asthma & copd - hadassah€¦ · -decreasing morbidity and related costs . 5 ... asthma/copd...

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Asthma & COPD

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Asthma synopsis

Asthma/COPD

chronic inflammation of bronchial airways

• bronchi lining

• bronchi muscles

• mucus

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Asthma synopsis

Asthma/COPD

acute broncho-constriction

cough

resolution?

shortness of breath

wheezing

chest tightness tachypnea

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Asthma synopsis

Asthma/COPD

• generally not progressive

• remitting-relapsing

• M vs. M

• goals of therapy:

- relieving symptoms

- preventing recurrence

- preventing bronchial remodeling

- decreasing morbidity and related costs

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Asthma pharmacotherapy

Asthma/COPD

oral vs. inhaled

inhalation Tx:

• main disadvantage -

• main advantage -

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Asthma/COPD

oral vs. inhaled

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Asthma/COPD

• corticosteroids

• cromolyn/nedocromil

• ipratropium

• leukotriene modifiers

• omalizumab

• theophylline

• β2-adrenergic agonists

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Asthma/COPD


• ipratropium


• omalizumab

• theophylline

• corticosteroids


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Asthma/COPD

Corticosteroids

inhaled corticosteroids (ICS) - 1st-line for:

rescue SABAs required> 2/wk

persistent asthma +

“ICS improve asthma control more effectively in both children and adults than … any other single, long-term control medication do.”[NHLBI guidelines 2007]

“ICS are currently the most effective anti-inflammatory medications for the treatment of persistent asthma [GINA report 2010]

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Asthma/COPD

ICS

• fluticasone (Flixotide®)

• budesonide (Budicort®)

• beclomethasone (Qvar®)

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Asthma/COPD

ICS - Mechanism:

• anti-inflammatory effect

• airway smooth muscle dilation

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Asthma/COPD

ICS - PK:

• fate of non-inhaled drug?

• proper inhalation reduces systemic exposure

• hepatic metabolism?

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Asthma/COPD

ICS - PK: poor inhaling technique

good inhaling technique

use of spacer

PREVENTION:

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Asthma/COPD

Spacer use

1. Shake the inhaler well before use (3-4 shakes)2. Remove the cap from your inhaler, and from your spacer, if it has one 3. Put the inhaler into the spacer 4. Breathe out, away from the spacer 5. Bring the spacer to your mouth, put the mouthpiece between your teeth

and close your lips around it 6. Press the top of your inhaler once 7. Breathe in very slowly until you have taken a full breath. If you hear a

whistle sound, you are breathing in too fast .Slowly breath in .8. Hold your breath for about ten seconds, then breath out .

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Asthma/COPD

ICS - benefits

• reduces airway hyper-responsiveness to various

bronchial stimulators

• oral-corticosteroids sparing

• the most effective Tx for long-term control of

asthma in children and adults

chronic use:

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Asthma/COPD

Systemic corticosteroids

• refractory cases may need PO support for certain periods

• long-term PO use rarely required

(persistent-severe uncontrolled asthma)

• upon improvement - tapering off over 1-2wk

• IV/PO: may be required in acute, severe exacerbations

(“status asthmaticus”)

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Asthma/COPD

Corticosteroids - general short-term ADEs

• increase appetite

• nervousness

• anxiety

• adrenal suppression

• growth retardation (children)

• insomnia

• Cushing’s syndrome

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Asthma/COPD

Corticosteroids - general long-term ADEs

• osteoporosis

• diabetes

• weight gain

• adrenal suppression

• growth retardation (children)

• peptic ulcers

• HTN

• immuno-suppression

• ↑↑↑↑ triglycerides, cholesterol

• infection masking

• skin thinning

• Cushing’s syndrome

• hypokalemia • more ……..

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Asthma/COPD

ICS - general ADEs

• overall, ADEs risk significantly reduced with ICS

• importance of . . . . . .

