View
1.094
Download
3
Category
Preview:
DESCRIPTION
Citation preview
Respiratory DrugsRespiratory Drugs(for Asthma & COPD)(for Asthma & COPD)
Phase III/Therapeutics
Asthma is a Major Public Health ProblemAsthma 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
Asthma TriggersAsthma 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.
What is it ?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 pathophysiologyKey features of its pathophysiologyo mucosal oedemao secretion of mucuso epithelial damageo bronchoconstriction
Therapy is thus aimed atTherapy is thus aimed at•Symptomatic relief - relieving bronchoconstriction•Disease modification - reducing inflammation and lung damage
Drug Treatment of AsthmaDrug Treatment of Asthma
Reflecting infiltration/activation of eosinophils, mast cells & Th2 cells
Anti-Asthma Drugs: 2-ADR agonistsAnti-Asthma Drugs: 2-ADR agonists
Short-acting (2-3h)Short-acting (2-3h)• salbutamol• terbutaline• fenoterol
Long-acting Long-acting (>12h)(>12h)• salmeterol• eformoterol( NB should not be used to relieve acute symptoms)
Side effects of 2-agonists
• Tremor • Hypokalaemia • Tachycardia
Generally worse withoral administration
Anti-Asthma Drugs: AntimuscarinicsAnti-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 agonists in chronic asthma – high vagal tone only in acute asthma
Anti-Asthma Drugs: TheophyllineAnti-Asthma Drugs: Theophylline
• Weak bronchodilator• Prominent immunomodulatory/anti-inflammatory effects• Oral dosing
Problems with its useProblems 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 StatusCurrent Status
•Probably 4th line following introduction of LTRAs ?
Arachidonic Acid
LTC4 D4 E4 (SRSA)
bronchoconstrictors
PGs
TxA2
Lipoxygenase Cyclo-oxygenase
Phospholipid
Phospholipase A2
Montelukast
NSAIDsZileuton
Anti-Asthma Drugs: LTRAsAnti-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.
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 AsthmaAspirin-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.
Drug Delivery by an Inhaled AerosolDrug Delivery by an Inhaled Aerosol
Large particles (>10 Large particles (>10 m) deposit in the m) deposit in the mouth and small ones (<0.5 mouth and small ones (<0.5 m) fail to m) fail to deposit in the distal airways - deposit in the distal airways - SPACER SPACER devices increase the fraction of devices increase the fraction of droplets in the critical 1-5 droplets in the critical 1-5 m range.m range.
Effect of first-pass can be dramatic e.g. Effect of first-pass can be dramatic e.g. equiactive doses of oral and pMDI SALBUTAMOL equiactive doses of oral and pMDI SALBUTAMOL differ 40-fold (4000 vs 100 differ 40-fold (4000 vs 100 g) and g) and FLUTICASONE is inactive orally because of 100% FLUTICASONE is inactive orally because of 100% first-pass.first-pass.
NB there is no advantage (I.e. a ‘sparing effect’) in NB there is no advantage (I.e. a ‘sparing effect’) in delivering a GCC with delivering a GCC with lowlow first-pass by first-pass by aerosolisation e.g. hydrocortisone or prednisolone.aerosolisation e.g. hydrocortisone or prednisolone.
Drug Delivery Systems: Metered-dose Inhalers MDIsDrug Delivery Systems: Metered-dose Inhalers MDIs
Pressurised MDI (pMDI)Pressurised MDI (pMDI)• CFC (being replaced by HFA) propellant• Require co-ordinated activation/inhalation
Orange [fluticasone]
Blue [short acting 2 agonist]
Green [salmeterol]
Brown [BDP or budesonide]
Dry Powder MDIDry Powder MDI• No propellant• Require only priming then sucking• Low PEFR a problem (<60L/min)• Delivery humidity dependent ?
