Respiratory Drugs

(for Asthma & COPD)

Phase III/Therapeutics
Asthma is a Major Public Health Problem

o 150 million sufferers Worldwide

o Prevalence rising in most countries - up to
50%/decade
o Large burden on health budgets
o Major economic impact from lost days at work &
school
o Causes 100,000 deaths p.a. Worldwide
 Drug Treatment of Asthma

What is it ? ‘A State of bronchial hyperreactivity resulting from

a persistent inflammatory process in response to a number of
stimuli in a genetically susceptible individual'

Key features of its pathophysiology

Airway inflammation
o mucosal oedema Reflecting infiltration/activation of
o secretion of mucus eosinophils, mast cells & Th2 cells
o epithelial damage
o bronchoconstriction
Bronchial hyperreactivity

Therapy is thus aimed at

•Symptomatic relief - relieving bronchoconstriction
•Disease modification - reducing inflammation and lung
damage
 Asthma Triggers

o Allergen exposure e.g. HDM, pet dander, pollens etc.

o Exercise/cold-air - drying airway mucosa.
o Drugs - Beta blockers, NSAIDs and anaphylactoids.
o Food additives - tartrazines , sulphites etc.
o Viral URTIs - especially rhinovirus.
o Gastroesophageal reflux (GORD).

NB a number of irritants can increase airway reactivity leading to

deterioration of symptom control without necessarily being
‘triggers’ - atmospheric pollutants (gases and particulates) are the
best example.
Anti-Asthma Drugs: β 2-ADR agonists

Short-acting (2-3h) Long-acting

• salbutamol (>12h)
• terbutaline • salmeterol
• fenoterol • eformoterol
( NB should not be used
to relieve acute
symptoms)
Side effects of β 2-agonists
• Tremor
Generally worse with
• Hypokalaemia oral administration
• Tachycardia
Using 2 or more canisters/month is marker of poor control
(>10 puffs/day)
 Long acting beta agonists
• Increased morbidity and mortality compared with placebo
– Meta-analysis, Annals of Internal Medicine 2006
– Increased exacerbations requiring admission (OR 2.6)
– Increased life threatening admissions (OR 1.8)
– Increased asthma related deaths
• OR 3.6, risk difference 0.07% over 6/12, I.e. 1 extra death per 1000 patient-years of use
• Mechanism
– Negative feedback with beta agonist use
– Internalization of receptors and downregulation
– Regular use increases bronchial hyperreactivity despite maintenance of some degree of
bronchodilatation
– These effects may worsen control without increased symptoms

• Polymorphisms at human beta2-adrenoreceptor gene

– Homozygous variant resulting in arginine at 16th position, Arg/Arg genotype
– May experience decline in airflow when using beta-agonists, racial distribution
 Anti-Asthma Drugs: Antimuscarinics

• Example Ipratropium bromide (aerosol or nebulized)

• Mechanism Vagolytic action due to competitive inhibition of

M3 receptors of bronchial SM cells
• Slower and less intense than adrenergic agonists

• Side-effects Limited absorption (quaternary N vs tertiary in

atropine) but atropine-like effects at high doses e.g. dry mouth,
mydriasis, urinary retention

• Notes Generally less effective than β 2 agonists in chronic

asthma – high vagal tone only in acute asthma
 Tiotropium

• Long-acting anticholinergic (once daily)

• Reduced OR for exacerbation (0.73) and hospitalisation (0.68)

but
not pulmonary or all cause mortality compared to placebo and
ipratropium

• Greater increase in FEV1 and FVC compared to placebo and

ipratropium (Meta-analysis, Thorax 2006)

• Side-effects increased reports of dry mouth and UTI

Anti-Asthma Drugs: Glucocorticoids (GCC)

Problems with inhaled GCC

TOPICAL (preventable by use of a spacer)

SYSTEMIC • Dysphonia
• Easy Bruising • Oropharyngeal Candida
• Adrenal suppression *
• Growth retardation ? (pre-pubertal)
• Increased bone catabolism *

* Typically a high-dose problem I.e.