• local infections in mouth and pharynx

• long-term high-dose ICS:

- cataract (monitor)

- osteoporosis (monitor, consider Ca+++vit. D)

• cough

- easy bruising

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Asthma/COPD

Corticosteroids - DDIs

• ↓↓↓↓ by CYP-450 inducers (phenytoin, phenobarbital, rifampin)

• antacids (↓↓↓↓ oral absorption)

• ↓↓↓↓/↑↑↑↑ anticoagulant effect

• estrogen (↑↑↑↑ clearance)

• live-attenuated vaccines (immuno-suppression)

• hypokalemic drugs, digoxin

• generally insignificant with ICS

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Asthma/COPD


• ipratropium


• omalizumab

• theophylline

• corticosteroids


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Asthma/COPD

β2-adrenergic agonists

• anti-inflammatory?

• bronchodilation?

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Asthma/COPD


short acting (SABAs):

• terbutaline (Bricalin®, Terbulin®)

• salbutamol=albuterol (Ventolin®)

• drugs of choice for mild asthma

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Asthma/COPD


short acting (SABAs):

• moderate duration (3-6hr)

• suitable for . . . .

• proper inhalation technique minimizes ADEs

• ADEs: tachycardia, hyperglycemia, hypokalemia, tremor

• rapid peak effect (0.5-2hr)

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Asthma/COPD


long acting (LABAs):

• formoterol (Foradil®, Oxis®)

• salmeterol (Serevent®)

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Asthma/COPD


long acting:

• long duration (12hr)

• acute vs. chronic use?

• ADEs generally similar to those of short-acting

• delayed peak effect (3-4hr)

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Asthma/COPD


Long-term safety concerns

Controversy has surrounded the use of beta-agonists in asthma

patients ever since their introduction over 50 years ago.

Numerous studies over many years have shown regular use of beta-agonists are associated with worsening of disease control.

Observational studies have consistently shown that the risk of life threatening and fatal asthma attacks increase with the use of

these medications .

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Asthma/COPD


Long-term safety concerns

SMART, Chest 2006;129:15-26.

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Asthma/COPD


Long-term safety concerns - SMART

• >6,100 centers

• >26,000 patients (of 60,000 intended)

• 28 weeks

• early termination

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Asthma/COPD


Long-term safety concerns - SMART

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Asthma/COPD


management:

• use LABAs in accordance with guidelines:

- not 1st-line!

- not for mild asthma!

- consider patient characteristics! (adherence, follow-up)

- not as monotherapy!

Long-term safety concerns - conflicting meta-analyses,

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Asthma/COPD


LABAs:

• Use of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of asthma.

• Use of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of asthma.

• LABAs should not be used in patients whose asthma is adequatelycontrolled on low or medium dose inhaled corticosteroids.• LABAs should not be used in patients whose asthma is adequatelycontrolled on low or medium dose inhaled corticosteroids.

June 2nd 2010

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Asthma/COPD


LABAs:

• LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an ICS.

• LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an ICS.

• Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an ICS.

• Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an ICS.

June 2nd 2010

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Asthma/COPD

Inhaled LABA-CS combinations

- salmeterol/fluticasone (Seretide®)

• for patients requiring both classes

- formoterol/budesonide (Symbicort®)

• adherence promotion

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Asthma/COPD


• ipratropium


• omalizumab

• theophylline

• corticosteroids


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Asthma/COPD

Theophylline (Theotrim®, Theotard®)

• methylxanthine derivative

• structurally-related to caffeine

• originally isolated from tea (1888)

• administered orally (sustained release)

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Asthma/COPD

Theophylline - mechanism

A number of proposed mechanisms

- adenosine receptor antagonist ? (adenosine ↑↑↑↑ histamine and leukotriene release)

- phosphodiesterase inhibitor (↑↑↑↑ cAMP…)

1. bronchodilator (higher dose, >10mg/kg/d):

