Respiratory Drugs for Asthma

1
Respiratory Drugs(for Asthma COPD)

• Phase III/Therapeutics

2
Asthma is a Major Public Health Problem

• 150 million sufferers Worldwide
• Prevalence rising in most countries - up to
  50/decade
• Large burden on health budgets
• Major economic impact from lost days at work
  school
• Causes 100,000 deaths p.a. Worldwide

3
Asthma Triggers

• Allergen exposure e.g. HDM, pet dander, pollens
  etc.
• Exercise/cold-air - drying airway mucosa.
• Drugs - Beta blockers, NSAIDs and
  anaphylactoids.
• Food additives - tartrazines , sulphites etc.
• Viral URTIs - especially rhinovirus.
• 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.

4
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
• mucosal oedema
• secretion of mucus
• epithelial damage
• bronchoconstriction
• Therapy is thus aimed at
• Symptomatic relief - relieving bronchoconstriction
  
• Disease modification - reducing inflammation and
  lung damage
•  

Reflecting infiltration/activation of
eosinophils, mast cells Th2 cells
5
Anti-Asthma Drugs ?2-ADR agonists

• Short-acting (2-3h)
• salbutamol
• terbutaline
• fenoterol

• Long-acting (gt12h)
• salmeterol
• eformoterol
• ( NB should not be used to relieve acute symptoms)

Side effects of ?2-agonists

• Tremor
• Hypokalaemia
• Tachycardia

Generally worse with oral administration
6
Anti-Asthma Drugs Antimuscarinics

• Example Ipratropium bromide (aerosol or
  nebulized)
• Mechanism Vagolytic action due to competitive
  inhibition of M3 receptors of bronchial SM cells
• 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 b2 agonists
  in chronic asthma high vagal tone only in acute
  asthma

7
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
  ?

8
Phospholipid
Phospholipase A2
Arachidonic Acid
NSAIDs
Zileuton
Cyclo-oxygenase
Lipoxygenase
LTC4 D4 E4 (SRSA) bronchoconstrictors
PGs TxA2
Montelukast
9
Anti-Asthma Drugs LTRAs

• Selective antagonists of CysLT1 receptor e.g.
  montelukast
• Cysteinyl-LTs (LTC4, D4 E4) are very potent
  airway spasmogens 1000-fold gt histamine.
• Released by mast cells and influxing
  eosinophils.
• 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.

10
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.
• LTRAs are agents of choice for aspirin-induced
  asthma.
• COX-2 selective NSAIDs are probably safe e.g.
  celecoxib.

11
Drug Delivery by an Inhaled Aerosol
Large particles (gt10 ?m) deposit in the mouth and
small ones (lt0.5 ?m) fail to deposit in the
distal airways - SPACER devices increase the
fraction of droplets in the critical 1-5 ?m range.
Effect of first-pass can be dramatic e.g.
equiactive doses of oral and pMDI SALBUTAMOL
differ 40-fold (4000 vs 100 ?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.
12
Drug Delivery Systems Metered-dose Inhalers MDIs

• Pressurised MDI (pMDI)
• CFC (being replaced by HFA) propellant
• Require co-ordinated activation/inhalation

• Dry Powder MDI
• No propellant
• Require only priming then sucking
• Low PEFR a problem (lt60L/min)
• Delivery humidity dependent ?

13
Anti-Asthma Drugs Glucocorticoids (GCC)
Problems with inhaled GCC
TOPICAL (preventable by use of a spacer)
SYSTEMIC

• Dysphonia
• Oropharyngeal Candida

• Easy Bruising
• Adrenal suppression
• Growth retardation ? (pre-pubertal)
• Increased bone catabolism
• Typically a high-dose problem I.e. gt1000?g/day

14
2003 BTS Guidelines for Chronic Asthma
Step 1 prn (lt once daily) short-acting ?2 Step
2 Inhaled anti-inflammatory agent ie GCC
400mg/day Step 3 ADD regular long-acting ?2
agonist. If fails or inadequate increase inhaled
GCC to 800mg/daylong-acting ?2. If inadequate,
trial of methylxanthines or leukotriene
antagonist Step 4 Increase GCC to 2000mg/day AND
long-acting ?2 agonist regularly, or
methylxanthines ,or leukotriene antagonist, or
oral b2 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 need to be stable for 1-3
months before attempting more gradual step down.
prn short-acting ?2 agonist
15
MANAGEMENT OF ACUTE SEVERE ASTHMA

• Life-threatening features
• Silent chest
• Cyanosis
• Bradycardia
• Exhausted appearance
• PEFR lt30 of predicted

16
Arterial Blood Gases in Acute ASTHMA
Mild ?? pH ? PaO2 ? PaCO2 ? HCO3-
Severe ? pH ? ? PaO2 ? PaCO2 ? HCO3-
Moderate ? pH ? PaO2 ? PaCO2 ? HCO3-

• Beware the following
• Speechless patient
• PEFR lt50
• Resp Rate gt25
• Tachycardia gt110 (pre ?2 agonist)

17
Management of acute severe asthma in adults in
AE PEF lt33 predicted
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
18
Requirements for Discharge

• Before discharge aim for the following
• On discharge medication for 24 hrs
• PEFR gt75 predicted or best
• lt25 diurnal variability
• Oral AND inhaled steroids else risk early
  relapse when oral stopped
• Give a PEFR meter for home use
• Mx plan based on home PEFR etc
• GP follow up arranged

19
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

20
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?
• gt15 rise (and gt200ml) in FEV1 after GCC trial
• Treatment
• Assess severity Spriometry, reversibility,
  CXR, ABG
• Stop smoking to decelerate loss of FEV1
• Use inhaled ?2-agonist /- IPRATROPIUM
• Trial of inhaled GCC, but use in the absence of
  reversibility ? . . .
• Consider adding theophylline or oral steroid
  trial
• Consider pulmonary rehabilitation
• Assess for home nebulizers/LTOT
• Annual Flu 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 X more prominent than in chronic
asthma
21
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)
• PaO2lt7.3, FEV1 lt1.5
• Or PaO2 7.3-8 AND pulmonary HT, oedema, nocturnal
  hypoxia
• STOP SMOKING
• Oxygen concentrator and nasal prongs (PaO2 gt8)
• Minimum of 15 hrs per day

22
Management of an Acute Exacerbation of COPD

• Oxygen 24 Ventimask
• - recheck ABG with an hour, monitor SaO2
• Nebulized salbutamol add Ipratropium if severe
• If no improvement consider aminophylline
• If deteriorating NIPPV, intubation, doxapram (?)
• - exercise tolerance, home O2, home nebulizers
  (?)
• CXR, FBF, UEs, PEFR
• Consider Abx, glucocorticoids, diuretics

23
Newer Therapeutic approaches

• Immunotherapy
• Not recommended by the BTS in its
  conventional form.
• Significant risk of anaphylaxis.
• Depletion of plasma IgE using rhuMab-E25 may be
  the way forward.
• Other drug developments
• Magnesium used IV in acute severe asthma.
• 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 (?2-agonist) and theophylline.
• Newer anti-T cell agents - FK506 and rapamycin

24
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