TurbuhalerTurbuhaler
DiskhalerDiskhaler
Anti-Asthma Drugs: Glucocorticoids (GCC)Anti-Asthma Drugs: Glucocorticoids (GCC)
SYSTEMICTOPICAL (preventable by use of a spacer)
• Dysphonia• Oropharyngeal Candida• Easy Bruising
• Adrenal suppression *• Growth retardation ? (pre-pubertal)• Increased bone catabolism *
* Typically a high-dose problem I.e. >1000g/day
Problems with inhaled GCCProblems with inhaled GCC
2003 BTS Guidelines for Chronic Asthma2003 BTS Guidelines for Chronic Asthma
prnshort-acting
2 agonist
Step 1Step 1 prn (< once daily) short-acting 2*
Step 2Step 2 regular short-acting 2 inhaled + anti-inflammatory agent* (low-dose GCC)
Step 3Step 3 ADD regular long-acting 2 agonist. If fails or inadequate increase inhaled GCC to 800g/day±long-acting 2. If inadequate trial of methylxanthines or leukotriene antagonist
Step 4 Step 4 Inhaled GCC to 800g/day AND long-acting 2 agonist regularly, plus: increase GCC to 2000g/day or methylxanthines or leukotriene antagonist or oral 2 agonist
Step 5Step 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.
MANAGEMENT OF ACUTE SEVERE ASTHMAMANAGEMENT OF ACUTE SEVERE ASTHMA
Life-threatening featuresLife-threatening features Silent chest Cyanosis Bradycardia Exhausted appearance PEFR <30% of predicted
Arterial Blood Gases in Acute ASTHMAArterial Blood Gases in Acute ASTHMA
Mild
pH
PaO2
PaCO2
HCO3-
Moderate
pH
PaO2
PaCO2
HCO3-
Severe*
pH
PaO2
PaCO2
HCO3-
* Beware the following:
• Speechless patient
• PEFR <50%
• Resp Rate >25
• Tachycardia >110 (pre 2 agonist)
Immediate managementImmediate 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
· 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/exhausted or deteriorating blood gases **.
* Alternatively 2 agonist can be given s.c.
** Beware severe hypoxia (p02<8.0 on high inspired O2) or high/rising pCO2
*** establish if patient on oral theophylline before giving any aminophylline IV.
MANAGEMENT OF ACUTE SEVERE ASTHMAMANAGEMENT OF ACUTE SEVERE ASTHMA
Before discharge aim for the following: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
• Mx plan based on home PEFR etc
• GP follow up arranged
Requirements for DischargeRequirements for Discharge
• 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
Why do Asthma Deaths still occur?Why do Asthma Deaths still occur?
• Inflammatory components in COPD airway distinct from asthma?
• Does asthma predispose smokers to COPD? (Dutch hypothesis)
Drug Therapy for COPD: differences vs. AsthmaDrug Therapy for COPD: differences vs. Asthma
Reversible airflow obstruction?Reversible airflow obstruction? • >15% rise (and >200ml) in FEV1 after GCC trial
TreatmentTreatment
• Stop smoking to decelerate loss of FEV1• Annual Flu vaccination • Use inhaled 2-agonist +/- IPRATROPIUM*• Use GCC in the absence of reversibility ? . . .
* effects of X more prominent than in chronic asthma
Pauwels et al (1999) - inhaled budesonide given in randomised fashion to 1000 smokers with COPD and FEV followed for 3 years. No significant effect!
Home Oxygen for COPDHome 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
Management of an Acute Exacerbation of COPDManagement 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, U&Es, PEFR
• Consider Abx, glucocorticoids, diuretics
Newer Therapeutic approachesNewer Therapeutic approaches
ImmunotherapyImmunotherapy
• 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 developmentsOther drug developments
• Magnesium – used IV in acute severe asthma but not evidence based yet!
• 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
Further InformationFurther Information
• Full BTS guidelines for asthma management (BTS website)• Full BTS guidelines for COPD management (BTS website)• NEJM review on Leukotrienes and LTRAs (pdf)
Click on link
Recommended