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)

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