efferents
• inhibit bronchoconstiction (in response to ACh)
• inhibit mucus secretion
• Effect varies in individuals (diff. vagal
  component)
• Ipratropium bromide inhaler (Atrovent), (also in
  COPD)
• poorly absorbed - no systemic effects
• Quaternary amine
• enhances albuterol (combo form, Combivent) effect
  in severe asthma
• Tiotropium inhaler long acting, good in COPD

26
Basic Pharmacology- Corticosteroids

• Clinical use
• Routine use in patients with all ranges of
  persistent asthma
• Profound antiinflammatory effect most effective
  treatment of asthma
• Used prophylactically to control asthma not used
  for acute reversal of symptoms
• Inhaled glucocorticoids greatly enhance
  therapeutic index
• Beclomethasone (Beclovent, etc.)
• Triamcinolone (Azmacort)
• Flunisolide (AeroBid)
• Budesonide (Pulmicort)
• Fluticasone (Flovent)
• Some systemic absorption controversial for fear
  of adverse effects of chronic use
• Oral (prednisone) and I.V. (methylprednisolone)
  reserved for urgent treatment (for lt10 days) of
  patients not improving with bronchodilators

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Basic Pharmacology- Corticosteroids

• Mechanism of action inhibit airway inflammation
  and hyperreactivity via inhibition of
• cytokine production
• Phospholipase A2 production of arachidonic acid
• ? prostaglandin and leukotriene
• ? vascular permeability
• potentiate ?-agonist effects on airway obstruction

s
s
R
hsp90
hsp90
s
R
hsp90
hsp90
R
s
s
R
Nongenomic direct effects
Production of antiinflammatory proteins and
repression of inflammatory proteins (cytokines,
COX2, etc.)
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Inhaled Corticosteroids

• Most effective long-term-control therapy for
  persistent asthma
• Small risk for adverse events at recommended
  dosage
• Reduce potential for adverse events by
• Using spacer and rinsing mouth
• Using lowest dose possible
• Using in combination with long-acting
  beta2-agonists
• Monitoring growth in children

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Inhaled Corticosteroids and Linear Growth in
Children

• Potential risks are well balanced by benefits.
• Growth rates in children are highly variable.
  Short-term evaluations may not be predictive of
  attaining final adult height.
• Poorly controlled asthma may delay growth.
• Children with asthma tend to have longerperiods
  of reduced growth rates prior to puberty (males gt
  females).

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Inhaled Corticosteroids and Possible Effect on
Linear Growth

• Most studies show no effect with low-to-medium
  doses,but some short-term studies show growth
  delay.
• Potential risk appears to be dose dependent
• Medium doses may be associated with possible, but
  notpredictable, effect on linear growth. The
  clinical significancehas not yet been
  determined.
• High doses have greater potential for growth
  delay or suppression.
• For severe persistent asthma, high doses of
  inhaled corticosteroids have less risk than oral
  corticosteroids.

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Inhaled Corticosteroids and Possible Effect on
Linear Growth (continued)

• Some caution is suggested while studies continue
• Monitor growth
• Use the lowest dose necessary to maintain
  control(step down therapy when possible)
• Administer with spacers/holding chambers
• Advise patients to rinse and spit following
  inhalation
• Consider adding a long-acting inhaled
  beta2-agonist to a low-to-medium dose of inhaled
  corticosteroids (vs. using a higher dose of the
  corticosteroid)

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Basic Pharm.- Corticosteroids (Cont.)