>1000µ g/day
 QVAR

• Beclometasone dipropionate (BDP)

• Utilizes a hydrofluoroalkane (HFA) not CFC propellant

• delivered in smaller-sized particles
• allows better penetration to small airways
• In trials, the improvement in FEV1 across doses was greater for QVAR
than for CFC-BDP, indicating a shift in the dose response curve for QVAR

Problem: cost
 Anti-Asthma Drugs: Theophylline

• Weak bronchodilator
• Prominent immunomodulatory/anti-inflammatory effects
• Oral dosing

Problems with its use

• Poorly tolerated (GI side-effects especially) in up to 1/3rd of patients

• Narrow therapeutic range (10-20mg/L)
• Biovailability varies widely between preparations
• Extensive P450 metabolism - source of many interactions

Current Status

•Probably 4th line following introduction of LTRAs ?

 Magnesium
• Evidence from meta-analysis for acute severe asthma where IV it
may provide additional bronchodilatation (Cochrane, Annals of
Emergency Medicine)

• Improved PEFR and FEV1 (10%)

• Reduced admission rates, NNT 8

• Single dose for

- Acute severe asthma (FEV1 <30% predicted on arrival) who

have responded poorly to inhaled bronchodilator therapy
- Life threatening or near fatal asthma

• 1.2 –2 g IV over 20 minutes

NB Beware using in myasthenics … unless as a diagnostic test!

 Phospholipid

Phospholipase A2

Arachidonic Acid

Zileuton NSAIDs

Lipoxygenase Cyclo-oxygenase

LTC4 D4 E4 (SRSA) PGs

bronchoconstrictors TxA2
Montelukast
 Anti-Asthma Drugs: LTRAs

❍ Selective antagonists of CysLT1 receptor e.g. montelukast

❍ Cysteinyl-LTs (LTC4, D4 & E4) are very potent airway spasmogens
~1000-fold > histamine.
❍ Released by mast cells and influxing eosinophils.
❍ improve lung function and symptoms, decrease in exacerbations
❍ LTRAs are agents of choice for aspirin-induced asthma.
❍ Role elsewhere still debated.
❍ Advantage of better compliance (orally active); efficacy similar to low-
dose inhaled GCC BUT without the side effects.
❍ Churg-Strauss very rarely associated with their use - disease probably
masked by previous GCC.
 Aspirin-Induced Asthma

❍ Spirometric evidence in up to 20% of all asthmatics

❍ COX-1 inhibition removes endogenous PGE2 inhibition of airway mast

cells?
❍ Why are a subpopulation of asthmatics affected?

❍ ? LTC4 synthase polymorphism(s) predispose.

❍ Paracetamol (AAP) safe alternative? - possibly NOT!

❍ ? AAP-induced depletion of glutathione levels in the airway the problem.

❍ Theoretical reasons for LTRAs as agents of choice for aspirin-induced

asthma

but little evidence

❍ COX-2 selective NSAIDs are probably safe e.g. celecoxib.
Drug Delivery by an Inhaled Aerosol

Large particles (>10 µ m) deposit in the

mouth and small ones (<0.5 µ m) fail to
deposit in the distal airways - SPACER
devices increase the fraction of
droplets in the critical 1-5 µ m range.

Effect of first-pass can be dramatic e.g.

equiactive doses of oral and pMDI SALBUTAMOL
differ 40-fold (4000 vs 100 µ g) and
FLUTICASONE is inactive orally because of 100%
first-pass.

NB there is no advantage (I.e. a ‘sparing effect’) in

delivering a GCC with low first-pass by
aerosolisation e.g. hydrocortisone or prednisolone.
Drug Delivery Systems: Metered-dose Inhalers MDIs

Blue [short acting β 2 agonist]

Green [salmeterol]
Pressurised MDI (pMDI)
• CFC (being replaced by HFA) propellant
• Require co-ordinated activation/inhalation
Brown [BDP or
budesonide]

Orange [fluticasone]

Turbuhaler
Dry Powder MDI
• No propellant
• Require only priming then sucking
• Low PEFR a problem (<60L/min)
• Delivery humidity dependent ?

