Clinical Pharmacology Unit

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Stage I seminars Respiratory Drugs(for Asthma
COPD)

• Clinical Pharmacology Unit

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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

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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.

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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
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Anti-Asthma Drugs ?2-ADR agonists

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

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

Side effects of ?2-agonists

• Tremor
• Hypokalaemia
• Tachycardia

Generally worse with oral administration
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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

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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
  ?

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Phospholipid
Phospholipase A2
Arachidonic Acid
NSAIDs
Zileuton
Cyclo-oxygenase
Lipoxygenase
LTC4 D4 E4 (SRSA) bronchoconstrictors
PGs TxA2
Montelukast
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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.

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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.
  etoricoxib.

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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.
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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 ?

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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

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2003 BTS Guidelines for Chronic Asthma
Step 1 prn (lt once daily) short-acting ?2 Step
2 regular short-acting ?2 inhaled
anti-inflammatory agent (low-dose GCC) 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
Inhaled GCC to 800mg/day AND long-acting ?2
agonist regularly, plus increase GCC to
2000mg/day 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
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MANAGEMENT OF ACUTE SEVERE ASTHMA

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

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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)

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MANAGEMENT OF ACUTE SEVERE ASTHMA

• Immediate management
• Oxygen therapy by tight fitting facemask (60).
• Nebulised ?2 agonist eg salbutamol 2.5 /- 0.5mg
  ipratropium
• Give Prednisolone 30-60mg p.o. or hydrocortisone
  300mg i.v.
• Urgent chest X-ray to exclude pneumothorax
• Urgent blood gas
• Reassess in 15 min or if life-threatening
  features appear
• Give a one-off infusion of Magnesium Sulphate
  1.2-2g over 20min (NOT evidence based)
• Consider i.v. aminophylline if life-threatening
  features or fails to improve after 15-30 mins
• Discuss all patients with ITU - ventilation
  needed if PEFR continues to fall despite medical
  therapy, patient becoming drowsy/confused/exhauste
  d or deteriorating blood gases .
• Alternatively ?2 agonist can be given s.c.
• Beware severe hypoxia (p02lt8.0 on high
  inspired O2) or high/rising pCO2
• establish if patient on oral theophylline
  before giving any aminophylline IV.

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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

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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

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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
• Stop smoking to decelerate loss of FEV1
• Annual Flu vaccination
• Use inhaled ?2-agonist /- IPRATROPIUM
• Use GCC in the absence of reversibility ? . . .

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
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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

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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

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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
• 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