• Adverse effects
• Local contact
• esophageal candidiasis (gargle and spit after
  aerosol)
• Small portion is swallowed
• Bone mineral density ? in women
• Systemic
• Extensive so limit duration to 5-10 days
• Mood disturbances
• Increased appetite
• Impaired glucose control in diabetics
• candidiasis

33
Older Adults Special Considerations (continued)

• Systemic corticosteroids can provoke confusion,
  agitation, changes in glucose metabolism
• Inhaled corticosteroids
• May be associated with dose-dependent reduction
  in bone mineral content
• Treat concurrently with
• Calcium supplements and
• Vitamin D and, when appropriate,
• Estrogen replacement

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34
Basic PharmacologyCromolyn (Intal) and
Nedocromil (Tilade)

• Extremely insoluble salts inhaled as
  metered-dose aerosol or microfine powder
• Prophylactic only
• prevent both antigen- and exercise-induced mild
  to moderate bronchial asthma
• reduce bronchial reactivity (chronic application)
• no direct effect on smooth muscle tone

35
Basic Pharmacology- Cromolyn and Nedocromil
(cont.)

• Mechanism of Action
• Alteration of the function of the delayed Cl-
  channel
• airway nerves prevent cough
• mast cells prevent early response to antigens
  (mediator release in lung)
• eosinophils inhibit late response
• Clinical Use
• Pretreatment blocks bronchoconstriction caused by
  antigen inhalation, exercise, aspirin (!)
• Reduces symptoms of perennial asthma (seasonal
  increase in bronchial reactivity) not in all
  patients 4-wk trial needed

36
Basic Pharmacology- Cromolyn and Nedocromil
(cont.)

• Clinical Use (cont.)
• Administration
• adult metered dose inhaler, 4x/d
• small children aerosol of 1 solution
• nasal spray or eye drops for allergic rhinitis
  (hay fever)
• Adverse effects Generally well tolerated
• minor, localized throat irritation, cough,
  wheezing
• severe rare dermatitis, myositis,
  gastroenteritis, pulmonary eosinophil
  infiltration, anaphylaxis
• Nedocromil is more potent than cromolyn

37
Basic Pharmacology- Leukotriene Pathway
Inhibitors

• LT-s
• produced in lung inflammatory cells (eosinophils,
  mast cells, macrophages and basophils)
• synthesized in the arachidonic acid pathway by
  5-lipoxygenase
• LTB4 neutrophil chemo-attractant
• LTC4 and LTD4 bronchoconstriction, bronchial
  reactivity, mucosal edema, mucus hypersecretion
• Inhaled LTs cause bronchoconstriction and
  increased bronchial reactivity for several days

38
Leukotriene Modifiers

• Indications
• Long-term-control therapy in mildpersistent
  asthma (currently second line to corticoids0
• Improve lung function
• Prevent need for short-acting beta2-agonists
• Prevent exacerbations
• Further experience and research needed

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Basic Pharm.- Leukotriene Pathway Inhibitors
(Cont.)

• Drugs Zileuton - 5-lipoxygenase inhibitor
• Zafirlukast, montelukast - LTD4 receptor
  antagonists
• Both effective prophylactic treatment of mild
  asthma
• Both block airway responses to exercise,
  allergens
• Both effective orally (less than inhaled
  cortico-steroids)
• Individual responses vary
• responders and nonresponders
• Both reduce aspirin -induced asthma
• Aspirin (and NSAID) sensitivity in 5-10 (!) of
  asthmatic patients
• Mech inhibition of prostaglandin synthetase
  shifts arachidonic acid metab. to leukotriene
  pathway
• Both generally safe (specificity of action)
• With Zileuton liver enzymes should be monitored
  to guard against potential liver toxicity

40
Anti-IgE monoclonal for Asthma
Strunk R and Bloomberg G. N Engl J Med
20063542689-2695
41
Basic Pharm.- Anti IgE monoclonal antibodies
Omalizumab (Xolair)

• Lowers IgE to undetectable levels inhibit the
  binding of IgE to mast cells
• Inhibits early and late responses to antigen
  challenge
• Adults (children older than 12) with moderate to
  sever persistent asthma (SC every 2-4 weeks)
• ? dependency on steroids
• ? frequency of attacks
• Well tolerated Injection site reactions,
  Malignancies?

42
Basic Pharmacology- Other Drugs for Asthma

• Bronchodilation can be achieved by
• Calcium channel blockers (aerosol)
• Inhaled NO gas - experimental
• Benefit from macrolide antibiotics possible role
  of Mycoplasma and/or Chlamydia pneumoniae

43
www. nhlbi.nih.gov/.