Diskhaler
2005 BTS Guidelines for Chronic Asthma

Step 1 prn (< once daily) short-acting β 2*

Step 2 Inhaled anti-inflammatory agent* ie GCC

200-800 mcg/day (titrate)
Step 3 ADD regular long-acting β 2 agonist.
prn
If fails or inadequate increase inhaled GCC to
short-acting
800µ g/day±long-acting β 2. If inadequate, trial of β 2 agonist
other: e.g. leukotriene antagonist or SR theophylline
Step 4 Increase GCC to 2000µ g/day
Addtion of fourth drug:e.g. methylxanthines or
leukotriene antagonist, or oral β 2 agonist
Step 5 Best of step 4 plus oral prednisolone
* ‘reliever’ or ‘rescue’ medication vs. anti-inflammatory agents as
‘preventers’
Points to note: 1. Patient treatment should be reviewed/adjusted at
least every 3-6 months. 2. Step down rapidly from high dose oral
steroids if PEFR responds promptly i.e. within a few days, otherwise
MANAGEMENT OF ACUTE SEVERE ASTHMA

Life-threatening features
 Silent chest
 Cyanosis
 Bradycardia
 Exhausted appearance
 PEFR <33% of predicted
 SpO2 <92%
 Normal PaCO2
 dysrhythmia, hypotension, exhaustion, confusion
 Arterial Blood Gases in Acute ASTHMA

Mild Moderate Severe*

↑ pH → pH ↓ pH
→ PaO2 ↓ PaO2 ↓ ↓ PaO2
↓ PaCO2 → PaCO2 ↑ PaCO2
→ HCO3- → HCO3- ↓ HCO3-

* Beware the following:

• Speechless patient
• PEFR <50%
• Resp Rate >25
• Tachycardia >110 (pre β 2
agonist)
 Management of acute severe asthma in
adults in A&E: PEF <33% predicted
Time Measure PEF and arterial saturations
PEF <33% best or predicted OR any life threatening features:
• SpO2 <92% • Silent chest, cyanosis, poor respiratory effort
• Bradycardia, arrhythmia, hypotension • Exhaustion, confusion, coma

5 min Obtain senior/ICU help now if any life-threatening features are present
IMMEDIATE • High concentration oxygen (>60% if possible)
15-30 minMANAGEMENT • Give salbutamol 5mg plus ipratropium 0.5mg via oxygen-driven nebuliser
• AND prednisolone 40-50mg orally or IV hydrocortisone 100mg
Measure arterial blood gases
Markers of • Normal or raised PaCO2 • Severe hypoxia (PaO2 <8 kPa; 60mm Hg)
severity: (PaCO2 >4.6 kPa; 35mm Hg) • Low pH (or high H+)
60 min • Give/repeat salbutamol 5mg • Consider continuous salbutamol • Correct fluid/ electrolytes,
with ipratropium 0.5mg by nebuliser 5-10mg/hr especially K+ disturbances
oxygen-driven nebuliser after 15 • Consider IV magnesium sulphate 1.2- • Chest X-ray
minutes 2g over 20 minutes

120 min ADMIT – Patient should be accompanied by a nurse or doctor at all times

Management of acute asthma. Thorax 2003; 58 (Suppl I): i1-i92

 Requirements for Discharge

Before discharge aim for the following:

• On discharge medication for 24 hrs
• PEFR >75% predicted or best
• <25% diurnal variability
• Oral AND inhaled steroids – else risk early relapse when oral
stopped
• Give a PEFR meter for home use
• Management plan based on home PEFR etc
• GP follow up arranged
 Why do Asthma Deaths still occur?

• Failure to recognize deterioration at home

• Underestimate severity – by patient, relatives or
doctors
• Lack of objective measurements – PEFR, SaO2, ABG
• Under treatment with systemic steroids
• Inappropriate drug therapy
• Lack of monitoring
• Inadequate specialist input
 COPD

What is it ? Airflow limitation that is not fully reversible

Includes
o Chronic bronchitis
o Emphysema
o Small airways disease

Aetiology
•Smoking!!
•Alpha1 antitrypsin deficiency
•Pollution, cadmium..