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Asthma/COPD

Theophylline - mechanism

A number of proposed mechanisms

2. anti-inflammatory (lower dose):

histone deacetylase

low-dose theophylline

active inflammatory gene transcription site

inflammatory process

acetylated core histones

inflammatory gene transcription

corticosteroids recruitment inhibition

increased activity

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Asthma/COPD

Theophylline - PK

• near-complete absorption

• significant hepatic metabolism

• mainly hepatic elimination (varies due to multiple effects)

• T1/2: adults - 8hr, smokers - 5hr, elderly - 12hr …

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Asthma/COPD

Theophylline - ADEs

adverse reactionsserum concentration

GI – nausea, vomiting, pain,CNS – insomnia, headache, agitation,

tremor, nervousness15-25 mcg/L

CV – tahcycardia, occasional PVBs25-35 mcg/L

VT, frequent PVBs, seizures>35 mcg/L

• narrow therapeutic index: target of 10-20 mcg/ml

• ADEs generally concentration-dependent:

TDM: 2hr post-oral dose

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Asthma/COPD

Theophylline - DDIs

↓↓↓↓ theophylline effect↑↑↑↑ theophylline effect

antacids (absorption), phenytoin, phenobarbital, rifampin, cigarette smoke, ritonavir, ketoconazole, more …..

cimetidine, corticosteroids, macrolides (erythromycin), quinolones (ciprofloxacin), CCBs, BBs, loop diuretics, more …

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Asthma/COPD

Theophylline - place in therapy

• decreasing use (ADEs, DDIs, better options); 3rd-line

• combination with ICS (steroid-sparing)

• refractory cases

• possible comeback as low-dose practice (anti-inflammatory)?

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Asthma/COPD


• ipratropium


• omalizumab

• theophylline

• corticosteroids


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Asthma/COPD

Cromolyn/nedocromil

• “mast-cell stabilizers”

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Asthma/COPD

Cromolyn/nedocromil

• “mast-cell stabilizers”

↓↓↓↓ histamine (+ leukotriene) release

↓↓↓↓ inflammatory response

block mast-cell calcium channels

↓↓↓↓ mast cell degranulation

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Asthma/COPD

Cromolyn/nedocromil

“mast-cell stabilizers” for acute asthma attacks:

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Asthma/COPD

Cromolyn/nedocromil

• only effective as prophylaxis (ineffective for acute episodes)

• given as inhalation

• minimal systemic effects (local: irritation, bitter taste, dry mouth)

• useful in prevention of allergen-induced asthma

• safe in children, pregnancy

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Asthma/COPD


• ipratropium


• omalizumab

• theophylline

• corticosteroids


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Asthma/COPD

Ipratropium (Atrovent®)

• anticholinergic agent (atropine derivative)

• blocks vagally-mediated contraction of smooth muscle

• peak effect: 1.5-2hr

• duration of effect: 4-6hr

• negligible ADEs (does not penetrate BBB)

• for preventive Tx

• rarely used for asthma

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Asthma/COPD


• corticosteroids


• ipratropium


• omalizumab

• theophylline

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Asthma/COPD

Leukotriene receptor antagonists (LTRAs)

cysteinyl leukotrienes

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Asthma/COPD


montelukast (Singulair®)

• selective, reversible antagonist of cysteinyl-1 receptor

• for long-term control

• once-daily (evening) oral administration (chewable)

• extensive hepatic metabolism

• fecal excretion

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Asthma/COPD



• selective, reversible antagonist of cysteinyl-1 receptor

• once-daily (evening) oral administration (chewable)

• extensive hepatic metabolism

• fecal excretion

• ADEs: headache (18%), impaired LFTs, dyspepsia, cough

• DDIs: ↓↓↓↓ 40% by phenobarbital (rifampin?)

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Asthma/COPD

LTRAs


• LABA/ICS sparing

• additional indication:

prophylaxis of exercise-induced bronchospasm

• for long-term control

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Asthma/COPD


• ipratropium


• omalizumab

• theophylline

• corticosteroids


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Asthma/COPD

Omalizumab (Xolair®)

recombinant DNA-derived selective IgE monoclonal antibody

USA 2003 data: 60% of asthma – allergen-induced

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Asthma/COPD


recombinant DNA-derived selective IgE monoclonal antibody

• peak serum concentrations after 7-8 days

• tissue elimination (intracellular)

• SC administration every 2 or 4 weeks

• T1/2 - 26 days

• anaphylactic reactions in 0.2%

• ↑ cancer?