• "What to Expect From Your Asthma Treatment--The
  Goals
• No symptoms or minor symptoms of asthma (symptoms
  include wheezing, coughing, shortness of breath,
  and chest tightness)
• Sleeping through the night without asthma
  symptoms
• No time off from school or work due to asthma
• Full participation in physical activities
• No emergency room visits or stays in the hospital
• Little or no side effects from asthma medicine
• Do not accept having symptoms as normal.

44
Stepwise Approach to Therapy Gaining Control
Use Dr. Weisss lecture for specific details
1. Start high and step down.


2.
Start at initial level of severity gradually
step up.
STEP 4
Severe Persistent
2
STEP 3
1
Moderate Persistent
STEP 2
Mild Persistent
STEP 1
Mild Intermittent
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Indicators of Poor Asthma Control

• Step up therapy if patient
• Awakens at night with symptoms
• Has an urgent care visit
• Has increased need for short-acting inhaled
  beta2-agonists
• Uses more than one canister of short-acting
  beta2-agonist in 1 month

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46
Older Adults Special Considerations (continued)

• Asthma medications may have increased adverse
  effects
• Bronchodilators
• Airway response to bronchodilators may
  changewith age
• Patients with pre-existing ischemic heart disease
  may experience tremor and tachycardia
• Concomitant use of anticholinergics and
  beta2-agonists may be beneficial

http//www.nhlbi.nih.gov/health/prof/lung/index.ht
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47
COPD

• Chronic obstructive pulmonary disease
• Inflammatory bronchospastic condition caused by
  smoking
• Management (lots of patient variability)
• Stop smoking
• Bronchodilators useful
• Muscarinic antagonist (ipratropium or tiotropium)
• b2 agonist
• Theophylline
• Antiinflammatory (patient response dependent)
• Inhaled steroids if they respond to short course
  of oral steroids
• If a1-proteinase deficient patient
• Antiproteinase (Prolastin) can be given

48
Clinical Summary

• Mild (intermittent)
• Bronchodilator used acutely to reverse
  bronchospasm as needed basis
• Preferred Short acting (SA) b2 agonist
• Mild (persistent)
• Antiinflammatory drugs to quell bronchial
  inflammation
• Inhaled steroid if persistent or exercise induced
  asthma
• Can consider chromones but steroids have better
  outcome
• Can consider leukotriene inhibitor
• Bronchodilator as needed
• Moderate (persistent)
• Bronchodilator as needed basis
• Preferred short acting b2 agonist
• OR long acting b2 if poor control with combo s.a.
  b2 steroid
• OR if poor control with combo try theophylline
  in combo
• OR in combination with muscarinic antagonist with
  more moderate asthma or COPD
• Anti-inflammatory
• Preferred Inhaled glucocorticoids
• Or a chromone if nonresponder to steroid, want to
  reduce steroid dose when used in combination, or
  when clear cut inciting stimulus is known
• OR leukotriene inhibitor if mild asthma

49
Drug List

• Bronchodilators
• Sympathomimetics
• Epinephrine, ephedrine
• Beta 2 selective agonist
• Albuterol (Proventil, etc.)
• L-albuterol (Xopenex)
• Metaproterenol (Alupent)
• Terbutaline (Brethaire)
• Pirbuterol (Maxair)
• Salmeterol (Serevent)
• Formoterol (Foradil)
• Methylxanthine
• Theophylline
• Caffeine
• Theobromine
• Muscarinic antagonist
• Ipratropium (Atrovent)
• tiotropium,

• Antiinflammatory
• Glucocorticoids
• Beclomethasone (Beclovent, etc.)
• Triamcinolone (Azmacort)
• Flunisolide (AeroBid)
• Budesonide (Pulmicort)
• Fluticasone (Flovent)
• Leukotriene inhibitors
• Zileuton (Zyflo)
• Zafirlukast (Accolate)
• Montelukast (Singulair)
• Chromones
• Nedocromil
• Cromolyn
• Anti-IgE
• Omalizumab (Xolair)