 
 COPD

Symptoms
Cough, sputum production, wheeze, exertional dyspnoea

Physical findings
o Tar staining …
o Hyperinflated chest, pursed lip breathing, paradoxical lower
chest
wall movement
o Cyanosis
o Signs of CO2 retention
o Cor pulmonale

Investigations
• PFT
• CXR
• ABG, O2 Saturation
 COPD

• According to NICE-British Thoracic Society

Mild airflow obstruction FEV1 50 – 80% predicted

Moderate FEV1 30 – 49% predictetd

Severe FEV1 <30% predicted

 
 Drug Therapy for COPD: differences vs. Asthma
• Inflammatory components in COPD airway distinct from asthma?
• Does asthma predispose smokers to COPD? (Dutch hypothesis)

Reversible airflow obstruction?

• >15% rise (and >200ml) in FEV1 after GCC trial
Treatment
• Assess severity – Spirometry, reversibility, CXR, ABG
• Stop smoking to decelerate loss of FEV1
• Use inhaled β 2-agonist +/- IPRATROPIUM*
• Trial of inhaled GCC, but use in the absence of reversibility ? . . .
• Consider adding theophylline or oral steroid trial
• if history of more purulent sputum
• Consider pulmonary rehabilitation
• Assess for home nebulizers/LTOT
• Annual ‘Flu Vaccination’ , pneumococcal vaccination

Pauwels et al (1999) - inhaled budesonide given in

randomised fashion to 1000 smokers with COPD and
FEV followed for 3 years. No significant effect!

* effects of vagus more prominent than in chronic asthma

 Home Oxygen for COPD

15hrs/day O2 improves 5 year survival from 25 to 41% (MRC)

Criteria for long-term home oxygen therapy
• Two ABG readings when well (3 weeks apart)
• PaO2<7.3, FEV1 <1.5
• Or PaO2 7.3-8 AND pulmonary HT, oedema, nocturnal hypoxia
• STOP SMOKING
• Oxygen concentrator and nasal prongs (PaO2 >8)
• Minimum of 15 hrs per day
 Nonpharmacological Treatment

• Pulmonary rehabilitation
• Volume reduction surgery
• NIV
• Invasive ventilation
• Lung transplantation
• Treatment of Cor pulmonale, oxygen and diuretics for
oedema
Management of an Acute Exacerbation of COPD

• Oxygen –24% Venturi mask

- recheck ABG with an hour, monitor SaO2, aim for >90%
• Nebulized salbutamol add Ipratropium if severe
• Steroids – Prednisolone 30 mg for 7-14 days
? Osteoporosis prophylaxis
• Antibiotics if more purulent sputum
• If no improvement consider aminophylline and monitor levels
• If deteriorating NIPPV, intubation, doxapram (?)
• CXR, FBF, U&Es, PEFR
 Newer Therapeutic approaches
Immunotherapy

• Not recommended by the BTS in its ‘conventional’ form.

• Significant risk of anaphylaxis.
• Depletion of plasma IgE using rhuMab-E25 (Omalizumab) may be the
way forward for a small number of subjects with difficult to control allergic
asthma – but very expensive (~£10-20k/year).

Other drug developments

• More topically potent GCCs - mometasone more potent than fluticasone.

• Single enantiomer salbutamol - (R)-salb is the active enantiomer; (S)-salb
inactive, metabolised 10-fold slower than (R) and can increase airway hyperresponsiveness.
• Type (4D) selective phosphodiesterase inhibitors - PDE4 is the
predominant isoform in inflammatory cells. Potential for fewer side-effects vs theophylline.
• Reproterol - monomolecular combination of orciprenaline (β 2-agonist) and
theophylline.
• Newer anti-T cell agents - FK506 and rapamycin
 PDE4 inhibitors
• Cilomast, Roflumilast

• Phosphodiesterases hydrolyse intracellular cyclic nucleotides

(cAMP,
cAMP into inactive 5’monophosphates
• found in variety of cells
• PDE4 inhibitors specifically prevent hydrolysis of cAMP leading to
•Airway smooth muscle relaxation
•inhibition of cellular inflammation and immune responses, cell
trafficking and chemokine and cytokine release

• Side effects – toxicity: Nausea and vomiting, arteritis

• Disappointing phase III trials with Cilomast

• Narrow therapeutic ratio
 Further Information

• Full BTS guidelines for asthma management (pdf)

• Full NICE guidelines for COPD management (pdf)
• BTS (Brit Thoracic Society) web site

Click on link to download