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Asthma/COPD


• poorly controlled moderate-severe persistent asthma

• year-round allergies (proven allergic reaction)

• inadequate control despite routine ICS use

indicated for children over 12 and adults with:

• free circulating IgE reduced by 96%

• decreased incidence of asthma exacerbations

in these patients:

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Asthma/COPD

long-term Txacute Tx

spirometry (FEV1)

episode frequency

Asthma classification

noneSABA>80%≤2/weekmild-intermittent

low-dose ICSSABA>80%>2/weekmild-persistent

Low/medium dose ICS + LABA

SABA60-80%dailymoderate-persistent

high-dose ICS

+ LABASABA<60%continuoussevere-persistent

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Asthma/COPD

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Asthma/COPD

Pharmacological markers for uncontrolled asthma

• acute SABA required >2/wk

• oral CS bursts required >2/yr

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Asthma/COPD

http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm .pdf

Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asth ma –

Summary Report 2007

http://www.ginasthma.org/

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COPD chronic obstructive pulmonary disease

Asthma/COPD

chronic, irreversible airflow obstruction

• two entities:

-

-

• slowly-progressive airway damage

• symptoms appear after years of exposure

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Asthma/COPD


• 4th leading cause of death (USA)

• deadlier than asthma

• morbidity and mortality rising

• estimated USA annual cost >$30,000,000,000

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Asthma/COPD


causes:

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Asthma/COPD


symptoms/diagnosis:

• chronic cough (productive/non-productive)

• excessive mucus production

• shortness of breath (mild exertion)

• frequent throat-clearing

• chest tightness

• respiratory function tests (spirometry)

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Asthma/COPD

Non-pharmacological Tx

avoid triggers

• smoking

• dust/chemicals

• air-pollution

[get better genes]

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Asthma/COPD

Pharmacotherapy

non-curable, non-reversible: control symptoms

• 1st-line: inhaled bronchodilators

- SABAs/LABAs (LABAs advantageous for nocturnal episodes)

- anticholinergic (tiotropium = Spiriva®)

- combination

once-daily anticholinergic bronchodilator

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Asthma/COPD

Pharmacotherapy


• 2nd-line: ICS

- moderate-severe COPD uncontrolled with 1st-line

- modest effect in most COPD patients

- differing efficacy in asthma vs. COPD related to different inflammatory mediators

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Asthma/COPD

Pharmacotherapy


- presently lost favor (ADEs)

• 2nd/3rd-line: theophylline

- past 1st-line

- option for those unable to optimally operate inhalers

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Asthma/COPD

Pharmacotherapy

Long-term TxFEV1Severity

SABA, as needed>80%mild

SABA/LABA/anticholinergic ± ICS30-80%moderate

as in moderate,

- antibiotics for acute exacerbations

- O2

<30%severe

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Asthma/COPD

Pharmacotherapy

http://www.nhlbi.nih.gov/health/public/lung/copd/campaign-materials/html/providercard.htm

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Asthma/COPD

COPD vs. asthma

COPDasthma

adulthood (>40s)childhood - young adulthoodtypical onset

respiratory infectionsallergen, exercise, cold airexacerbation

LABA (→ ICS)ICS → LABATx sequence

nearly daily symptomssymptom-free periodsTx effect

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• inhaled corticosteroids – fluticasone• beta-2 adrenergic agonists

- short-acting: salbutamol - long-acting: salmeterol

• theophylline• cromolyn• ipratropium/tiotropium• montelukast• omalizumab

Pharmacotherapy – asthma/COPD

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Asthma/COPD

asthma & copd - hadassah€¦ · -decreasing morbidity and related costs . 5 ... asthma/copd...

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